Diagnosis & management of renal failure

Diagnosis & Management of Renal Failure A R N O L D S. R E L M A N

COPYRIGHT 1956 BY THE YEAR BOOK PUBLISHERS, INC. PRINTED IN

U.S,A,

CONTENTS

Differential Diagnosis of Renal Failure ....................

6

Is t h e D i s o r d e r A c u t e o r C h r o n i c ? . . . . . . . . . . . . . . . . . . . . . .

7

The Diagnosis of Acute Renal Failure ...................

8

The Differential Diagnosis of Chronic Renal Disease .........

16

X-ray Exan~nation

19

of the Urinary Tract ...................

Urinalysis and the Urine Sediment .......................

21

Use and Interpretation of Some Simple Tests of Renal Function

24

Concentration and Dilution Tests .......................

28

Kidney Biopsy ......................................

29

The Management

of Acute Renal Failure with Oliguria .......

30

The Management

of Chronic Renal Failure ................

38

Recognition and Management

of Disorders of Fluid

and Electrolyte Balance ..........................

40

The Use of Drugs in Uremic Patients .....................

58

Hormones

58

and Renal Failures ...........................

Use of the Artificial Kidney .............................

59

Surgery in the Uremic Patient ...........................

60

Transplantation Summary

of the Kidney .........................

............................................

61 61

receK'ed his M.D. dcgrcc from Columbia University College of Physicians and Surgeons and was an intern and resident in Medicine at the New Haven Hospital. He came to the Massachusetts Memorial Hospitals in Boston as a National Research Council Fellow in the Medical Sciences and has remained there since as a member of the faculty of Boston University School of Medicine. At present, he is Associate Professor of Medicine and an Associate Member of the Robert Dawson Evans Memorial Department of ClJnlcal Research and Preventive Medicine. He is Physician-in-Charge of the Renal and Metabolic Divisions of that institution. His chief research interests are in the field of renal and electrolyte physiology.

THE PERFORMANCE of the kidneys, like that of the heart, is best understood when viewed in relation to the demands put upon them. The kidneys are mainly responsible for the elimination of most of the end products of nitrogen metabolism and for the final regulation of water, electrolyte and acid-base balance. The m a i n t e n a n c e of normal blood pressure is also dependent in some way on renal function. In addition, there are probably m a n y other vital activities carried on in the kidneys which still remain undefined. With slight to moderate degrees of i m p a i r m e n t the kidneys m a y still be able to m e e t ordinary demands, and signs of failure will appear only w h e n the kidneys must deal with unusual situations, such as ]arge nitrogen loads and deficits or excesses of water and electrolytes. On the other hand, w h e n renal function is grossly inadequate, some or all of the signs of renal failure will be obvious even under normal or resting conditions. These signs m a y include the accumulation of non-protein nitrogenous substances in the blood, disturbances in electrolyte and water metabolism, and the development of acidosis and hypertension. Clinical tests of renal function are most useful in the recognition and evaluation of minor degrees of renal impairment, before the kidneys

r e a c h the point of failure at re,~t. W i t h more severe disease, m o s t or all of the various clinical tests of r e n a l f u n c t i o n will be m a r k e d l y a b n o r m a l . T h e kidneys possess a very large f u n c t i o n a l reserve. T h e i r essential excretory activities c a n still be carried on after m o s t of the o r g a n h a s b e e n destroyed by disease, a n d therefore r e d u c t i o n of the f u n c t i o n i n g r e n a l m a s s to 5 to 10% of norm a l is not necessarily i n c o m p a t i b l e w i t h a n active life. However, at these levels of f u n c t i o n the kidneys h a v e lost t h e i r flexibility as regulatory o r g a n s a n d survival d e p e n d s u p o n m a n a g e m e n t carefully designed to m i n i m i z e h o m e o s t a t i c a n d excretory d e m a n d s a n d to avoid all complications w h i c h m i g h t f u r t h e r c o m p r o m i s e r e n a l efficiency. Relatively s m a l l c h a n g e s i n p r o t e i n metabolisra, circulatory f u n c t i o n , a n d fluid a n d electrolyte m e t a b o l i s r a m a y m a k e large a n d sometimes critical differences i n the degree of r e n a l failure a n d the clinical state of the patient. DIFFERENTIAL DIAGNOSIS OF RENAL FAILURE The differential diagnosis of r e n a l disorders m a y once h a v e b e e n chiefly a n a c a d e m i c exercise, of i n t e r e s t only to pathologists a n d professors. At the :present time, however, such vague ]abels as "Bright's disease," "chronic n e p h r i t i s , " or "hypertensive c a r d i o v a s c u l a r r e n a l disease" need to be a b a n d o n e d i n favor of more specific terms. This is b e c a u s e the r a t i o n a l m o d e r n m a n a g e m e n t of r e n a l failure b e g i n s w i t h the precise identification of its causes. A great variety of physiological a n d morphological disturba n c e s are n o w k n o w n to be capable of i m p a i r i n g r e n a l f u n c tion. A m o n g the different causes are disorders w i t h vastly different prognoses. Some types of r e n a l disease are at prese n t irreversible, others are tractable to various degrees, a n d some are relatively simple a n d r e m e d i a b l e problems. It therefore follows t h a t failure to p i n p o i n t the precise cause of r e n a l failure m a y result in overlooking opportunities for effecting a cure or m a r k e d i m p r o v e m e n t . At the very least, it should be obvious t h a t i n this field, as i n all others, efforts at more accurate diagnosis inevitably provide a basis for e x t e n d i n g our i n f o r m a t i o n a b o u t the prognosis a n d n a t u r a l history of disease. Such i n f o r m a t i o n is at p r e s e n t sadly lacking with respect to m a n y f o r m s of kidney disease. Tables 1 a n d 2 p r e s e n t outlines for the classification of

most of the clinical disorders leading to acute and chronic renal impairment. These lists should be regarded merely as tentative working outlines which will undoubtedly require modification as knowledge of renal disease expands. A complete discussion of the differential diagnosis of all the listed types of renal disorder is beyond the scope of this article. Only certain f u n d a m e n t a l considerations will be discussed, together with a few other points, perhaps not widely enough appreciated, which the author has found particularly useful in the diagnosis of renal disease. TABLE 1.--CAusEs OF THE SYI~IDRO~IEOF ACUTE I ~ N A L FAILURE A. Often Associated with Oliguria or Anuria

1. 2. 3. 4.

C i r c u l a t o r y collapse Obstruction R e n a l i n f a r c t i o n a n d cortical necrosis A c u t e g l o m e r u l o n e p h r i t i s or a c u t e e x a c e r b a t i o n of c h r o n i c glomerulonephritis 5. Diffuse angiitis 6. A c u t e t u b u l a r necrosis ( a n d its m i n o r v a r i a n t s ) 7. Ureeero-intestinal i m p l a n t a t i o n 8. " t t e p a t o - r e n a l s y n d r o m e " B. Occasionally Associated with Oliguria 1. A c u t e p y e l o n e p h r i t i s a n d neczotizing papillitis 2. W a t e r a n d electrolyte depletion 3. Congestive h e a r t f a i l u r e 4. A m m o n i u m chloride p o i s o n i n g IS THE DISORDER A C U T E OR C H R O N I C ?

W h e n considering the patient with renal insufficiency it is important to decide first whether or not one is dealing with an acute problem of recent onset. A careful history usually establishes this point, but sometimes it is necessary to rely on other clues. Shock, oliguria or anuria usually indicate an acute process, with the obvious exception of terminal states of any sort. Renal failure associated with any type of acute vascular or septic condition is very likely of recent onset. Severe hyponatremia or dehydration suggest at least an acute exacerbation of a chronic process, and possibly may be adequate causes in themselves of acute renal failure. Moderate or severe azotemia without significant a n e m i a should always raise the suspicion of an acute renal disorder because a n e m i a tends to be roughly proportional to the duration as well as to the severity of uremia. Finally, it should be obvious that a

TABLE 2.--CAusEs O]~ ~ Z SYNDROME OF CttRONIC I~]~NAL FAILURE Group

I: Metabolic Disturbances

a. Chronic hypercalcemia: vitamin D poisoning, hyperparathyroidism, sarcoido~is, chronic milk and alkali ingestion b. Chronic potassium depletion c. Chronic alkalosis ( ? ) Group II: Postrenal Obstruction a. Prostatic enlargement b. Urethral strictures c. Ureteral calculi d. Pelvic and retroperitoneal tumors e. Congenital valves, fibrous bands, aberrant vessels and strictures Group III: Generalized Diseases a. Vascular diseases: ( I ) Hypertensive v~scular disease (benign or malignant

nephrosclerosis ) (2) Generalized arteriosclerosis(benign nephrosclerosis) (3) Diabetic vascular disease (intercapillary glomerulosclerosis) (4) Diffuse angiitis (including periarteritis nodosa and hypersensitivity reactions) b. "'Collagen diseases" (disseminated lupus erythematosus, scleroderma ) c, Amyloidosis d. Leukemia, lymphom 9 and multiple myeloma e. Gout f. Saxcoidosis g. Subacute bacterial e:~docarditis Group IV: Primary Renal Disease a. Chronic pyelonephritis; non-tuberculous and tuberculous b. Chronic glomerulonephritis c. Polycystic disease of the kidney d. Tubular dysfunction (e.g., DeToni-Fanconi syndrome and "renal tubular acidosis") e. Radiation nephritis Group V: Any Combination of the Above

c o n t i n u o u s l y a n d rapidly rising blood n i t r o g e n level denotes e i t h e r a n accelerated p h a s e of chronic insufficiency or a n acute process of r e c e n t onset. THE DIAGNOSIS OF ACUTE I~ENAL FAILURE O l i g u r i a - - t h a t is, t h e d a i l y e x c r e t i o n of l e s s t h a n 4 0 0 cc. o f u r i n e - - o f t e n o c c u r s w i t h t h e t y p e s of a c u t e r e n a l d i s o r d e r s l i s t e d u n d e r p a r t A o f T a b l e 1. I n t h e s e c a s e s i t i s i m p o r t a n t to d e t e r m i n e w h e t h e r o r n o t a n y u r i n e is b e i n g e x c r e t e d . T o t a l a n u r i a i s r a r e l y s e e n e x c e p t i n : ( a ) u r e t e r a l or u r e t h r a l

obstruction, (b) profound vascular collapse, (c) total renal infarction or bilateral cortical necrosis, or (d) occasional cases of acute glomernlonephritis and diffuse angiitis. The presence of anuria should make one seriously question a diagnosis of acute tubular necrosis (what used to be called "lower nephron nephrosis"), because in the latter disease there is almost always some urine excreted each day. Obstruction should always come to mind when one sees a totally anuric patient. However, partial obstruction may be present even when urine output is adequate. Intermittent, or varying, degrees of obstruction may be responsible for bizarre patterns of urine output. Irregular wide fluctuations in urine volume, in the presence of acute renal failure, are almost diagnostic of this condition. It must be remembered that obstructive lesions may be totally asymptomatic, particularly when they develop slowly. Sudden onset of obstruction is apt to cause pain, colic and tenderness in the flanks. In any event, when dealing with patients in acute renal failure, any legitimate question of obstruction--regardless of the presence or absence of symptoms--must be immediately settled by retrograde ureteral catheterization. The chief risk in carrying out this procedure is of introducing or exacerbating urinary infection, but the author considers this distinctly less dangerous than the possibility of overlooking a remediable obstructing lesion. There is a general impression that it is inadvisable to perform retrograde pyelography in patients with advanced renal failure. Not only infection, but also an ill-defined entity referred to as "reflex anuria" has been reputed occasionally to result. The latter condition, if it does occur at all, must be exceedingly rare. A reasonable compromise would be to carry out bilateral catheterization in order to exclude obstruction, but to inject dye (with a minimum of pressure) on only one side, preferably that from which the least volume of urine issues. Acute tubular necrosis, a common cause of acute oliguric renal failure, has received much attention in the literature of the past decade and now stands revealed as a new and fairly well-defined clinico-pathologic entity (or group of entities). It is produced by an abrupt toxic or vascular insult to the kidney which results in sudden necrosis of tubular epithelium. During the 10-20 day period required for regeneration of epithelium, glomerular filtrate passively diffuses back through the denuded, disrupted and impotent tubular walls,

leaving for urine formation only a greatly reduced volume of more or less undifferentiated filtrate. In severe cases there may be direct c o m m u n i c a t i o n between tubular l u m i n a and peritubular capillaries. The resulting clinical picture is usually quite characteristic, at least w h e n the physician has the advantage of retrospection. The initiating trauma (shock, sepsis, sudden hemolysis, ingestion or inhalation of renal toxins, etc.) is immediately followed by a period of oliguria and a steadily m o u n t i n g blood nitrogen concentration. During the period of oliguria the urine volume characteristically tends to increase slightly each day. This feature distinguishes acute tubular necrosis (and possibly some cases of healing acute nephritis) from most other forms of acute oliguric renal disorders, because in the latter conditions urine volume either varies irregularly (e.g., in obstruction), or else tends to r e m a i n constant or decrease progressively (e.g., renal infarction or cortical necrosis)..(~fter 2 to 3 weeks the urine volume in acute tubular necrosis rises to supernormal levels and a period of diuresis then ensues. At first the tubules are unable to modify the glomerular filtrate and the urine is quite dilute. Urea in the filtrate continues to diffuse back into the blood and blood nitrogen levels therefore continue to rise. Only after a further lag period of several days, w h e n the newly regenerated epithelium has developed the capacity to produce urine with a high urea concentration, does the blood nitrogen concentration begin to fall. This m u c h about tubular necrosis is now well known. W h a t is not generally appreciated is that there are m a n y clinical variants of this disorder, which occur after transient periods of shock, dehydration or electrolyte imbalance. Not infrequently one sees patients (particularly elderly people with pre-existing hypertensive or arteriosclerotic vascular disease) who develop brief periods of oliguria and renal insufficiency following recovery from episodes of shock or relative hypotension. The reduction in urine volume m a y be slight, but the blood non-protein nitrogen level rises abruptly, just as in patients with fully developed acute tubular necrosis. Diuresis begins after a few days and renal function usually is restored nearly to normal within a week or two. These cases, m u c h more c o m m o n in the author's experience than the more protracted form of the disease, apparently represent the .effects of a less severe and more spotty renal tubular lesion, produced by less intense degrees of renal ischemia. 10

Cortical necrosis, on the other hand, appears to be at the other end of the spectrum of acute tubular injury. Intense or prolonged renal anoxia results in total irreversible necrosis of all tissues in the cortex. Renal shutdown is apt to be permanent if the infarcted areas are extensive and confluent. It must be remembered that renal function may cease during hypotension even without any structural damage to the kidney. The minimum mean arterial pressure necessary to maintain glomerular filtration is about 60-70 ram. Hg in the normal kidney and may be considerably higher in hypertensive and arteriosclerotic kidneys damaged by occlusive disease of pre-glomerular vessels. Thus, relative hypotension in previously hypertensive subjects or marked absolute hypotension in previously normotensive subjects must be corrected before other possible causes of oliguria receive consideration. A few patients with acute glomerulonephritis may become severely oliguric or totally anuric at some stage of their disease. It is usually easy to recognize acute glomerulonephritis when it runs a "classical" course following a streptococcal respiratory infection: edema, hypertension, brown-colored urine, and heavy hematuria and albuminuria constitute the characteristic clinical picture. The disease is more apt to be typical in children and young adults. In older patients, the disease is less common and also much more atypical. In some of these patients in whom the cause of their oliguria and rising blood nitrogen is obscure, the diagnosis may be made simply by the urinalysis. Heavy albuminuria (more than 5 Gm./L.) and numerous red cell casts, are rarely seen in any of the acute oliguric renal disorders other than glomerulonephritis and diffuse angiitis. The latter group of disorders, which include periarteritis, disseminated lupus, and the socalled allergic purpuric diseases, may produce acute renal syndromes almost indistinguishable from that of acute glomerulonephritis. The distinction between post-infectious glomerulonephritis and one of these may depend entirely upon the finding of vascular lesions in other organs. Brief periods of oliguria are not uncommon in severe cases of glomerulonephritis and they do not necessarily portend a fatal outcome. However, when oliguria persists for more than a few days or the patient becomes totally anuric, the outlook becomes much more grave. The author has seen two patients with autopsy-proved acute glomerulonephritis who remained continuously anuric for more than three weeks before suc.|1

cumbing. The prognosis of acute renal failure resulting from acute angiitis is generally much poorer than that of glomerulonephritis. A number of disorders can produce the syndrome of acute and progressive renal failure without significant reduction in urine volume. These include certain of the conditions already discussed, such as glomerulonephritis, obstruction and diffuse vascular disease. In this group should also be included the various types of acute renal infections. Necrotizing papillitis (a particularly fulminating variety of pyelonephritis occurring mainly in diabetics, elderly patients with arteriosclerosis, and in those with some degree of urinary obstruction) may sometimes cause moderate oliguria, but most patients with acute renal infections continue to put out more than 400 cc. of urine daily. Except in necrotizing papillitis, when septic and ischemic gangrene of renal papillae may rapidly destroy the urinary function of the kidney, acute infections do not by themselves often produce acute renal failure. The latter is much more likely to occur when acute infection occurs in a kidney previously damaged by other disease. It is usually easy to recognize acute pyelonephritis when it produces the typical picture of chills and fever, flank pain, dysuria, pyuria and baeilluria, but it is important to remember that some of these findings are often lacking in any given case. Asymptomatic urinary infections are exceedingly common. Since increased numbers of white cells are not always in evidence it may be difficult to recognize such cases. It has been suggested that a bacterial count of more than 10,000 organisms per ec. of unspun freshly voided urine may be taken as evidence of active infection, because the number of organisms derived from accidental contamination during the collection of urine is usually much less (1). Negative urine cultures, however, do not rule out renal infection. Pus casts are a very important diagnostic finding because they are usually pathognomonic and may be found in urines containing few leukocytes or bacteria. The diagnosis of renal infection should always be suspected in patients with a previous history of pyelonephritis and in patients who have stones, congenital anomalies, urinary obstruction of all sorts, and particularly in those with indwelling catheters. PractfcaUy all

patients with indwelling bladder catheters and gravity drainage develop urinary infections, regardless of whether or not they are receiving antibiotics prophylactically. 12

