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Enteric hyperoxaluria: A hidden cause of early renal graft failure in two successive transplants: Spontaneous late graft recovery
CASE REPORT
Enteric Hyperoxaluria: A Hidden Cause of Early Renal Graft Failure in Two Successive Transplants: Spontaneous Late Graft Recovery Charles Cuvelier, MD, Eric Goffin, MD, Jean-Pierre Cosyns, MD, PhD, Michel Wauthier, MD, and Charles van Ypersele de Strihou, MD, PhD ● A 37-year-old patient underwent two successive renal transplantations 7 months apart. He remained dialysis dependent. Early biopsy of both grafts revealed widespread calcium oxalate deposition suggestive of acute oxalate nephropathy. Several causes of oxalate nephropathy, including primary oxalosis and an increased intake of oxalic acid precursors, were excluded. Two years later, the identification of steatorrhea with radiologic signs of chronic pancreatitis led to the hypothesis of enteric hyperoxaluria. Surprisingly, 11 months after the second transplantation, graft function improved progressively allowing interruption of dialysis. Three years later, renal function is stable. The causes and prevention of acute oxalate-induced graft failure are highlighted. Subclinical evidence of enteric hyperoxaluria should be looked for and appropriate therapy instituted as early as possible. The possibility of a late recovery of renal function warrants attentive patience from attending physicians. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Oxalate nephropathy; early renal graft failure; hyperoxaluria; renal transplantation.
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ELAYED GRAFT function usually is defined as failure of the graft to function immediately after transplantation and the need for dialysis during the first week after transplantation.1 It is common after cadaveric renal transplantation, usually as a result of transplant acute tubular necrosis. Renal graft failure usually subsides within the first days after transplantation, although it may last for 4 to 6 weeks.1 In less than 5% of renal allografts with delayed graft function, graft function never resumes, and this is referred to as primary nonfunction.2 We report the case of a patient who received two cadaveric renal transplants 7 months apart and remained oliguric and dialysis dependent after both transplantation procedures. Surprisingly, 11 months after the second transplantation, graft function improved sufficiently to allow interruption of dialysis. Three years later, renal function is still adequate. Early biopsy of both grafts disclosed an unusual, widespread calcium oxalate deposition suggestive of acute oxalate nephropathy. The search for the underlying disorder led to the exclusion of primary oxalosis or the administration of metabolic precursors of oxalic acid as the source of oxalate. Later the discovery of steatorrhea associated with radiologic signs of chronic pancreatitis led to the hypothesis that oxalate intestinal overabsorption with an attendant hyperoxaluria (enteric hyperoxaluria) was the cause.
CASE REPORT The patient, born in March 1959, suffered from hypogonadism, mental retardation, and multiple bone malformations attributed to a variant of Klinefelter syndrome (karyotype 48, XXYY). Hemodialysis (4 hours three times a week with bicarbonate dialysate) was initiated in August 1991 for end-stage renal failure (ESRF) resulting from bilateral renal dysplasia. Subsequent evolution was complicated by recurrent episodes of vascular access dysfunction and thrombosis. Baseline medications included calcitriol (0.25 g/wk), calcium carbonate (3,000 mg/d), and aluminum hydroxide (3,000 mg/d). Acetylsalicylic acid (100 mg/d), buflomedil (600 mg/d), and subcutaneous enoxaparin (2,000 UI/d) were given to prevent vascular access dysfunction. Ascorbic acid (500 mg/d) was added in December 1994 and naftidrofuryl (600 mg/d) in August 1995. A first renal transplantation with a cadaveric kidney was performed on April 30, 1996. Initial immunosuppressive regimen included antithymocytic immunoglobulins, 100 mg/d, for 10 days; azathioprine, 50 mg daily, and oral prednisolone, 25 mg daily, at a progressive tapered dosage, and tacrolimus from the 10th day. The postoperative course
From the Department of Nephrology, Cliniques Universitaires St. Luc, Brussels; Departments of Internal Medicine and Pathology, Universite´ Catholique de Louvain, Brussels; and Renal Unit, Cliniques St. Pierre, Ottignies, Belgium. Work done at the Cliniques Universitaires St. Luc, Brussels, Belgium. Received December 10, 2001; accepted in revised form February 22, 2002. Address reprint requests to Charles van Ypersele de Strihou, MD, PhD, Department of Nephrology, Avenue Hippocrate, 1200 Brussels, Belgium. E-mail [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4001-0029$35.00/0 doi:10.1053/ajkd.2002.33934
American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: E3
