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Suggestions for the Treatment of Kidney Disease
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
GEORGE W. THORN, M.D., F.A.C.P.* and FRANK H. TYLER, M.D.t RENAL malfunction is characterized by excessive excretion or retention of normal constituents of the blood. Evidence of renal malfunction is usually manifested by the presence of protein, casts or cellular elements in the urine and by impaired performance of standardized tests of renal function. For purposes of discussion the principal causes of kidney disease may be grouped as follows: 1. Infections of the Kidney
2. 3. 4. 5.
Pyelonephritis, pyonephrosis, cortical abscesses and perinephric inflammation "Allergic" Disorders of the Kidney Acute and chronic glomerulonephritis including the nephrotic syndrome, disseminated lupus erythematosus and polyarteritis Disturbances in Renal Circulation Arteriolar nephrosclerosis, heart failure, arterial and venous obstruction Renal Injury from Chemical and Metabolic Agents Mercury, bismuth, sulfonamides and gout Malformations (congenital or acquired) of the kidney Hypoplasia, polycystic disease, tumors and aberrant vessels GENERAL CONSIDERATIONS
Infections of the Kidney.-The recognition of infections of the kid-
ney and the institution of appropriate medical and surgical measures may prevent progressive and widespread destruction of kidney substance in many patients. The use of the sulfonamides, penicillin and mandelic acid represents a great advance in specific therapy. Acute Glomerulonephritis.-There is no specific therapy for patients with acute glomerulonephritis. Fortunately more than 85 per cent of patients suffering from this disease recover completely.1 The number of recoveries may be increased appreciably by intelligent and diligent medical care. There is some evidence to suggest that patients who continue to have positive throat cultures for beta hemolytic streptococci are benefited by the use of sulfonamide therapy.2 Disturbances in Renal Circulation.-In patients with renal insufficiency r~sulting from vascular disease there remains a great field for From the Department of Medicine, Harvard Medical School, ;md the Medical Clinic of the Peter Bent Brigham Hospital. The authors wish to acknowledg\! the assistance of Miss Janet E. Clark, nurse-in-charge of the metabolism unit, and Miss Marion J. Brian, dietitian-in-charge. • Hersey Professor of the Theory and Practice of Physic, Harvard Medical School; Physician-in-Chief, Peter Bent Brigham Hospital. t Research Fellow in Medicine, Harvard Medical School; Resident Physician, Peter Bent Brigham Hospital. 1173
1174
GEORGE W. THORN, FRANK H. TYLER TABLE I.-THERAPEUTIC MAN
TREATMENT
EDEMA I III Il Edema Edema Edema Hypoalbumin- Hypoalbumin- Hypoalbuminemia emia emia Hypertension Hypertension Heart failure
Total Fluids .. ....... 1500 cc. daily
Diet ...
Protein
2-3 gm./kg. daily
NaCI
Salt free
Ash
Acid
IV Azotemia
1000-1500 cc. 4000 cc. daily milk daily for 2-5 days; no 1 gm./kg. daily 1-2 gm./kg. additional daily fluid or food No restriction; Salt free 1-3 gm. daily supplement§
1500 cc. daily
Alkaline
Acid
Plasma or 25-50 gm. LV. 10-15 gm. I.V. albumin'" daily b.i.d. Ureat
Diu-
relics
30-60 gm. daily 30-60 gm. daily 30 gm. daily
Glucose
1000 cc. 5% LV. daily 3-7 days
Digitalis
Digi talizationt
Aminophylline
0.1 gm. I.V. O.i.d.
In the presence In the presence In the presence Oxygen. of nausea and nausea Paracentesis. anemia of of and vomitipg gluwhole blood and vomit- Fluids protein solucose solution ing glucose transfusions are indicated. solution 500 tions should 3000 cc. 10% I.V., sodium not be given cc. 10% I.V. ,
.
'" The products of plasma fractionation employed in this work were deveJoped from blood collected by the American Red Cross by the Department of Physical Chemistry, Harvard Medical School, Boston, Massachusetts, under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Develop· ment and Harvard University. Albumin will not be available for general clinical use during the war because of the needs of the armed forces. t Urea may be given in fruit juice. If anorexia or nausea occurs, the dose of urea should be reduced or discontinued.
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1175
AGEMENT OF KIDNEY DISEASE
EDEMA
AZOTEMIA
V Azotemia Acidosis
4000 cc. daily 1 gm./kg. daily No restriction; 1-3 gm. daily supplement§
VI Azotemia Acidosis Hypertension
VII Edema Azotemia Acidosis Hypertension
AND AZOTEMIA
VIII Edema Hypoalbuminemia Azotemia Hypertension
IX Edema Azotemia Acidosis Heart Failure
1000 cc. milk daily with aluminum hydroxide ad1 gm./kg. daily 1 gm./kg. daily 1 gm./kg. daily ded\\; 500-1000 cc. fruit juice No restriction Salt free Salt free 3000 cc. daily
2000 cc. daily
2000 cc. daily
Alkaline; 3-6 Alkaline Alkaline; 3-6 gm. NaHCO. gm. NaHCO, daily daily
Alkaline
10 gm. b.i.d.
LV. 15 gm. b.i.d.
LV.
1000 cc. 5% I.V. SO cc. 20% LV. daily 3-7 days daily 3-7 days
See footnote'if Digi talizationt 0.1 gm. h.i.d.
The contents of In the presence one SO cc. am- of nausea and pule of sodium vomiting glulactate (11%) cose solution may be added 10% LV. slowto the above ly not to exinfusion daily ceed 1000 cc. for 3-7 days in q. 8 hrs., 500 place of sodi- cc. 0.85% urn lactate by NaCI q. 3rd mouth. day in absence of edema may be substituted for above.
l.V. 0.1 gm. b.Ld.
LV. 0.1 gm. I.V. b.Ld.
In the presence of nausea and vomiting glucose solution 750 cc. 10% I.V. q. 8 hrs., or albumin plasma 8 gm. LV. q. 8 hrs. may be subfor stituted above.
Oxygen. Paracentesis. in Venesection presence of high venous pressure. Fluids and protein solutions should not be given intravenously.
fIn the absence.of previous digitalis therapy, 3 cat units intramuscularly and 2 cat units intravenously may be given. § Enteric-coated sodium chloride tablets (1 gm. each). \\ Eight to 16 cc. of aluminum hydroxide may be added to each glass of milk. 'if If azotemia persists and cardiac status improves, SO cc. of 10 per cent glucose may be given intravenously very slowly once or twice a day.
1176
GEORGE W. THORN, FRANK H. TYLER
therapeutic progress. At present therapy is limited to the treatment of congestive heart failure and attempts to lower blood pressure by medical and surgical methods. Renal Insufficiency from Chemical and Metabolic Agents.-The widespread use of chemotherapeutic agents undoubtedly will increase the occurrence of renal disease. Here the problem is largely one of prophylaxis, since the incidence of renal insufficiency can be greatly reduced if precautions are taken to ensure an adequate urine volume. Malformations of the Kidney.-In hypoplasia and cystic disease of the kidney little can be done other than to prevent secondary infection. In the presence of renal stasis resulting from calculus, an aberrant vessel or tumor, surgery may be effective in improving kidney function or in preventing further damage. It is apparent from these considerations that the elimination of the agent responsible for renal damage is not possible in most patients with kidney disease. Hence treatment must be concerned largely with the application of measures designed to preserve nephrons and prevent development of gross chemical and metabolic abnormalities. It is not generally appreciated that a useful life including moderate activity may be carried on for many years despite the reduced functioning kidney mass. This is particularly true of patients with renal insufficiency without hypertension. THERAPEUTIC CONSIDERATIONS
I. Water Requirement Principles: A. In the absence of circulatory failure water will not be retained in the body in significant quantity without the concomitant retention of sodium; hence in patients with "renal" edema there is little justification for the restriction of fluids on a salt-free regimen. B. A large urine volume is advantageous in the presence of azotemia. In patients with edema without azotemia (nephrotic syndrome) a daily fluid intake of 1500 cc. is usually adequate (Table 1: Types I and 11). The quantity of fluid may be reduced if the patient so desires. In the presence of azotemia without edema (chronic glomerulonephritis, arteriolar nephrosclerosis, chronic pyelonephritis) it is distinctly advantageous to increase the 24-hour urine volume to 20003000 cc. This usually requires the administration of approximately 4000 cc. of fluid daily (Table 1: Types IV, V and V.I). Under these circumstances, however, essential as well as nonessential substances may be "washed out;" hence the need for replenishing the former. In patients with azotemia and edema it is obvious that some compromise in fluid intake is necessary; thus in the absence of cardiac failure 2000 cc. fluid intake is suggested (Table 1: Types VII and VIII).