Acute disorders of fluid and electrolyte balance, as well as severe congestive heart failure, may impair renal circulation severely enough to compromise renal function. These disorders may, of course, be severe enough to produce f r a n k vascular collapse with oliguria and almost total loss of renal function. More often, the signs of collapse are not overt and the blood nitrogen level rises progressively despite nearly norreal urine volumes. Provided one thinks of it, the diagnosis should offer no problems. Severe dehydration, hyponatremia and congestive failure are easily recognized. Aside from perhaps a trace of albumin and a few hyaline casts or finely granular casts, the urine in these cases contains little of note. Specific gravity m a y be high or intermediate. Again, as in the case of acute renal infection, the presence of pre-existing renal disease enhances the vulnerability of the kidney. A c o m m o n clinical dilemma is engendered by the fact that water and electrolyte disorders m a y not only be associated with, or result from, acute renal failure, but also m a y in themselves cause the renal dysfunction. Given a dehydrated and salt-depleted patient with oliguria and renal failure, how can one determine whether or not the prime cause is organic renal disease? Some advocate giving such patients rapid intravenous infusions of saline or glucose solutions as a diagnostic test. Failure of the urine output to rise is taken as an indication of some underlying renal disease, probably acute tubular necrosis. Routine use of th~s test is unnecessary and m a y be dangerous. Severe water and electrolyte depletion, particularly w h e n associated with circulatory collapse, obviously calls for prompt and vigorous treatment. But far too often fluids are administered with equal enthusiasm to oliguric patients who are only slightly depleted. Under these circumstances pulmonary edema or water intoxication m a y be very real hazards. History and physical examination, together with a meticulous examination of the urine sediment are m u c h safer and more reliable diagnostic guides. If there is no renal disease, only the most extreme and clinically obvious degrees of dehydration or salt depletion are capable of producing severe azotemia. Even then, urine volume is rarely less than 400 cc. per day, unless frank vascular collapse supervenes. In the absence of shock and obstruction, very small volumes (i.e., below 200 cc. per day) are almost always caused by organic renal disease. The urine sediment is another very helpful 13

clue: absence of a b n o r m a l f o r m e d e l e m e n t s i n a freshly voided a n d properly e x a m i n e d s p e c i m e n virtually rules out p r i m a r y r e n a l disease as a cause of oliguria. On the o t h e r h a n d , the specffie gravity of the u r i n e is often of n o help, since m a n y p a t i e n t s depleted of electrolyte a n d w a t e r do not h a v e very c o n c e n t r a t e d urines, a n d o t h e r p a t i e n t s w h o h a v e acute r e n a l disease m a y excrete u r i n e w i t h a specific gravity as h i g h as 1.018 or 1.020 for the first day or two. Ammonium chloride poisoning m a y occur in p a t i e n t s being treated for congestive failure w h o also h a v e some degree of u n d e r l y i n g r e n a l damage. U n a b l e to excrete the a d m i n i s tered load of n i t r o g e n a n d acid with o p t i m a l efficiency, these p a t i e n t s m a y develop a r i s i n g blood n i t r o g e n level a n d progressively severe metabolic acidosis. The r e s u l t i n g clinical picture, a l t h o u g h chiefly due to a n excessive load o n the kidney, m a y exactly m i m i c o t h e r types of acute non-oliguric r e n a l disorders r e s u l t i n g f r o m r e n a l disease. It usually is a self-limiting situation, b e c a u s e w h e n the p a t i e n t gets too sick h e is u n a b l e to c o n t i n u e i n g e s t i n g the offending compound. However, prior to this time the absorbed load m a y h a v e b e e n large e n o u g h to produce a very serious acidosis w h i c h requires i m m e d i a t e a n d i n t e n s i v e therapy. E v e n patients with n o r m a l r e n a l f u n c t i o n c a n be b r o u g h t to this state by s u d d e n ingestion of h u g e quantities of a m m o n i u m chloride. T h e a u t h o r once saw a y o u n g w o m a n w i t h o u t r e n a l disease w h o took a n u n d e t e r m i n e d b u t obviously very large q u a n t i t y of a m m o n i u m chloride with suicidal i n t e n t a n d was b r o u g h t to the hospital i n acidotic coma. T h e diagnosis of a m m o n i u m chloride poisoning should be suspected in any azotemic p a t i e n t w i t h acidosis w h o h a s been taking this drug. T h e r e s u l t i n g electrolyte p a t t e r n of the blood is quite c h a r a c t e r i s t i c a n d differs distinctly f r o m t h a t produced by u r e m i a due to p r i m a r y r e n a l failure. Figure 1 illustrates the p l a s m a electrolyte p a t t e r n i n n o r m a l s , i n p a t i e n t s w i t h u r e m i a a n d i n those with a m m o n i u m chloride poisoning. I n A is s h o w n the n o r m a l p a t t e r n . The s u m of the c o n c e n t r a t i o n s of total C02 a n d chloride is a p p r o x i m a t e l y 8 to 12 m E q . / L , less t h a n the sodium c o n c e n t r a t i o n . T h i s difference, labelled " R - " in the d i a g r a m s is m a d e up of a n i o n s w h i c h are n o t usually m e a s u r e d ( p h o s p h a t e , sulfate, organic acids, etc.). The r e m a i n i n g cations in the p l a s m a ( p o t a s s i u m , c a l c i u m a n d m a g n e s i u m ) are approximately b a l a n c e d by the p r o t e i n anions. T h e total c o n c e n t r a t i o n s of these moieties, 14

indicated in the diagrams by "C+" and "P-", respectively, remain fairly constant under most conditions and may therefore be neglected for the purposes of this discussion. Diagram B shows a typical electrolyte pattern in uremia caused by primary renal failure. As a result of reduced gIomerular illtration, excretion of phosphate, sulfate and other constituents of '~R-" is reduced, and these substances accumulate in the plasma. Simultaneously, impaired tubular function limits

'~mRilii!i

HCO~"

~li=!il No 14~ := ~i

'I, ',,

m

I!i]]1 ar.=l

t'itl

103

III, i.. ;2! i,,, ,~,,~, 103

118

i,ii, i I iii

i!i != II

I

C.=A.

NORMAL

B.

UREMIC ACIDOSIS

G. AMMONIUM CHLORIDE AGIDOSIS

FIG, 1.--Plasma electrolyte patterns. renal excretion of acid and therefore plasma CO2 falls, being replaced mainly by the accumulating "R-" ions. Plasma sodium and chloride may be high, low or normal, depending on individual circumstances. The essential change in pattern is the rise in "R-", which is measured by an increase in the difference between the sodium concentration and the sum of the COs and chloride. Diagram C illustrates the changes produced by ammonium chloride. In this case, HC1 is, in effect, the acid accumulating in the blood. Plasma bicarbonate is therefore replaced by an exactly equivalent amount of chloride. The sum of COx and chloride remains unchanged and, despite the development of acidosis and azotemia, there is no great rise in "R-'. Chloride concentration is usually increased, but this is not an infallible guide, because the par15

ticular circumstances may result in enough loss of sodium and chloride to prevent the development of a significant rise in the concentration of chloride. However, the chloride concentration is always relatively high compared to sodium. The key to the chemical diagnosis of this condition is the uremia and acidosis without much increase in "R-". A similar chemical picture may be produced by ion exchange resins containing hydrogen or ammonium. Diamox, a carbonic anhydrase inhibitor, also may cause this type of acidosis, but there is no azotemia. Furthermore, in contradistinction to ammonium chloride and the acidifying resins the tendency of diamox t o produce hyperchloremic acidosis is greatly reduced in patients with decreased renal function. The only other common clinical situation apt to result in acute renal failure and hyperchloremic acidosis of this type is uretero-intestinal transplantation. In this situation the puddling of urine in the colon permits reabsorption of urea and the exchange of chloride in the urine for the bicarbonate of the blood. As a result, the urine, when finally extruded from the bowel, has a lower content of urea and chloride, and a higher concentration of bicarbonate than when it was first formed. Reciprocal changes occur in the blood, producing a chemical picture indistinguishable from that of ammonium chloride poisoning. Ureteral obstruction and renal infection are complications which often damage the kidney and add to the severity of the clinical picture. THE DIFFERENTIAL DIAGNOSIS OF CHRONIC RENAL DISEASE

Chronic renal failure may result from a great variety of pathological processes; these are listed in Table 2. The natural history of the resulting disorder, its clinical manifestations and its response to therapy will depend considerably upon the nature of the etiologic factor. The main purpose of the classification presented in Table 2 is to emphasize that some forms of chronic renal insufficiency are curable, or at least tractable, while others are not. In general renal failure caused by the disorders listed under Groups I and II may be permanently arrested or cured by removal of the offending circumstance. The natural history of the renal failure occurring as part of the systemic disorders of Group III is usually determined by the progress of the underlying diseases. With but 16

few exceptions the latter are mainly intractable, and so the resulting renal failure is likewise unremitting. In these diseases renal damage is sometimes clinically unimportant and in other cases it may be prominent and actually be the prime cause of death. The diseases listed in Group IV are chronic diseases of the kidney which, at the present time, must all be considered incurable. With the exception of the primary tubular diseases, these disorders usually lead to progressive renal failure and terminate in chronic uremia with or without hypertensive cardiovascular disease. Since so little is known about the mechanisms initiating and maintaining these diseases, most of our present therapy is mainly palliative. Chronic disturbances in electrolyte metabolism account for a small group of cases (Group I). Hypercalcemia appears to be injurious to the kidney, often causing diffuse or localized deposition of calcium in the renal substance or pelvis. Any disorder producing sustained elevation of blood calcium may therefore be associated with some degree of renal failure. In the early stages of renal damage these disturbances may be recognized by the fact that the blood calcium is elevated, or at least in the high normal range. As renal insufficiency advances and the serum phosphorus level rises the blood calcium tends to become depressed. Thus, for example, the elevated calcium and depressed phosphorus characteristic of uncomplicated hyperparathyroidism gradually changes to a state of hyperphosphatemia and hypocalcemia as the blood nitrogen level increases. Metastatic calcification, intra- or extra-renal, may provide the diagnostic clue, but often calcification in the kidney may be visible only on microscopic examination. Severe potassium depletion has recently been revealed as a cause of chronic renal insufficiency (2). Whenever substantial deficits of potassium occur, such as in chronic diarrhea, anorexia, vomiting, or hyperadrenalism, hydropic degenerative lesions may develop in the tubular epithelium. Tubular and, to a lesser extent, glomerular function may become severely impaired, but both may be at least partly restored a short while after body potassium stores are replenished. The diagnosis should be suspected in any patient with hypokalemia and signs of renal insufficiency. This possibility should also be entertained in patients with normal serum potassium levels if there is a history strongly suggestive of recent severe potassium depletion, since there may be a lag 17

of as much as several weeks between the restoration of chemical deficits and recovery of renal function. Potassium depletion may of course occur as a secondary complication of underlying renal disease. It may be produced by the renal potassium-wasting tendencies of some of the primary tubular diseases (Group IV, d), or as the result of the anorexia, vomiting or diarrhea so commonly associated with severe renal failure of any sort. Under these circumstances, the potassium depletion may act further to impair already reduced renal function. Repair of the electrolyte disturbance should not be expected to produce complete recovery or essentially to alter the course of the disease. Chronic alkalosis, particularly that caused by pyloric obstruction, vomiting and ingestion of absorbable alkalis, is sometimes associated with renal insufficiency. Many of these patients are liypercalcemic as a result of chronic milk drinkhag and others are severely potassium-depleted, sodiumdepleted or dehydrated. It is therefore difficult to know whether alkalosis per se is harmful to the kidneys, and hence a question mark follows this item in the table. Postrenal obstruction. It is worth remembering that obstructive lesions, depending on their nature and severity, can produce the picture of acute or chronic renal failure, with or without reduction in urine volume. Some types of obstruction may produce few or no symptoms and one should not depend upon the occurrence of such clues as colic, dysuria, frequency, narrowing of the urinary stream, etc. It needs to be emphasized that to avoid the tragedy of overlooking symptomatic obstruction it is necessary to obtain adequate urographic studies on almost every patient with renal failure. Little needs to be said about the differential diagnosis of the renal disorders in Group III, since as a rule their characteristic features are those of the generalized disease. There are, however, certain peculiarities which are diagnostically useful. Hypertensive and arteriosclerotic disease of the kidney never produce the nephrotie syndrome. Except for a few cases of malignant hypertensive disease, urine protein excretion in nephrosclerosis is usually less than 5 grams a day and in almost all instances serum albumin is within normal limits. Those systemic diseases which produce vascular lesions in the glomerulus such as lupus, amyloid, and intereapillary glomerulosclerosis, are the disorders which may result in a nephrotic picture quite indistinguishable from that occurring in chronic glomerulonephritis. 18

In the absence of the nephrotic syndrome the separation of the various hypertensive renal disorders may pose a considerable problem, particularly when renal insufficiency is greatly advanced. Nevertheless, the author firmly believes that in the great majority of instances an accurate clinical diagnosis can be made. The four most common causes of renal failure with hypertension are: (1) primary hypertensive vascular disease with malignant nephrosclerosis, (2) pyelonephritis, (3) glomerulonephritis, and (4) diabetic intereapfllary glomeruloselerosis. The latter is easily recognized by virtue of the associated diabetic syndrome and the usually typical lesions in the eyegrounds. The three remaining diseases are usually distinguishable if the total clinical picture is carefully considered. A most useful clue is whether or not hypertension precedes the development of albuminuria. If an accurate history can be obtained, the clear establishment of this sequence of events will usually be sufficient to make the distinction between "essential" hypertension and that secondary to chronic renal disease. The relative severity of the hypertensive disease and the renal insufficiency is also an important point. Patients with glomerulonephritis who develop severe hypertension usually have well-advanced renal insufficiency, although very rarely one may see a case of glomerulonephritis manifesting malignant hypertension before the onset of marked uremia. Most patients with malignant nephrosclerosis have signs of severe hypertension for many months or years before they begin to develop renal failure, and the severity of the latter is usually overshadowed by the vascular disease. In pyelonephritic patients the relative severity of renal and vascular involvement is variable. Heavy albuminuria, even without the other elements of the nephrotic syndrome indicates a glomerular disease and therefore is in favor of glomerulonephritis. Malignant nephrosclerosis may produce heavy albuminuria, but this disorder and pyelonephritis characteristically are associated with minimal or even intermittent excretion of protein. The examination of the urine sediment is also very helpful in the differential diagnosis of hypertensive renal disease, and this will be discussed below. X-RAY EXAMINATION OF THE URINARY TRACT