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was characterized by persistent oligoanuria (daily urine output 100 to 200 mL) until the second transplantation. Hemodialysis was continued. Renal graft ultrasound disclosed no dilation of the excretory cavities. Serial nuclear imaging studies with technetium 99m (TechneScan MAG3) showed preserved renal blood flow but altered radiotracer concentration without excretion. The diagnosis of primary nonfunction was considered. A first kidney graft biopsy specimen obtained on the 10th postoperative day showed no glomerular, vascular, or rejection lesions but tubular epithelial necrosis and numerous crystals in the tubular lumen (Fig 1A). The crystals had a polyhedral or rhomboid shape and appeared as doubly refractile under polarized light, characteristics consistent with calcium oxalate crystals. A second biopsy specimen obtained 2 months after transplantation disclosed interstitial fibrosis, tubular atrophy, and persistent calcium oxalate crystals (Fig 1B). Oxalate crystals were absent in the native kidney removed at the time of transplantation and in the graft biopsy specimen obtained just before transplantation. The renal transplant was not removed. The immunosuppressive regimen was tapered, and only prednisolone (5 mg/d) was maintained. Other baseline drugs included calcium carbonate (2,000 mg/d), ranitidine (150 mg/d), and subcutaneous enoxaparin (3,000 UI Axa/d). Administration of ascorbic acid and naftidrofuryl, interrupted at the time of first transplantation, was not resumed to avoid any increase in the oxalate burden. On December 12, 1996, a second cadaveric renal transplantation was performed. Immunosuppression included a 500-mg intravenous methylprednisolone bolus followed by oral prednisolone, 20 mg daily; mycophenolate mofetil, 500 mg twice a day; and tacrolimus, 5 mg twice a day. The patient remained oligoanuric and required continued hemodialysis. Serial scintigraphic studies and Doppler ultrasound studies excluded vascular graft thrombosis. There was no evidence of ureteral obstruction or urinary leak at ultrasonography. The first graft biopsy specimen, obtained on the 10th postoperative day, revealed extensive tubular damage and massive intratubular calcium oxalate deposition (Fig 1C). Plasma oxalate concentration, measured immediately before transplantation (enzyme oxalate oxidase method), was 890 g/dL (98.8 mol/L), well within the range observed in patients with ESRF resulting from common nephropathies (mean value, 712 ⫾ 141 g/dL [79.0 ⫾ 15.7 mol/L]) and lower than that observed in patients with ESRF related to primary hyperoxaluria (mean value, 1296 ⫾ 287 g/dL [143.9 ⫾ 31.9 mol/L]). These results were provided by the Service de Biochimie Me´dicale–CHU Pitie´ Salpe´trie`re (Paris, France). The patient remained on dialysis with the following treatment: tacrolimus, 7 mg daily; prednisolone, 5 mg daily; and ticlopidine, 250 mg twice daily. Seven months later, predialysis serum creatinine fell progressively, from 7.3 mg/dL (645 mol/L) in early September to 4.1 mg/dL (362 mol/L) on November 3, 1997, with a concomitant rise of urinary output. On November 3, 1997, creatinine clearance reached 13 mL/min (0.217 mL/s), and hemodialysis was interrupted. Six months later, in May 1998, the serum creatinine fell to 2.4 mg/dL (212 mol/L) with a creatinine clearance of 28 mL/min (0.468 mL/s). Urinary oxalate levels, measured repeatedly between February and May
CUVELIER ET AL
1998, were significantly increased, ranging from 44.8 to 60.3 mg daily (497 to 669 mol) (normal range, 10 to 45 mg [111 to 500 mol] daily). On June 4, 1998, the patient developed pneumoccocal pneumonia and septic shock. Continuous hemodiafiltration followed by hemodialysis was required until July 9, 1998. Recurrent diarrhea during the revalidation phase was investigated further. A 3-day fecal fat collection showed increased fat loss (43.8 g; normal range, 0 to 7 g/d). An abdominal ultrasound revealed pancreatic calcifications and ductal dilation. Chronic pancreatitis with fat malabsorption and secondary hyperoxaluria was diagnosed. Review of the past history disclosed no alcohol consumption but an episode of acute cephalic pancreatitis in November 1994. At that time, serum levels of amylase and lipase were increased (1,540 IU/L; normal range, 20 to 220 IU/L, and 4,476 IU/L; normal range, 14 to 220 IU/L), and on computed tomography scan, the pancreas appeared enlarged with a single fluid collection without signs of chronic pancreatitis. The patient’s mother remembered foul-smelling stools for several years and intermittent diarrhea for about 1 year. The patient was treated with calcium carbonate and lipase supplementation (Creon). In December 1999, the serum creatinine was 2.1 mg/dL (185 mol/L) with a creatinine clearance of 27 mL/min (0.451 mL/s). Oxaluria reached 40.2 mg/d (446 mol). Serum creatinine was stable in September 2001 (3.0 mg/dL [265 mol/L]).