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1177
In the presence of infections of the kidney a large output of urine is to be desired. When the volume of urine is increased in the treatment of pyuria the dose of chemotherapeutic substance may need to be increased to provide an adequate concentration of bacteriostatic agent in the urine. Edema and dehydration are frequent complications of renal malfunction; hence the necessity for a study of "water balance" frequently arises. Unfortunately, to most physicians the term "water balance" implies only measurement of fluid intake and urine output. TABLE 2.-DETERMINATION OF WATER BALANCE
Intake 1. Liquids: Measure fluid intake directly. 2. Water content of solid food: Calculate by weighing aliquot of day's diet before and after drying or by consulting tables for average water content of foods. 3. Water of oxidation: 1 gm. protein = 0.4 gm. water 1 gm. carbohydrate = 0.6 gm. water 1 gm. fat = 1.0 gm. water Output 1. Urine: Measure urine volume. 2. Feces: Determine wet and dry weight of feces. 3. Insensible water loss and perspiration: Weigh patient at 9:00 p.m. and again at 9:00 a.m. under standard conditions with. out food or fluid intake in the interim. 4. Abnormal water losses: Saliva, sputum, draining fistulae, etc. measure directly. Example Diet: Carbohydrate 220 gm., protein 70 gm., fat 120 gm. Fluid intake. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1500 cc. Water content of food. . . . .. . .... . . . . .. . . . . .. . .. 600 cc. Water of oxidation ....................... , . . . .. 280 cc.
2380 cc.
Urine volume ................................ . 1200 cc. Water content of feces ......................... . 250 cc. Insensible water loss and perspiration (465 X 2) .. . 930 cc. Abnormal loss ................................ . o cc.
2380 cc.
This may lead to erroneous conclusions (Table 2), since it is apparent that the water content of solid foods (average 500 to 700 cc. per day) is quite appreciable and is frequently overlooked as a source of water. Furthermore, the water loss through ventilation, evaporation and perspiration may be quite considerable. Fortunately, there are reliable clinical signs of changes in water balance, namely changes in body weight, presence of edema, dry skin, dry tongue, enophtlialmos and oliguria which make the more elaborate measurements of water balance unnecessary for routine clinical treatment. Unfortunately, the
1178
GEORGE W. THORN, FRANK H. TYLER
presence of oliguria, a most helpful method of detecting dehydration in most circumstances, cannot be relied upon in patients with nephritis. Parenteral administration of fluids and nutritive substances must be employed in patients with renal insufficiency who are unable to retain fluids and food by mouth. Fluid absorption by rectum is rarely sufficient to meet daily body requirements. The absorption of nutritive substances from the rectum is unpredictable. In the presence of nausea and vomiting it may be stated that the minimum body requirements are as follows: Water ..................... 2500 cc. daily Calories ................... 1200 daily Protein .................... 25-50 gm. daily
For parenteral fluid administration one is limited to the use of solutions of glucose, saline, protein or amino acids. Since in most instances protein administered parenterally will supply less than 200 calories per day (i.e., 25-50 gm. X 4 calories per gm.) it is apparent that most of the caloric requirement must of necessity be derived from glucose solutions. Two hundred and fifty grams of glucose is needed to provide 1000 calories (250 gm. X 4 calories per gm.), and therefore the administration of 2500 cc. of 10 per cent glucose daily will provide both fluid and minimum caloric requirement. Continued use of parenteral glucose solutions, however, may result in a striking fall in the serum level of sodium and chloride, and the possible need for supplementary sodium chloride therapy during periods of active diuresis induced by glucose solutions must always be kept in mind (Table 1: Types IV, V and VI). 11. Dietary Management Principles: Patients with nephritis should be provided with basic dietary requirement necessary for health: Water sufficient to provide a urine volume large enough to permit excretion of endproducts of metabolism; calories sufficient to maintain weight; protein sufficient to meet the body needs (1 gm. per kg. per day for adults) and to compe.nsate for abnormal losses in the urine; essential minerals and vitamins. Protein Content of Diet.-Patients with disease of the kidneys frequently are deficient in protein. In the absence of azotemia high-protein diets are indicated, i.e., 2 to 3 gm. of protein per kilogram of body weight per day. High-protein intake is of advantage in the treatment" of patients with edema without azotemia for the following reasons: (1) improved nitrogen balance, (2) increased urea excretion (diuretic), (3) increased renal blood flow and (4) acid ash (diuretic).
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1179
In the presence of azotemia protein intake may be restricted to the basic ,requirement of 1 gm. per kilogram of body weight per day. Plasma and albumin solutions recommended in the treatment of edema are useful sources of protein, but their prime function when given intravenously in quantities now available is their diuretic action. Patients who are nauseated and who are unable to retain food for more than 2 or 3 days may be given amino acid solution, plasma, albumin or blood parenterally at regular intervals as a source of required dietary protein. It should be borne in mind that it is practically impossible to induce a positive nitrogen balance by parenteral protein or amino acid therapy alone! TABLE 3.-APPROXIMATE CAJ.CULATIONS FOR ACID-BASE CONTENT OF DIET*
Grams
--
Vegetablest ....... , . , '" ... , , Fruit§ .............. ' . , .... , . Meat, fish, poultry II........... Eggs .................. , ..... Cereal~ ..................... Bread ......... : .......... , . , Milk ........................ Milk .... , ................... Milk ...... . ............... Cheese ...................... Potato .... , ............. , ... Macaroni, noodles, rice and spaghetti~ ..........•...... Cornstarch or tapioca pudding .. Rice pudding ................. Raked custard ................ Plain cake .... , ..............
100 100 100 100 180 30 120 180 240 20 100 150 100 100 60
Household Measure
Excess Acidt
t cup 3i oz. 2
cup .1 slice 2
t cup
10.5 11.0 3.2 2.0
! cup
1 cup
I" cube ! cup
1.1
i cup t cup
3.1
t cup
0.1 2.5
Excess Baset
6.2 5,1
2.1 3.2
4."
7.0 1.5 1.3
* Chaney, Margaret S., and Ahlborn, Margaret: Nutrition. Boston, Houghton Miffiin Company, 1939, pp. 386-409. t Expressed as cc. normal solution required to neutralize the ash. t Average does not include spinach and dandelion greens (excess base 27.0) or corn (excess acid 1.8). § Average does not include prunes, plums and cranberries which are excess acid foods. II Average does not include oysters (excess acid 15.2). ~ Cooked weight.
Sodium Chloride Content of Diet.-Patients wth edema should be given a salt-free diet (Table 1: Types I, II, Ill, VII, VIII and IX). Patients with azotemia without edema (Table 1: Types IV and V) will 'frequently be benefited by the administration of supplementary sodium chloride 3 to 5 gm. daily. In the presence of marked hypertension supplementary sodium chloride must be given very cautiously (Table 1: Type VI). Patients with azotemia and acidosis will do well to have part of their supplementary sodium given as sodium bicarbonate (Table 1: Types V and VI). For example: Instead of 5 gm. of
1180
GEORGE W. THORN, FRANK H. TYLER
sodium chloride, 2 to 3 gm. of sodium chloride and 5 to 6 gm. of sodium bicarbonate (sodium content of sodium bicarbonate is approximately one-half that of sodium chloride) may be given. In chronic renal insufficiency with a large fluid intake and output it is possible to "wash out" excessive quantities of sodium and chloride with disastrous results; hence the need of replacement therapy. Ash of the Diet.-In the presence of edema without azotemia or acidosis (nephrotic syndrome) (Table 1: Types I and II) an acidash diet may be of some aid in promoting diuresis. Furthermore, since the ideal diet for such patients is one containing a large quantity of protein, the ash will most certainly be acid. A problem is presented in the treatment of patients with azotemia and acidosis (Table 1: Types V, VI and VII). In this situation the kidneys are unable to conserve base, since the ability to form ammonia from urea is greatly reduced. Sodium and other fixed bases are drawn from the body and excreted to assist in neutralizing acid end-products. Decreasing the acid ash residue of the diet by ingesting a diet of neutral or alkalineash composition may be helpful (Table 3). Aluminum hydroxide may also be added to milk or taken with food. By so doing a great reduction in phosphorus (fixed acid) absorption can be demonstrated and the relative alkalinity of milk can be greatly increased. s Supplementary sodium bicarbonate therapy may be given to patients with renal acidosis without edema. The water retaining effect of sodium bicarbonate is equivalent to approximately one-half to one-third that of sodium chloride, i.e., 2 to 3 gm. of sodium bicarbonate is equivalent to 1 gm. of sodium chloride. In patients without edema with renal acidosis, nausea and vomiting, sodium lactate or sodium bicarbonate may be given intravenously. One 50-cc. ampule of sodium lactate (11 per cent) may be added to the glucose solution and given once or twice a day until a satisfactory increase in carbon dioxide combining power has been attained (Table 1: Type V). Ill. Diuretics
Principles: There are two indications for increasing urine output in patients with renal malfunction, (1) edema and (2) azotemia. In patients with kidney disease one can scarcely justify the use of diuretics which depend for their action on an irritative or toxic effect on the renal tubules. It would appear more rational to employ agents which act by increasing plasma volume and renal circulation, i.e., protein solutions intravenously, glucose solutions intravenously, urea and. possibly xanthine derivatives. The presence of circulatory failure, however, is a contraindication to the use of substances which depend for their action on a relatively large increase in plasma volume.
