Renal hypouricemia: Prevention of exercise-induced acute renal failure and a review of the literature

Renal Hypouricemia: Prevention of Exercise-Induced Acute Renal Failure and a Review of the Literature Jane Y. Yeun, MD, and James A. Hasbargen,

MD

0 Isolated renal hypouricemia from defective uric acid reabsorption and/or secretion is a well-described entity, with a prevalence of 0.12% to 0.20% in Japan. It is rarely associated with exercise-induced acute renal failure (ARF). The etiology of ARF is debated. Prevention of ARF in renal hypouricemia has not been previously addressed. A 29-year-old Pakistani man had recurrent exercise-induced ARF. He was found to have isolated renal hypouricemia: serum uric acid 0.5 mg/dL, 24-hour urine uric acid 472 t- 25 mg (-t-SD), and fractional excretion of uric acid 55.2% to 69.4%. Both pyrazinamide and probenecid decreased fractional excretion of uric acid and uric acid in our patient, suggesting either a partial presecretory and postsecretory reabsorption excretion rate (UV,,d defect or increased secretion. We investigated renal uric acid excretion during exercise in our patient and four control subjects. All five subjects underwent a physical fitness test (PFI). Our patient developed ARF. Uric acid excretion rate increased in our patient, from 0.46 mg/min at baseline to 1.49 mg/min 4 hours after the PFT, as did the urine uric acid to urine creatinine ratio (U&J,J (0.29 to 1.49). In the controls, UVurate and Uua/lJcr were unchanged after the PFR UVurate was 0.46 2 0.10 mg/min at baseline and 0.59 -f 0.04 mg/min 4 hours after the PFT, while UuA/UCr was 0.30 lr 0.04 at baseline and 0.36 2 0.04 at 4 hours. All five subjects took allopurinol 300 mg daily for 5 days and repeated the PFT. In our patient, allopurinol prevented the ARF as well as the exerciseinduced increases in UVumte (0.28 mg/min to 0.22 mg/min) and Uun/lJcr (0.25 to 0.17). In the controls, the UVurat. and Uun/Ucr responses to exercise were not altered. We conclude that increased renal excretion of uric acid during exercise was responsible for the ARF in our patient with renal hypouricemia and that successful prophylaxis with allopurinol is possible. This is a US government work. There are no restrictions on its use. INDEX

WORDS:

Renal

hypouricemia;

exercise;

acute

R

ENAL HYPOURICEMIA results from an isolated renal tubular defect in reabsorption and/or secretion of uric acid that is genetically determined in an autosomal recessive inheritance pattern.’ It is a rare condition with a reported incidence of 0.12% to 0.20% in Japan.233There are many cases of renal hypouricemia reported in the literature.3-54 However, until 1989, the only adverse effects of renal hypouricemia were thought to be decreased bone density,4 uric acid nephrolithiasis,3*5-13 and possibly calcium nephrolithiasis,4,‘4-20 as documented in case reports. Since then, eight cases of exercise-induced acute renal failure (ARF) have been reported in patients with renal hypouricemia.2’~26 However, only one of these eight patients had recurrent ARFz2 (two episodes). The prevention of exercise-induced ARF has not been addressed. We report an individual with renal hypouricemia who developed recurrent ARF after exercise on at least three occasions. Because of his desire to remain active, we explored potential methods of preventing the ARF. We performed a review of the literature on isolated renal hypouricemia and provide a summary of our results. CASE An otherwise to the emergency American

Journal

REPORT

healthy 29-year-old Pakistani man presented department on March 3, 1993, with nausea, of Kidney

Diseases,

renal

failure;

hypouricemia;

allopurinol;

prophylaxis.

vomiting, and abdominal pain 4 hours after a semiannual physical fitness test (PFT). The PFf consisted of a 2-mile run, sit-ups, and push-ups. He denied any illness, viral prodrome, or nonsteroidal anti-inflammatory drug ingestion prior to exercising. He had been training 3 days a week for the PFT, although at lesser levels of exertion. Of interest, our patient had two prior episodes of similar symptoms occurring shortly after the PFf that were associated with non-oliguric AW. The first episode occurred elsewhere in May 1992; no further evaluation was performed during that admission. The second episode occurred in Denver, CO, in October 1992, with serum creatinine (Sc,) peaking at 4.0 mg/dL. Past medical history was otherwise unremarkable. There is no family history of muscle disorders. However, the patient’s father had end-stage renal disease from nephrolithiasis of unknown composition; a brother has a history of calcium

