Sodium wasting, acidosis and hyperkalemia induced by methicillin interstitial nephritis

Sodium Wasting, Acidosis and Hyperkalemia Induced by Methicillin Interstitial Nephritis Evidence for Selective Distal Tubular Dysfunction

MARTIN C. COGAN, M.D ALLEN I. ARIEFF, M.D. San Francisco, California

A 61 year old male patient was studied who manifested dehydration, azotemia, acidosis and hyperkalemia six weeks after exposure to methicillin. Thyroid and adrenal glucocorticoid and mineralocorticoid function were normal. The dehydration was found to be caused by a profound sodium-losing nephropathy; urinary sodium ranged from 76 to 101 meq/day during a salt restricted diet. A distal renal tubular acidosis and a quantitively impaired ability to excrete potassium were also found. These defects were relatively unresponsive to mineralocorticoid or prednisone therapy. A renal biopsy specimen showed an interstitial nephritis which selectively affected distal tubules and was thought to be secondary to methicillin. The data suggest functional impairment specific for the distal tubule, but with only a modest decrease in the glomerular filtration rate. Renal insufficiency

due to interstitial nephritis has been increasingly recognized as a complication of methicillin administration. Several studies have alluded to the possible existence of functional tubular impairment [ 1,2] in addition to azotemia. However, the nature and significance of these tubular dysfunctions have not been elucidated. We were recently able to study a patient in whom interstitial nephritis was associated with methicillin therapy. In addition to renal insufficiency, the patient also had evidence of renal salt wasting, hyperchloremic acidosis and hyperkalemia. Evaluation of this patient’s renal tubular dysfunction forms the basis of this report. CASE REPORT The patient is a

6 1 year old white male truck driver who had been in excellent

life. A coin lesion was discovered on a routine chest roentgenogram. He underwent a left upper lobectomy on April 26, 1976, for excision of this lesion, which was found to be a benign hamartoma. Preoperatively the patient’s blood urea nitrogen was 22 mg/dl, creatinine 1.3 mg/dl, sodium 146 meq/liter, potassium 4.1 meq/liter, bicarbonate 24 meq/liter and chloride 109 meq/liter; his white blood cell count was 6,400/mm3 with a normal differential. One week postoperatively, his blood urea nitrogen was 20 mg/dl, creatinine 1.0 mg/dl, sodium 136 meq/liter, potassium 4.7 meq/ liter, bicarbonate 29 meq/liter and chloride 96 meq/liter. Because of a persistent air leak, it was necessary to leave the chest tube in place for 15 days. On the 12th day his temperature was noted to be elevated. The tract of the chest tube grew Staphylococcus aureus, but cultures of blood and pleural fluid were sterile. A second thoractomy was performed on the 18th hospital day because of the suspicion of an empyema, but none was found. Following this second operation the administration of methicillin, health his entire

From the Division of Nephrology, Department of Medicine, Fort Miley Veterans Administration Hospital and University of California, San Francisco, California. This work was supported by the VA Medical Research Services. Request for reprints should be addressed to Dr. Martin C. Cogan, Veterans Administration Hospital (Ill J). 4150 Clement Street, San Francisco, California 9412 1. Manuscript accepted January 12, 1977