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1181
Edema.-Edema is usually related to hypoalbuminemia and is most commonly observed in the nephrotic syndrome (Table 1: Types I and II). Salt restriction is indicated under these circumstances. Administration of urea may be quite effective in many cases (Fig. 93). It may require 10 to 20 days of urea therapy (30 to 60 gm. daily) before the diuretic action of this substance is manifested. Fluid intake should be limited to 1000 to 1500 cc. daily during the period of urea administration, and blood nonprotein nitrogen determinations should be made at 5 to 7 day intervals. Little effect of urea as a diuretic can be expected unless the administration of urea results in an elevation of blood urea nitrogen. It is obvious, however, that the mechanism re-
100
EFFECT Or: UREA TI-JERAPY £O£MA .~Neph,-ot!c.
Patient I'i.M. ~
55
Body
Wei~ht
I'\~
J.I YPOPROTE/N£MIA
Synd..-ome
50
45
40
i~~ ~f------------~-~'/---------'-v/----l Urea (\m
daily 10
20
30
40
50
100
70
80
90
100
liD
120
Fig. 93.
sponsible for edema in these patients is largely hypoalbuminemia, and hence a diet high in protein and particularly frequent intravenous administration of protein solutions are definitely indicated. A daily dose of 25 to 50 gm. of human albumin is also an excellent physiological diuretic (Figs. 94 and 95). The use of infusions of sufficient quantities of albumin for purposes of diuresis should be clearly differentiated from attempts to induce a positive nitrogen balance with parenteral protein therapy. The latter is almost impossible to obtain unless massive therapy is attempted. Unfortunately, at present human albumin is not available for civilian use. Plasma solutions, therefore, will have to be substituted until adequate quantities of human albumin are made availahle. It is ohvious that 1 gm. of plasma protein does not
1182
GEORGE W. THORN, FRANK H. TYLER
(;FFE:CT 01= INTRAVI;NOUS ALBUMIN ON URINE: OUTPUT Patient
J. G. 9
Nephmtic Syndmme
EOEMA
J./VPOPJ
Unne
Volume cc
"Of'
Body Weilfht
91.0
90.0
K~.
890
._---
Con,tanl _._--"'~-----.""
, "'...
e-----e--
_--------.--
__ ....
880
i-Juman Albumin ~m.
DAYS
2
4
?>
5
7
8
10
Fig. 94.
Patient B.B.
Nephrot~'
Syndr-ome
1201,---~~-~-~---~~---~-----,
110~----.
......---- ..,
Body 100
Weight k~.
,,
,, ,,
..""
90
80
" " -......
......
10 I?<
....- - - - •• - - -e
~uma.n 50
Albumin ~m.
day!:>
19
24
13
1B
2B
1 teb.
Fig. 95.-Changes in body weight and edema following the long-continued intravenous administration of human albumin in nephrotic syndrome. (From Thorn, G. W., New England J. Med., 1943.)
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1183
exert as potent a colloid osmotic effect as 1 gm. of albumin. As a diuretic agent for patients with edema it is extremely important to point out that human albumin can be prepared with it low sodium chloride content. In the treatment of edema such a preparation would have a great advantage over plasma solutions which contain rather appreciable quantities of sodium chloride (Table 1: Types I and 11). Azotemia.-Patients with azotemia without significant hypoalbuminemia will usually have a diuresis following the administration of large quantities of fluid by mouth (Table 1: Types IV, V and VI). In marked azotemia, however, it is many times helpful to give 3 to 7 days' treatment of 1000 cc. of 5 per cent glucose intravenously in conjunction with a large fluid intake. In the absence of edema it is desirable to give some supplementary sodum chloride during this period of therapy, e.g., 1 to 3 gm. daily. In acute nephritis with striking edema and azotemia there is usually moderate reduction in serum albumin level4 and an increase in blood nonprotein nitrogen. It is obvious that the reduction in colloid osmotic pressure is not sufficient to explain the edema in most patients. Protein solutions administered intravenously to patients with acute nephritis do not have as striking a diuretic effect as in patients with the nephrotic syndrome and marked hypoalbuminemia. Furthermore, great care must be exercised in the administration of protein solutions to patients with acute nephritis and edema in order to prevent cardiac dilatation following a sudden increase in plasma volume. Fluids by mouth or intravenously are not as effective in reducing azotemia as is the case in azotemia due to chronic nephritis. The treatment of oliguria and azotemia in patients with acute nephritis with nausea and vomiting requires considerable skill and judgment in the use of small quantities of protein solution intravenously in conjunction with glucose solution. Serum chloride levels and carbon dioxide combining power must be followed carefully, as occasionally a striking degree of hypochloremia may develop even in the presence of edema (Table 1: Type VIII). TREATMENT OF PYELONEPHRITIS (INCLUDING PYELITIS)
Since infections of the kidney are so frequently secondary to stasis, it is extremely important to study each patient for the presence of hydronephrosis, renal calculus, prostatic hypertrophy and anomalies of the urogenital tract. Fluid intake should average 2500 to 3000 cc. daily. The sulfonamide drugs are the most effective agents available at present for the treatment of urinary tract infection. To date sulfathiazole and sulfadiazine have been shown to be effective against Escherichia coli, Aerobacter aerogenes, Bacillus pyocyaneus, proteus, enterococcus, staphylococcus and beta hemolytic streptococcus (Groups A and D). Frequently doses of sui fa diazine as small as 0.5 gm. three times a day are adequate. This low dosage, i.e., 1.5 gm. daily, is in-
1184
GEORGE W. THORN, FRANK H. TYLER
dicated particularly in patients with infections of the kidney with renal insufficiency. The possibility of renal damage from sulfonamide therapy must be kept in mind. Illustration Patient N. S., P.B.B.H. Med. No. 66,182, male, aged 68. Diagnosis: Bilateral pyelonephritis (E. coli). Complication: Diabetes mellitus. Examination: Blood pressure was 140/70 mm. of mercury; temperature ranged between 98.6 and 101 F.; white blood count was 13,000 with 65 to 80 per cent polymorphonuclears; blood urea nitrogen was 9 mg. per 100 cc. There was no evidence of significant impairment in renal function. The urine was observed to contain sugar 1 to 2+, protein 1 to 2+, clumps of pus cells and white blood cells, no casts, an occasional red cell, specific gravity 1.010-1.018. Treatment: Fliuds 2500 to 3500 cc. daily; sulfadiazine 1 gm. three times a day. Four days after therapy was instituted pus cells and white blood cells in the urine were reduced to 0 to 2 per high-power field. There were no casts, no red cells. Protein was 0, sugar±. These findings remained constant during the next 8 days. The treatment was discontinued at the end of a total of 12 days. The patient was then discharged from the hospital. 0
0
Recurrence of urinary tract infections in such patients occurs frequently. There is still considerable debate as to the therapeutic management of such cases after the initial infection has cleared. Two courses are open: 1. Continued administration of small doses of sulfadiazine as a prophylactic measure. 2. Withdrawal of treatment after evidence of acute infection has subsided, with the administration of a therapeutic agent with recurrence of infection. The strongest argument against continued administration of small doses of a sulfonamide as a prophylactic measure is the possibility of developing a strain of "drug-fast" organisms. In urinary tract infections which are resistant to sulfonamide therapy or as an alternate method of therapy, mandelic acid treatment5 should be considered. This form of therapy is not effective against certain genera of proteus, Bacillus pyocyaneus and other urea-splitting organisms, since the ammonia so formed from urea breakdown as the result of bacterial action prevents the urine from becoming sufficiently acid to permit the bacteriostatic action of mandelic acid. Calcium mandelate or mandelic acid should be given in quantities sufficient to attain a concentration of 0.5 to 1.0 per cent in the urine. The hydrogen ion concentration of the urine should be maintained below 5.5 (red to methyl red indicator). Example: In the presence of a urine volume of 1000 cc. daily 10 gm. of calcium mandelate must be given daily to attain a concentration of 1 per cent in the urine. In most instances fluid intake is restricted to approximately 1500 cc. daily. Calcium mandelate tablets are given in a dose of 3 gm. four times a day (a total daily dose of 12 gm.). Treatment should be continued for 10
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1185
to 12 days and then discontinued. Treatment should not be reinstituted before the expiration of a 2 weeks' interval. Note: Patients with renal insufficiency (azotemia) should not be treated with acid salts (ammonium chloride and mandelic acid). TREATMENT OF TUBERCULOSIS OF THE KIDNEY
Nephrectomy is desirable in patients with unilateral active renal tuberculosis. Under these conditions it is important that such patients receive the equivalent of sanatorium care prior to and following operation. The possibility of latent adrenal insufficiency should be considered in all patients with urogenital tuberculosis. 6 Adrenal cortical hormone therapy should be available during and following operation. TREATMENT OF ACUTE GLOMERULONEPHRITIS
Patients with acute glomerulonephritis who continue to have positive throat cultures for beta hemolytic streptococci may be benefited by the use of sulfonamide therapy.2 Because of the possibility of renal complications which might arise from sulfonamide therapy the use of penicillin in such patients should be seriously considered. Illustration Patient M. K., P.B.B.H. Med. No. 65,806, male, aged 21. Diagnosis: Mild glomerulonephritis with persistent positive throat culture for beta hemolytic streptococcus. Present Illness: Eight days prior to entry the patient had a severe sore throat. Beta hemolytic streptococci were cultured from the throat. Five days before entry the sore throat had markedly cleared, but the patient had general malaise. Three days before admission the patient noted pain in his back. Examination: On admission blood pressure was 130/85 mm. of mercury, temperature 99.6 F. and pulse rate 96. There was slight generalized edema. The throat was injected and the heart slightly enlarged. Urinalysis revealed 1+ protein, 5 to 75 red blood cells per high power field, 2 to 10 white blood cells per highpower field and an occasional granular cast. Treatment: Because beta hemolytic streptococci· persisted in cultures of the throat sulfadiazine was given 6 gm. daily for 5 days and then 3 gm. daily. Three to 6 gm. daily of sodium bicarbonate was administered in conjunction with this. On the eleventh hospital day the urine was free of protein and formed elements. The patient was discharged from the hospital on the twenty-fourth hospital day. 0
An urgent consideration in the treatment of patients with acute glomerulonephritis is the need for rapid digitalization in the presence of impending heart failure. Four per cent1 of the patients with acute glomerulonephritis die from heart failure. In many instances the possibility of heart faiulre is not fully appreciated in this disease. The use of digitalis therapy, oxygen, aminophylline and venesection in the presence of high venous pressure would appear to be rational treatment of cardiac dilatation and congestive failure (Table 1: Type IX).