X-ray of the urinary tract is a very powerful diagnostic tool. On a plain film of the abdomen one may immediately ]9

identify stones or calcification in the kidney. The size of the kidneys may be estimated by comparison with the bodies of the lumbar vertebrae, which lie approximately in the same frontal plane and which tend to bear the same relationship to body size as do the kidneys. On the standard plain film of the abdomen normal kidneys appear to be approximately as long as 3-31/2 vertebral bodies. Slight, bilateral and symmetrical enlargement of the kidneys is seen in acute glomerulonephritis, the nephrotic syndrome, and infiltrative diseases of the kidney (amyloid~ leukemia, lymphoma). Marked enlargement, usually unequal, is characteristic of hydronephrosis or of polycystic disease. The latter is further distinguished by the irregular outline of the renal cortex. Aside from these two diseases the only other conditions apt to produce gross inequality of renal size are chronic pyelonephritis, and in rare cases, unilateral ischemia or congenital hypoplasia. In these disorders there is usually one very small kidney with compensatory hypertrophy of the other. Marked bilateral atrophy is the almost exclusive hallmark of chronic glomerulonephritis and chronic pyelonephritJs but when these diseases progress rapidly renal failure may develop before significant loss of renal substance has occurred. The diffuse vascular diseases of the kidney do note as a rule, cause much atrophy unless they are of extremely long duration. The writer believes that intravenous or retrograde pyelography should be carried out in almost every patient with renal disease. When disease has damaged the ability of the renal tubules to secrete and concentrate the various radioopaque dyes, visualization of the urinary tract is possible only with retrograde pyelography. As a general rule, dyeconcentrating ability is better indicated by the excretion of PSP than by the level of non-protein nitrogen in the blood. Patients who excrete less than 15 per cent of the injected PSP within 15 minutes are not apt to be satisfactory subjects for intravenous pyelography. There is no a priori reason to interdict retrograde studies in patients with renal failure, but if there is reason to suspect acute infection of the urinary tract, and obstruction needs to be ruled out, it is probably best to restrict the initial retrograde examination to the mere passage of catheters. Instillation of dye under pressure may exacerbate or disseminate the septic process. Pyelography provides definitive information about the size, shape and position of the kidneys and in addition reveals 20

internal details which cannot be obtained in plain films. Often the diagnosis of polycystic disease, tuberculosis, hydronephrosis, non-opaque stones, or various types of obstructive lesions can only be made in this manner. Much interest centers about the possibility of recognizing asymptomatic chronic non-obstructive pyelonephritis (an elusive diagnosis at best) from minor degrees of blunting of the minor calyces. In the writer's experience these changes are frequently associated with chronic pyelonephritis but this association is neither specific nor invariable. Aortography is said to be useful in the localization of neoplasms and vascular lesions but the author has not had any experience with this technique as applied to the usual medical disorders of the kidney. URINALYSIS AND THE URINE SEDIMENT

Urinalysis. The urine is a great source of useful diagnostic and prognostic information, which is all too often neglected. Only a few selected aspects of this topic will be mentioned here. For a more thorough review the reader is referred to Lippman's excellent monograph (3). In the presence of renal failure the excretion of a urine free of albumin and abnormal formed elements suggests that some extra-renal factor is at work, particularly obstruction. The color of the urine may occasionally be a valuable diagnostic point. The smoky mahogany or greenish brown color of the urine in acute glomerulonephritis is very characteristic as axe the darker reddish brown hues imparted to the urine by hemoglobin or myoglobin. The diagnostic value of quantifying protein excretion has already been alluded to. The diseases characterized by heavy albuminuria are those in which the lesions appear to be primarily in the glomerular structures. The excretion of five, or more grams of protein a day is strong evidence in favor of glomerulonephritis, intercapiUaxy glomerulosclerosis, or any of the other disorders listed in Table 3 which are potentially capable of producing the nephrotic syndrome. Obstructive and metabolic disorders usually cause little or no albuminuria. Pyelonephritis and nephrosclerosis (except in the malignant phase) also tend to cause relatively slight degrees of albuminuria. These generalizations are usually valid, but it must be remembered that patients with glomerulo21

n e p h r i t i s do n o t always h a v e h e a v y a l b u m i n u r i a , while patients with p y e l o n e p h r i t i s s o m e t i m e s m a y excrete 4 or 5 Gin. daily. TABLE 3.--RENAY~DISOP~U~aSSOmETiMES ASSOCIATED WITH THE NEPHROTIC SYNDROME

Almost all patients who excrete more than 5 Gin. protein daily have o n e o f the following: 1. Glomerulonephritis 2. Diabetic intercapillary glomerulosclerosis 3. Amyloidosis 4. D i f f u s e v a s c u l a r disease 5. Thrombosis of renal veins 6. Allergic reactions to drugs and toxins 7. Secondary syphilis The urine sediment m a y be e x a m i n e d i n a qualitative m a n n e r , or m o r e q u a n t i t a t i v e l y with the m e t h o d s described by Addis ( 4 ) . E a c h t e c h n i q u e h a s its advocates b u t there c a n be n o question t h a t m e t i c u l o u s a p p l i c a t i o n of one or the o t h e r of these techniques by a n experienced observer, preferably the p h y s i c i a n directly c o n c e r n e d w i t h the patient, is a n essential p a r t of the e x a m i n a t i o n of the p a t i e n t with r e n a l insufficiency. T h e writer's experience h a s b e e n largely with the qualitative method. T h e u r i n e s p e c i m e n to be e x a m i n e d should be the first or second m o r n i n g voiding after eight to twelve h o u r s of a b s t i n e n c e f r o m fluids. Longer periods of d e h y d r a t i o n are best avoided w i t h p a t i e n t s w h o h a v e serious r e n a l disease. T h e f r e s h u r i n e m a y be c e n t r i f u g e d directly, b u t if it is very dilute it should be first c o n c e n t r a t e d by allowing it to s t a n d for a n h o u r or two i n a wide beaker, to p e r m i t settling of f o r m e d elements. Delays longer t h a n this m a y allow c e r t a i n of these e l e m e n t s to disintegrate a n d bacterial overgrowth to start. A centrifuge tube is filled with u r i n e pipetted f r o m the b o t t o m of the b e a k e r a n d s p u n at h i g h speeds for t e n m i n u t e s . A drop of the s e d i m e n t is t h e n m o u n t e d o n a clean slide with a coverslip a n d e x a m i n e d u n d e r the low power w i t h the light t u r n e d down. E n o u g h time should be allowed to complete a systematic survey of the entire area u n d e r the coverslip. Objects first located u n d e r low power m a y be definitively identified u n d e r the high-dry objective w i t h i n c r e a s e d sub-stage lighting. W i t h this t e c h n i q u e all f o r m e d e l e m e n t s p r e s e n t in the u r i n e are almost c e r t a i n to be seen a n d it is possible to o b t a i n a r o u g h idea of t h e i r n u m b e r s .

22

The following are some generalizations which apply to sediment examinations carried out in this m a n n e r : 1. Heavy h e m a t u r i a may be found in such a large variety of renal and extrarenal disorders that it is really of little diagnostic value unless it is accompanied by red blood cell casts. The latter, however few in number, are fairly specific signs of an acute hemorrhagic lesion in the glomerulus such as occurs in active (acute or chronic) glomerulonephritis, diffuse angiitis and malignant nephrosclerosis. They are also occasionally found in acute tubular necrosis, presumably as the result of the rupture of small vessels through the necrotic tubular wails. 2. Leukocytes, when few in number, m a y be seen in almost any renal affliction, but w h e n found in profusion or in clumps they usually indicate infection. Pus cells packed together in casts usually indicate active pyelonephritis but they need to be distinguished from other less specific casts which contain fragmented epithelial ceils together with a few leukocytes. Leukocyte casts are also sometimes formed in acute glomerulonephritis of the exudative variety, with large numbers of polymorphs in the glomeruli. 3. Hemoglobin casts and bile-stained casts m a y be found in acute tubular necrosis and '~epato-renal syndrome" respectively but they are not pathognomonie of these conditions because they m a y occur in any situation where the serum concentration of these pigments is elevated. 4. In general, casts are rare in normal urine and they are almost always narrow ( 1 0 - 1 5 micra in diameter) and of the hyaline or very finely granular varieties. Wide casts (i.e., those formed in the collecting tubules or papillary ducts and therefore about 2 0 - 5 0 micra wide) are always indicative of renal disease as are casts containing cells or coarsely granular cellular debris. 5. Droplets of fatty debris and cells or casts showing fatty degeneration are fairly specific for the nephrotic syndrome or for certain stages of any of the conditions listed in Table 3 in which albuminuria is profuse. Fat is best seen through crossed polarizing filters; another satisfactory technique is to add a saturated alcoholic solution of Sudan III to the urine sediment and examine under ordinary light 15 to 30 minutes later. 6. Epithelial cells sloughed from the lining of renal tubules are sometimes hard to distinguish from swollen leukocytes 23

and macrophages. Usually they can be identified by the fact that they are considerably larger than these cells, although smaller than squamous epithelial cells, and by their tendency to contain fatty material. In acute tubular necrosis and occasionally in cases of necrotizing papillltis whole plaques of renal epithelial cells, representing necrotic fragments of tubular walls, may be found in the urine. Broad casts containing large fragments of fresh epithelial cells are also indicative of an active necrotizing process in the tubules. They are characteristically found not only in acute tubular necrosis, cortical necrosis and necrotizing papillitis, but also sometimes in very active pyelonephritis. USE AND INTERPRETATION OF SOME SIMPLE TESTS OF RENAL FUNCTION

The proper use of a few simple clinical tests of renal function may provide information about the nature, as well as the degree, of renal damage (5). These tests include: the blood urea nitrogen, the serum creatinine, the twenty-fourhour creatinine clearance, the excretion of PSP dye and the m a x i m u m concentration of the urine. Urea and creatinine are end products of nitrogen metabolism which are removed from the body almost exclusively through the kidneys, largely by the process of glomerular filtration. The efficiency with which the kidneys clear these substances from the blood is measured by the rate of excretion per unit concentration in the blood. This quantity, which is the clearance of each substance, is directly proportional to the glomerular filtration rate and m a y be used as a rough clinical guide to this important aspect of kidney function. The actual determination of a clearance requires accurate collection and analysis of timed urine specimens and therefore is not easily applied in routine clinical practice. A m u c h simpler and almost as satisfactory alternative is to estimate the clearance from the blood urea nitrogen or the serum creatinine concentration. This can be done because of the predictable relationship between blood level and clearance, which is illustrated in Figure 2. As shown in the figure, clearance and blood level are reciprocally related. If the clearance is reduced by half, concentration doubles; if the clearance increases by three-fold, the blood level is reduced to one-third, and so on. 24

It h a s o f t e n b e e n stated t h a t the blood u r e a n i t r o g e n level does n o t b e g i n to rise u n t i l h a l f or m o r e of r e n a l f u n c t i o n h a s b e e n lost. This is n o t so, because, as the d i a g r a m shows, a n y r e d u c t i o n i n c l e a r a n c e is followed by a rise i n p l a s m a level. However, a given p e r c e n t a g e fall in u r e a clearance, s t a r t i n g f r o m a n o r m a l level, produces a s m a l l e r absolute i n c r e a s e i n blood u r e a n i t r o g e n t h a n the s a m e p e r c e n t a g e

,o0 \

UREAor GREATININE GLEARANGE 75

RELATIONBETWEEN RENALCLEARANCE ~ BLOODLEVEL OF

~ ~

Normol~550

I

I00

f

I

I

I

I

I

I

;;'00 300 4 0 0 500 600 700 BOO 8.U.N,or SERUMGREATININE %Normol FZG, 2.--Relation between clearance and blood level of urea and creatinine. r e d u c t i o n i n a p a t i e n t with a low u r e a clearance. This fact, t a k e n together with the r a t h e r broad r a n g e of n o r m a l blood c o n c e n t r a t i o n s of urea, m a k e s it difficult to recognize the very earliest reductions i n clearance. The n o r m a l r a n g e of c o n c e n t r a t i o n for u r e a is fairly wide, chiefly b e c a u s e several factors other t h a n g l o m e r u l a r filtration rate d e t e r m i n e the blood level. At a n y given state of r e n a l f u n c t i o n the blood u r e a m a y be i n c r e a s e d by accelerating the rate of u r e a synthesis. This c a n be done by i n c r e a s i n g the dietary i n t a k e of protein or by i n c r e a s i n g the rate of tissue catabolism. T h e latter m a y be caused by fever, t r a u m a a n d starvation, as well as m a n y e n d o c r i n e factors. A n o t h e r i m p o r t a n t influence on the blood u r e a is the u r i n e flow. W h e n this is r e d u c e d by deh y d r a t i o n or other factors to a rate less t h a n 2 c c . / m i n . , u r e a clearance is progressively d i m i n i s h e d a n d the blood u r e a 25

rises e v e n t h o u g h the g l o m e r u l a r filtration r a t e h a s not necessarily c h a n g e d . T h e s e e x t r a n e o u s factors of u r i n e flow, diet a n d protein c a t a b o l i s m h a v e very little influence o n t h e s e r u m c r e a t i n i n e c o n c e n t r a t i o n . For this r e a s o n the s e r u m c r e a t i n i n e is probably to be preferred to the blood u r e a as a guide to g l o m e r u l a r filtration rate. T h e s e r u m c r e a t i n i n e c o n c e n t r a t i o n is determ i n e d solely by the r a t e of c r e a t i n i n e p r o d u c t i o n a n d the c r e a t i n i n e clearance. T h e rate of production, in t u r n , is fairly c o n s t a n t in a n y one i n d i v i d u a l a n d t e n d s to be related to the m a s s of m u s c l e tissue. T h e n o r m a l s e r u m c r e a t i n i n e concent r a t i o n is therefore apt to be slightly h i g h e r in a large m u s c u lar i n d i v i d u a l t h a n i n someone with a m o r e a s t h e n i c build. Muscle w a s t i n g c a u s e d by severe c h r o n i c illness also tends to affect the r a t e of c r e a t i n i n e production. It is therefore usually h e l p f u l to o b t a i n at least one t w e n t y - f o u r - h o u r collection of u r i n e for c r e a t i n i n e i n order properly to e v a l u a t e the s e r u m c r e a t i n i n e level i n a n e w patient. T h e r e a f t e r a n y c h a n g e s i n g l o m e r u l a r f u n c t i o n m a y be followed by the fluct u a t i o n s i n s e r u m level alone. One rarely sees p a t i e n t s w i t h slowly progressive c h r o n i c r e n a l disease w h o r e s p o n d to t r e a t m e n t a f t e r the s e r u m crea t i n i n e h a s r i s e n above 15 rng. % . A s s u m i n g a n average n o r m a l value of a p p r o x i m a t e l y 0.7 nag. % , a c o n c e n t r a t i o n of 15 nag. % or more i n d i c a t e s a loss of more t h a n 95% of g l o m e r u l a r f u n c t i o n , since t h e r e h a s b e e n a m o r e t h a n 20-fold rise i n blood level. Unless t h e r e h a s b e e n a r e c e n t acceleration of r e n a l failure due to e x t r a n e o u s a n d r e m e d i a b l e factors, this level of c r e a t i n i n e a p p r o x i m a t e l y defines a degree of r e n a l failure n o longer compatible with n o r m a l activity. This does not necessarily apply to p a t i e n t s with oliguria a n d acute r e n a l failure. Acute loss of r e n a l f u n c t i o n results i n a progressive rise in u r e a a n d c r e a t i n i n e w h i c h usually c o n t i n u e s for the d u r a t i o n of the period of shutdown. D u r i n g this t i m e the level of c r e a t i n i n e or u r e a h a s n o direct r e l a t i o n to e i t h e r the e x t e n t of the r e n a l d a m a g e or its u l t i m a t e prognosis. J u s t as the s e r u m c r e a t i n i n e (or, u n d e r special circumstances, the blood u r e a ) m a y be t a k e n as a r o u g h clinical i n d e x of g l o m e r u l a r filtration rate, so m a y the excretion of injected PSP dye be used as a n e s t i m a t e of r e n a l p l a s m a flow a n d t u b u l a r excretory function. More t h a n h a l f of the dye i n the p l a s m a is r e m o v e d i n one circulation t h r o u g h the kidneys by a c o m b i n a t i o n of g l o m e r u l a r filtration a n d t u b u l a r seere26

tion. I n n o r m a l kidneys, therefore, the clearance of PSP is a relatively c o n s t a n t f r a c t i o n ( a b o u t 60 % ) of the r e n a l p l a s m a flow. T h e latter is m o r e accurately m e a s u r e d by the c l e a r a n c e of p a r a - a m i n o h i p p u r i c acid ( P A H ) or Diodrast| W h e n r e n a l t u b u l a r f u n c t i o n is d a m a g e d extraction of PSP is m u c h less complete, a n d the clearance r a t e is reduced i n r e l a t i o n to the p l a s m a flow. T h e c l e a r a n c e of PSP, like t h a t of PAH or Diodrast| is therefore r e d u c e d by loss of t u b u l a r secretory f u n c t i o n as well as by r e n a l ischemia. M e a s u r e m e n t of the c l e a r a n c e of PSP, like the c l e a r a n c e of u r e a or creatinine, is not very practical for r o u t i n e clinical use. A satisfactory substitute is the m e a s u r e m e n t of the total dye excreted at specified i n t e r v a l s following i n t r a v e n o u s injection of a s t a n d a r d 6 rag. dose. This is the basis for the clinical PSP test so widely employed a n d yet so o f t e n misunderstood. If the test is to be a sensitive a n d accurate i n d e x of r e n a l f u n c t i o n c e r t a i n prerequisites m u s t be m e t : ( 1 ) the exact a m o u n t of dye (1 cc. = 6 m g . ) should be i n j e c t e d cleanly into a vein, ( 2 ) u r i n e flow should be rapid, ( 3 ) the first u r i n e collection should be 10 or 15 m i n u t e s a f t e r injection, a n d ( 4 ) the p a t i e n t should be able to e m p t y his b l a d d e r completely. It is certainly n o t possible to m e a s u r e 1 co. of dye accurately i n a s t a n d a r d 5 or 10 ce. syringe. For this purpose a I ec. t u b e r c u l i n or i n s u l i n syringe should be used, a n d special care t a k e n to i n s u r e t h a t the syringe c o n t e n t s are delivered completely a n d directly into a vein. T h e p a t i e n t m u s t be h y d r a t e d i n advance,* so t h a t h e feels the urge to void before the i n j e c t i o n is m a d e a n d will be able to void p r o m p t l y o n d e m a n d , t e n or fifteen m i n u t e s later. This i n s u r e s a rapid flow of urine, a ]arge u r i n e s p e c i m e n a n d a m i n i m a l percentile error i n e m p t y i n g the bladder. U n d e r these conditions the a m o u n t of dye c o n t a i n e d in the initial s p e c i m e n is closely related to the PSP c l e a r a n c e a n d is therefore a fairly satisfactory m e a s u r e of t u b u l a r f u n c t i o n and r e n a l p l a s m a flow. Normally, 25 to 40% of the i n j e c t e d dye will be excreted i n the first fifteen-minute specimen, a n d a n equivalent total a m o u n t will be excreted at a progressively d i m i n i s h i n g rate d u r i n g the n e x t h o u r a n d three quarters. Dye a p p e a r i n g in l a t e r s p e c i m e n s h a s e i t h e r b e e n excreted p r o m p t l y by n o r m a l #Three or four glasses of water in the 90 minutes preceding the test is adequate for this purpose. I t sho*dd be remembered that some patients with renal dysfunction have a m a r k e d i m p a i r m e n t of w a t e r diuresls, a n d m a y become water intoxicated if m u c h larger a m o u n t s are given or even if this quantity is given over a short period of t i m e .