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12 g/day for eight days, was begun followed by one day of dicloxacillin therapy. The patient was exposed to no other drugs. Dicloxacillin therapy was then terminated because of the development of a morbilliform rash. A white blood cell count at that time was 11 ,400/mm3 with 5 per cent eosinophils. No tests of renal function were performed. With the discontinuation of all drugs, the patient’s rash resolved and his temperature declined although it never remitted completely. The surgical incision and chest tube track healed uneventfully. The patient was discharged on the 37th hospital day. During the next month he had anorexia, nausea, occasional vomiting, malaise and fatigue. The patient thought that his urine output was normal, although he had to void approximately three times during the day and three times during the night. There was no dysuria, hematuria or pyuria. He was readmitted one month after leaving the hospital. His weight on admission was 63.2 kg, representing a loss of 8.6 kg from his weight at the time of discharge. He was afebrile, blood pressure was 126/76 mm Hg with a 20 mm Hg systolic orthostatic change, and he appeared to be dehydrated, having poor skin turgor. The rest of his physical examination was essentially within normal limits. Laboratory values on admission showed the patient to be azotemic with a blood urea nitrogen of 96 mg/dl and a creatinine of 3.6 mg/dl. The sodium was 131 meq/liter, potassium 6.3 meq/liter, bicarbonate 11 meq/liter and chloride 108 meq/liter, with an arterial pH of 7.25. Urinalysis showed a specific gravity of 1.008, pH of 6, no glucose or ketones, 6 to 8 white blood cells/hpf, 0 to 2 red blood cells/hpf and no casts. Urine sodium concentration was 47 meq/liter and urine potassium concentration 32 meq/liter. Serum calcium was 8.8 mg/dl, phosphorus 3.0 mg/dl, albumin 3.1 g/dl, total protein 6.4 g/dl and liver function tests were all within normal limits. The hemotocrit value was 31 per cent, hemoglobin was 10.3 g/dl and the white blood cell count 11,000 with a total eosinophil count of 1,400/mm3. An electrocardiogram showed occasional premature ventricular contractions and signs of hyperkalemia. A chest film disclosed no abnormalities except for the results of the previous surgery. Because the patient had evidence on admission suggestive of mineralocorticoid deficiency (weight loss, dehydration, hyponatremia, hyperkalemia and acidosis), testing for adrenocortical function was carried out. Serum cortisol was 13.8 pg/lOO ml at 8 A.M. and 7.5 Fg/lOO ml at 4 P.M. An ACTH stimulation test was performed using 250 pg of cosyntropin, and the cortisol was 15.3 Fg/dl at 0 minutes, 30.6 pg/dl at 30 minutes and 38 kg/d1 at 60 minutes. The patient was, therefore, considered not to have Addison’s disease. Thyroid function was also normal with a thyroxine of 6.0 pg/dl (normal 4 to 11 kg/dl) and a free thyroxine index of 0.74 (normal 0.5 to 1.5). The fasting blood sugar level was within normal limits. The urine 24-hour protein excretion was only 136 mg, and there was no measurable urinary glucose. The 24-hour phosphorus excretion was 230 mg (normal 900 to 1,300 mg), and amino acid excretion was normal. Cultures for bacteria and mycobacteria were repeatedly negative. An intravenous pyelogram showed slightly large kidneys (15 cm) without obstruction.

March

AND METHICILLIN INTERSTITIAL NEPHRITIS-COGAN,

ARIEFF

The antistreptoliysin (ASO) titer was 1:250. The serologic test for syphilis (VDRL), fluorescent treponemal antibody test, Coombs’ test and cryoglobulins all yielded negative results. The antinuclear antibody test was weakly positive at a dilution of 1:20 in a diffuse pattern. The serum protein electrophoresis was normal. Serum CHs,, was 115 U/ml (normal 58 to 103 U/ml) and the third component of complement (Cs) was 89 mg/dl (normal 55 to 120 mg/dl). METHODS The patient was studied during five experimental periods as shown in Figure 1. Period I. Large amounts of sodium chloride (both oral and intravenous), totaling approximately 420 meq/day, were given to correct the patient’s volume deficiency. Fifty grams of oral potassium exchange resin (Kayexelatee) was given six times during the first week to correct the patient’s hyperkalemia, and 100 meq/day of intravenously administered sodium bi-

,PRMIISONE

P

Figure 1. Periods of metabolic testing showing that after stabilization and hydration during period I, the patient exhibited progressive weight loss with azotemia, hyperkalemia, acidosis and marked sodium wasting during the sodium restriction of period II. After re-expansion with sodium chloride and sodium bicarbonate loading in period III, the response to 9 alpha fluorocotiisol is shown in period IV and to prednisone in period V.