1186
GEORGE W. THORN, FRANK H. TYLER TREATMENT OF THE NEPHROTIC SYNDROME
Suggestions for the treatment of patients with the nephrotic syndrome are outlined in Table 1: Types I, 11 and Ill. The use of plasma or albumin solutions for their diuretic effect is illustrated in Figs. 94 and 95. The possible value of continued administration of parenteral protein solutions over long periods of time is illustrated in the treatment of patient B.B. (Fig. 95). Unfortunately, at the present time the supply of albumin available for civilian use is very limited. It should be pointed out that there is no doubt that human albumin given intravenously to patients with the nephrotic syndrome is an excellent physiological diuretic agent especially if a preparation of human albumin low in sodium chloride is employed. There is no proof to date, however, that the continued administration of albumin intravenously has any effect on the course of the disease. 7 One of the safest and most effective diuretics for use in patients with the nephrotic syndrome without edema is urea. The effectiveness of treatment with this agent is illustrated in Fig. 93. When urea is not well tolerated it is best discontinued, since the induction of nausea and vomiting coincidental with its administration offsets greatly the value of urea therapy by reducing the dietary protein intake. It is difficult for many patients with the nephrotic syndrome to ingest a diet of high-protein content (2 to 3 gm. per kg. of body weight). Under these circumstances supplementary amino acid solution by mouth may provide a very effective means of maintaining nitrogen balance. Twenty to 60 gm. of amino acid may be taken daily by most patients with little discomfort. TREATMENT OF RENAL INSUFFICIENCY ASSOCIATED WITH CHRONIC GLOMERULONEPHRITIS, CHRONIC PYELONEPHRITIS AND ARTERIOLAR NEPHROSCLEROSIS
The majority of patients with these disorders exhibit high-grade renal insufficiency and azotemia. In the absence of active infection and in the absence of indications for surgical intervention, therapy is indicated largely by the physiological needs required to correct the underlying chemical and metabolic disturbances. Suggestions for the treatment of patients with high-grade renal insufficiency are summarized in Table 1: Types IV, V, VI and VII. Patients with azotemia without hypertension may be rehabilitated for periods of months to years despite high-grade renal insufficiency (Table 1: Types IV and V). Illustration
Patient J. T., P.B.B.H. Med. No. 63,653, male, aged 53. Diagnosis: Pyelonephritis with azotemia and acidosis. Examination: There was considerable cardiac enlargement without edema or anemia with high-grade azotemia and moderate acidosis. Blood pressure ranged from 165/100 to 185/110 mm. of mercury. Urinalysis revealed a maximum concentration of 1.012, protein 1+, many red blood cells and leukocytes in the sediment.
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1187
Treatment: The patient was given a fluid intake of 3000 to 4000 cc. per day and 1 gm. of protein per kg. of body weight. Sodium chloride content of the diet was not restricted. The diet, however, was alkaline ash, and aluminum hydroxide (8 cc.) was added to each glass of milk. In addition a daily injection of 50 cc. of 20 per cent glucose was given intravenously for 7 days. On this regimen the blood urea nitrogen fell from 78 to a level of 27 mg. per 100 cc. The serum carbon dioxide combining power increased from 10.2 to 23.4 milli11101s per liter. On this regimen the patient was able to return to work. Because of a gradual reduction in serum chloride level the patient was given 2 to 3 gm. of added sodium chloride and 3 gm. of sodium bicarbonate. Increasing the dose of sodium chloride or bicarbonate above this quantity resulted in edema fonnation. Reducing the sodium chloride below this level resulted in an increase in azotemia. SUMMARY AND CONCLUSIONS
In the absence of active infection and in the absence of indications for surgical intervention, therapy for patients with renal malfunction is dictated largely by the physiological needs required to correct the underlying chemical and metabolic disturbances. The disorders which commonly attend renal malfunction are as follows: Edema and hypoalbuminemia Anemia Anorexia, nausea and vomiting Azotemia and acidosis Hypertension and heart failure In the care and treatment of patients with kidney disease one should have available facilities for determining blood urea nitrogen or nonprotein nitrogen, total serum protein concentration, serum chloride and carbon dioxide combining power. It is also desirable from time to time to obtain accurate measurement of heart size with teleroentgenograms. Practically all that can be accomplished in correcting the metabolic disturbances associated with renal malfunction can be accomplished by the judicious use of relatively simple agents, I.e.: Water Minerals-NaCl, NaHC0 3 , Na lactate and Al(OHh Urea Glucose solutions Solutions containing protein-plasma, albumin and whole blood A diet containing the basic nutritional requirements for health Fundamental considerations in the treatment of patients with kidney disease have been presented, and an outline of therapy has been suggested. No attempt has been made to suggest forms of therapy for all conditions which result in renal malfunction. BIBLIOGRAPHY
1. EIlis, Arthur: Natural History of Bright's Disease-Clinical, Histological and Experimental Observations. Lancet, 1:1, 34, 72, 1942. 2. Williams, Robert H., Longcope, Warfield T. and ]aneway, Charles A.: The
Use of Sulfanilamide in the Treannent of Acute Glomerular Nephritis. Am. ]. M. Sc., 203:157, 1942.
1188
GEORGE W. THORN, FRANK H. TYLER
3. Thorn, George W.: Physiologic Considerations in the Treatment of Nephritis. New England J. Med. 229:33, 1943. 4. Longcope, Warfield T.: Unpublished data. 5. Helmholz, H. F.: A Comparison of the Bactericidal Effects of Sulfathiazole and Organic Acids in Urine Inoculated with Huge Numbers of Bacteria. Proc. Staff Meet., Mayo Clin., 18:481, 1943. 6. Thorn, George W., Dorrance, Samuel S. and Day, Emerson: Addison's Disease: Evaluation of Synthetic Desoxycorticosterone Acetate Therapy in 158 Patients. Ann. Int. Med., 16:1053, 1942. 7. ]aneway, c. A., Gibson, S. T., Woodruff, L. M., Heyl, ]. T., Bailey, O. T. and Newhouser, L. R.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. VII. Concentrated Human Serum Albumin. Part Ill. Albumin in the Treatment of Hypoproteinemia . .J. Clin. Investigation, 23:478, 1944.