From the Department of Medicine, Nephrology Service, Fitzsimons Army Medical Center, Aurora, CO; and Indiana University and Veterans Administration Medical Center, Indianapolis, IN. Received September 8, 1994; accepted in revisedform January 20, 1995. The opinions and research contained herein are theprivate ones of the authors and are not to be considered as ofjcial or rejlecting the views of the Department of the Army or the Department of Defense. Address reprint requests to Jane Y. Yeun, MD, Nephrology Service, MCHG-MD& Fitzsimons Army Medical Center, Aurora, CO 80045. This is a US government work. There are no restrictions on its use. 0272-6386/95/2506-0018$0.00/O

Vol 25, No 6 (June), 1995: pp 937-946

937

YEUN

oxalate stones. We were unable to obtain serum uric acid (St,*) levels in any of the relatives. On physical examination, the blood pressure was 132/74 mm Hg without orthostasis and the pulse was 80 beats/min. Examination was entirely unremarkable except for mild abdominal tenderness to palpation, poorly localized, without rebound tenderness. There was no muscle swelling or tenderness. Laboratory evaluation revealed a sodium of 138 mmol/L, potassium 4.1 mmol/L, chloride 108 mmol/L, bicarbonate 18 mmol/L, urea nitrogen 30 mg/dL, creatinine 4.7 mg/dL, calcium 8.8 mg/dL, phosphate 3.6 mg/dL, uric acid 2.1 mg/ dL, creatine kinase 107 U/L, and fractional excretion of sodium 3.3%. Urinalysis revealed a specific gravity of 1.004, 2+ blood, no glucose, pH 6.0, 2 to 4 white blood cells/highpowered field, 0 to 2 red blood cells/high-powered field, rare renal tubular epithelial cells, and rare uric acid crystals. Renal ultrasound was unremarkable, demonstrating normal-sized kidneys without hydronephrosis. The nausea, vomiting, and abdominal pain resolved spontaneously in 24 hours. With conservative therapy, the nonoliguric ARF improved and S, was 1.9 mg/dL at discharge (8 days after initial presentation). During follow-up on April 12, 1993, Scr was 1.1 mg/dL, accompanied by a SuA of 0.5 mgl dL and serum bicarbonate of 26 mmol/L. Subsequent 24hour urine collections revealed 472 ? 25 mg of uric acid (n = 3), uric acid clearance (Cu,) of 57.4 to 65.8 mL/min, fractional excretion of uric acid (F&A) of 55.2% to 69.4%, and normal phosphate (8 14 mg) and calcium (70 to 110 mg; normal range, 42 to 353 mg) excretion. There was no glycosuria or abnormal amino acid excretion. Our patient underwent repeat exercise testing to assess reproducibility of ARF. During the first exercise testing, ARF was reproduced with Seepeaking at 2.5 mg/dL on day 2 after PFT. Magnetic resonance imaging with gadolinium contrast was performed less than 24 hours after the PFT, while a dimercaptosuccinic acid (DMSA) renal scan was done within 48 hours of the PFT to assessrenal cortical perfusion. Subsequent exercise tests were performed to assess the effect of exercise on renal function and uric acid excretion. Four normal male volunteers underwent concomitant exercise testing and served as controls. Informed consent was obtained from all subjects. MATERIALS

AND

Uric acid excretion rate (UVurate) , FaUA, and creatinine clearance (C,) were measured at baseline and after pyrazinamide 3.0 g orally, following the modified method of Steele and Rieselbach.55 After establishing free water diuresis, 30minutes urine collections were obtained, two at baseline and three starting 1 hour after pyrazinamide administration. The effect of probenecid 2.0 g orally on UVurater F&A, and Cc, were measured in an identical fashion 4 days later.

ESfect of Exercise on Renal Function Timed urine collections and blood were obtained at baseline for measurement of Ccr, F&A, S*, U,,/&, and UV,, in our patient and four healthy volunteers from 21 to 41 years

HASBARGEN

of age. Each subject then underwent a standardized PFT, consisting of push-ups and sit-ups to exhaustion over 2 minutes each, and a 2-mile run. Timed urine collections and blood were again obtained at 1 hour, 4 hours, and 24 hours after exercise to allow calculation of the same parameters. All urine samples were spontaneously voided. All subjects ate and drank ad libitum. After each subject had taken allopurinol 300 mg daily for 5 days, the above studies were repeated.