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carbonate was given for the three days to correct the acidosis. Dietary potassium was 40 meqlday. Period II (Low Sodium and Low Potassium Intake). Intravenously administered sodium chloride was terminated and the patient was maintained on 140 meq/day sodium, 40 meq/day potassium diet for three days (period IIn) at the end of which time a 20 meq/day sodium and 20 meq/day potassium diet was instituted for one week (period lie). Daily measurements of the 24 hour urinary excretion of sodium, potassium and creatinine excretion were made. Morning measurements of plasma renin activity and aldosterone were performed at the beginning and the end of this period with the patient in the supine position. The patient was Period Ill (Salt and Bicarbonate LoadI&). rehydrated with oral and intravenously administered 154 mM sodium chloride as in period I but with a larger amount of bicarbonate, 200 meq/day for four days followed by 100 meq/day for one and a half days. Potassium intake was 40 meq/day. Urinary pH, carbon dioxide tension pC02, and bicarbonate were determined at the beginning, middle and end of this period. After serum bicarbonate was maintained at greater than 23 meq/liter for one week, liquid ammonium chloride was given (0.1 gm/kg), and urine pH was measured according to the method of Wrong and Davies [3]. Perlod IV (g-Alpha Fluorocortlsol Admlnlstratlon). The patient was again given a 40 meq/day sodium and potassium diet, this time for five days, to assess the efficacy of the mineralocorticoid S-alpha-fluorocortisol, 0.2 mg/day, on the urinary excretion of sodium and potassium, and on serum concentrations of potassium and bicarbonate. Period V (Prednlsone Admlnlstratlon). Prednisone was given for one week at a dose of 60 mg/day. Oral sodium intake was initially 140 meq/day, but this was raised incrementally to 230 meq/day during the last three days of this period as the oral administration of bicarbonate was instituted at 60 meq/day. Potassium intake was continued at 40 meqlday. Daily blood urea nitrogen, creatinine and electrolyte levels were measured throughout this study. All laboratory measurements were made according to standard laboratory technics. Urine for pH, Pco2 and bicarbonate was collected by having the patient void spontaneously. The urine was immediately taken up into a syringe and was freed of any

0

6 NO+

FRACTIONAL EXCRETION (%)

r

4

l

t 2

80 n

1 n

0

0

t

o-0

Ccr

60

K' 40

0

FRACTIONAL EXCRETION (% )

l

March 1979

RESULTS Period I. In this and subsequent periods the course of the patient’s weight, blood urea nitrogen and creatinine, serum bicarbonate and potassium, and intake and urinary excretion of sodium and potassium are shown in Figure 2.

During the seven days of sodium chloiide loading, the patient’s weight increased by 5 kg. Subjectively, the patient felt much better, with a return of his appetite and strength. The systolic blood pressure increased by an average of 25 mm Hg, and there was no longer any orthostatic hypotension. The plasma bicarbonate increased to 19 meq/liter with a total of 300 meq/liter of bicarbonate given during days 2 to 4 and remained stable even after the bicarbonate supplement was terminated. The serum potassium concentration initially decreased after treatment with salt and dicarbonate loading, and oral Kayexelate. The initial value was 6.3 meq/liter and it decreased to 4.4 meq/liter, but then gradually increased again to 5.7 meq/liter requiring more Kayexelate. Serum sodium increased rapidly to 139 meq/liter on the third day and remained normal. Serum chloride after hydration was 111 meq/liter without an anion gap (serum sodium(bicarbonate + chloride)). Period II. While adhering to a normal (140 meq/day) sodium diet for three days, the patient lost 2.3 kg with an increase in serum creatinine from 2.6 to 3.4 mg/dl. On further reduction of the sodium and potassium intake to 20 meq/day of each for a week, progressive weight loss (5.5 kg), relative hypotension (systolic blood pressure 110 mm Hg) azotemia (blood urea nitrogen to

?O

I

F&e 2. The fractional excretion of sodium and uotassium isrepresented as a function of the creatinine cleirance (in mllmin). Lines were constructed for databelow a creatinine clearance of 38 mllmin.