DISCUSSION
The present case is unique in two ways: first, early graft failure resulting from massive intratubular calcium oxalate precipitation in the absence of primary oxalosis in two successive grafts; second, a late unexpected graft function improvement after 11 months. The adequate graft blood flow and the absence of urologic complications despite postoperative oligoanuria led twice to a putative diagnosis of post-transplant acute tubular necrosis, the most common cause of delayed graft function in cadaveric transplant recipients.1 Transplant biopsy specimens performed 10 days after each transplantation displayed a unique picture, however, reminiscent of acute oxalate nephropathy: severe tubular epithelial necrosis with widespread intratubular calcium oxalate deposits. To our knowledge, this is the first report of immediate post-transplant graft failure attributed to acute oxalate nephropathy outside primary oxalosis. An extensive review of the literature revealed a similar case, reported in a veterinary journal.3 A cat, given two renal allografts, 14 days apart, for nonhyperoxaluric chronic renal failure, developed oxalate nephrosis in both allografts. The cause of the extensive calcium oxalate deposition was not identified.
RECURRENT GRAFT FAILURE AND ENTERIC HYPEROXALURIA
Fig 1. (A) Extensive oxalate crystal deposition in tubular lumen observed under half-polarized light in a biopsy specimen obtained 10 days after the first transplantation. (H&E, original magnification ⴛ 310.) (B) Biopsy specimen obtained 2 months after the first transplantation shows oxalate crystals occupying the lumen of atrophic tubules surrounded by interstitial fibrosis. (H&E, original magnification ⴛ 310.) (C) Recurrent crystal deposition in the tubular lumen in a biopsy specimen obtained 10 days after the second transplantation. (H&E, original magnification ⴛ 310.)
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In our patient, the recurrence of the same unusual picture in two successive grafts suggested not only a causal relationship between the massive deposition of calcium oxalate crystals and the transplants’ failure, but also the existence of a patient-related underlying disorder (ie, an abnormality of the oxalate metabolism). In humans, oxalic acid is either absorbed from the gastrointestinal tract or generated as an end product of the metabolism of glycine and ascorbic acid. Its only route of elimination is the kidney, with daily urinary oxalate excretion ranging from 10 to 45 mg.4 Hyperoxaluria, defined as a 24hour urinary oxalate excretion exceeding the 10to 45-mg range,5 may result in urolithiasis, nephrocalcinosis, progressive renal failure, and, rarely, acute renal failure secondary to massive intrarenal deposition of calcium oxalate.4 Hyperoxaluria is either inborn (primary hyperoxaluria) or acquired (secondary hyperoxaluria) as a consequence of increased oxalate production from exogenous precursors or from enhanced intestinal oxalate absorption. Primary oxalosis, a rare autosomal recessive disease, was excluded in our patient on clinical grounds. No calcium oxalate deposits were present in the native kidney removed at the time of first transplantation. Among the causes of secondary hyperoxaluria, accidental massive exposure to oxalate precursors was ruled out: ethylene glycol poisoning,6 star fruit ingestion,7 methoxyflurane anesthesia,8 or parenteral administration of large doses of naftidrofuryl or ascorbic acid.9-11 Serum oxalate levels increase in chronic renal failure as a result of impaired renal clearance, and significant oxalate retention occurs when the glomerular filtration rate falls to less than 20 mL/min/1.73 m2.12 Serum oxalate levels remain elevated despite the removal of oxalate during dialysis,13,14 a finding confirmed in our patient on maintenance hemodialysis for about 5 years. Before his first transplantation, the patient had been given ascorbic acid and naftidrofuryl, both oxalate precursors likely to augment the oxalate burden.15-18 As a result of oxalate retention, the newly grafted kidney excretes large amounts of oxalate during the first 24 to 48 hours after transplantation and returns serum oxalate to normal levels.19 A transient oxalate supersaturation and precipitation within the renal tubules may occur. It is unlikely that the additional burden