GEORGE W. THORN, M.D., F.A.C.P.* and FRANK H. TYLER, M.D.t RENAL malfunction is characterized by excessive excretion or retention of normal constituents of the blood. Evidence of renal malfunction is usually manifested by the presence of protein, casts or cellular elements in the urine and by impaired performance of standardized tests of renal function. For purposes of discussion the principal causes of kidney disease may be grouped as follows: 1. Infections of the Kidney
2. 3. 4. 5.
Pyelonephritis, pyonephrosis, cortical abscesses and perinephric inflammation "Allergic" Disorders of the Kidney Acute and chronic glomerulonephritis including the nephrotic syndrome, disseminated lupus erythematosus and polyarteritis Disturbances in Renal Circulation Arteriolar nephrosclerosis, heart failure, arterial and venous obstruction Renal Injury from Chemical and Metabolic Agents Mercury, bismuth, sulfonamides and gout Malformations (congenital or acquired) of the kidney Hypoplasia, polycystic disease, tumors and aberrant vessels GENERAL CONSIDERATIONS
Infections of the Kidney.-The recognition of infections of the kid-
ney and the institution of appropriate medical and surgical measures may prevent progressive and widespread destruction of kidney substance in many patients. The use of the sulfonamides, penicillin and mandelic acid represents a great advance in specific therapy. Acute Glomerulonephritis.-There is no specific therapy for patients with acute glomerulonephritis. Fortunately more than 85 per cent of patients suffering from this disease recover completely.1 The number of recoveries may be increased appreciably by intelligent and diligent medical care. There is some evidence to suggest that patients who continue to have positive throat cultures for beta hemolytic streptococci are benefited by the use of sulfonamide therapy.2 Disturbances in Renal Circulation.-In patients with renal insufficiency r~sulting from vascular disease there remains a great field for From the Department of Medicine, Harvard Medical School, ;md the Medical Clinic of the Peter Bent Brigham Hospital. The authors wish to acknowledg\! the assistance of Miss Janet E. Clark, nurse-in-charge of the metabolism unit, and Miss Marion J. Brian, dietitian-in-charge. • Hersey Professor of the Theory and Practice of Physic, Harvard Medical School; Physician-in-Chief, Peter Bent Brigham Hospital. t Research Fellow in Medicine, Harvard Medical School; Resident Physician, Peter Bent Brigham Hospital. 1173
1174
GEORGE W. THORN, FRANK H. TYLER TABLE I.-THERAPEUTIC MAN
TREATMENT
EDEMA I III Il Edema Edema Edema Hypoalbumin- Hypoalbumin- Hypoalbuminemia emia emia Hypertension Hypertension Heart failure
Total Fluids .. ....... 1500 cc. daily
Diet ...
Protein
2-3 gm./kg. daily
NaCI
Salt free
Ash
Acid
IV Azotemia
1000-1500 cc. 4000 cc. daily milk daily for 2-5 days; no 1 gm./kg. daily 1-2 gm./kg. additional daily fluid or food No restriction; Salt free 1-3 gm. daily supplement§
1500 cc. daily
Alkaline
Acid
Plasma or 25-50 gm. LV. 10-15 gm. I.V. albumin'" daily b.i.d. Ureat
Diu-
relics
30-60 gm. daily 30-60 gm. daily 30 gm. daily
Glucose
1000 cc. 5% LV. daily 3-7 days
Digitalis
Digi talizationt
Aminophylline
0.1 gm. I.V. O.i.d.
In the presence In the presence In the presence Oxygen. of nausea and nausea Paracentesis. anemia of of and vomitipg gluwhole blood and vomit- Fluids protein solucose solution ing glucose transfusions are indicated. solution 500 tions should 3000 cc. 10% I.V., sodium not be given cc. 10% I.V. ,
.
'" The products of plasma fractionation employed in this work were deveJoped from blood collected by the American Red Cross by the Department of Physical Chemistry, Harvard Medical School, Boston, Massachusetts, under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Develop· ment and Harvard University. Albumin will not be available for general clinical use during the war because of the needs of the armed forces. t Urea may be given in fruit juice. If anorexia or nausea occurs, the dose of urea should be reduced or discontinued.
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1175
AGEMENT OF KIDNEY DISEASE
EDEMA
AZOTEMIA
V Azotemia Acidosis
4000 cc. daily 1 gm./kg. daily No restriction; 1-3 gm. daily supplement§
VI Azotemia Acidosis Hypertension
VII Edema Azotemia Acidosis Hypertension
AND AZOTEMIA
VIII Edema Hypoalbuminemia Azotemia Hypertension
IX Edema Azotemia Acidosis Heart Failure
1000 cc. milk daily with aluminum hydroxide ad1 gm./kg. daily 1 gm./kg. daily 1 gm./kg. daily ded\\; 500-1000 cc. fruit juice No restriction Salt free Salt free 3000 cc. daily
2000 cc. daily
2000 cc. daily
Alkaline; 3-6 Alkaline Alkaline; 3-6 gm. NaHCO. gm. NaHCO, daily daily
Alkaline
10 gm. b.i.d.
LV. 15 gm. b.i.d.
LV.
1000 cc. 5% I.V. SO cc. 20% LV. daily 3-7 days daily 3-7 days
See footnote'if Digi talizationt 0.1 gm. h.i.d.
The contents of In the presence one SO cc. am- of nausea and pule of sodium vomiting glulactate (11%) cose solution may be added 10% LV. slowto the above ly not to exinfusion daily ceed 1000 cc. for 3-7 days in q. 8 hrs., 500 place of sodi- cc. 0.85% urn lactate by NaCI q. 3rd mouth. day in absence of edema may be substituted for above.
l.V. 0.1 gm. b.Ld.
LV. 0.1 gm. I.V. b.Ld.
In the presence of nausea and vomiting glucose solution 750 cc. 10% I.V. q. 8 hrs., or albumin plasma 8 gm. LV. q. 8 hrs. may be subfor stituted above.
Oxygen. Paracentesis. in Venesection presence of high venous pressure. Fluids and protein solutions should not be given intravenously.
fIn the absence.of previous digitalis therapy, 3 cat units intramuscularly and 2 cat units intravenously may be given. § Enteric-coated sodium chloride tablets (1 gm. each). \\ Eight to 16 cc. of aluminum hydroxide may be added to each glass of milk. 'if If azotemia persists and cardiac status improves, SO cc. of 10 per cent glucose may be given intravenously very slowly once or twice a day.
1176
GEORGE W. THORN, FRANK H. TYLER
therapeutic progress. At present therapy is limited to the treatment of congestive heart failure and attempts to lower blood pressure by medical and surgical methods. Renal Insufficiency from Chemical and Metabolic Agents.-The widespread use of chemotherapeutic agents undoubtedly will increase the occurrence of renal disease. Here the problem is largely one of prophylaxis, since the incidence of renal insufficiency can be greatly reduced if precautions are taken to ensure an adequate urine volume. Malformations of the Kidney.-In hypoplasia and cystic disease of the kidney little can be done other than to prevent secondary infection. In the presence of renal stasis resulting from calculus, an aberrant vessel or tumor, surgery may be effective in improving kidney function or in preventing further damage. It is apparent from these considerations that the elimination of the agent responsible for renal damage is not possible in most patients with kidney disease. Hence treatment must be concerned largely with the application of measures designed to preserve nephrons and prevent development of gross chemical and metabolic abnormalities. It is not generally appreciated that a useful life including moderate activity may be carried on for many years despite the reduced functioning kidney mass. This is particularly true of patients with renal insufficiency without hypertension. THERAPEUTIC CONSIDERATIONS
I. Water Requirement Principles: A. In the absence of circulatory failure water will not be retained in the body in significant quantity without the concomitant retention of sodium; hence in patients with "renal" edema there is little justification for the restriction of fluids on a salt-free regimen. B. A large urine volume is advantageous in the presence of azotemia. In patients with edema without azotemia (nephrotic syndrome) a daily fluid intake of 1500 cc. is usually adequate (Table 1: Types I and 11). The quantity of fluid may be reduced if the patient so desires. In the presence of azotemia without edema (chronic glomerulonephritis, arteriolar nephrosclerosis, chronic pyelonephritis) it is distinctly advantageous to increase the 24-hour urine volume to 20003000 cc. This usually requires the administration of approximately 4000 cc. of fluid daily (Table 1: Types IV, V and V.I). Under these circumstances, however, essential as well as nonessential substances may be "washed out;" hence the need for replenishing the former. In patients with azotemia and edema it is obvious that some compromise in fluid intake is necessary; thus in the absence of cardiac failure 2000 cc. fluid intake is suggested (Table 1: Types VII and VIII).