Assays Uric acid was measured using the uricase method,56 with reported accuracy down to 0.2 mg/dL. Creatinine measurements were performed using the Kodak Ektachem system (Rochester, NY).

Literature Review A review of the literature on isolated renal hypouricemia3-54 was performed through use of a MEDLINE search and perusal of bibliographic citations. Any patients who had another potential etiology for uricosuria and resultant hypouricemia (eg, diabetes mellitus,26,39renal tubular damage from renal tuberculosisi or interstitial nephritisI and nephrotic syndrome33) were excluded from this review. The articles were reviewed for the number of individuals or families with isolated renal hypouricemia, gender, age, ethnicity, S“AI F&A, the type of tubular transport defect, and any complications arising directly or indirectly from the renal hypouricemia. Any individual reported as having a similarly affected family member was included in the family category. Turkish Jews, Iraqi Jews, and Libyan Jews were included under the non-Ashkenazi Jew ethnic group. The investigators’ classification of the tubular transport defect after pyrazinamide, probenecid, and/or benzbromarone testing was assumed to be correct. When a classification was not attempted, Sperling’s’ criteria for the classification of type of defect was applied to the data. Complications from renal hypouricemia were summarized as the number of individuals with the complication when there was no family history of renal hypouricemia and as the number of families with the complication when there was a family history of renal hypouricemia, even if only one member of the family was described in sufficient detail.

METHODS

Tubular Function

AND

RESULTS

Tubular Function Administration of pyrazinamide decreased CuA (421 + 38 mL/min to 113 t- 4 mLknin), F&A (360% -+ 24% to 112% + l%), and UVu,,JCc, (3.59 ? 0.23 yg/rnL to 1.12 + 0.01 pg/mL) (Table 1). Pyrazinamide is thought to inhibit secretion of uric acid in the proximal tubule. In our patient, pyrazinamide decreased the excretion of uric acid nearly fourfold. Although probenecid at lower doses can inhibit secretion of uric acid, at the doses used here, it inhibits predominantly postsecretory re-

RENAL

HYPOURICEMIA Table

1. Effect

AND

EXERCISE-INDUCED

of Pyrazinamide

and

939

ARF

Probenecid

on Renal

Tubular

Handling

Pyrazinamide

Time (min)

%A (mg/dL)

C (ml/&)

C (ml.IGin)

of Uric

Acid

in Our

Patient

Probenecid wra&c, WmL)

FEUA (%)

-60 to -30 -30 to 0 Mean 2 SE

0.1 0.1 0.1

459 383 421 238

120 383 114 336 117+-3 360+-24 3 g orally

3.82 3.36 3.59-t0.23

T=O +60 to +90 +90 to +120 +I20 to +150 Mean + SE

0.1 0.1 0.1 0.1

105 115 120 113 i 4

92 104 106 101 ? 4

1.14 1.10 1.12 1.12 e 0.01

114 111 112 112 ?z 1

absorption of uric acid and, to a lesser extent, presecretory reabsorption.‘y57 Therefore, probenecid administration should increase uric acid excretion if reabsorptive function is intact and should have no effect on uric acid excretion if reabsorptive function is defective. In our patient, probenecid was observed to decrease urinary uric acid excretion (Table 1) by nearly half of all calculated parameters. The baseline values for CuA and F&A in the pyrazinamide test are markedly disparate from those in the probenecid test (Table 1) because of the wide variations in measuring our patient’s SuA (0.1 to 0.6 mg/dL) at the lower end of resolution of the assay. However, since UVu,,/Cc, does not include SuA, these data are directly comparable at baseline between the two tests. Renal Cortical Per@sion During Acute Renal Failure

S (mg:L)

C”, (mUmin)

C cr (mUmin)

0.6 0.5 0.55 t 0.05

82.8 91.6 87.2 f 4.4

120 111 116 t 4 2 g orally

69.2 82.2 75.7 i 6.5

4.14 4.13 4.14

0.5 0.5 0.5 0.5

61.2 55.6 51.7 56.2 -c 2.8

102 104 110 105 ? 2

60.3 53.5 47.1 53.6 I 3.8

3.00 2.67 2.35 2.67 ? 0.19

FJJA (%)

wJra&cr WmL)