502

trapped air; the syringe was then placed in crushed ice. Plasma renin activity and aldosterone were measured according to the method of Haber [4] and Drewes [5] et al., respectively.* The kidney percutaneous biopsy was performed under ultrasound guidance and the specimen was processed for light, electron and immunofluorescent microscopy by standard technics. A IO:1 tenkers/Formalin preservative was used for the light microscopic specimen. The electron microscopic specimen was fixed in glutaraldehyde and postfixed in osmium tetroxide. Fluorescent immunoglobulins G (IgG), M (IgM), A (IgA), CJ and fibrin were used for the immunofluorescent microscopy. Tubular deposition of methicillin was sought by indirect immunofluorescence using rabbit antidimethoxyphenyl penicilloyl globulin and fluorescent goat antirabbit globulin antibody.

88 mg/dl and creatinine to a high of 4 mg/dl), acidosis (pH of 7.34 and bicarbonate of 14 meq/liter), hyperkalemia (6.0 meqiliter), and hyponatremia (134 meq/ liter) ensued. Serum chloride was 108 meq/liter with an anion gap of 11 meq/liter.

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BiskindLabs, 45 AdrianCourt,Burlingame,Calif.

DISTAL TUBULAR DYSFUNCTION

The urinary

excretion

of sodium

was markedly

TABLE I

in-

The lowest urinary sodium recorded was 78 rneq/day on the third day, but on all the other days sodium excretion ranged from 90 to 101 meqlday. The urinary excretion of potassium was fairly constant, ranging from 36 to 53 meq/day. Although there was a net loss of potassium during this period, plasma potassium increased. The fractional excretion of potassium varied inversely to the creatinine clearance over the course of these studies, varying from 20 per cent at a creatinine clearance of 38 ml/min to 68 per cent at a creatinine clearance of 20 ml/min. This relationship is in marked contrast to the fractional excretion of sodium, which was constant at 2 per cent over the same range of creatinine clearances (Figure 2). At the beginning of this period, when salt repletion had been completed, the plasma renin activity, with the patient supine, was 0.59 ng/ml/hour (normal 0 to 2.1 ng/ml/hour) and the plasma aldosterone was d 1.2 ng/dl (normal 1 to 15 ng/dl). After salt depletion as evidenced by a 6.4 kg weight loss, an increase in blood urea nitrogen from 40 to 88 mg/dl, but with a relatively stable potassium (5.2 to 5.6 meq/liter), was observed. The plasma renin activity increased by a factor of 12 to 6.87 ng/ml/hour (normal 1.2 to 5.4 ng/ml/hour) and aldosterone increased by a factor of at least 12 to 15.1 ng/dl. A normal increment in plasma aldosterone in response to salt depletion is considered to be a two to fivefold increase over the salt-repleted value (see Table 1). Period III. The patient was re-expanded with sodium chloride and sodium bicarbonate. These maneuvers resulted in a 5.5 kg weight gain and a progressive decrease in blood urea nitrogen from 88 to 25 mg/dl and in creatinine to 2.2 mg/dl. The creatinine clearance during maximal salt depletion was 20 ml/min and, following salt repletion, it increased to 38 ml/min. The effect of sodium bicarbonate administration was to increase serum bicarbonate from 15 to 32 meq/liter in five days. During this same interval, serum potassium decreased from 6.0 to 4.1 meq/liter while serum sodium increased to 143 meq/liter and serum chloride decreased

TABLE II

AND METHICILLIN INTERSTITIAL NEPHRITIS-COGAN,

during this period.