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1177
In the presence of infections of the kidney a large output of urine is to be desired. When the volume of urine is increased in the treatment of pyuria the dose of chemotherapeutic substance may need to be increased to provide an adequate concentration of bacteriostatic agent in the urine. Edema and dehydration are frequent complications of renal malfunction; hence the necessity for a study of "water balance" frequently arises. Unfortunately, to most physicians the term "water balance" implies only measurement of fluid intake and urine output. TABLE 2.-DETERMINATION OF WATER BALANCE
Intake 1. Liquids: Measure fluid intake directly. 2. Water content of solid food: Calculate by weighing aliquot of day's diet before and after drying or by consulting tables for average water content of foods. 3. Water of oxidation: 1 gm. protein = 0.4 gm. water 1 gm. carbohydrate = 0.6 gm. water 1 gm. fat = 1.0 gm. water Output 1. Urine: Measure urine volume. 2. Feces: Determine wet and dry weight of feces. 3. Insensible water loss and perspiration: Weigh patient at 9:00 p.m. and again at 9:00 a.m. under standard conditions with. out food or fluid intake in the interim. 4. Abnormal water losses: Saliva, sputum, draining fistulae, etc. measure directly. Example Diet: Carbohydrate 220 gm., protein 70 gm., fat 120 gm. Fluid intake. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1500 cc. Water content of food. . . . .. . .... . . . . .. . . . . .. . .. 600 cc. Water of oxidation ....................... , . . . .. 280 cc.
2380 cc.
Urine volume ................................ . 1200 cc. Water content of feces ......................... . 250 cc. Insensible water loss and perspiration (465 X 2) .. . 930 cc. Abnormal loss ................................ . o cc.
2380 cc.
This may lead to erroneous conclusions (Table 2), since it is apparent that the water content of solid foods (average 500 to 700 cc. per day) is quite appreciable and is frequently overlooked as a source of water. Furthermore, the water loss through ventilation, evaporation and perspiration may be quite considerable. Fortunately, there are reliable clinical signs of changes in water balance, namely changes in body weight, presence of edema, dry skin, dry tongue, enophtlialmos and oliguria which make the more elaborate measurements of water balance unnecessary for routine clinical treatment. Unfortunately, the
1178
GEORGE W. THORN, FRANK H. TYLER
presence of oliguria, a most helpful method of detecting dehydration in most circumstances, cannot be relied upon in patients with nephritis. Parenteral administration of fluids and nutritive substances must be employed in patients with renal insufficiency who are unable to retain fluids and food by mouth. Fluid absorption by rectum is rarely sufficient to meet daily body requirements. The absorption of nutritive substances from the rectum is unpredictable. In the presence of nausea and vomiting it may be stated that the minimum body requirements are as follows: Water ..................... 2500 cc. daily Calories ................... 1200 daily Protein .................... 25-50 gm. daily
For parenteral fluid administration one is limited to the use of solutions of glucose, saline, protein or amino acids. Since in most instances protein administered parenterally will supply less than 200 calories per day (i.e., 25-50 gm. X 4 calories per gm.) it is apparent that most of the caloric requirement must of necessity be derived from glucose solutions. Two hundred and fifty grams of glucose is needed to provide 1000 calories (250 gm. X 4 calories per gm.), and therefore the administration of 2500 cc. of 10 per cent glucose daily will provide both fluid and minimum caloric requirement. Continued use of parenteral glucose solutions, however, may result in a striking fall in the serum level of sodium and chloride, and the possible need for supplementary sodium chloride therapy during periods of active diuresis induced by glucose solutions must always be kept in mind (Table 1: Types IV, V and VI). 11. Dietary Management Principles: Patients with nephritis should be provided with basic dietary requirement necessary for health: Water sufficient to provide a urine volume large enough to permit excretion of endproducts of metabolism; calories sufficient to maintain weight; protein sufficient to meet the body needs (1 gm. per kg. per day for adults) and to compe.nsate for abnormal losses in the urine; essential minerals and vitamins. Protein Content of Diet.-Patients with disease of the kidneys frequently are deficient in protein. In the absence of azotemia high-protein diets are indicated, i.e., 2 to 3 gm. of protein per kilogram of body weight per day. High-protein intake is of advantage in the treatment" of patients with edema without azotemia for the following reasons: (1) improved nitrogen balance, (2) increased urea excretion (diuretic), (3) increased renal blood flow and (4) acid ash (diuretic).
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1179
In the presence of azotemia protein intake may be restricted to the basic ,requirement of 1 gm. per kilogram of body weight per day. Plasma and albumin solutions recommended in the treatment of edema are useful sources of protein, but their prime function when given intravenously in quantities now available is their diuretic action. Patients who are nauseated and who are unable to retain food for more than 2 or 3 days may be given amino acid solution, plasma, albumin or blood parenterally at regular intervals as a source of required dietary protein. It should be borne in mind that it is practically impossible to induce a positive nitrogen balance by parenteral protein or amino acid therapy alone! TABLE 3.-APPROXIMATE CAJ.CULATIONS FOR ACID-BASE CONTENT OF DIET*
Grams
--
Vegetablest ....... , . , '" ... , , Fruit§ .............. ' . , .... , . Meat, fish, poultry II........... Eggs .................. , ..... Cereal~ ..................... Bread ......... : .......... , . , Milk ........................ Milk .... , ................... Milk ...... . ............... Cheese ...................... Potato .... , ............. , ... Macaroni, noodles, rice and spaghetti~ ..........•...... Cornstarch or tapioca pudding .. Rice pudding ................. Raked custard ................ Plain cake .... , ..............
100 100 100 100 180 30 120 180 240 20 100 150 100 100 60
Household Measure
Excess Acidt
t cup 3i oz. 2
cup .1 slice 2
t cup
10.5 11.0 3.2 2.0
! cup
1 cup
I" cube ! cup
1.1
i cup t cup
3.1
t cup
0.1 2.5
Excess Baset
6.2 5,1
2.1 3.2
4."
7.0 1.5 1.3
* Chaney, Margaret S., and Ahlborn, Margaret: Nutrition. Boston, Houghton Miffiin Company, 1939, pp. 386-409. t Expressed as cc. normal solution required to neutralize the ash. t Average does not include spinach and dandelion greens (excess base 27.0) or corn (excess acid 1.8). § Average does not include prunes, plums and cranberries which are excess acid foods. II Average does not include oysters (excess acid 15.2). ~ Cooked weight.
Sodium Chloride Content of Diet.-Patients wth edema should be given a salt-free diet (Table 1: Types I, II, Ill, VII, VIII and IX). Patients with azotemia without edema (Table 1: Types IV and V) will 'frequently be benefited by the administration of supplementary sodium chloride 3 to 5 gm. daily. In the presence of marked hypertension supplementary sodium chloride must be given very cautiously (Table 1: Type VI). Patients with azotemia and acidosis will do well to have part of their supplementary sodium given as sodium bicarbonate (Table 1: Types V and VI). For example: Instead of 5 gm. of
1180
GEORGE W. THORN, FRANK H. TYLER
sodium chloride, 2 to 3 gm. of sodium chloride and 5 to 6 gm. of sodium bicarbonate (sodium content of sodium bicarbonate is approximately one-half that of sodium chloride) may be given. In chronic renal insufficiency with a large fluid intake and output it is possible to "wash out" excessive quantities of sodium and chloride with disastrous results; hence the need of replacement therapy. Ash of the Diet.-In the presence of edema without azotemia or acidosis (nephrotic syndrome) (Table 1: Types I and II) an acidash diet may be of some aid in promoting diuresis. Furthermore, since the ideal diet for such patients is one containing a large quantity of protein, the ash will most certainly be acid. A problem is presented in the treatment of patients with azotemia and acidosis (Table 1: Types V, VI and VII). In this situation the kidneys are unable to conserve base, since the ability to form ammonia from urea is greatly reduced. Sodium and other fixed bases are drawn from the body and excreted to assist in neutralizing acid end-products. Decreasing the acid ash residue of the diet by ingesting a diet of neutral or alkalineash composition may be helpful (Table 3). Aluminum hydroxide may also be added to milk or taken with food. By so doing a great reduction in phosphorus (fixed acid) absorption can be demonstrated and the relative alkalinity of milk can be greatly increased. s Supplementary sodium bicarbonate therapy may be given to patients with renal acidosis without edema. The water retaining effect of sodium bicarbonate is equivalent to approximately one-half to one-third that of sodium chloride, i.e., 2 to 3 gm. of sodium bicarbonate is equivalent to 1 gm. of sodium chloride. In patients without edema with renal acidosis, nausea and vomiting, sodium lactate or sodium bicarbonate may be given intravenously. One 50-cc. ampule of sodium lactate (11 per cent) may be added to the glucose solution and given once or twice a day until a satisfactory increase in carbon dioxide combining power has been attained (Table 1: Type V). Ill. Diuretics
Principles: There are two indications for increasing urine output in patients with renal malfunction, (1) edema and (2) azotemia. In patients with kidney disease one can scarcely justify the use of diuretics which depend for their action on an irritative or toxic effect on the renal tubules. It would appear more rational to employ agents which act by increasing plasma volume and renal circulation, i.e., protein solutions intravenously, glucose solutions intravenously, urea and. possibly xanthine derivatives. The presence of circulatory failure, however, is a contraindication to the use of substances which depend for their action on a relatively large increase in plasma volume.