PFI after allopurinol(75% to 74%, 93% to 94%, 92% to 95%) except for one subject, whose performance improved during the second PIT (59% to 73%). Effect of Exercise on Renal Function

Acute renal failure was reproduced in our patient during PIT, with Ccr decreasing from 151 to 77 mL/min by 4 hours and 46 mL/min by 24 hours (Fig 1). The control subjects retained normal renal function with exercise (138 +- 14 mL/min baseline to 141 + 12 r&/mm at 4 hours and 135 2 22 mL/min at 24 hours; Fig 1). Interestingly, UuA/UCr ratio was markedly elevated in our patient at 4 hours after exercise (0.29 at baseline to 1.49 at 4 hours; Fig 2), associated with a UVUratethat increased from 0.48 mg/min at baseline to 1.49 mg/min at 4 hours (data not shown

Magnetic resonance imaging with gadolinium contrast performed less than 24 hours after an episode of exercise-induced ARF revealed no cortical perfusion defects. A DMSA renal scan performed within 48 hours also revealed no perfusion defects.

1

Extent of Exercise Petiormed

There are age-specific standards set for the PIT, with 100% being a perfect score for the particular age group and 60% a passing score. Compared with other individuals in his age group, our patient performed at 62% for his baseline PFI and 65% for the PFT after allopurinol ingestion. The control subjects’ performances were comparable from the baseline PPT to the

Fig 1. Effect of exercise on Ccr in control subjects and patient with renal hypouricemia at baseline and after allopurinol.

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Fig 2. Effect of exercise jects and patient with renal and after allopurinol.

on Uun/Ucr hypouricemia

in control subat baseline

in graphic form since the graph is almost identical in appearance to that for UUA/UCrr shown in Fig 2). Such an increase in U&U,, (0.30 2 0.04 at baseline to 0.36 5 0.04 at 4 hours; Fig 2) and uvurate (0.46 + 0.10 mg/min baseline to 0.59 + 0.04 mg/min at 4 hours) was not seen in the control subjects. In fact, in control subjects U,,/ Ucr never exceeded 1, and UUA/UCr and UVurate decreased significantly at 1 hour postexercise (Fig 2). Treatment with allopurinol prevented exercise-induced ARF in our patient (Fig l), prevented the UUA/Ucr ratio from exceeding 1 (0.25 to 0.17; Fig 2), and ameliorated the UVurat, peak after exercise (0.28 to 0.22 mg/min). In the control subjects, treatment with allopurinol had no effect on the responses of UUAAJCr (Fig 2) and UV”ra, to exercise. Literature

Review

The summary of the literature review is presented in Table 2; the data are self-explanatory. DISCUSSION

The true incidence of renal hypouricemia is unclear. Although several studies reported the incidence of hypouricemia of unknown etiology,58-60ranging from 0.16% to 0.18%, only Hisatome et al2 reported specifically the incidence of renal hypouricemia in an outpatient Japanese population (0.12%, or four of 3,258 patients). The incidence of renal hypouricemia in other pa-

AND

HASBARGEN

tient populations is not known, although the majority of case reports appear in patients of Japanese or non-Ashkenazi Jewish descent (Table 2). Uric acid excretion in humans is thought to occur in four steps.‘S57,61The four-component model proposes that uric acid is freely filtered at the glomerulus, nearly completely reabsorbed in the proximal tubule (presecretory reabsorption), subsequently secreted into the proximal tubule, and again reabsorbed (postsecretory reabsorption). Defective presecretory and/or postsecretory reabsorption as well as enhanced secretion can all result in renal hypouricemia. Pyrazinamide inhibits uric acid secretion, while probenecid blocks uric acid reabsorption, mainly at the postsecretory site. However, at lower doses, probenecid can also inhibit uric acid secretion. Since pyrazinamide decreased UV,,,/Cc, substantially (Table l), but not to normal, the mechanism of renal hypouricemia is most likely due to a failure to reabsorb filtered uric acid, although a concomitant postsecretory reabsorption defect or increased secretion cannot be completely excluded. With a presecretory reabsorption defect, probenecid administration will increase UVUrate/CCr. If there is a concomitant postsecretory reabsorption defect, UVu,,t&, should remain unchanged or increase slightly after probenecid administration. The paradoxic decreases in UVu,t&,, F,UA, and CUA in our patient suggest that probenecid is inhibiting secretion rather than presecretory or postsecretory reabsorption, either due to decreased delivery of probenecid into the tubule (through increased uric acid secretion at the expense of probenecid) or to a total/subtotal defect in reabsorption. In both these instances, probenecid has no effect on reabsorption, resulting in unopposed inhibition of uric acid secretion. Our patient’s response to pyrazinamide and probenecid most closely resembles that described by Akaoka et al6 (patients Y.A. and Y.K.), Akaoka et a13’, and Matsuda et a13’. Although a subtotal defect (in a total reabsorptive defect F,UA is >lOO%) in both presecretory and postsecretory reabsorption is the most likely mechanism in these patients, increased secretion of uric acid cannot be completely excluded. Reported complications arising as a result of renal hypouricemia are rare, consisting of case reports of decreased bone density associated with hypercalciuria and hypouricemia,4 uric acid