Acidification

PCOP (mm H9) HCOa (meqlliter) Urine PH PC& (mm Hg) HC03 (meqlliter)

Day 15

Day7 Weight (kg) Blood urea nitrogen (mg/dl) Potassium (meq/liter) Plasma renin activity (ng/ml/hour) Patient Normal Plasma aldosterone (ng/dl) Patient Normal

to 103 meq/liter

VolumeDepleted Day 18

68.2 40

64.4 80

61.8 88

5.2

5.1

5.6

0.59 o-2.1

6.87 1.2-5.4

1.2 1-15

13.1 15.1 2-5 fold increase

with an anion gap of 9 meq/

Urinary acidification was also testedduring this period and the results are shown in Table II. At the start of this

period when the patient’s arterial pH was 7.34, the corresponding urine pH was 5.83. During bicarbonate loading, no urinary bicarbonate was detected until the patient’s arterial pH was 7.43, at which point urine bicarbonate concentration was 4 meq/liter and urine pCO* was 47 mm Hg, with a simultaneous arterial pC02 of 42 mm Hg. In order to assess the patient’s true ability to acidify the urine, rather than a stimulated state induced by metabolic acidosis, it was necessary to correct the acidosis. This was done for a period of one week, after which the patient was again made acidotic (pH 7.34) by the oral administration of ammonium chloride. At that time a urine pH was abnormally high at 6.29. On day 25, while the patient was being expanded with 77 mM sodium chloride and his weight reached a plateau of 67 kg, a modification of the hypotonic volume expansion protocol of Chaimovitz et al. [6] was employed. On that day his urinary volume (0) was 6.5 ml/min. The CHZOwas 5.2 ml/min/lOO ml glomerular

Studies

Spontaneous Arterial PH

Renin and Aldosterone Responsiveness to Volume Depletion Volume Replete

creased liter.

ARIEFF

7.34 31 14 5.83 0

BicarbonateLoading 4 Days 8 Days

NH&l

Steroid 7 Days

7.40 38 26

7.43 42 28

7.34 37.5 20

7.34 35 18

6.57 41 0

6.64 47 4

6.29

6.50

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Figure 3. Low power photomicrograph of renal biopsy specimen. There is focal cellular infiltration surrounding distal tubules with relative sparing of surrounding proximal tubules. The glomeruli show slight mesangial hypercellularity. Hematoxylin and eosin stain; original magnification X 80, reduced 32 per cent.

filtration rate, the sodium clearance (r&J was 2.4 ml/min/iOO ml glomerular filtration rate, the distal delivery of sodium (CHzO+ C,,) was depressed at 7.6 ml/min/lOO ml glomerular filtration rate, and the distal reabsorption of sodium (C~+o/Cn~o + C,,) was somewhat low at 68 per cent. Normal (fl SD) for a V of 13.7 f 3.9 ml/min are a CHzOof 9.0 = 3.1 ml/min/lOO ml glomerular filtration rate, CNaof 2.1 f 0.9 ml/min/ 100 glomerular filtration rate, CH20 + Cr.raof 11.1 f 3.5 ml/min/ 100 ml glomerular filtration rate and Cr+o/Cr+o + CNa of 80 f 9.2 per cent [6]. Period IV. Five days of treatment with a physiologic

Figure 4. Higher power view of the same renal biopsy specimen. There is distal tubular inflammation (arrows) with preservation of nearby proximal tubules. Hematoxylin and eosin stain; original magnification X 250, reduced by 32 per cent.