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1181
Edema.-Edema is usually related to hypoalbuminemia and is most commonly observed in the nephrotic syndrome (Table 1: Types I and II). Salt restriction is indicated under these circumstances. Administration of urea may be quite effective in many cases (Fig. 93). It may require 10 to 20 days of urea therapy (30 to 60 gm. daily) before the diuretic action of this substance is manifested. Fluid intake should be limited to 1000 to 1500 cc. daily during the period of urea administration, and blood nonprotein nitrogen determinations should be made at 5 to 7 day intervals. Little effect of urea as a diuretic can be expected unless the administration of urea results in an elevation of blood urea nitrogen. It is obvious, however, that the mechanism re-
100
EFFECT Or: UREA TI-JERAPY £O£MA .~Neph,-ot!c.
Patient I'i.M. ~
55
Body
Wei~ht
I'\~
J.I YPOPROTE/N£MIA
Synd..-ome
50
45
40
i~~ ~f------------~-~'/---------'-v/----l Urea (\m
daily 10
20
30
40
50
100
70
80
90
100
liD
120
Fig. 93.
sponsible for edema in these patients is largely hypoalbuminemia, and hence a diet high in protein and particularly frequent intravenous administration of protein solutions are definitely indicated. A daily dose of 25 to 50 gm. of human albumin is also an excellent physiological diuretic (Figs. 94 and 95). The use of infusions of sufficient quantities of albumin for purposes of diuresis should be clearly differentiated from attempts to induce a positive nitrogen balance with parenteral protein therapy. The latter is almost impossible to obtain unless massive therapy is attempted. Unfortunately, at present human albumin is not available for civilian use. Plasma solutions, therefore, will have to be substituted until adequate quantities of human albumin are made availahle. It is ohvious that 1 gm. of plasma protein does not
1182
GEORGE W. THORN, FRANK H. TYLER
(;FFE:CT 01= INTRAVI;NOUS ALBUMIN ON URINE: OUTPUT Patient
J. G. 9
Nephmtic Syndmme
EOEMA
J./VPOPJ
Unne
Volume cc
"Of'
Body Weilfht
91.0
90.0
K~.
890
._---
Con,tanl _._--"'~-----.""
, "'...
e-----e--
_--------.--
__ ....
880
i-Juman Albumin ~m.
DAYS
2
4
?>
5
7
8
10
Fig. 94.
Patient B.B.
Nephrot~'
Syndr-ome
1201,---~~-~-~---~~---~-----,
110~----.
......---- ..,
Body 100
Weight k~.
,,
,, ,,
..""
90
80
" " -......
......
10 I?<
....- - - - •• - - -e
~uma.n 50
Albumin ~m.
day!:>
19
24
13
1B
2B
1 teb.
Fig. 95.-Changes in body weight and edema following the long-continued intravenous administration of human albumin in nephrotic syndrome. (From Thorn, G. W., New England J. Med., 1943.)
SUGGESTIONS FOR THE TREATMENT OF KIDNEY DISEASE
1183
exert as potent a colloid osmotic effect as 1 gm. of albumin. As a diuretic agent for patients with edema it is extremely important to point out that human albumin can be prepared with it low sodium chloride content. In the treatment of edema such a preparation would have a great advantage over plasma solutions which contain rather appreciable quantities of sodium chloride (Table 1: Types I and 11). Azotemia.-Patients with azotemia without significant hypoalbuminemia will usually have a diuresis following the administration of large quantities of fluid by mouth (Table 1: Types IV, V and VI). In marked azotemia, however, it is many times helpful to give 3 to 7 days' treatment of 1000 cc. of 5 per cent glucose intravenously in conjunction with a large fluid intake. In the absence of edema it is desirable to give some supplementary sodum chloride during this period of therapy, e.g., 1 to 3 gm. daily. In acute nephritis with striking edema and azotemia there is usually moderate reduction in serum albumin level4 and an increase in blood nonprotein nitrogen. It is obvious that the reduction in colloid osmotic pressure is not sufficient to explain the edema in most patients. Protein solutions administered intravenously to patients with acute nephritis do not have as striking a diuretic effect as in patients with the nephrotic syndrome and marked hypoalbuminemia. Furthermore, great care must be exercised in the administration of protein solutions to patients with acute nephritis and edema in order to prevent cardiac dilatation following a sudden increase in plasma volume. Fluids by mouth or intravenously are not as effective in reducing azotemia as is the case in azotemia due to chronic nephritis. The treatment of oliguria and azotemia in patients with acute nephritis with nausea and vomiting requires considerable skill and judgment in the use of small quantities of protein solution intravenously in conjunction with glucose solution. Serum chloride levels and carbon dioxide combining power must be followed carefully, as occasionally a striking degree of hypochloremia may develop even in the presence of edema (Table 1: Type VIII). TREATMENT OF PYELONEPHRITIS (INCLUDING PYELITIS)
Since infections of the kidney are so frequently secondary to stasis, it is extremely important to study each patient for the presence of hydronephrosis, renal calculus, prostatic hypertrophy and anomalies of the urogenital tract. Fluid intake should average 2500 to 3000 cc. daily. The sulfonamide drugs are the most effective agents available at present for the treatment of urinary tract infection. To date sulfathiazole and sulfadiazine have been shown to be effective against Escherichia coli, Aerobacter aerogenes, Bacillus pyocyaneus, proteus, enterococcus, staphylococcus and beta hemolytic streptococcus (Groups A and D). Frequently doses of sui fa diazine as small as 0.5 gm. three times a day are adequate. This low dosage, i.e., 1.5 gm. daily, is in-
1184
GEORGE W. THORN, FRANK H. TYLER
dicated particularly in patients with infections of the kidney with renal insufficiency. The possibility of renal damage from sulfonamide therapy must be kept in mind. Illustration Patient N. S., P.B.B.H. Med. No. 66,182, male, aged 68. Diagnosis: Bilateral pyelonephritis (E. coli). Complication: Diabetes mellitus. Examination: Blood pressure was 140/70 mm. of mercury; temperature ranged between 98.6 and 101 F.; white blood count was 13,000 with 65 to 80 per cent polymorphonuclears; blood urea nitrogen was 9 mg. per 100 cc. There was no evidence of significant impairment in renal function. The urine was observed to contain sugar 1 to 2+, protein 1 to 2+, clumps of pus cells and white blood cells, no casts, an occasional red cell, specific gravity 1.010-1.018. Treatment: Fliuds 2500 to 3500 cc. daily; sulfadiazine 1 gm. three times a day. Four days after therapy was instituted pus cells and white blood cells in the urine were reduced to 0 to 2 per high-power field. There were no casts, no red cells. Protein was 0, sugar±. These findings remained constant during the next 8 days. The treatment was discontinued at the end of a total of 12 days. The patient was then discharged from the hospital. 0
0
Recurrence of urinary tract infections in such patients occurs frequently. There is still considerable debate as to the therapeutic management of such cases after the initial infection has cleared. Two courses are open: 1. Continued administration of small doses of sulfadiazine as a prophylactic measure. 2. Withdrawal of treatment after evidence of acute infection has subsided, with the administration of a therapeutic agent with recurrence of infection. The strongest argument against continued administration of small doses of a sulfonamide as a prophylactic measure is the possibility of developing a strain of "drug-fast" organisms. In urinary tract infections which are resistant to sulfonamide therapy or as an alternate method of therapy, mandelic acid treatment5 should be considered. This form of therapy is not effective against certain genera of proteus, Bacillus pyocyaneus and other urea-splitting organisms, since the ammonia so formed from urea breakdown as the result of bacterial action prevents the urine from becoming sufficiently acid to permit the bacteriostatic action of mandelic acid. Calcium mandelate or mandelic acid should be given in quantities sufficient to attain a concentration of 0.5 to 1.0 per cent in the urine. The hydrogen ion concentration of the urine should be maintained below 5.5 (red to methyl red indicator). Example: In the presence of a urine volume of 1000 cc. daily 10 gm. of calcium mandelate must be given daily to attain a concentration of 1 per cent in the urine. In most instances fluid intake is restricted to approximately 1500 cc. daily. Calcium mandelate tablets are given in a dose of 3 gm. four times a day (a total daily dose of 12 gm.). Treatment should be continued for 10
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to 12 days and then discontinued. Treatment should not be reinstituted before the expiration of a 2 weeks' interval. Note: Patients with renal insufficiency (azotemia) should not be treated with acid salts (ammonium chloride and mandelic acid). TREATMENT OF TUBERCULOSIS OF THE KIDNEY