27

n e p h r o n s b u t delayed in t r a n s i t by r e t e n t i o n of u r i n e i n the bladder or u p p e r u r i n a r y tract, or else it h a s b e e n r e m o v e d f r o m the blood by d a m a g e d tubules only a f t e r r e p e a t e d recirculations t h r o u g h the kidneys. W i t h early r e n a l d a m a g e or w i t h slight degrees of u r i n a r y retention, one m a y therefore find a slight b u t definite r e d u c t i o n i n the 15 m i n u t e excretion, w i t h a n o r m a l total excretion i n two hours. T h e a m o u n t excreted in the first s p e c i m e n is t h u s a m u c h m o r e sensitive i n d e x of r e n a l a n d u r i n a r y f u n c t i o n t h a n the total q u a n t i t y of dye excreted i n two hours. T h e l a t t e r value, or e v e n t h e total dye excreted i n 60 m i n u t e s , is significantly r e d u c e d only w h e n r e n a l disease is well established. W i t h more a d v a n c e d degrees of r e n a l i m p a i r m e n t b o t h the 15 m i n u t e a n d total excretions are reduced a n d t h e r e t e n d s to be a relative increase in the p e r c e n t a g e of dye excreted i n the l a t e r specim e n s . W h e n the dye i n the second h o u r exceeds t h a t excreted in the first hour, one should suspect u r i n a r y obstruction. M a n y cases of a s y m p t o m a t i c b l a d d e r n e c k o b s t r u c t i o n h a v e b e e n diagnosed i n this m a n n e r . One of the d i s a d v a n t a g e s in u s i n g excretion of PSP as a n i n d e x of r e n a l f u n c t i o n is t h a t it t e n d s to be r e d u c e d to i m m e a s u r a b l y s m a l l levels i n the l a t e r stages of r e n a l insufficiency. T h e excretion of dye o f t e n r e a c h e s levels of less t h a n 5% long before c h r o n i c r e n a l insufficiency h a s r u n its course. By contrast, the level of s e r u m c r e a t i n i n e c a n be followed as a guide to c h a n g e s i n filtration r a t e r i g h t u p to the very t e r m i n a l stages of r e n a l failure. CONCENTRATION AND DILUTION TESTS

Tests of c o n c e n t r a t i n g a n d d i l u t i n g ability h a v e held a time-honored place a m o n g the clinical tests of kidney function. T h e y are, however, of very limited value. A u r i n e specific gravity of 1.025 or m o r e is fairly reliable evidence of n o r m a l t u b u l a r f u n c t i o n , b u t it does not necessarily exclude m i n i m a l i m p a i r m e n t of g l o m e r u l a r f u n c t i o n , n o r does it rule out l a t e n t r e n a l disease w i t h o u t f u n c t i o n a l i m p a i r m e n t . A single r a n d o m s p e c i m e n with a h i g h specific gravity is m o r e i n f o r m a t i v e t h a n m a n y s p e c i m e n s with a low or i n t e r m e d i a t e specific gravity. W h e n all r a n d o m u r i n e s are dilute, it is necessary to s t i m u l a t e the r e n a l c o n c e n t r a t i n g m e c h a n i s m by a 12 to 18 h o u r period of d e h y d r a t i o n or w i t h the use of Pitressin| i n order to be sure t h a t it is intact. I n p a t i e n t s 28

with renal disease a prolonged period of dehydration is not advisable because it m a y lead to excessive loss of body water. In m a n y cases, therefore, it is better to test concentrating ability by injecting 1 ec. of Pitressin| tannate in oil at bedtime and collecting the first specimen voided in the morning. Pitressin| is contraindicated in patients with serious hypertension and vascular disease. The normal kidney can reduce the urine specific gravity to 1.001 during the diuresis following a large water load (20 cc./kg. ). However, tests of diluting ability are m u c h less reliable than concentration tests because diluting ability tends to be affected later and with less regularity. Another disadvantage of the dilution test is the risk of administering large, sudden water loads to patients with renal disease. Inability to excrete the load rapidly m a y result in water intoxication. Both types of tests suffer from the defect that they are not strictly quantitative. The concentration test m a y be used as a rough quantitative guide in following the course of recovery from acute tubular damage, but in general neither test is a satisfactory index of the exact extent of renal impairment. The author has found no particular use for the dilution test in practice; the concentration test is mainly useful as a simple screening procedure in patients suspected of early tubular dysfunction. KIDNEY BIOPSY

In recent years a n u m b e r of investigators have become interested in the use of percutaneous needle biopsy of the kidney ( 6 ) . This is a technique which requires a well-trained and thoroughly experienced operator. Even in the most experienced hands, kidney biopsy is not without some hazard, and it needs to be asked whether this risk is justified by the value of the information obtained. A satisfactory biopsy can be expected usually to provide definitive diagnostic information, but the author is of the opinion that a correct diagnosis can be m a d e in over 90% of all renal cases simply by the proper use of the more conventional diagnostic methods already discussed. There is no doubt, however, that proper use of the biopsy, particularly when correlated with clinical and physiological studies, will provide an enormous amount of much-needed information about the pathogenesis and natu29

ral history of renal disease. At the present time it should not be considered a safe routine diagnostic procedure. THE MANAGEMENT OF ACUTE RENAL FAILURE WITH OLIGURIA

In the following brief discussion we shall confine ourselves mainly to the treatment of acute tubular necrosis, but many of the principles to be elucidated apply equally well to other varieties of acute renal failure. When sudden loss of renal function occurs in a background of some acute systemic crisis such as circulatory collapse or sepsis, the patient's fate initially hinges on the outcome of the extrarenal events. Immediate treatment must be directed toward the latter. If no great structural damage has been done to the kidneys, prompt and effective therapy of the systemic condition may result in immediate increase in urine output and complete recovery from the brief period of renal shutdown. On the other hand, if enough tubular injury has occurred oliguria will continue even after complete removal of the primary cause of the injury, and the natural history of acute tubular necrosis will run its course (7). It needs to be re-emphasized at this point that the possibility of obstruction must always be considered carefully whenever one confronts a case of sudden renal failure. As already pointed out, the signs and symptoms of obstruction may be so minimal as to escape notice. Main reliance must be placed on a high index of suspicion, and a willingness to use retrograde catheterization when in doubt. Hypotension, relative or absolute, should be immediately corrected. Patients suffering hemorrhagic shock should have transfusions, but care must be taken to use fresh blood. The serum potassium level tends to rise in citrated blood after several days and may reach potentially lethal levels when such blood is administered rapidly and in large quantities to oliguric patients. Needless to say, every precaution must be taken to avoid transfusion reactions. There should be no hesitation in using vasoconstrictor agents such as neosynephrine or norepinephrine when they are indicated. Although these drugs produce renal ischemia in normal subjects, it seems likely that renal vasoconstriction is already maximal in shocked patients. Renal blood flow will therefore increase if systemic arterial pressure rises in response to these agents. 30

Superimposed febrile illness is a very dangerous complication of acute renal disease because it greatly accelerates the breakdown of tissue and the rate of accumulation of nitrogen, endogenous acids and potassium. Most of the clinical and chemical manifestations of uremia are thereby rapidly intensified. Mortality is highest in oliguric patients with febrile complications. In any type of renal failure, infections are therefore much to be feared and should be treated vigorously and promptly. Therapy of the infection with antibiotics should not be withheld merely because of oliguria; however, streptomycin should be administered only in reduced doses, and such potentially nephrotoxic agents as the sulfonamides, polymyxin B, bacitracin, and neomycin probably should never be used. Ice bags, alcohol sponging, cool oxygen tents, or other appropriate measures should be employed if temperature becomes excessively high. How much of the catabolic response to infection is due to the accompanying fever and how much to the nonspecific response to "stress" has never been clearly established, but it seems safe to assume that reduction in temperature will have some effect in slowing metabolism and thereby lightening the excretory load. Serious fluid and electrolyte deficits should be at least partially restored, promptly but with caution. Severe dehydration or salt depletion may be contributing to vascular collapse and renal insufficiency. Marked acidosis, even if it does no direct harm to renal function, may be contributing significantly to the gravity of the general clinical state and should therefore also be corrected. Detailed recommendations for parenteral therapy will be found in the section on management of chronic renal failure, but it needs to be stressed here that restoration of deficits of water, sodium and alkali must be made cautiously and should not be complete. Patients with acute renal failure do not tolerate acute expansion of their extracellular volume and may be rendered hypertensive or thrown into pulmonary edema with relative ease by this procedure. It is probably best to allow replacement therapy to fall just a little short in order to insure against the dangers of overhydration. Endogenous water production appears to be increased in these patients and they tend to become overhydrated unless the greatest restraint is exercised. It is always easy to add a little to the daily ration of water and electrolyte if the subsequent course of events makes this seem wise. Overhydration, on the other 31

h a n d , is n o t so simply m a n a g e d , because excess fluid is n o t easily r e m o v e d f r o m the oliguric patient. I n the early stages of acute t u b u l a r necrosis m o s t p a t i e n t s h a v e slightly elevated c o n c e n t r a t i o n s of s e r u m potassium, d e p e n d i n g u p o n the particular c i r c u m s t a n c e s s u r r o u n d i n g the onset of the disease. An occasional p a t i e n t m a y be f o u n d w i t h hypokalemia, b u t except for the m o s t e x t r e m e c i r c u m s t a n c e s in w h i c h potass i u m deficiency m i g h t be jeopardizing life, it is best to r e f r a i n f r o m giving any p o t a s s i u m to oliguric patients. If the p a t i e n t c o n t i n u e s to be oliguric the s e r u m c o n c e n t r a t i o n will start to rise soon enough. Anemia should be corrected only w h e n extremely severe (i.e., w h e n the h e m o g l o b i n c o n c e n t r a t i o n is less t h a n 8 Gm. % ) or w h e n associated w i t h m a r k e d h y p o v o l e m i a a n d shock. In the absence of shock, it is probably best to use s m a l l q u a n tities of h i g h - h e m a t o c r i t s u s p e n s i o n s of w a s h e d red cells in isotonic glucose. After the initial p h a s e s of e m e r g e n c y a n d r e p l a c e m e n t t h e r a p y are over, there follows the period of " w a t c h f u l waiting" w h e n one a t t e m p t s merely to replace insensible w a t e r loss, m a i n t a i n n u t r i t i o n as well as possible, a n d forestall complications. D u r i n g the period of oliguria, w h i c h m a y last for 10 to 20 days, n o t h i n g m u s t be done to a t t e m p t to "force" the a p p e a r a n c e of diuresis by i n c r e a s i n g the fluid intake. This h o a r y practice, as futile as it is dangerous, was undoubtedly responsible for m a n y of the d e a t h s i n this disease. F a r f r o m h a s t e n i n g diuresis, excessive a d m i n i s t r a t i o n of fluid c a n only result i n overhydration, h y p e r t e n s i o n a n d p u l m o n a r y edema. A l t h o u g h insensible w a t e r losses i n the average n o r m a l adult kept i n bed at n o r m a l room t e m p e r a t u r e are probably in the n e i g h b o r h o o d of 6 0 0 - 8 0 0 cc. p e r day, this figure n e e d s to be reduced by a few h u n d r e d cc. to allow for the i n c r e a s e i n e n d o g e n o u s w a t e r p r o d u c t i o n w h i c h a p p e a r s to o c c u r i n acute r e n a l s h u t d o w n , as well as i n o t h e r acute illnesses. I n c r e a s e d c a t a b o l i s m of fat, w h i c h yields a b o u t twice as m u c h w a t e r of oxidation as protein or carbohydrate, r e d u c e s the n e t w a t e r loss of the fasting, oliguric p a t i e n t in the basal state to s o m e w h e r e n e a r 400 to 500 cc./day. This a m o u n t , therefore, probably r e p r e s e n t s the m a x i m u m q u a n t i t y of fluid w h i c h should be a d m i n i s t e r e d e a c h day, unless o t h e r factors are p r e s e n t w h i c h i n c r e a s e w a t e r expenditure. Perspiration, h y p e r v e n t i l a t i o n a n d a n y i n c r e a s e i n a m b i e n t or i n t e r n a l 32

temperature tend to increase the rate of water loss and, in extreme instances, may combine to produce losses of two or three liters daily. In addition, any overt losses of fluid such as from vomiting, diarrhea or drainage, as well as any urine passed, m u s t all be added to the total volume which needs daily replacement. The amount of fluid given each day should never be greater than the total amount lost and preferably should be 100 or 200 cc. less. Insensible losses can rarely be estimated with accuracy, and therefore it is best to check the estimates of fluid requirements by following daily weights whenever possible. Ideally, an a m o u n t of fluid should be given each day which causes the patient, while in caloric balance, to lose .1 or .2 kilograms daffy (.25 to .50 lbs./day). The daily ration of water should contain as m u c h carbohydrate as possible, because this provides a ready source of calories and thereby minimizes the breakdown of protein and fat. Large quantities of carbohydrate may have some additional value insofar as they may delay the rise of serum potassium. At all events, it is not usually possible to administer m u c h carbohydrate through a small peripheral vein w h e n fluid volume must be restricted to m u c h less than 1000 cc. Various techniques have been devised for circumventing this problem. Some advocate the administration of high caloric tube feedings; others suggest a slow drip of very concentrated glucose solutions through a plastic catheter threaded into a large vein. The author's experience has been largely with the latter method, which has proved to be quite satisfactory. A long polyvinyl catheter is threaded through the saphenous vein into the deep femoral system, or through the antecubital vein into the cephalic or brachial veins. These catheters are comfortable and they permit the patient considerable freedom of motion. If 25 to 50 rag. heparin is added to each day's infusion, clotting is not apt to occur, even when catheters are left in place for a week. Solutions of 50% glucose may be given with impunity in this m a n n e r if administered by slow, continuous drip throughout the day. The average oliguric patient, who does not have any abnormal loss of fluid can be quite satisfactorily maintained on 4 0 0 500 cc. of 50% glucose daily, plus an added amount of this solution equal to the measured urine volume of the day before. One or two ampules of a parenteral multivitamin preparation should be added to the glucose infusion. Absolutely no protein should be given, and electrolytes should be 33