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dose (0.2 mg/day) of the mineralocorticoid g-alpha fluorocortisol during a 40 meq/day sodium intake failed to prevent a weight loss of 2.7 kg, progressive azotemia (creatinine increased from 2.6 to 3.1 mg/dl), acidosis (bicarbonate decreased from 22 to 20 meqiliter), and hyperkalemia (serum potassium increased from 4.4 to 5.3 meq/liter), The urinary sodium loss declined to 49 meq/day, however, suggesting a partial renal response to mineralocorticoid. Potassium excretion remained constant at 47-50 meqlday. Period V. Treatment with prednisone for one week seemed to be without benefit. The creatinine clearance did not change. Sodium intake was kept relatively high (140 meq/day) and then was increased incrementally to 230 meq/day. Weight remained constant and did not increase until extra salt was given. The plasma bicarbonate continued to decrease until supplemental bicarbonate was given and serum potassium decreased slightly with the increment in sodium intake. Urinary sodium remained inappropriately high (79 to 197 meq/day) even though the patient was at a suboptimal weight which was sufficient to induce azotemia. Urinary potassium excretion increased transiently to 91 mg/day but decreased to 55 meq/day by the end of this period. Urine pH was abnormally high at 6.50 when the arterial pH was 7.34 at the end of this treatment period. A further trial of one month of prednisone, 60 meq/ day, was also without benefit. The patient was discharged on a regimen of 4 g of sodium bicarbonate and 4 g of sodium chloride. Six months later, his creatinine remains slightly increased at 2.2 mg/dl and his electrolytes are normal. The patient was restudied eight months later and was found to have an increased creatinine clearance of 61 ml/min and near normal urine sodium conserving ability (18 meq/day urinary sodium excretion after one week of a 10 meq/day sodium diet with a fractional excretion of 0.2 per cent) and normal urinary acidification response without hyperkalemia developing while adhering to a low sodium diet. Renal Biopsy. On light microscopy 10 glomeruli were examined and showed moderate mesangial hypercellularity with some retracted capillary tufts. The predominant finding was a dense inflammatory infiltrate with lymphocytes, monocytes, eosinophils with a variable number of plasma cells surrounding distal tubules. The proximal tubules were spared (See Figures 3 and 4). Electron microscopic examination of the glomeruli confirmed collapse of some capillary tufts with wrinkling of the basement membrane, but open tufts were normal in architecture. lmmunofluorescent staining of the glomeruli was negative. The tubules, especially those less damaged, stained for dimethoxyphenyl penicilloyl antigen (2-F) IgM (2+) and C3 (2+).

DISTAL TUBULAR DYSFUNCTION AND METHICILLININTERSTITIAL NEPHRITIS-COGAN. ARIEFF

COMMENTS

These data demonstrate that in a patient with interstitial nephritis and a minimal impairment of glomerular filtration rate, there was marked inability to conserve sodium during sodium restriction, inability to appropriately acidify the urine and impaired ability to excrete potassium. These features were found not to be related to impaired elaboration of aldosterone or to a deficiency of renin, but rather to be related to distal renal tubular dysfunction which was probably caused by methicillin administration. Markedly impaired ability to conserve sodium during sodium restriction in patients with renal disease was described by Thorne et al. in 1944 [7], and there have been many subsequent cases reported since then [8-121. A similar syndrome exists in children without renal insufficiency [ 131. In most of the aforementioned cases, both glucocorticoid and mineralocorticoid concentration have been found to be normal or supernormal. The syndrome of salt-losing nephropathy with intact adrenal function has been previously described in patients with moderately severe renal insufficiency (glomerular filtration rate of 4 to 20 per cent of normal) in whom the underlying pathology usually consisted of a chronic interstitial or cystic process [ 141. No documented case of acute interstitial nephritis has been reported in which a similar clinical picture was described. The salient feature of this syndrome is the inappropriately high sodium chloride excretion (in the range of 50 to 150 meq/day) under conditions of dietary salt restriction. Patients with advanced renal disease are well known to have a modestly impaired ability to appropriately retain sodium when subjected to stress, usually a loss of less than 20 meq/day of urinary sodium while adhering to a low sodium diet [ 151. Sodium Balance. The patient presented here exhibited a marked exaggeration (78 tp 101 meq/day) of the impaired renal sodium conservation which may be seen in renal disease. This salt loss resulted in progressive weight loss, a profound decrease in the glomerular filtration rate, a decline in plasma sodium and bicarbonate, and an increase in plasma potassium. During this period of dehydration, the fractional excretion of sodium declined, but then stabilized at approximately 2 per cent. Potassium Balance. In contrast to sodium, the fractional excretion of potassium increased more than threefold at a time when there was a reduction in glomerular filtration rate. Since plasma potassium increased, the total amount of potassium excreted was remarkably constant. The increase in serum potassium seemed to be coincident with decrease in plasma bicarbonate and may have been the result of intracellular