Nephrectomy is desirable in patients with unilateral active renal tuberculosis. Under these conditions it is important that such patients receive the equivalent of sanatorium care prior to and following operation. The possibility of latent adrenal insufficiency should be considered in all patients with urogenital tuberculosis. 6 Adrenal cortical hormone therapy should be available during and following operation. TREATMENT OF ACUTE GLOMERULONEPHRITIS
Patients with acute glomerulonephritis who continue to have positive throat cultures for beta hemolytic streptococci may be benefited by the use of sulfonamide therapy.2 Because of the possibility of renal complications which might arise from sulfonamide therapy the use of penicillin in such patients should be seriously considered. Illustration Patient M. K., P.B.B.H. Med. No. 65,806, male, aged 21. Diagnosis: Mild glomerulonephritis with persistent positive throat culture for beta hemolytic streptococcus. Present Illness: Eight days prior to entry the patient had a severe sore throat. Beta hemolytic streptococci were cultured from the throat. Five days before entry the sore throat had markedly cleared, but the patient had general malaise. Three days before admission the patient noted pain in his back. Examination: On admission blood pressure was 130/85 mm. of mercury, temperature 99.6 F. and pulse rate 96. There was slight generalized edema. The throat was injected and the heart slightly enlarged. Urinalysis revealed 1+ protein, 5 to 75 red blood cells per high power field, 2 to 10 white blood cells per highpower field and an occasional granular cast. Treatment: Because beta hemolytic streptococci· persisted in cultures of the throat sulfadiazine was given 6 gm. daily for 5 days and then 3 gm. daily. Three to 6 gm. daily of sodium bicarbonate was administered in conjunction with this. On the eleventh hospital day the urine was free of protein and formed elements. The patient was discharged from the hospital on the twenty-fourth hospital day. 0
An urgent consideration in the treatment of patients with acute glomerulonephritis is the need for rapid digitalization in the presence of impending heart failure. Four per cent1 of the patients with acute glomerulonephritis die from heart failure. In many instances the possibility of heart faiulre is not fully appreciated in this disease. The use of digitalis therapy, oxygen, aminophylline and venesection in the presence of high venous pressure would appear to be rational treatment of cardiac dilatation and congestive failure (Table 1: Type IX).
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GEORGE W. THORN, FRANK H. TYLER TREATMENT OF THE NEPHROTIC SYNDROME
Suggestions for the treatment of patients with the nephrotic syndrome are outlined in Table 1: Types I, 11 and Ill. The use of plasma or albumin solutions for their diuretic effect is illustrated in Figs. 94 and 95. The possible value of continued administration of parenteral protein solutions over long periods of time is illustrated in the treatment of patient B.B. (Fig. 95). Unfortunately, at the present time the supply of albumin available for civilian use is very limited. It should be pointed out that there is no doubt that human albumin given intravenously to patients with the nephrotic syndrome is an excellent physiological diuretic agent especially if a preparation of human albumin low in sodium chloride is employed. There is no proof to date, however, that the continued administration of albumin intravenously has any effect on the course of the disease. 7 One of the safest and most effective diuretics for use in patients with the nephrotic syndrome without edema is urea. The effectiveness of treatment with this agent is illustrated in Fig. 93. When urea is not well tolerated it is best discontinued, since the induction of nausea and vomiting coincidental with its administration offsets greatly the value of urea therapy by reducing the dietary protein intake. It is difficult for many patients with the nephrotic syndrome to ingest a diet of high-protein content (2 to 3 gm. per kg. of body weight). Under these circumstances supplementary amino acid solution by mouth may provide a very effective means of maintaining nitrogen balance. Twenty to 60 gm. of amino acid may be taken daily by most patients with little discomfort. TREATMENT OF RENAL INSUFFICIENCY ASSOCIATED WITH CHRONIC GLOMERULONEPHRITIS, CHRONIC PYELONEPHRITIS AND ARTERIOLAR NEPHROSCLEROSIS
The majority of patients with these disorders exhibit high-grade renal insufficiency and azotemia. In the absence of active infection and in the absence of indications for surgical intervention, therapy is indicated largely by the physiological needs required to correct the underlying chemical and metabolic disturbances. Suggestions for the treatment of patients with high-grade renal insufficiency are summarized in Table 1: Types IV, V, VI and VII. Patients with azotemia without hypertension may be rehabilitated for periods of months to years despite high-grade renal insufficiency (Table 1: Types IV and V). Illustration
Patient J. T., P.B.B.H. Med. No. 63,653, male, aged 53. Diagnosis: Pyelonephritis with azotemia and acidosis. Examination: There was considerable cardiac enlargement without edema or anemia with high-grade azotemia and moderate acidosis. Blood pressure ranged from 165/100 to 185/110 mm. of mercury. Urinalysis revealed a maximum concentration of 1.012, protein 1+, many red blood cells and leukocytes in the sediment.
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Treatment: The patient was given a fluid intake of 3000 to 4000 cc. per day and 1 gm. of protein per kg. of body weight. Sodium chloride content of the diet was not restricted. The diet, however, was alkaline ash, and aluminum hydroxide (8 cc.) was added to each glass of milk. In addition a daily injection of 50 cc. of 20 per cent glucose was given intravenously for 7 days. On this regimen the blood urea nitrogen fell from 78 to a level of 27 mg. per 100 cc. The serum carbon dioxide combining power increased from 10.2 to 23.4 milli11101s per liter. On this regimen the patient was able to return to work. Because of a gradual reduction in serum chloride level the patient was given 2 to 3 gm. of added sodium chloride and 3 gm. of sodium bicarbonate. Increasing the dose of sodium chloride or bicarbonate above this quantity resulted in edema fonnation. Reducing the sodium chloride below this level resulted in an increase in azotemia. SUMMARY AND CONCLUSIONS
In the absence of active infection and in the absence of indications for surgical intervention, therapy for patients with renal malfunction is dictated largely by the physiological needs required to correct the underlying chemical and metabolic disturbances. The disorders which commonly attend renal malfunction are as follows: Edema and hypoalbuminemia Anemia Anorexia, nausea and vomiting Azotemia and acidosis Hypertension and heart failure In the care and treatment of patients with kidney disease one should have available facilities for determining blood urea nitrogen or nonprotein nitrogen, total serum protein concentration, serum chloride and carbon dioxide combining power. It is also desirable from time to time to obtain accurate measurement of heart size with teleroentgenograms. Practically all that can be accomplished in correcting the metabolic disturbances associated with renal malfunction can be accomplished by the judicious use of relatively simple agents, I.e.: Water Minerals-NaCl, NaHC0 3 , Na lactate and Al(OHh Urea Glucose solutions Solutions containing protein-plasma, albumin and whole blood A diet containing the basic nutritional requirements for health Fundamental considerations in the treatment of patients with kidney disease have been presented, and an outline of therapy has been suggested. No attempt has been made to suggest forms of therapy for all conditions which result in renal malfunction. BIBLIOGRAPHY
1. EIlis, Arthur: Natural History of Bright's Disease-Clinical, Histological and Experimental Observations. Lancet, 1:1, 34, 72, 1942. 2. Williams, Robert H., Longcope, Warfield T. and ]aneway, Charles A.: The
Use of Sulfanilamide in the Treannent of Acute Glomerular Nephritis. Am. ]. M. Sc., 203:157, 1942.
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3. Thorn, George W.: Physiologic Considerations in the Treatment of Nephritis. New England J. Med. 229:33, 1943. 4. Longcope, Warfield T.: Unpublished data. 5. Helmholz, H. F.: A Comparison of the Bactericidal Effects of Sulfathiazole and Organic Acids in Urine Inoculated with Huge Numbers of Bacteria. Proc. Staff Meet., Mayo Clin., 18:481, 1943. 6. Thorn, George W., Dorrance, Samuel S. and Day, Emerson: Addison's Disease: Evaluation of Synthetic Desoxycorticosterone Acetate Therapy in 158 Patients. Ann. Int. Med., 16:1053, 1942. 7. ]aneway, c. A., Gibson, S. T., Woodruff, L. M., Heyl, ]. T., Bailey, O. T. and Newhouser, L. R.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. VII. Concentrated Human Serum Albumin. Part Ill. Albumin in the Treatment of Hypoproteinemia . .J. Clin. Investigation, 23:478, 1944.