added only to replace significant a n d c o n t i n u i n g losses. It is usually n o t a good idea to offer oliguric p a t i e n t s a n y fluid or n o u r i s h m e n t by m o u t h . W h e n this is p e r m i t t e d n a u s e a a n d v o m i t i n g sooner or l a t e r a p p e a r a n d t h e n the m a i n t e n a n c e of fluid a n d electrolyte b a l a n c e becomes a complicated a n d difficult problem. T h e a u t h o r ' s practice h a s therefore b e e n to interdict all oral i n t a k e a n d rely entirely o n the i n t r a v e n o u s route. If the p a t i e n t c o m p l a i n s of a dry or u n p l e a s a n t - t a s t i n g m o u t h , considerable relief m a y be afforded by allowing h i m to suck on a little h a r d candy. A p a t i e n t will rarely c o m p l a i n of t h i r s t if the m o u t h is kept m o i s t a n d if proper a t t e n t i o n is paid to the p a r e n t e r a l m a i n t e n a n c e of fluid balance. T h e r e is h a r d l y a n o t h e r clinical condition w h i c h requires such m e t i c u l o u s bookkeeping i n m a t t e r s of fluid a n d electrolyte balance. Accurate records of daily i n t a k e a n d o u t p u t are essential. W h e n e v e r possible, the p a t i e n t should be weighed e a c h day to forestall u n d e r h y d r a t i o n or overhydration. C h a n g e s in electrolyte a n d acid-base b a l a n c e m u s t be followed by f r e q u e n t d e t e r m i n a t i o n s of s e r u m sodium, potassium, C02, a n d chloride, a n d the electrolyte c o n t e n t of all m e a s u r a b l e fluid losses should be d e t e r m i n e d w h e n e v e r possible. Electrolytes should n o t be given u n l e s s there are cont i n u i n g e x t e r n a l losses w h i c h n e e d r e p l a c e m e n t . I n the absence of a c c u r a t e m e a s u r e m e n t s , the c h a n c e s of overt r e a t m e n t will be m i n i m i z e d if one waits u n t i l the s e r u m c o n c e n t r a t i o n s are clearly below n o r m a l limits before instit u t i n g therapy. E v e n t h e n , it is p r o b a b l y best to restore somew h a t less t h a n the e s t i m a t e d daily losses of s o d i u m a n d chloride. A m o d e r a t e degree of h y p o n a t r e m i a w i t h o u t e x t e r n a l s o d i u m loss is fairly c o m m o n i n oliguric patients. It somet i m e s results f r o m overhydration, b u t not i n f r e q u e n t l y hypon a t r e m i a seems to develop as a non-specific r e a c t i o n to severe illness, w i t h o u t gain of w a t e r or e x t e r n a l loss of sodium. T h i s type of situation does n o t call for a d m i n i s t r a t i o n of sodium. Most oliguric p a t i e n t s slowly become progressively m o r e acidotic. Acidosis p r o b a b l y n e e d s no special t h e r a p y w h e n mild or m o d e r a t e i n degree. A d m i n i s t r a t i o n of sodium bicarb o n a t e or lactate is i n d i c a t e d only w h e n acidosis b e c o m e s severe e n o u g h to cause h y p e r p n e a ( u s u a l l y this b e g i n s at CO2 levels below 15 m E q . / L . ) , or w h e n h y p e r k a l e m i a h a s become a problem. Potassium intoxication is, of course, one of the m a j o r haz34

ards during the oliguric period. The best way to detect and to follow the progress of this complication is to obtain daffy electrocardiograms, as well as daily determinations of serum potassium. The major toxic effect of hyperkalemia is mediated through its action on the conducting system of the heart, and therefore serial electrocardiograms can be counted on to detect dangerous elevations in potassium concentration. The essential hallmark of hyperkalemia, when it first appears, is a tent-shaped peaking of the T-waves, usually accompanied by an increase in height. The exact chemical concentration of potassium at which this occurs depends on several factors, including the acid-base balance and the simultaneous serum concentrations of sodium and calcium. At any given concentration of potassium, cardio-toxicity is increased by acidosis, hyponatremia and hypocalcemia. Usually, however, the first changes in the electrocardiogram are noticed when potassium levels are between 5.5 and 6.0 mEq./L. With more severe degrees of potassium intoxication, P-waves may flatten and disappear, the QRS complex widens, and the S-T segment becomes depressed. The earliest cardiographic changes usually precede the development of clinical signs and symptoms. The latter are, in fact, quite variable. Muscle weakness and hyporeflexia may develop in patients with severe intoxication; numbness, paresthesias, and cardiac arrhythmias may also appear. However, none of these clinical manifestations can be relied on to give adequate warning of the sudden death which always threatens the patient with advanced hyperkalemia. Potassium intoxication is much better prevented than treated. A potassium-free intake, large quantities of glucose, maintenance of normal temperature and prevention of severe acidosis, hyponatremia, and hypocalcemia, will all help to achieve this end. Even after two or more weeks of oliguria the well-managed patient may not develop any significant degree of hy-perkalemia. If the serum potassium reaches concentrations of 6 mEq./L, or more, despite all these measures, or if, regardless of chemical concentration, the electrocardiograin begins to show definite signs of potassium intoxication, then the physician must begin to take active measures to remove potassium from the blood. Serum potassium concentration may be transiently lowered and the electrocardiographic signs of toxicity improved by any of the following procedures: (1) infusions of hypertonic sodium chloride or sodium bicar35

bonate (mainly effective w h e n there is hyponatremia or significant acidosis, (2) infusions of hypertonic solutions of glucose with insulin, (3) intravenous injections of calcium chloride or calcium gluconate, and (4) oral or rectal administration of a potassium-free cation exchange resin in the sodium or a m m o n i u m cycle. If an ammonium-containing resin is employed, acidosis can be prevented by the simultaneous intravenous administration of sodium bicarbonate. More detailed suggestions for the medical m a n a g e m e n t of potassium intoxication are available elsewhere. The most effective treatment of potassium intoxication is artificial dialysis, either by extracorporeal techniques using an artificial kidney, or by transperitoneal irrigation. In the writer's opinion this constitutes the chief indication for the use of artificial dialysis in the m a n a g e m e n t of acute renal failure. To be m a x i m a l l y effective this type of procedure must be employed before the clinical situation has become desperate. Marked elevation of the serum potassium from the very outset, or progressive rise in the level despite proper medical treatment should be adequate warning of the need for dialysis. Details of the techniques of transperitoneal and extracorporeal dialysis and the relative merits of each procedure need not concern us here. It has been stated that transperitoneal irrigation is a relatively simple technique which can be carried out at the bedside in any hospital. The artificial kidney is m u c h more effective in removing potassium and restoring electrolyte equilibrium, but its operation requires experienced and specially trained medical and nursing teams such as are available only in a relatively few medical centers. Future models may be simple enough in their operation to permit their safe and effective use in almost any hospital. How often in practice is artificial dialysis required? It is obviously impossible to carry out the kind of controlled observations necessary to answer this question, and current opinions therefore vary widely on this point. The writer would guess that dialysis would be a life-saving measure in probably a very small percentage of well-managed cases. It is as an adjunct to good medical m a n a g e m e n t that the artificial kidney should find its greatest use, for there can be little doubt that dialysis can do m u c h to improve the symptoms as well as the chemical disturbances caused by renal failure. Drowsiness, prostration and troublesome nausea and vomit36

ing m a y all be markedly improved by dialysis. The chief contraindication to the use of the artificial kidney is the presence of hemorrhagic diathesis, or some m a j o r bleeding lesion. Peritonitis, of course, prevents the use of the transperitoneal method. Some oliguric patients slowly develop progressive hypertension; others tend to develop congestive heart failure and pulmonary edema. These complications are more apt to occur w h e n patients are given too m u c h sodium and water. As in any patient with renal failure, one should not hesitate to use full doses of digitalis when they are required. Digoxin is a very satisfactory preparation for this purpose, because it can be given parenterally, acts fairly rapidly, and does not tend to have a prolonged action after it is discontinued. In m a n y clinics testosterone is administered parenterally in large doses to oliguric patients. The rationale is based on the ability of this steroid to increase synthesis of protein, and hence decrease urea production, under certain circumstances in m a n and in experimental animals. The practical value of this somewhat theoretical benefit has never been critically demonstrated, but it is the impression of several observers, including the author, that testosterone makes uremic patients look and feel better. This seems to be particularly true of w o m e n and elderly men. The dose usually employed is 25 to 50 mg. of testosterone propionate in a single daily injection, for periods of 10 days or 2 weeks. The diuretic phase of acute tubular necrosis begins when the slowly rising urine volume finally reaches a daily total of 500 cc. or more. One of the m a i n problems in the treatment of this phase is the prevention of water and electrolyte depletion. Renal tubular control of water and electrolyte balance is regained only slowly, and for a variable length of time after the onset of diuresis renal excretion of water and electrolyte may be unrestrained. The urine may contain sodium and potassium at concentrations in the range of 30-60 mEq./L. Without adequate intake of these substances patients may rapidly become depleted of water, sodium, potassium, or even calcium. Measurement of urinary losses and careful following of serum concentrations are particularly important in the prevention of these complications. It should be remembered that the blood nitrogen level may continue to rise, or at least not begin to fall, for several days after diuresis begins. This is because normal renal function is only slowly regained. For 37

weeks or months after the urine volume and the blood nitrogen level have returned to normal, appropriate tests may indicate some persisting i m p a i r m e n t of tubular function. In some patients, at least, normal function ultimately is entirely restored. THE MANAGEMENT OF CHRONIC RENAL FAILURE

Chronic renal insufficiency produced by any of the factors in Groups I and II (Table 2) is most effectively treated by removal of the cause. In some instances (e.g., the nephropathy of potassium depletion) it may be possible to restore function entirely to normal, but in most of these conditions a certain a m o u n t of residual renal damage will remain despite elimination of pathogenetic factors. This latter generalization applies to most of the instances with renal failure due to chronic hypercalcemia as well as those caused by postrenal obstruction. Obstruction is so often associated with chronic infection, and the latter, once established, becomes so resistant to therapy, that kidneys relieved of chronic obstruction are rarely restored entirely to normal. Nevertheless, very marked improvement in function m a y be achieved, and for this reason obstruction must be just as assiduously sought for in patients with chronic disease as in those with more abrupt onset of renal insufficiency. This subject is considered at greater length in a subsequent section. In most of the generalized diseases listed under Group III significant involvement of the kidney occurs in a relatively late stage and its appearance is usually an ominous prognostic sign. T r e a t m e n t of the underlying disease may or m a y not be effective in the kidney. Thus, leukemic, lymphomatous, or myelomatous disease of the kidney is usually rapidly fatal despite all measures, but treatment of disseminated lupus or sarcoidosis with cortisone may arrest or improve renal damage for long periods of time. W h e n hypertensive vascular disease produces advanced renal insufficiency, treatment of any sort is usually unavailing. Lumbosacral sympathectomy and the use of ganglionic blocking agents, which are often effective in severe hypertension without renal damage, not infrequently seem to accelerate the relentless downhill coul:se of the disease. Occasionally, if they succeed in lowering blood pressure, drug therapy or dietotherapy m a y effect considerable improvement in renal function. This is particularly true 38

in those patients with relatively mild renal insufficiency and in those in whom there is a significant element of congestive heart failure. For the most part, the primary chronic diseases of the kidney produce lesions which are irreversible. Nephrons destroyed by these processes cannot be regenerated. Chemotherapy may arrest the progress of tuberculosis and occasionally of chronic non-tuberculous infection of the kidney, but for the most part there is no specific treatment for primary renal diseases. Severe renal insufficiency may be surprisingly well tolerated, if it develops gradually enough to permit compensatory TABLE 4.--COMPLICATIONS OF CHRONIC I~ENAL DISEASE I. Disorders of Fluid a n d Electrolyte Balance a. W a t e r depletion ( d e h y d r a t i o n ) a n d excess ( o v e r h y d r a t i o n ) b. Sodium depletion a n d excess c. Potassium depletion a n d excess II. Acid-Base Disorders a, Metabolic acidosis: with, or without, anion retention b. Metabolic alkalosis III. A n e m i a IV, Congestive H e a r t Failure and Hypertensive Vascular Disease V. Infections: Renal a n d Other VI. Obstruction VII. Malnutrition and Gastrointestinal Disturbances VIII. Disturbances of Calcium and Phosphorus Metabolism IX. N e u r o m u s c u l a r Manifestations

adjustments and if there are no major complications. The author recently saw a 24-year-old man with chronic glomerulonephritis of five years' duration who, despite a BUN of 185 rag. %, stated that he felt entirely well and was leading a normal active life. Another 19-year-old boy with chronic glomerulonephritis was able to work without difficulty as a delivery boy in a grocery market until two days before he was admitted to the hospital with an NPN of 325 mg. %. Present-day management is centered around the concept of the prevention and treatment of the frequent complications associated with renal failure. These complications, listed in Table 4, often exacerbate and accelerate renal failure to such a degree that they determine the natural history of the underlying disease. It needs to be appreciated that many of these complications are remediable or preventable, and that 39

their proper management can do much to prolong life. Furthermore, since these complications are responsible for most of the discomfort and disability attending renal failure, it is often possible to provide patients with considerable symptomatic improvement which may last for long periods until the slow destruction of renal tissue makes all further treatment futile. By and large, those patients without significant heart failure or malignant hypertensive vascular disease have the best prognosis. The coexistence of severe renal and cardiovascular disease often results in the establishment of a vicious circle. Not only may each condition directly aggravate the other, but also the treatment of one may at times be detrimental to the other. RECOGNITION AND MANAGEMENT OF DISORDERS OF FLUID AND ELECTROLYTE BALANCE

Patients with chronic renal diseases frequently become dehydrated and sodium-depleted either through vomiting and diarrhea or through urinary losses (8). Extensive loss of sodium and water reduces extracellular volume, lowers renal circulation and glomerular filtration and ultimately increases the signs and symptoms of renal failure. Many a patient with chronic renal damage of moderate degree is thrown into frank uremia by excessive loss of salt and water. Urinary salt wasting of severe degree occurs mostly in patients who have large urine volumes and are not edematous. It may safely be assumed that edematous patients do not excrete much sodium, since if they did they would not have accumulated and retained their edema. Extreme degrees of salt wasting are rather uncommon, but the great majority of patients with chronic renal disease will show some impairment of sodium conservation at some time during their illness. Thus, strict abstention from sodium in the diet may gradually lead to depletion as a result of long continued small urinary losses. In non-edematous, normotensive patients restriction of sodium is of dubious value. Patients with renal damage who have severe hypertension may experience some moderation of their blood pressure on salt-free diets, and they may hecome somewhat more sensitive to the effects of hypotensive drugs. But these advantages are gained only at the risk of inducing sodium-depletion, with its attendant further loss of renal function. Before it is finally decided to keep a non40

edematous patient on a low sodium diet, it is advisable to measure the daily excretion of sodium after the patient has been on the diet for five or six days. Persistence os a relatively high sodium excretion (i.e., sodium in the urine equal to or greater than that in the diet) would be a clear indication that such a regimen will lead to sodium depletion. The symptoms of sodium depletion are not specific, but when severe they include loss of weight, strength and appetite, increasing fatigue and a tendeney to feel lightheaded and faint when assuming an erect position. Muscle cramps may develop. Physical examination usually reveals some degree of orthostatic hypotension, and since losses of water and electrolyte usually occur together, there is also some degree of dehydration. Dehydration is not easily recognized when it is mild, but advanced stages produce characteristic clinical findings. The countenance has a pinched, sunken-in appearance; the eyeballs are soft and deep-set; and the skin of the forehead, having lost its normal elasticity, can be easily drawn up into folds which disappear but slowly. The tongue may he dry but this is a most unreliable and misleading sign since most people who breathe through the mouth will have dry mucous membranes. Skin turgor and elasticity are reduced all over the body, but this is most reliably tested on the forehead and over the upper chest, where changes due to loss of weight are less apt to be present. Elderly, emaciated patients tend to look chronically dehydrated; in their case the tension of the eyeballs is probably the most reliable physical sign of dehydration. Since the proportion of sodium to water in the fluid lost will determine the final concentration of sodium in the blood, it is possible to have sodium depletion without reduction in serum sodium below the normal range of 136 to 145 mEq./L. Most commonly sodium depletion is revealed by: (a) hyponatremia with some degree of dehydration or (b) a normal sodium concentration with very severe dehydration. Dehydration tends to increase the hematocrit and the concentration of plasma proteins. These changes may be masked by the tendency to anemia and hypoproteinemia resulting from chronic renal disease. Theoretically, the amount of sodium required to raise a low serum concentration to normal (140 mEq./L) can be calculated from the formula: A = (140 - Na) • BW, where A -- the required sodium in mEq., Na is the actual sodium 41