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resulting from the previous intake of ascorbic acid and naftidrofuryl was instrumental in the graft failure because the same picture with oxalate crystals in the tubular lumen recurred in the second allograft despite the withdrawal of both medications. The serum oxalate concentration measured before the first transplantation was within the range observed in hemodialyzed patients with ESRF not related to primary oxalosis. Overabsorption of oxalate and hyperoxaluria (enteric hyperoxaluria) have been reported in association with a variety of gastrointestinal disorders, such as Crohn’s disease, celiac sprue, intestinal lymphangiectasia, pancreatic insufficiency, extensive ileal resection, and jejunoileal bypass surgery for obesity.20-25 These conditions share a fat malabsorption with steatorrhea. In the absence of weight loss, abdominal pain, or diarrhea, no investigations had been undertaken in our patient before the onset of recurrent diarrhea in June 1998. A diagnosis of chronic pancreatitis with fat malabsorption and increased oxaluria was then made on the basis of steatorrhea, pancreatic calcifications with ductal dilation, and slightly but consistently elevated urinary oxalate levels. The episode of acute pancreatitis 4 years earlier further supported the diagnosis. The repeated graft failure likely resulted from an undiagnosed enteric hyperoxaluria caused by chronic pancreatitis with steatorrhea. Renal transplantation is not contraindicated in patients with enteric hyperoxaluria. Two such cases have been reported. The first patient with short-bowel syndrome maintained stable renal function 10 months after a successful cadaveric graft transplantation; the transplant biopsy specimen showed no evidence of recurrent oxalosis.26 The second patient, with ESRF after extensive small bowel resection, maintained good renal function 7 years after a successful transplantation despite persistent hyperoxaluria.27 In both cases, measures were taken to reduce hyperoxaluria and prevent graft oxalosis, including a diet low in oxalate and fat, oral calcium supplements to bind oxalate in the intestinal lumen, high fluid intake, and inhibitors of crystallization such as magnesium and citrate to prevent tubular precipitation of the filtered oxalate. Patients with enteric hyperoxaluria also might benefit from the additional measures advocated in patients with primary oxalosis: high-efficiency daily dialysis for
RECURRENT GRAFT FAILURE AND ENTERIC HYPEROXALURIA
5 to 7 days before transplantation with the intent to remove as much oxalate as possible, extreme post-transplantation urinary dilution, and early intensive post-transplantation dialysis.28 The late improvement of allograft function, 11 months after the second transplantation, is of interest. We previously reported the spontaneous recovery of renal function in a kidney transplant recipient who had developed an acute oxalate nephropathy after a parenteral overdose of naftidrofuryl.9 Renal function recovery from acute oxalate nephropathy is not unusual. Outside transplantation, several cases of spontaneous acute renal dysfunction were observed in association with enteric hyperoxaluria, most frequently in the setting of intestinal bypass operations for obesity.20,24 It was proposed that widespread intratubular precipitation of calcium oxalate led to tubular obstruction and damage but was followed by the subsequent dissolution of the crystals and the recovery of renal function. The outcome is not always as good, however: ESRF or limited recovery was reported in several other cases,21,23 perhaps as a result of the severity and the extent of the renal damage, the inability to resorb the calcium oxalate salts from the renal parenchyma, and a continuing oxalate deposition. Before concluding an unfavorable outcome, it would be wise to keep our patient’s history in mind and adopt a conservative course of action. In conclusion, this is the first description of a patient with ESRF not related to primary oxalosis who developed acute oxalate nephropathy in two renal allografts, 7 months apart, most probably secondary to enteric hyperoxaluria. This observation highlights the fact that in the presence of oxalate nephropathy or hyperoxaluria, intensive investigations are needed to uncover and treat the cause of hyperoxaluria, even in the absence of overt symptoms. Recovery from oxalate-induced graft failure may be slow and require an attentive patience from the attending physicians. REFERENCES 1. McKay DB, Milford EL, Tolkoff-Rubin NE: Clinical aspects of renal transplantation, in Brenner BM, Rector FC (eds): The Kidney. Philadelphia, PA, Saunders, 2000, pp 2542-2590 2. Hricik DE, Zarconi J, Schulak JA: Influence of lowdose cyclosporine on the outcome of treatment with OKT3