to extracellular shifts of potassium in addition to possible protein breakdown [lo]. Hyperkalemia could be corrected either by sodium chloride plus sodium bicarbonate administration or by sodium chloride administration alone. The increased serum potassium, therefore, probably reflected changes in extracellular volume and pH [ 10,111, rather than changes in total body potassium balance [ 121. Hydrogen Ion Balance. The patient’s acidosis during volume contraction was very unusual considering the expected increased bicarbonate reabsorption during extracellular fluid depletion. The fact that the urinary pH was inappropriately high (5.83) during a time when metabolic acidosis was present suggests a distal acidifying defect. After correction of the systemic acidosis for one week in order to curtail ammoniagenesis, the urinary pH was 6.29. This confirms the fact that the acidifying defect was of the distal variety (type I renal tubular acidosis) [ 161. The absence of bicarbonaturia until the arterial pH was greater than 7.40, and the ability to significantly increase serum bicarbonate with only 3 meq/kg/day of oral sodium bicarbonate supports the distal nature of the acidification abnormality. The finding of a urinary pCOp which was not significantly increased above the corresponding arterial pCO* (46.7 versus 41.5 mm Hg) also suggests a distal renal tubular acidosis [17]. Site of Tubular Defect. The distal site of this patient’s tubular defects is supported by several lines of evidence. In micropuncture experiments it is the distal tubule, defined as the diluting segment (ascending limb of Henle), distal convoluted tubule, and cortical and papillary collecting duct, that modulates the final concentration of sodium in the urine [ 181. Glomerulotubular balance for sodium is maintained in the proximal tubule but can be separated in the distal tubule in response to volume status [ 19,201. The fixed fractional excretion of sodium in this case suggests a defect in this distal modulation of sodium reabsorption. In rats, roughly 10 to 16 per cent of the filtered sodium is presented to the distal tubule but only about 1 to 3 per cent enters the collecting duct [ 18-211. Further sodium transport then occurs in the collecting duct which can potentially reabsorb almost all the remaining sodium against high concentration and electrical gradients [2 1,221. A defect in the final segments of the distal tubule would be expected to result in a fixed percentage of filtered sodium excreted, as was present in our patient. If the defect were in the proximal tubule, a decline in the fractional excretion of sodium with decreasing glomerular filtration rate would have been expected. This defective sodium reabsorption may result from an inability to reabsorb sodium against a concentration gradient in the distal convoluted tubule or collecting duct, as has been surmised in a milder form for patients with significant renal disease [ 151.

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The type of renal tubular acidosis and the lack of any of the components of the Fanconi syndrome support the thesis that the principal tubular defect is located distally. That a structural correlation between sodium reabsorption and hydrogen ion secretion may exist in the distal tubule has been recently suggested [23]. The distal delivery of sodium as reflected by the (C&o -t C&/100 ml glomerular filtration rate in this patient was somewhat low, suggesting enhanced rather than diminished sodium reabsorption in the proximal tubule. The decreased distal reabsorption of sodium (Cr+oC&o + C,,) supports a diminished sodium reabsorptive capacity of those parts of the nephron impermeable to water [24]. The persistence of ADH or a tubular water permeability leak cannot be excluded in this study as both would tend to lower (C~~o/Cyo + CN,). The fact that aldosterone was unmeasurably low under the conditions which these studies were performed may imply sufficient volume expansion had occurred to also suppress ADH secretion. It is of interest to compare our patient’s pattern of renal salt loss to that of patients with Bartter’s syndrome, in which a proximal sodium reabsorptive defect has been postulated [25]. In contrast to our patient, a patient with Bartter’s syndrome can normally decrease urinary sodium excretion during salt deprivation [26] as well as normally excrete potassium in response to mineralocorticoids. The tubular defect in our patient thus is probably distal to that in Bartter’s syndrome. Aldosterone Secretion. The response to the mineralocorticoid 9 alpha fluorocortisol was equivocal. Partial response was suggested by a decrease in total daily