c o n c e n t r a t i o n i n mEq. a n d B W is the total body w a t e r i n liters. T h e latter figure m a y be e s t i m a t e d as 40 to 60% of the body weight d e p e n d i n g o n the degree of h y d r a t i o n a n d the a m o u n t of obesity. All o t h e r t h i n g s b e i n g equal, body w a t e r c o n t e n t is h i g h e r i n lean t h a n i n obese people. If the p a t i e n t is well h y d r a t e d a n d requires n o e x p a n s i o n of body water, the sodium required to replace the body deficit should be given as a two or t h r e e p e r cent solution. If t h e r e is deh y d r a t i o n as well as depletion of sodium one m u s t a d m i n i s t e r in addition to the above a m o u n t of sodium a q u a n t i t y of isotonic sodium solution e q u a l to the e s t i m a t e d v o l u m e deficit. This l a t t e r figure m u s t be e s t i m a t e d r o u g h l y f r o m t h e general a p p e a r a n c e of the patient. P a t i e n t s w i t h d e h y d r a t i o n a n d h y p e r n a t r e m i a should h a v e t h e i r volume deficits restored with w a t e r alone, given in the f o r m of isotonic glucose solution. W h e n p a t i e n t s are acidotic as well as sodiumdepleted or dehydrated, sodium should be a d m i n i s t e r e d at least partly as the b i c a r b o n a t e salt, a n d even w h e n acidosis is m i n i m a l it is best to include some sodium b i c a r b o n a t e i n a very large r a t i o n of salt, lest the acidosis be m a d e m o r e severe by dilution. To illustrate the foregoing principles, let u s consider the case of a p a t i e n t w i t h c h r o n i c r e n a l disease who, after a n episode of v o m i t i n g a n d d i a r r h e a , is a d m i t t e d to the h o s p i t a l with signs a n d s y m p t o m s of sodium-depletion a n d dehydration. The p a t i e n t weighs 70 kilograms. Clinical e x a m i n a t i o n suggests t h a t h e h a s lost r o u g h l y two to three liters of body water. The c o n c e n t r a t i o n of sodium in his s e r u m is 125 m E q . / L , and the CO2 c o n t e n t is 18 m M . / L . The p a t i e n t ' s total body w a t e r ( B W ) is e s t i m a t e d to be a b o u t 40% of his w e i g h t ( t a k i n g into a c c o u n t his a s t h e n i c h a b i t u s a n d his d e h y d r a t e d s t a t e ) , or .40 • 70 = 28 L. According to the f o r m u l a given above, the total a m o u n t of sodium required to raise his s e r u m c o n c e n t r a t i o n f r o m 125 to 140 m E q . / L would be: A = ( 1 4 0 -- 195) X ( 2 8 ) A = ( 1 5 ) x ( 2 8 ) = 420 mEq. To this q u a n t i t y m u s t be added 140 mEq. for each liter of fluid b e i n g given. T h u s , if the p a t i e n t is to receive 3 liters of fluid, we m u s t add 3 X 140, or 420 mEq., to the original a m o u n t . The final total sodium prescription would therefore be 840 mEq., given i n a volume of three liters. Since the 42

p a t i e n t is m o d e r a t e l y acidotic it would be best to give some of t h e n e e d e d sodimn as b i c a r b o n a t e or lactate, i n s t e a d of chloride. A satisfactory proportion b e t w e e n sodium a n d b i c a r b o n a t e ions i n the r e p a i r solution would be 5 : 1 , w h i c h is a p p r o x i m a t e l y t h a t f o u n d i n n o r m a l serum. T h u s , the final composition of the r e p a i r solution would be as follows: Total volume

: 3000 co. 700 mEq. 140 mEq.

Sodium chloride S o d i u m bicarbonate ----

These calculations are at best approximate. T h e i r chief u s e f u l n e s s is to provide some r o u g h idea of the a m o u n t s of sodium a n d w a t e r required i n a n y given situation. However, n o m a t h e m a t i c a l f o r m u l a c a n substitute for c o m m o n sense a n d clinical j u d g m e n t . C o m m o n sense dictates t h a t only a q u a r t e r to a h a l f of the calculated total deficits should be a d m i n i s t e r e d at any one time, a n d due care m u s t be t a k e n n o t to overload the circulation. The r e m a i n i n g salt a n d w a t e r deficits a n d the rate at w h i c h it m a y safely be a d m i n i s t e r e d a r e best j u d g e d i n the light of the p a t i e n t ' s initial response to therapy. It is always safest to a d m i n i s t e r fluid a n d electrolyte by m o u t h , b u t u r e m i c p a t i e n t s are so f r e q u e n t l y nauseated t h a t this is usually n o t feasible. Disorders of potassium metabolism are f r e q u e n t i n chronic r e n a l disease. Most p a t i e n t s are s o m e w h a t depleted of potass i u m as the result of m a l n u t r i t i o n , v o m i t i n g or diarrhea. Occasionally, r e n a l disease is associated with excessive excretion of p o t a s s i u m i n the urine.* T h e s e r u m p o t a s s i u m c o n c e n t r a t i o n will not necessarily reflect the depletion of the bodily stores, for the c o n c e n t r a t i o n m a y be high, low or normal. P a t i e n t s with a large u r i n e o u t p u t a n d little or no azot e m i a are apt to be hypokalemic. On the other h a n d , m o s t p a t i e n t s w i t h chronic u r e m i a a n d a n o r m a l u r i n e volume m a i n t a i n n o r m a l or slightly elevated s e r u m p o t a s s i u m levels. In s u c h p a t i e n t s the s e r u m p o t a s s i u m rarely exceeds 6.5 m E q . / L except i n the t e r m i n a l or n e a r - t e r m i n a l p h a s e s of t h e i r disease, w h e n the u r i n e o u t p u t begins to diminish. All other t h i n g s b e i n g equal, acidosis tends to elevate the s e r u m p o t a s s i u m c o n c e n t r a t i o n a n d alkalosis to depress it. T h e i m p o r t a n c e of potassium depletion as a factor cont r i b u t i n g to the s y n d r o m e of r e n a l failure is difficult to evalu*Some cases of so-called "potagsium-losing nephritis" are plobably in fact instances of primary aldosteronism (9). In these patients the manifestations of renal disease are probably secondary to potassium deficiency. 43

ate. In the oligurie or severely uremic and acidotic patient tissue depletion of potassium may be masked by normal or elevated serum concentrations. Administration of potassium to these patients is dangerous and unwarranted even though their tissues are deficient. On the other hand, the occasional patient with marked hypokalemia, large urine volumes, and not too m u c h azotemia will undoubtedly benefit from the administration of potassium. Severe potassium depletion in itself causes kidney damage, and in the presence of preexisting renal disease it may be responsible for rapid acceleration of the development of renal failure. Potassium depletion may produce tubular damage with a diabetes insipidus-like syndrome; apparent reductions in urea clearance have also been observed. Restoration of potassium deficits may not only improve the general state of the patient, increasing his appetite, morale and m u s c u l a r strength, but it m a y also produce a marked and sometimes unexpected improvement in renal function. It is always better to give potassium by mouth than by vein since the latter route offers the possibility of fatal intoxication. Potassium may be administered orally as coated potassium chloride tablets (0.3 grams = 4 m E q . ) , or it m a y be given as a 10% potassium citrate solution mixed with fruit juice. One cc. of the 10% solution contains one mEq. of potassium. Except in extraordinary circumstances it is never wise to give more than 100 mEq. of potassium per day and under no circumstances should potassium ever be given to oliguric or anurie patients. Potassium chloride solution should be infused at concentrations of 20 to 60 m E q . / L , with 5% glucose and the rate of administration should not exceed 30 m E q . / h o u r . It is usually impossible to estimate the total potassium deficit accurately from either the serum potassium concentration, the electrocardiogram, or the clinical history and physical findings. Clinically significant deficits m a y range from 200 to 1000 mEq. In attempting to restore such deficits it is best to give a moderate amount of potassium each day, approximately 100 mEq., and follow the serum potassium and the electrocardiogram. Excretion of potassium in the urine may be another useful guide. Except in the rare instances when potassium depletion has resulted from excessive urinary loss, the amount of potassium in the urine tends to mirror the state of body stores. Most patients with severe 44

c h r o n i c p o t a s s i u m depletion, even those with r e n a l disease, excrete less t h a n E0 mEq. of p o t a s s i u m p e r day. I n these p a t i e n t s a g r a d u a l rise of p o t a s s i u m u r i n a r y excretion coincid e n t with the a d m i n i s t r a t i o n of p o t a s s i u m c a n be t a k e n as a sign t h a t body stores are b e c o m i n g repleted. T h e a d m i n i s t r a tion of p o t a s s i u m should c o n t i n u e u n t i l the s e r u m concentration is n o r m a l a n d the u r i n e o u t p u t is approximately e q u a l to the intake. I m p r o v e m e n t in r e n a l f u n c t i o n m a y not be appare n t u n t i l several weeks a f t e r p o t a s s i u m deficits h a v e b e e n restored. Potassium intoxication is occasionally a serious p r o b l e m i n the e n d stages of chronic u r e m i a , a n d i n d e e d is probably a f r e q u e n t modus exeundi. As already indicated, it is encountered m u c h more f r e q u e n t l y with acute oliguric failure. In e i t h e r acute or chronic r e n a l disease, p o t a s s i u m intoxication is easier to p r e v e n t t h a n to treat. T h e avoidance of a large p o t a s s i u m intake, the r e m o v a l of influences f a v o r i n g r a p i d catabolism of tissue a n d release of e n d o g e n o u s p o t a s s i u m (e.g., fever, infections, necrosis of tissue, ACTH a n d a d r e n a l steroids) a n d the e l i m i n a t i o n of severe acidosis m a y all contribute toward this end. T h e t r e a t m e n t of p o t a s s i u m intoxication, once it is established, calls for the same m a n e u v e r s described in the section on acute r e n a l failure with the exception t h a t there is probably less r e a s o n to use the artificial kidney. T h e p r o b l e m of extracorporeal dialysis in the m a n a g e m e n t of chronic r e n a l failure will be considered i n more detail below. Acidosis. Almost all u n t r e a t e d u r e m i c p a t i e n t s are more or less acidotic. T h e r e is no evidence t h a t m o d e r a t e acidosis per se h a s a n y clinically significant h a r m f u l effects, a n d even extremely severe e x p e r i m e n t a l acidosis f a t s to affect r e n a l h e m o d y n a m i c s i n the dog, T h e r e is n o r e a s o n to believe, therefore, t h a t mild or m o d e r a t e degrees of acidosis call for a n y specific therapy. O n the o t h e r h a n d , severe acidosis ( u s u a l l y p r e s e n t w h e n the p l a s m a C02 c o n t e n t is less t h a n 15 m E q . / L . ) causes m a r k e d fatigue a n d anorexia, a n d m a y therefore be a m a j o r cause of disability a n d discomfort in u r e m i c patients. Accordingly, it h a s b e e n the writer's practice to a d m i n i s t e r alkali w h e n e v e r the CO~ c o n t e n t is f o u n d to be less t h a n 15 m E q . / L , or w h e n it would tend to fall below this level w i t h o u t such t r e a t m e n t . As is the case with sodium deficits, calculation of the a m o u n t of alkali required to produce a given c h a n g e in the blood c o n c e n t r a t i o n at equilibrium 45

is at best a m a t t e r of a p p r o x i m a t i o n . T h e a p p a r e n t volume of distribution of b i c a r b o n a t e is s o m e w h a t larger t h a n the extracellular space because b i c a r b o n a t e seems to be capable of p e n e t r a t i n g cells, or at least a p p e a r s to be n e u t r a l i z e d by i n t r a c e l l u l a r buffers. Despite the various f o r m u l a e w h i c h h a v e b e e n proposed for this purpose the a u t h o r believes t h a t clinical trial is still the best guide i n the t h e r a p e u t i c use of alkali. For the p r o m p t a m e l i o r a t i o n of severe acidosis a h u n dred to two h u n d r e d mEq. of alkali m a y be given i n the course of a day. F u r t h e r t h e r a p y should be guided by t h e response to this initial t r e a t m e n t . Alkali m a y be given orally as sodium b i c a r b o n a t e or it m a y be a d m i n i s t e r e d intravenously as a 1/6 m o l a r ( i s o t o n i c ) s o d i u m b i c a r b o n a t e or sod i u m lactate solution. More c o n c e n t r a t e d solutions ( u p to 1/z m o l a r ) m a y be used w h e n the alkali deficit is e x t r e m e l y large a n d it is desired to give little or no water. Dilute solutions ( m a d e isotonic with glucose) c a n be given w h e n acidosis is relatively less severe a n d w a t e r deficits large. T h e r e are two h a z a r d s i n t r e a t i n g acidosis: ( 1 ) r a p i d correction of acidosis m a y precipitate l a t e n t or m a n i f e s t t e t a n y a n d ( 2 ) too rapid e x p a n s i o n of the extracellular fluid m a y result i n congestive failure. Both of these m a y usually be avoided by p r o p e r caution. Occasionally it is n e c e s s a r y to a d m i n i s t e r i n t r a v e n o u s c a l c i u m to relieve the c r a m p s a n d p a r e s t h e s i a s caused by the r e d u c t i o n in ionized c a l c i u m att e n d i n g the rise i n blood pH. This p r o b l e m will be discussed later on. A n e m i a is a n i m p o r t a n t a n d almost i n v a r i a b l e c o m p o n e n t of the u r e m i c complex. Its p a t h o g e n e s i s is not u n d e r s t o o d , a l t h o u g h there is evidence t h a t a p l a s m a a b n o r m a l i t y is responsible for s h o r t e n i n g the life-span of t r a n s f u s e d red cells. A n e m i a is usually of the n o r m o c h r o m i c , n o r m o c y t i c type a n d is not associated w i t h a n y c h a r a c t e r i s t i c c h a n g e s i n the per i p h e r a l blood or bone marrow. T h e r e is usually n o reticulocytosis unless r e c e n t blood loss h a s occurred. Since u r e m i c p a t i e n t s m a y h a v e a bleeding diathesis a n d m a y occasionally lose significant a m o u n t s of blood t h r o u g h epistaxis, m e n o r rhagia, m e l e n a or h e m a t e m e s i s , a secondary iron-deficiency type of a n e m i a m a y occasionally be s u p e r i m p o s e d o n the p r i m a r y a n e m i a of r e n a l failure. T h e severity of the p r i m a r y a n e m i a is usually p r o p o r t i o n a l in a r o u g h way to the degree a n d the d u r a t i o n of the n i t r o g e n retention. Notable exceptions are occasionally seen b u t as a 46

general rule the m o r e severely u r e m i c a p a t i e n t is a n d the longer h e h a s h a d his u r e m i a the lower his h e m o g l o b i n will be. A n e m i a w h i c h is out of proportion to the u r e m i a a n d w h i c h c a n n o t be e x p l a i n e d by chronic or r e c e n t blood loss is apt to be the result of chronic i n f e c t i o n (e.g., p y e l o n e p h r i t i s ) or else a reflection of a p r i m a r y blood dyscrasia such as multiple myeloma. A n e m i a of a mild degree is usually of no p a r t i c u l a r conseq u e n c e i n the p a t i e n t with r e n a l failure, b u t m o r e m a r k e d r e d u c t i o n s i n h e m o g l o b i n are likely to cause fatigue, a n o r e x i a a n d all the o t h e r signs a n d s y m p t o m s associated with severe a n e m i a . Circulatory i n a d e q u a c y m a y be aggravated. I n a p a t i e n t already debilitated by the n u m e r o u s defects r e s u l t i n g from, or associated with, r e n a l failure, the d e v e l o p m e n t of a severe a n e m i a m a y be the crucial f a c t o r in tipping the scales i n a n u n f a v o r a b l e direction. For this r e a s o n it is felt t h a t severe a n e m i a should be treated i n s o f a r as possible. Exactly w h a t constitutes "severe a n e m i a " i n this context is h a r d to define a n d will probably d e p e n d o n the p a r t i c u l a r clinical situation. Some p a t i e n t s a p p e a r to tolerate m a r k e d chronic a n e m i a w i t h n o ill effect while others are obviously incapacitated. It is a r a r e p a t i e n t with r e n a l failure w h o will c o n t i n u e to feel well w h e n his h e m o g l o b i n is m u c h less t h a n 8 g r a m s per cent. The decision w h e t h e r to t r e a t a n e m i a or not, however, n e e d s to be m a d e more on the basis of clinical j u d g m e n t t h a n on the exact level of the hemoglobin. The writer feels t h a t a n y p a t i e n t w i t h a h e m o g l o b i n below 8 g r a m s p e r cent who seems to be deteriorating clinically or f u n c t i o n a l l y deserves the benefit of a trial of correcting his anemia. Failure to r e s p o n d to t r e a t m e n t or failure to m a i n t a i n significantly h i g h e r levels of h e m o g l o b i n for m o r e t h a n a few weeks probably constitute valid e o n t r a i n d i e a t i o n s to f u r t h e r a t t e m p t s in this direction. O n the other h a n d , there are p a t i e n t s who, with the assistance of a few t r a n s f u s i o n s spaced at several m o n t h intervals c a n be m a i n t a i n e d in a state of well-being n o t otherwise possible. T h e only effective way to raise the h e m o g l o b i n level is by transfusions. T h e r e is n o theoretical or practical justification for u s i n g iron, v i t a m i n B,z, liver, folio acid or a n y other h e m a t o p o i e t i c substance. Cobaltous chloride h a s been used i n some clinics recently, the only r a t i o n a l e b e i n g t h a t it a p p a r e n t l y s t i m u l a t e s the bone m a r r o w i n e x p e r i m e n t a l animals. A l t h o u g h this c o m p o u n d m a y produce significant ele47