RENAL Table

HYPOURICEMIA

AND

2. Summary

EXERCISE-INDUCED

of Characteristics

of Patients and Literature

Families Review

with

Individuals

Characteristics No. Age, range Sex Male Female Unknown Ethnicity Japanese

941

ARF

54 W

3-66

Non-Ashkenazi Jew Other Not described Sun range (mg/dL) FEUA range (%) Tubular transport defect Presecretory reabsorption Increased secretion

Postsecretory reabsorption defect Combined reabsorption defect Total/subtotal transport defect Unknown Complications Acute renal failure Hypercalciuria Nephrolithiasis (uric acid) Nephrolithiasis (calcium oxalate) Nephrolithiasis (mixed) Nephrolithiasis (unknown type) Decreased bone density Hematuria (gross and microscopic) * Italian, 1; Turk, 1. T Iraqi, 1; Arab, 1; Gypsy,

Hypouricemia

as Described

(%)

Families

(27 persons (16 persons 0

28 (51.8)

11 (44)

18 (33.3) 6 (11.1)

(%)

or 62.8) or 37.2)

8 (32) 3 um 3 (12) 0.08-2.6 17-181.5 12 (48) 0

11 6 3 10

(20.4) (11.1) (5.6) (18.5)

3 4 3 3

6 8 6 9 2 3 0 3

(11.1) (14.8) (11.1) (16.7) (3.7) (5.6)

2 (8)

(5.6)

in a

25 (43 persons) 2-71

25 (46.3) 25 (46.3) 4 (7.4)

0 2 (3.7) 24 (44.4) 0.1-2.5 18.1-260 defect

Renal

(12) (16) (12) (12)

4 (16) 1 (4) 1 (4)

2 (8) 2 (8) 1 (4) 0

1.

nephrolithiasis,3~5-13 and calcium nephrolithiasis4,14-20 (Table 2). More recently, eight patients with renal hypouricemia were reported to have exercise-induced ARF21-26(Table 3). Erley et al*l described a man who presented with nausea, vomiting, loin pain, and oliguric ARF requiring transient dialysis. The UuA/UCr during ARF was greater than 1.O, and a renal biopsy demonstrated uric acid crystals in tubular lumina with mild to moderate interstitial inflammation. The investigators postulated uric acid nephropathy as the etiology of the ARF. There was no mention of exercise preceding the episode of ARF. Sakurauchi et a12’ presented a man with two episodes of loin pain, fatigue, hypertension, and ARF after a marathon. These investigators did not speculate on the etiology of the ARF. Ishikawa et a123subsequently described three patients with nausea,

vomiting, loin pain, and ARF after exercise. Renal biopsy 2 to 4 weeks later revealed either acute tubular necrosis or normal tissue in all three patients. Two biopsies were preceded by a contrastenhanced computed tomography scan showing patchy contrast uptake with wedge-shaped defects. The investigators suggested that ARF may be part of a spectrum of exercise-induced ischemit ARF in young, previously healthy individuals who have no evidence of myoglobinuria or uric acid nephropathy. Numabe et a124reported an episode of ARF (peak Scr of 8.7 mg/dL) in a man presenting with nausea, vomiting, loin pain, and abdominal pain after playing scuffle. Renal biopsy at 2 weeks revealed acute tubular necrosis. No further comment was offered concerning the etiology of the ARF. Igarashi et a125 described a boy with isolated renal hypouricemia