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for acute renal allograft rejection. Transplantation 47:272277, 1989 3. Gregory CR, Olander HJ, Kochin EJ, Gourley IM, Cousyn D, Levy J: Oxalate nephrosis and renal sclerosis after renal transplantation in a cat. Vet Surg 22:221-224, 1993 4. Williams HE: Oxalic acid and the hyperoxaluric syndromes. Kidney Int 13:410-417, 1978 5. Wandzilak TR, Williams HE: The hyperoxaluric syndromes. Endocrinol Metab Clin 19:851-867, 1990 6. Parry MG, Wallach R: Ethylene glycol poisoning. Am J Med 57:143-150, 1974 7. Chien-Liang C, Hua-Chang F, Kang-Ju C, Jyh-Seng W, Hsiao-Min C: Acute oxalate nephropathy after the ingestion of star fruit. Am J Kidney Dis 37:418-422, 2001 8. Frascino JA, Vanamee P, Rose PP: Renal oxalosis and azotemia after methoxyflurane anaesthesia. N Engl J Med 283:676-679, 1970 9. Cuvelier C, Goffin E, Cosyns JP, et al: Acute renal failure due to naftidrofuryl oxalate (Praxilene) overdose in a kidney transplant recipient. Nephrol Dial Transplant 10:17561758, 1995 10. Wong K, Thomson C, Bailer RR, McDiarmid S, Gardner J: Acute oxalate nephropathy after massive intravenous dose of vitamin C. Aust N Z J Med 24:410-411, 1994 11. Alkhunaizi AM, Chan L: Secondary oxalosis: A cause of delayed recovery of renal function in the setting of acute renal failure. J. Am Soc Nephrol 7:2320-2326, 1996 12. Morgan SH, Purkiss P, Watts RWE, Mansell MA: Oxalate dynamics in chronic renal failure. Nephron 46:253257, 1987 13. Ramsay AG, Reed RG: Oxalate removal by hemodialysis in end-stage renal disease. Am J Kidney Dis 4:123127, 1984 14. Mydlik M, Derzsiova K: Renal replacement therapy and secondary hyperoxalemia in chronic renal failure. Kidney Int 59:S-304-S-307, 2001 (suppl 78) 15. Thompson CS, Weinman EJ: The significance of oxalate in renal failure. Am J Kidney Dis 4:97-100, 1984 16. Shah GM, Ross EA, Sabo A, Pichon M, Reynolds RD, Bhagavan H: Effects of ascorbic acid and pyridoxine supplementation on oxalate metabolism in peritoneal dialysis patients. Am J Kidney Dis 20:42-49, 1992 17. Ono K: Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clin Nephrol 26:239-243, 1986 18. Moesch C, Charmes JP, Bouthier F, Leroux-Robert C: Calcium oxalate crystalluria in elderly patients and treatment with naftidrofuryl oxalate. Age Ageing 24:464-467, 1995 19. Worcester EM, Fellner SK, Nakagawa Y, Coe FL: Effect of renal transplantation on serum oxalate and urinary oxalate excretion. Nephron 67:414-418, 1994 20. Mandell I, Krauss E, Millan JC: Oxalate-induced acute renal failure in Crohn’s disease. Am J Med 69:628631, 1980 21. McDonald GB, Earnest DL, Admirand WH: Hyperoxaluria correlates with fat malabsorption in patients with sprue. Gut 18:561-566, 1977 22. Allen A, Clutterbuck E, Maidment G, Thompson E,
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Watts R, Pusey C: Enteric hyperoxaluria and renal failure associated with lymphangiectasia. Nephrol Dial Transplant 12:802-806, 1997 23. Wharton R, D’Agati V, Magun AM, Whitlock R, Kunis L, Appel GB: Acute deterioration of renal function associated with enteric hyperoxaluria. Clin Nephrol 34:116121, 1990 24. Ehlers SM, Posalaky Z, Strate RG, Quattlebaum FW: Acute reversible renal failure following jejunoileal bypass for morbid obesity: A clinical and pathological (EM) study of a case. Surgery 82:629-634, 1977
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25. Dobbins JW: Oxalate and intestinal disease. J Clin Gastroenterol 1:165-169, 1979 26. Roberts RA, Sketris IS, MacDonald AS, Belitsky P: Renal transplantation in secondary oxalosis. Transplantation 45:985-986, 1987 27. Kitsler H, Peter T, Thiel G, Brunner FP: Seven-year survival of renal transplant for oxalate nephropathy due to short-bowel syndrome. Nephrol Dial Transplant 10:14661469, 1995 28. Scheinman JI: Primary hyperoxaluria: Therapeutic strategies for the 90s. Kidney Int 40:389-399, 1991