vations in circulating hemoglobin levels, it has a very high incidence of undesirable side effects, mainly gastrointestinal disturbances. Furthermore, there is a rapid remission in hematological improvement as soon as treatment is stopped. For these reasons, and because not enough is known yet about the possible toxic effects of chronic use of this substance, cobaltous chloride cannot be recommended for general use. Unless there is some specific indication to administer plasma, uremic patients are best treated with infusions of packed red cells. Small infusions, 200-300 cc. each, given very slowly are usually well tolerated. More rapid infusions, as well as administration of whole blood instead of packed red cells are more likely to result in unpleasant circulatory, pyrogenic or allergic reactions. To minimize the danger of overloading the circulation the patient should be sitting up in a chair while receiving the transfusion. It is best to give no more than one infusion per day. In patients with circulatory insuffLciency, even this rate of treatment may not be slow enough to allow the circulatory adjustments necessary to prevent congestive failure. Congestive heart failure. Chronic renal failure is often complicated by congestive heart failure because it is so frequently accompanied by hypertensive and arteriosclerotic cardiovascular disease. Patients with normal blood pressure and those with large urine volumes and a tendency to waste fixed cation rarely develop congestive failure. The latter is most apt to appear in patients with marked hypertension and relatively low urine output. Congestive failure often develops following attempts to correct deficits of hemoglobin, water and electrolyte. In such instances a gradual rise in blood pressure usually heralds the development of circulatory failure. This situation offers an almost impossible therapeutic problem: optimal treatment of the renal failure requires correction of anemia and electrolyte depletion, but treatment of the circulatory failure demands removal of electrolyte and water and reduction of blood volume. Caught on the horns of this dilemma, the physician can only attempt to find some neutral middle course which will do the least h a r m to both kidney and heart. T r e a t m e n t of congestive failure in renal disease is usually not very effective unless the failure is the result of overtreatm e n t with fluid and electrolyte, Digitalis can be given in full 48

therapeutic doses and it presumably will improve cardiac failure to some extent by virtue of its direct action on the myoeardium. However, circulatory congestion is not relieved until excess extracellular fluid is removed from the body, and in the presence of severe kidney disease diuresis in response to digitalis may be impossible. Significant degrees of uremia usually also preclude any response to mercurial diuretics. Ammonium chloride (which is a poor choice in congestive failure anyhow, because it tends to have more kaliuretic than natriuretic action) is contraindicated in renal failure. Diamox| and the xanthines are also without diuretic effect in uremia. Aside from the use of digitalis, the only other effective way to treat congestive failure in the uremic patient is to curtail sharply the intake of sodium and allow the renal excretion of this ion gradually to reduce extracellular volume. In .emergencies venous tourniquets, oxygen and small doses of morphine or demerol are effective. Plasmapheresis has been recommended by some as an effective method of reducing plasma volume without removing any of the much-needed hemoglobin. In this procedure whole blood is removed from the patient, the plasma separated from the cells and the latter reinfused. Removal of whole blood not followed by return of the cells to the patient should be used only as an emergency procedure and then only in those who do not have severe anemia. When blood pressure is very high, congestive heart failure may also be controlled by measures which bring'about moderate reductions in the levels of pressure. Drastic and rapid reductions are to be avoided, because they occasionally accelerate the development of renal failure. Such moderate hypotensive agents as the rauwolfia derivatives and the veratrum compounds are worth a trial. Ganglionic blocking agents are probably best omitted except in an occasional case of severe hypertension which has resisted all other drugs and appears to be responsible for progressive circulatory compensation. Acute episodes of hypertensive encephalopathy may also respond well to the more powerful blocking agents. In using digitalis it is well to bear in mind the relationship between this drug and the potassium ion. Potassium depletion, or at least hypokalemia, sensitizes the heart to the action of digitalis. When the serum potassium is low, digitalis must be given with the greatest caution. There does not appear to be any undue risk of digitalis intoxication in patients 49

with severe renal failure, even in those with oliguria. Aside from the modifications noted above in relation to potassium metabolism, the usual doses should be employed. Infections. Infections in the urinary tract and elsewhere often complicate the life of the patient with renal failure. Pyelonephritis is the most common kidney disease but even in patients with other types of primary kidney involvement superimposed urinary infection is quite common. One suspects that this is partly due to the fact that such patients are subjected to frequent instrumentation of the urinary tract. It may also be the case that other types of renal disease in some way predispose to the development of bacterial infections. In any event, a search for urinary infection should be a routine and essential part of the examination of every patient with renal failure. The physician must do everything possible to avoid introducing infection into the urinary tract by casual or unnecessary use of catheters and diagnostic instruments. This should be an important concern under all circumstances, but in patients with pre-existing renal damage the consequences of superimposed infection are particularly grave. Very often active renal infection is the final straw which breaks the back of renal compensation and is immediately responsible for producing rapid deterioration of the clinical state. Indwelling bladder catheters are especially common offenders in this regard. Their use, except when specifically and urgently indicated in the drainage of a chronically and intractably obstructed or paralyzed bladder, is strongly condemned. Practically every patient with an indwelling catheter develops an active urinary infection regardless of whether he is receiving antibiotics prophylactically (1, 10). The absence of fever or other overt signs and symptoms of urinary infection should not lull one into a false sense of security. Meticulous culture and microscopic examination of the urine sediment will almost always disclose the evidences of an infection, and if the patient has been maintained on one or another of the "broad-spectrum" antibiotics, the infecting organism will probably prove to be a resistant gram-negative bacillus such as B. proteus or B. pyocyaneus. Before resorting to an indwelling catheter, the physician should always stop to ask himself whether the possible benefits of the procedure clearly outweigh the risks of the infection which will inevitably follow. It is the author's firm opinion that in a great number 50

of i n s t a n c e s i n w h i c h inlying c a t h e t e r s are presently being employed the a n s w e r to t h a t question should be m o s t emphatically i n the negative. I n f e c t i o n s a n y w h e r e i n the body m a y h a v e a deleterious effect o n the course of r e n a l failure. By virtue of t h e i r effect o n the catabolic processes of i n t e r m e d i a r y m e t a b o l i s m infections t h r o w a n added excretory b u r d e n on the kidney. Since the m a n i f e s t a t i o n s of r e n a l failure are the result of a n imb a l a n c e b e t w e e n the excretory load a n d the ability of the kidney to h a n d l e this load, a s u d d e n i n c r e a s e i n tissue catabolism m a y h a v e the s a m e effect as a loss of r e n a l s u b s t a n c e or function. M a n y a p a t i e n t w i t h stabilized r e n a l insufficiency is t h r o w n into a state of progressive decline with the developm e n t of a n acute infectious process. For this r e a s o n it is always n e c e s s a r y to consider infections as a cause of progressive r e n a l failure. The t r e a t m e n t of u r i n a r y t r a c t infections, a large a n d complex subject, was the topic of a previous m o n o g r a p h i n this series ( 1 1 ) , a n d c a n n o t be considered i n a n y detail here. It n e e d s to be emphasized, however, t h a t the presence of azot e m i a requires c e r t a i n modifications in the use of antibiotics a n d o t h e r a n t i b a c t e r i a l agents. Specific r e c o m m e n d a t i o n s i n this regard are outlined i n a l a t e r section. Obstruction. I n every p a t i e n t with r e n a l failure it is essential to search for organic o b s t r u c t i o n in the u r i n a r y tract. Obstruction with h y d r o n e p h r o s i s a n d i n f e c t i o n is a c o m m o n cause of r e n a l disease a n d i n m a n y other i n s t a n c e s it exists as a c o m p l i c a t i n g a n d a g g r a v a t i n g factor s u p e r i m p o s e d on other types of r e n a l disease. T h e i m p o r t a n t points here are: ( 1 ) o b s t r u c t i o n is frequently totally a s y m p t o m a t i e a n d will not necessarily call itself to the a t t e n t i o n of the p h y s i c i a n or the patient, ( 2 ) the d e v e l o p m e n t of obstruction superimposed on pre-existing r e n a l disease is often responsible for sudden progressive loss of r e n a l function, ( 3 ) o b s t r u c t i o n is usually remediable, a n d ( 4 ) o b s t r u c t i o n m a y be responsible for rec u r r e n t or r e s i s t a n t infections. Relief of t h a t obstruction w h i c h exists i n the presence of active u r i n a r y infection frequently affords the only m e t h o d of controlling the infection. To avoid overlooking o b s t r u c t i o n i n t r a v e n o u s or retrograde pyelography should be done in every p a t i e n t with chronic r e n a l failure. T h e possibility of bladder neck o b s t r u c t i o n with a s y m p t o m a t i c p r o s t a t i s m m u s t be considered carefully in every m a l e p a t i e n t beyond middle age. Percussion a n d palpa51

tion of the suprapubic region should be a routine part of the physical examination; careful rectal palpation of the prostate is particularly important in the detection of obstructing prostatic disease, but it should be borne in mind that an obstructing hypertrophied median bar will not be palpable. A delayed pattern of PSP excretion may sometimes supply the clue to the presence of bladder neck obstruction. Patients with stones and those complaining of colicky pain in the flanks or abdomen are apt to have obstructing lesions. Dilatation of pelvis or ureter on x-ray does not necessarily mean obstruction and it needs to be considered carefully in each such instance whether or not there is sufficient evidence of an obstructing lesion. It is often difficult to know which types of obstruction are apt to be improved by surgical intervention. Ill-advised surgery can do much more harm to renal function in the long run than the obstructing lesion which the surgery was intended to remove. In general, surgery for severe obstruction of relatively short duration, caused by tumors, stones, or an enlarged prostate is likely to improve renal function. Mild degrees of chronic obstruction, such as that produced by strictures and congenital valves, are less likely to respond well. Azotemia in itself should not be considered a contraindication to necessary surgery, particularly if the latter is designed to improve renal function. Nutrition, 7nalnutrition and gastrointestinal disturbances. The kidney is the organ chiefly responsible for excretion of the end-products of protein metabolism and it is natural that much interest should be focused on problems relating to the role of protein in the diet of patients with kidney disease. There are those who maintain that it is best to restrict the intake of protein while other students believe this to be unnecessary or even undesirable. The problem is a complex one and an exposition of its many facets is beyond the scope of this article. In the following paragraphs an attempt will be made to summarize the present status of this subject very briefly. Two main arguments have been used in support of restricted protein intake. The first is that it reduces the amount of "work" required of the kidney. For this reason, it is believed that high protein diets or even normal intakes of protein may in some way damage the kidney. The second argument is that low intakes of protein, by reducing the excretory load, reduce the blood levels of non-protein nitro52

gen, phosphate and sulfate as well as the concentration of other u n m e a s u r e d nitrogenous metabolites. This in turn improves the symptoms and the metabolic abnormalities associated with uremia. There is no convincing theoretical or clinical support for the first argument. With regard to the second a r g u m e n t there can be no doubt that reduction in the rate of protein cataboh s m will improve certain of the disturbances in blood chemistry. It remains to be proven, however, that by virtue of this chemical improvement patients with renal failure are significantly benefited. Certain principles are gaining general acceptance. Patients with chronic renal disease need a certain m i n i m u m amount of protein in their diet to m a i n t a i n nitrogen balance, just as do normal people. A diet containing 30-40 grams of protein a day will probably keep an adult in nitrogen balance, provided that his total caloric intake is adequate. If caloric intake does not meet total energy requirements, utilization of body protein will occur and protein combustion will not be kept at a m i n i m u m . W h e n the patient is in the nephrotic stage, the large losses of protein in the urine need to be considered in the calculation of m i n i m u m needs and should be replaced by appropriate increments in the diet. Proteinuria m a y account for as m u c h as 20 or 30 grams per day and can rapidly lead to serious protein deficiency in a patient taking a restricted diet. Another important consideration is that patients with severe renal disease often suffer from chronic anorexia and gastrointestinal disturbances which are responsible for producing a state of severe protein depletion and malnutrition. There can be no doubt that these factors are often responsible for a good deal of the weakness, fatigue and malaise ordinarily considered to be a part of the uremic syndrome. Such patients would naturally require more than the m i n i m u m protein intake in order to repair their deficits. At present, therefore, there would seem to be no good reason for restricting protein in patients with renal disease who do not have azotemia. In those with azotemia a m i n i m a l but adequate intake of protein offers some theoretical advantages, the practical importance of which remains uncertain. The total caloric content of the diet must be carefully maintained, because chronic caloric undernutrition leads to catabolism of tissue protein and progressive inanition. The bulk of the caloric content of the diet should be provided by 53

fruits, vegetables, butter, c r e a m , potatoes, rice, sweet desserts a n d pastries, m o s t of w h i c h h a v e relatively little p r o t e i n a n d a n alkaline or only slightly acid ash. In p a t i e n t s w h o are able to tolerate t h e m , a d m i n i s t r a t i o n of oral f a t e m u l s i o n s such as Lipomul| or Ediol| is a p a r t i c u l a r l y u s e f u l way of i n c r e a s i n g caloric i n t a k e a n d thereby r e d u c i n g p r o t e i n catabolism. T h e first p r e p a r a t i o n h a s a caloric value of 4 c a l o r i e s / cc., the latter 5 calories/cc., a n d therefore a n o u n c e a n d a h a l f t a k e n t h r e e t i m e s daily with m e a l s will add 540 or 675 calories to the daffy diet. W h e n the p a t i e n t is too sick or too n a u s e a t e d to take adequate n o u r i s h m e n t by m o u t h , it m a y be wisest to tide h i m over for a few days with p a r e n t e r a l a d m i n i s t r a t i o n of glucose solutions. If t h e r e is n o u r g e n t need to restrict water, one c a n usually m a n a g e to give the p a t i e n t at least 1000 or 1200 calories i n the f o r m of 10 or 15% glucose solution. Frequently, a few days w i t h o u t oral i n t a k e will quite efficiently stop a prolonged cycle of vomiting. Should the l a t t e r r e c u r or persist the use of c h l o r p r o m a z i n e m a y be w o r t h a trial. T e n to twenty-five rag. of this d r u g 3 or 4 t i m e s daily m a y be used i n the u r e m i c p a t i e n t w i t h excellent effect. However, the d r u g should n o t be used as a substitute for m o r e general m e a s u r e s designed to i m p r o v e t h e overall condition a n d thereby improve appetite. It m u s t be r e m e m b e r e d t h a t anemia, acidosis, a n d depletion of s o d i u m or p o t a s s i u m m a y be the u n d e r l y i n g causes of persistent n a u s e a a n d vomiting. I n m a n y cases g a s t r o i n t e s t i n a l d i s t u r b a n c e s will n e v e r entirely d i s a p p e a r unless these m a l a d j u s t m e n t s are corrected. U r e m i a is often associated w i t h diarrhea. T h e l a t t e r is c o m m o n l y t h o u g h t to be due to the i r r i t a t i n g effect o n the m u c o s a of h i g h c o n c e n t r a t i o n s of u r e a in the i n t e s t i n a l secretions. Actually, very little is k n o w n about this p h e n o m e n o n , a n d it is possible t h a t o t h e r factors m a y be m o r e i m p o r t a n t . Very severe degrees of u r e m i a often result in bleeding into the g a s t r o i n t e s t i n a l tract. At post m o r t e m shallow a b r a s i o n s a n d u l c e r a t i o n s of the m u c o s a m a y be scattered over wide areas. T h e s e lesions m a y r e s u l t i n gross m e l e n a or h e m a t e m e sis a n d on occasions this m a y be the i m m e d i a t e cause of death. Usually, however, bleeding is less severe a n d is import a n t only i n s o f a r as it c o n t r i b u t e s to the severity of the seco n d a r y u r e m i a of r e n a l failure. T r e a t m e n t of these m a n i f e s t a t i o n s is m o s t d i s c o u r a g i n g unless the u r e m i c state itself c a n be i m p r o v e d by o t h e r meas54

ures. Like so many other functional disorders associated with renal failure, diarrhea and bleeding may disappear rapidly once the uremia is controlled. In the absence of improvement in uremia effective control of gastrointestinal symptoms may be impossible. A bland diet with frequent doses of aluminum gel preparations may occasionally be helpful in patients with relative minor bleeding. Severe bleeding has a most ominous prognosis. Little or nothing specific can be done except to replace blood as needed.