sodium excretion and increase in potassium excretion several days after the drug’s termination but while there was some effect remaining. A distal tubular defect is thus suggested with a relative unresponsiveness to mineralocorticoids (so called “pseudohypoaldosteronism) because of the impaired ability to conserve sodium or excrete potassium and hydrogen ion. Morphologic and Clinical Findings. The morphologic accompaniment of the distal tubular dysfunction is afforded in the kidney biopsy specimen, in which preferential distal tubular inflammation is seen (Figures 3 and 4). Although methicillin usually results in a diffuse interstitial nephritis in which there is tubular basement membranes staining for the methicillin antigen dimethoxyphenyl penicilloyl [ 1,271, only distal tubular inflammation was observed in this patient. The rash and eosinophilia were typical of methicillin-induced interstitial nephritis [27-301. The clinical course was unusual in regard to the long duration of renal insufficiency, although permanent renal impairment has been reported [28]. The response to steroids is usually prompt and effective [29-301, but it is not invariably successful [27], as in this case. Marked salt wasting and well documented defective acidification has not previously been reported to be a hazard of methicillin therapy. ACKNOWLEDGMENT We would like to thank Drs. A. Sebastian, M. Schambelan, F. Rector, Jr. and R. C. Morris, Jr. for their valuable criticisms of this case and Dr. C. Biava for help with the interpretation of the renal biopsy specimen.

REFERENCES 1.

5.

6.

7.

8. 9.

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Baldwin DS, Levine BB, Gallo GR: Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279: 1245, 1968. Woodroffe AJ, Thomas NM, Meadows R, et al: Nephropathy associated with methicillin administration. Aust NZJ Med 4: 256, 1974. Wrong 0, Davies HEF: The excretion of acid in renal disease. Q J Med 28: 259, 1959. Haber E, Koerner T, Page LB, et al: Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects. J Clin Endocrinol Metab 29: 1349, 1969. Drewes PA, Demetriou JA, Pileggi VJ: Measurement of urinary aldosterone by a simplified radioimmunoassay procedure. Clin Biochem 6: 88, 1973. Chaimovitz C, Levi J, Better OS, et al: Studies on the site of renal salt loss in a patient with Bartter’s syndrome. Pediat Res 7: 89, 1973. Thorne GW, Koepf GF, Clinton M: Renal failure simulating adrenocortical insufficiency. N Engl J Med 231: 76, 1944. Sawyer WH, Solez C: Salt-losing nephritis simulating adrenocortical insufficiency. N Engl J Med 240: 210, 1949. Joiner CL, Thorne MG: Salt-losing nephritis. Lancet 2: 454,

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14. 15.

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17.

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1952. Stanbury SW, Mahler RF: Salt-wasting renal disease. Metabolic observations on a patient with salt-losing nephritis. Q J Med 28: 425, 1959. Walker WG, Jost W, Johnson JR, et al: Metabolic observations on salt wasting in a patient with renal disease. Am J Med 39: 505, 1965. Popovtzer MM, Katz FH, Pinggera WF, et al: Hyperkalemia in salt wasting nephropathy. Study of the mechanism. Arch Intern Med 132: 203, 1973. Rosler A. Gazit E, Theodor R, et al: Salt wastage, raised plasma-renin activity and normal or high plasma-aldostel rone: A form of pseudohypoaldosteronism. Lancet 1: 959, 1973. Enticknap JB: The condition of the kidneys in salt-losing nephritis. Lancet 2: 458, 1952. Coleman AJ, Arias M, Carter NW, et al: The mechanism of salt wastage in chronic renal disease. J Clin Invest 45: 1116, 1966. Sebastian A, McSherry E, Morris RC Jr: Metabolic acidosis with special reference to the renal acidoses, chap 16. The Kidney (Brenner BM, Rector FC Jr., eds), Philadelphia, W B Saunders Co, 1976. Halperin ML, Goldstein MB, Haig A, et al: Studies on the

DISTAL TUBULAR DYSFUNCTION

18.

19.

20.

21.

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Journal of Medlclne

Volume 64

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