942

YEUN

Table

3. Summary

of Patients

With

Renal

Hypouricemia

Who

Developed

Exercise-Induced

AND

HASBARGEN

Acute

Renal

Renal Biopsy (no. of days after ARF)

SJA Age 641 Sex

Source Erley et al*’ Sakurauchi lshikawa

et al** et alp3

Ethnicity

(md W

FsUA w

Defect*

Exercise

0.1-0.3

128-260

3

-

1

Yes

NR

Yes

1

Yes

23/M

Turk

21/M

Japanese

0.7

79

17/M

Japanese

0.6

79.3

22/M

Japanese

0.7

52.8-60

Numabe

et alz4

16/M 17/M

Japanese Japanese

1.0 0.6

43.2 52-70

lgarashi

et alz5

12/M

Japanese

0.3

loo-136

46/M 29/M

Japanese Pakistani

0.9 0.5

50 55-69

Hiroshige Present

et alz6

1 1 or4

4 1 4 or2

Yes Yes

Yes Yes

Symptoms

Dialysis

Episodes

N/V, loin pain

Yes

1

Loin pain, malaise, edema Abdominal and loin pain, NN NN, malaise, abdominal and loin pain, fever NN NN, malaise, abdominal and loin pain N, anorexia, back and loin pain -

No

2

Uric acid nephropathy -

No

1

ATN (13)

No

1

ATN (35)

Yes Yes

1 1

NL (18) ATN (14)

No

1

-

No No

1 5

-

N, abdominal back pain

and

Abbreviations: NR, not reported; N, nausea; V, vomiting; ATN, acute tubular necrosis; NL, nomal. l Types of tubular defects in uric acid handling: 1, presecretory reabsorption defect; 2, increased secretion; defect; 4, presecretory and postsecretory reabsorption defect.

who developed ARF associated with nausea, anorexia, and loin pain after exercise. Of interest, this patient’s mother had a history of recurrent uric acid nephrolithiasis. The investigators proposed that exercise-induced ARF be included as a potential complication of renal hypouricemia, but were unable to comment on the pathogenesis. Hiroshige et alz6 described two patients with isolated renal hypouricemia; one had an episode of exercise-induced ARF 4 years ago. No details are available. Interestingly, two other patients had diabetes mellitus associated with renal hypouricemia and one presented with exercise-induced ARF. This patient was not included in this review because of the diabetes. We hypothesize that ARF occurs with exercise in patients with renal hypouricemia because of the increase in uric acid production during exercise. Several studies have documented an increase in SuA after exhaustive exercise62-66due to either decreased renal excretion or increased production.63 With exhaustive exercise, the resultant lactic acidosis can directly interfere with tubular secretion of urate.‘j3 Decreased glomerular filtration rate and a contracted extracellular volume’j3 can further decrease uric acid excretion. However, hyperuricemia also is a marker for cell energy crisis.67 During cellular energy depletion,

Failure

3, postsecretory

(1)

reabsorption

consumption of adenosine triphosphate (ATP) exceeds its synthesis, resulting in an accumulation of adenosine diphosphate (ADP) and adenosine monophosphate (AMP) and their subsequent degradation to inosine, xanthine, hypoxanthine, and, finally, uric acid. That the hyperuricemia seen during exhaustive exercise is due to overproduction of uric acid is supported by the observation that aerobic exercise does not result in hyperuricemia,64~66768whereas anaerobic exercise causes a sequential increase in first hypoxanthine,63 then uric acid levels. 63-66368 In addition, Fry et a169demonstrated that SuA remained elevated at 24 hours after exercise, while lactic acid levels and Scr had normalized by 2 hours, making decreased excretion an unlikely explanation for the persistent hyperuricemia. Finally, the combined studies of Sutton et ak7’ Sahlin et alyl and Hellsten-Westing et a172 demonstrate conclusively that hyperuricemia postexercise is the result of increased uric acid production. Sutton et a17’ demonstrated through muscle biopsies that intracellular ATP levels decreased after exhaustive exercise while ADP and AMP levels increased. Sahlin et a171showed a step-up in arterial to venous hypoxanthine levels after exhaustive exercise of a muscle group, suggesting increased release of hypoxanthine from the involved mus-