Disturbances of calcium and phosphorus metabolism. Severe degrees of uremia are almost always accompanied by reduction in phosphate clearance and consequent elevation of serum phosphate. This, in turn, by some mechanism not yet clearly defined, tends to depress serum calcium levels. Approximately half of the calcium normally in the serum is bound to protein. A low serum calcium may be due either to a reduction in the bound fraction, such as produced by the reduction in serum albumin, or it may be due to the reduction in the ionized calcium, which is the fraction usually affected by the plasma phosphate. Although most patients with uremia have some reduction in ionized calcium, they rarely develop tetany because of it. One reason for this is that acidosis tends to offset the effects of hypocalcemia, either by a direct depressant action on neuromuscular irritability or by increasing the degree of ionization of serum calcium. At any rate, true hypocalcemic tetany is uncommon in uremia except when large quantities of alkali have been administered. The hyperirritability, muscle twitching and convulsive tendencies manifested by patients not treated with alkali are usually unaffected by administration of calcium, and presumably therefore are not due to calcium deficiency. It is the author's practice not to administer calcium routinely to uremic patients unless large quantities of alkali are being given. In that case, 1 or 2 grams of calcium gluconate daily given parenterally are usually adequate to prevent tetany. Prolonged administration of calcium is best avoided in patients with renal disease because of the danger that excess calcium may be deposited in the kidneys or may favor stone formation. Oral administration of aluminum hydroxide or aluminum carbonate (Amphojel| Gelusil| Basaljel| may help to maintain a more normal serum calcium level by combining with phosphate in the gut and lowering serum phosphorus concentration. The author does not use these preparations 55

very often because: (a) they often increase nausea and anorexia and (b) there is little reason to suppose that hyperphosphatemia and hypoealcemia per se are injurious.

Twitching, convulsions and other neuromuscular manifestations. Neuromuscular disturbances are common in uremia. Patients frequently complain of cramps and twitchings in large muscle groups in the extremities. Nocturnal cramps in the calf muscles are particularly common. Little is known about the etiology of these manifestations. Occasionally, when occurring in association with marked hyponatremia or hypocalcemia, muscle cramps may be promptly relieved by administration of calcium or sodium. More often, however, no cause more specific than uremia can be implicated. In the terminal stages of renal failure coarse jerking movements of the limbs and trunk become more frequent and prominent. They usually appear first during sleep or when the patient is dozing in that semi-stuporous state which is so characteristic of advanced uremia. Deep tendon reflexes are usually hyperactive at this stage and the patient in general tends to be quite hyper-reactive when awake and stimulated. It is at this time that generalized convulsive seizures are apt to occur. They are more common in hypertensive patients than in those with normal blood pressure. Seizures, and even frequent twitching, should be prevented if possible. Not only do they frighten the patient and his family but they also speed the development of uremia and acidosis by virtue of the accelerated breakdown of muscle tissue which they produce. Serious neuromuscular disorders are often terminal manifestations, but they do not necessarily lead to death. No uremic patient should be considered hopeless simply because of these symptoms. If the uremia can be improved, twitching and convulsions will disappear. The treatment of twitching and convulsions has two facets. The physician must first attempt to control all factors which might be contributing to the production of hyperirritability. Deficits in the blood levels of calcium and sodium should be corrected. Severe degrees of hypertension must be controlled. For this purpose, any of the currently available rapidly acting hypotensive agents may he used but due care must be taken to avoid too sudden and too marked reductions in blood pressure. The second, and usually more effective, therapeutic approach involves the use of sedatives. Frequent small doses of short-acting depressants such as chloral hydrate or sodium 56

amytal will usually prove effective. Long-acting barbiturates such as phenobarbital and narcotic sedatives such as morphine and Demerol| should be avoided. Dilantin is used as an anti-convulsant, but its value has not been proved, and the writer has had little personal experience with it. The proper use of sedatives in the uremic patient is much more art than science. There are few general rules valid for all eases. Some patients in terminal uremia appear to sedate themselves, gradually drifting into a deepening state of coma interrupted by merely an infrequent muscle twitch. Such patients are best left alone. Others, quite the contrary, are roused frequently from their stupor by repeated episodes of wild agitation and confusion or by almost continuous involuntary muscular activity. It is only the latter group who require some sort of sedation. Overzealous use of sedatives must be guarded against. Excessive employment of sedative drugs may so severely depress the patient that he cannot be roused to take nourishment. Distention of the bladder is another frequent result of oversedation. When convulsive seizures develop, or when twitching becomes incessant and severe, parenteral sodium amytal should be used as needed. Usually 0.25 grams given intramuscularly every few hours will be adequate. Parenteral administration of magnesium sulfate has been recommended by some, but the margin between an effective therapeutic dose and the toxic dose of this ion is so narrow that the author hesitates to employ it, particularly when renal failure may allow rapid accumulation in the blood. The toxic effects of magnesium include circulatory and respiratory depression and hypo. reflexia. These can usually be instantly counteracted by intravenous injection of calcium. Occasionally patients with uremia develop severe signs and symptoms of peripheral neuritis. Disorders of sensory function are the most evident. The patient may complain of numbness, tingling, paresthesias and sometimes lancinating pains. There may be marked tenderness of muscles and nerve trunks. Reflexes may be diminished or absent. Little or nothing is known about either pathogenesis or treatment of these interesting manifestations but they, like almost all the neuromuscular disorders, are clearly related to the uremic state and may disappear entirely if the latter improves significantly. 57

THE USE OF DRUGS iN UREMIC PATIENTS

Severe impairment of renal function imposes restrictions on the clinical use of certain drugs. Some of the more important interdictions are as follows: 1. Acidifying salts such as ammonium chloride or calcium chloride and acidifying cation exchange resins should never be used in severely uremic patients because they will result in dangerous acidosis. 2. Mercurial diuretics should be used only if there is edema and only if they result in a good diuretic response. If there is little or no diuresis, the administered mercury will tend to accumulate in the body and may cause serious mercury poisoning. 3. Magnesium salts and potassium salts should be given with the greatest of care because the likelihood of reaching toxic blood levels is so great. These compounds are contraindicated when there is oliguria. 4. Sedatives of all kinds should be used sparingly. Morphine and Demerol| may produce severe depression in patients already drowsy or stuporous from uremia. Long-acting barbiturates such as phenobarbital are best avoided. The most satisfactory sedatives are short-acting barbiturates and chloral hydrate or paraldehyde. The latter two drugs are particularly safe because they are not excreted by the kidneys. 5. Penicillin and most of the commonly used antibiotics can usually be given in full therapeutic doses with safety, but there are certain important exceptions. Streptomycin may accumulate in the blood and cause serious eighth-nerve toxicity. The strongly nephrotoxic agents such as bacitracin, polymixin B, and neomycin are contraindicated. Absorbable sulfonamides must be given in reduced doses to avoid toxic blood levels. The nitrofuran germicides are probably also not safe to use in patients with advanced uremia. HORMONES AND RENAL FAILURES

Endocrine function has an important though indirect relation to renal failure. To the extent that certain hormones affect the rates of critical reactions in the intermediary metabolism of protein they may influence the severity of the uremic state resulting from any given degree of renal impairment. Excessive thyroid or adrcnocortieal activity, by 58

accelerating protein catabolism, m a y increase the blood u r e a level at a n y stage of r e n a l disease i n m u c h the same m a n n e r as i n f e c t i o n s a n d stress. Conversely, p a t i e n t s w i t h depressed p r o t e i n m e t a b o l i s m r e s u l t i n g f r o m h y p o t h y r o i d i s m or hypoa d r e n a l i s m m a y show less evidence of r e n a l failure t h a n others w i t h similar r e n a l f u n c t i o n b u t i n t a c t e n d o c r i n e systems. ACTH a n d the various a d r e n a l corticoid substances m u s t therefore be considered potentiaily d a n g e r o u s in r e n a l failure. O n the o t h e r h a n d , t h e i r use m a y be i n d i c a t e d i n c e r t a i n types of i n f l a m m a t o r y diseases involving the kidney despite the p r e s e n c e of r e n a l failure. Large doses of steroids m a y favorably modify the tissue reactions i n s u c h disorders as the allergic p u r p u r a s , hypersensitivity angiitis, a n d dissemin a t e d lupus, a n d i n this m a n n e r m a y greatly improve r e n a l function. W h e t h e r the net effect in a given case will be to improve or e x a c e r b a t e the m a n i f e s t a t i o n s of r e n a l failure is difficult to predict. For this reason, there r e m a i n s a good deal of c o n f u s i o n a n d u n c e r t a i n t y about the precise i n d i c a t i o n s a n d c o n t r a i n d i c a t i o n s for the use of a d r e n a l steroids i n the p r e s e n c e of r e n a l failure. T h e i n c r e a s i n g evidence t h a t large doses of steroids m a y favorably modify the clinical course of the n e p h r o t i c s y n d r o m e i n c h i l d r e n a n d adults h a s encouraged some investigators to t r e a t p a t i e n t s with nephrotic e d e m a w h o also h a v e some degree of azotemia. T h e use of steroids i n the m a n a g e m e n t of n e p h r o s i s is discussed at l e n g t h elsewhere ( 1 2 ) a n d will not be considered f u r t h e r in this srtiele. Earlier experience with steroids i n acute a n d chronic g l o m e r u l o n e p h r i t i s was d i s c o u r a g i n g b u t it is still possible t h a t larger doses for longer periods of time m a y prove to be of value in c e r t a i n selected cases with mild or m o d e r a t e azotemia. The a d v e n t of the delta-1 u n s a t u r a t e d cortisone a n d hydro-cortisone derivatives w h i c h h a v e little or n o direct effect o n sodium a n d p o t a s s i u m m e t a b o l i s m m a y offer a p r o m i s i n g n e w lead since m a n y of the u n d e s i r a b l e side-effects of a d r e n a l steroids in r e n a l disease have b e e n related to sodium r e t e n t i o n a n d p o t a s s i u m loss. USE OF THE ARTIFICIAL KIDNEY

T h e i n d i c a t i o n s for tile use of the artificial kidney in acute oliguric r e n a l failure h a v e already b e e n discussed. It h a s been reported t h a t dialysis with the artificial kidney m a y also be 59

used to improve u r e m i c s y m p t o m s i n p a t i e n t s with chronic r e n a l disease w h o do n o t h a v e a n y o t h e r c o m p l i c a t i n g condition such as h y p e r t e n s i v e v a s c u l a r disease, congestive h e a r t failure or h e p a t i c insufficiency. I m p r o v e m e n t is only transient, a n d w i t h i n a m a t t e r of days, weeks, or m o n t h s the situation is back to its pre-dialysis level. Response to s u b s e q u e n t dialysis m a y or m a y n o t be as satisfactory as the first. Sooner or later a state is r e a c h e d in w h i c h the p a t i e n t e i t h e r n o longer r e s p o n d s to dialysis or simply c a n n o t be dialyzed a g a i n for t e c h n i c a l reasons. W h e t h e r or n o t the artificial kidney should properly be used i n the m a n a g e m e n t of chronic r e n a l failure is therefore a m o o t question at present. T h e r e is n o doubt t h a t dialysis m a y be of great value i n p r e p a r i n g u r e m i c p a t i e n t s for essential surgery or i n tiding s u c h a p a t i e n t over the u n t o w a r d effects of postoperative stress. SURGERY IN THE UREMIC PATIENT M a j o r surgery constitutes a f o r m of stress w h i c h m a y exacerbate r e n a l insufficiency by virtue of its effect o n n i t r o g e n metabolism. I n addition, d e h y d r a t i o n , hypotension, oligemia a n d s t a r v a t i o n a n d various electrolyte d i s t u r b a n c e s w h i c h m a y occur in the postoperative period m a y all c o n t r i b u t e toward f u r t h e r i m p a i r i n g r e n a l function. Following operation, p a t i e n t s with a z o t e m i a almost always show some rise i n blood n i t r o g e n levels. For these reasons, it is a c o m m o n l y held opinion t h a t m a j o r surgery is always c o n t r a i n d i c a t e d i n uremic patients. The a u t h o r does not entirely concur. Careful m a n a g e m e n t of the p a t i e n t i n the preoperative a n d postoperative periods with avoidance of the h a z a r d s already m e n tioned m a y p e r m i t p a t i e n t s w i t h r e n a l failure to go t h r o u g h m a j o r surgery w i t h little or n o u n t o w a r d effects. U r g e n t l y needed surgical procedures need not be deferred even i n patients w i t h B U N levels i n d i c a t i n g loss of 5 0 - 7 5 % of r e n a l function. Elective surgery c a n be done in m o s t p a t i e n t s w i t h mild to m o d e r a t e degrees of r e n a l insufficiency provided t h a t their condition is stable a n d r e a s o n a b l y well c o m p e n s a t e d a n d provided also t h a t m e t i c u l o u s care is exercised i n the preoperative a n d postoperative periods to avoid all t h i n g s potentially deleterious to r e n a l f u n c t i o n . T h e r o u t i n e use of indwelling c a t h e t e r s i n the postoperative period is p a r t i c u l a r l y d a n g e r o u s i n p a t i e n t s with r e n a l damage. E v e r y t h i n g possible should be done to avoid u r i n a r y t r a c t infections. 60

TRANSPLANTATION OF THE KIDNEY

A new approach to the treatment of chronic irreversible renal disease has been opened up recently by attempts at homotransplantation of the human kidney (13). Single normal kidneys taken from volunteer donors undergoing elective nephreetomy or from fresh cadavers have been successfully grafted into patients suffering from far-advanced renal failure. In several instances the grafted kidneys, after a short initial period of anuria, functioned well for a few weeks or months. To date, however, all such cases have ended in failure because tissue immune responses ultimately caused the death of the transplanted kidney. Very recently it has been reported that a kidney transplanted from one normal identical twin to another with advanced glomerulonephritis has been functioning adequately for more than one year and has resulted in dramatic reversal of the renal and vascular disease (14). This exciting development does not, of course, offer any immediate promise of widespread application, but it does highlight the fact that kidney transplantation is technically feasible. Further progress in this field must await solution of the problem of tissue immunity. SUMMARY The rational management of renal failure begins with accurate diagnosis of the specific functional or morphological factors responsible for its development. Many types of acute renal failure, as well as those varieties of chronic failure associated with metabolic disturbances, obstruction, and certain generalized diseases, may be completely or partially reversed by specific treatment of the cause. Even when the disease is irreversible, therapeutic efforts directed at the numerous complications which tend to accompany renal failure may still be very effective in relieving symptoms and prolonging life. As more and more renal substance is destroyed, life and health become dependent on progressively smaller changes in renal function and excretory load. Meticulous attention to all the details of management described above may therefore make the difference between compensation and renal failure. No matter how hopeless the situation may at first appear, every uremic patient should have the benefit of a systematic search for all possible factors involved in the 61

pathogenesis of his disease, followed by an intensive trial of whatever therapeutic measures seem applicable. REFERENCES 1. Kass, E. H. : Chemotherapeutic and antibiotic drugs in the manage-

m e n t of infections of the u r i n a r y tract, Am. J. Med. 18:764, 1955. 2. Relman, A. S. and Schwartz, W. B.: The nephropathy of p o t a s s i u m depletion: A clinical and pathological entity, New E n g l a n d J. Med. I n press. 3. Lippman, R. W.: Urine and the Urinary Sediment. A Practical Manual and Atlas (Springfield, IlL: Charles C Thomas, Publisher, 1952). 4. Addis, T.'. Glomarular Nephritis'. Diagnosis and T r e a t m e n t ( N e w York: M a c m i l l a n Company, 1949). 5. Goldring, W.: Clinical application of current tests of renal function, J.A.M.A. 153:1245, 1953. 6. Iversen, P., Bj0rneboe, M. and Krarup, N. B : Biopsy Studies of the Liver and Kidney'. A d v a n c e s i n I n t e r n a l M e d i c i n e (Chicago: Year Book Publishers, 1954), Vol. VI, p. 161. 7. Swan, R. C. and Merrill, J. P.: The clinical course of acute renal failure, Medicine 32: 215, 1953. 8. Relman, A. S. and Schwartz, W. B.: The recognition and managem e n t of sodium depletion, M. Clin. North America 35:1533, 1951. 9. Conn, J. W. and Louis, L. H.; P r i m a r y aldosterouism, a new clinical entity, Ann. Int. Med. 44:1, 1956. 10. Beeson, P. B.: Factors in the pathogenesis of pyelonephritis, Yale J. Biol. & Med. 28:81, 1955. 11. Jawetz, E.: Urinary tract infections, Disease-a-Month, November, 1954. 12. Proceedings of the Sixth A n n u a l Conference on the Nephrotie Syndrome (J. Metcoff, ed.) ( N e w York: National Nephrosis Foundation, 1955). 13. Hume, D. M., et al.: Experiences w i t h r e n a l h o m o t r a n s p l a n t a t i o n in the h u m a n : Report of nine cases, J. Clin. Invest. 34:327, 1955. 14. Merrill, J. P., et al.: Successful h o m o t r a n s p l a n t a t i o n of the h u m a n kidney between identical twins, J.A.M.A. 160:277, 1956. GENERAL R~FER~NCES : Bull, G. M.: The Uraemias, Lancet ( 1 ) 731,777, 1955. Fishberg, A. M.: Hypertension and Nephritis (Philadelphia: Lea & Febiger, 1954). Merrill, J'. P.: The T r e a t m e n t of Renal Failure ( N e w York: (]rune & Stratton, Ine., 1955). Smith, H. W.: The Kidney (New York: Oxford University Press, 1951). Strauss, M. B. and Raisz, L. G. : Clinical M a n a g e m e n t of Renal Failure (Springfield, Ill. : Charles C Thomas, Publisher, 1956).

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