RENAL

HYPOURICEMIA

AND

EXERCISE-INDUCED

ARF

cles. Finally, Hellsten-Westing et al” demonstrated not only an arteriovenous increase in hypoxanthine levels in the involved muscle groups, but also an increased uptake of hypoxanthine and inosine by the liver with concomitant increased uric acid release. Taken together, these three studies confirm that during exhaustive exercise, muscles switch to anaerobic metabolism, and ADP and AMP accumulate and are converted to inosine and hypoxanthine, which are then released into the circulation, taken up by the liver, and converted to uric acid. All the uric acid is then promptly filtered and eliminated by the kidney, increasing the urinary uric acid load and, hence, UuA/Ucr and UVurat,. Volume depletion and/or decreased renal blood flow during exercise can further contribute to concentration of urinary uric acid. In addition, lactic acidosis during exercise may lead to increased urinary acidification, favoring uric acid crystallization. There are several theoretic ways of preventing the ARF if the above hypothesis is true. First, administration of allopurinol should decrease basal production of uric acid, ameliorate its increased production during exercise, decrease its subsequent elimination during exercise, and, therefore, ameliorate the ARF. Second, prophylactic alkalinization of the urine prior to exercising should prevent the ARF by increasing the solubility of uric acid. Third, prophylactic administration of pyrazinamide should decrease urinary uric acid and prevent ARF. We elected to test the hypothesis with the administration of allopurinol. The patient we describe here had recurrent exercise-induced ARF. Although a renal biopsy was not performed, there is indirect evidence implicating uric acid nephropathy in the pathogenesis of ARF. First, UuA/Ucr was greater than 1.O in our patient after exercise, associated with ARF. Kelton et a173noted that UuA/UCr greater than 1 .O accurately correlated with the presence of uric acid nephropathy. None of the controls had a Uu,/Uc, greater than 1.0, and none had ARF. Second, our patient had a dramatic increase in UV”rate after exercise, associated with ARF. In contrast, the controls had only a small increase in UVUrate. The observation of uric acid crystals in the urine after exercise and during episodes of ARF lend further support to this theory. Perhaps more importantly, the administration of allopurino1 was effective in preventing exercise-induced

943

ARF in our patient by preventing the increased uric acid excretion after exercise (Fig 2). In a study of patients with hematologic malignancies, Rieselbach et a174 concluded that uric acid excretion and urinary uric acid concentration are more important determinants than hyperuricemia for the development of uric acid nephropathy. Our data directly support this contention, since urinary indices (UuJUc, and UVurate) are elevated in the face of hypouricemia. Our hypothesis of uric acid nephropathy as the cause of exercise-induced ARF in patients with renal hypouricemia concur with the findings of Erley et al.‘l Although Ishikawa et a123and Numabe et al% did not find evidence for uric acid nephropathy in their kidney biopsy specimens, the renal tissue may have been obtained too late in the course of the renal failure. In addition, if the kidney tissue was fixed with formaldehyde, the uric acid crystals may have leached out of the tissue.75 The acute tubular necrosis observed in Ishikawa et al’s study23 also may have been a direct result of the administered contrast. Their observation of patchy contrast uptake by the renal cortex may have been a result of the administered contrast or residual changes from uric acid nephropathy rather than a cause of the renal failure. Our patient demonstrated no renal cortical perfusion defects on magnetic resonance imaging with gadolinium and renal scan performed within 48 hours of ARF in the absence of intravenous contrast administration. Although Loffler et al49concluded that patients with renal hypouricemia may not respond to allopurinol administration because of increased excretion of the active metabolite oxypurinol, this does not clinically appear to be the case. Frank et al’ and Sasaki et al” treated three patients with uric acid nephrolithiasis and renal hypouricemia with allopurinol and achieved stone dissolution as well as prevented further episodes of stone formation. In the present study, our patient clinically responded to allopurinol with prevention of an increase in UuA/UCr and ARF. In conclusion, although renal hypouricemia is a rare condition, it can be associated with significant morbidity to include uric acid nephrolithiasis and exercise-induced ARF. We propose that the ARF is a result of uric acid nephropathy and can be prevented with the administration of allopurinol.

944

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ACKNOWLEDGMENT The authors thank Frances Matsumoto for her expertise in translating papers from the Japanese literature.

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