Enteric Hyperoxaluria: A Hidden Cause of Early Renal Graft Failure in Two Successive Transplants: Spontaneous Late Graft Recovery Charles Cuvelier, MD, Eric Goffin, MD, Jean-Pierre Cosyns, MD, PhD, Michel Wauthier, MD, and Charles van Ypersele de Strihou, MD, PhD ● A 37-year-old patient underwent two successive renal transplantations 7 months apart. He remained dialysis dependent. Early biopsy of both grafts revealed widespread calcium oxalate deposition suggestive of acute oxalate nephropathy. Several causes of oxalate nephropathy, including primary oxalosis and an increased intake of oxalic acid precursors, were excluded. Two years later, the identification of steatorrhea with radiologic signs of chronic pancreatitis led to the hypothesis of enteric hyperoxaluria. Surprisingly, 11 months after the second transplantation, graft function improved progressively allowing interruption of dialysis. Three years later, renal function is stable. The causes and prevention of acute oxalate-induced graft failure are highlighted. Subclinical evidence of enteric hyperoxaluria should be looked for and appropriate therapy instituted as early as possible. The possibility of a late recovery of renal function warrants attentive patience from attending physicians. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Oxalate nephropathy; early renal graft failure; hyperoxaluria; renal transplantation.
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ELAYED GRAFT function usually is defined as failure of the graft to function immediately after transplantation and the need for dialysis during the first week after transplantation.1 It is common after cadaveric renal transplantation, usually as a result of transplant acute tubular necrosis. Renal graft failure usually subsides within the first days after transplantation, although it may last for 4 to 6 weeks.1 In less than 5% of renal allografts with delayed graft function, graft function never resumes, and this is referred to as primary nonfunction.2 We report the case of a patient who received two cadaveric renal transplants 7 months apart and remained oliguric and dialysis dependent after both transplantation procedures. Surprisingly, 11 months after the second transplantation, graft function improved sufficiently to allow interruption of dialysis. Three years later, renal function is still adequate. Early biopsy of both grafts disclosed an unusual, widespread calcium oxalate deposition suggestive of acute oxalate nephropathy. The search for the underlying disorder led to the exclusion of primary oxalosis or the administration of metabolic precursors of oxalic acid as the source of oxalate. Later the discovery of steatorrhea associated with radiologic signs of chronic pancreatitis led to the hypothesis that oxalate intestinal overabsorption with an attendant hyperoxaluria (enteric hyperoxaluria) was the cause.
CASE REPORT The patient, born in March 1959, suffered from hypogonadism, mental retardation, and multiple bone malformations attributed to a variant of Klinefelter syndrome (karyotype 48, XXYY). Hemodialysis (4 hours three times a week with bicarbonate dialysate) was initiated in August 1991 for end-stage renal failure (ESRF) resulting from bilateral renal dysplasia. Subsequent evolution was complicated by recurrent episodes of vascular access dysfunction and thrombosis. Baseline medications included calcitriol (0.25 g/wk), calcium carbonate (3,000 mg/d), and aluminum hydroxide (3,000 mg/d). Acetylsalicylic acid (100 mg/d), buflomedil (600 mg/d), and subcutaneous enoxaparin (2,000 UI/d) were given to prevent vascular access dysfunction. Ascorbic acid (500 mg/d) was added in December 1994 and naftidrofuryl (600 mg/d) in August 1995. A first renal transplantation with a cadaveric kidney was performed on April 30, 1996. Initial immunosuppressive regimen included antithymocytic immunoglobulins, 100 mg/d, for 10 days; azathioprine, 50 mg daily, and oral prednisolone, 25 mg daily, at a progressive tapered dosage, and tacrolimus from the 10th day. The postoperative course
From the Department of Nephrology, Cliniques Universitaires St. Luc, Brussels; Departments of Internal Medicine and Pathology, Universite´ Catholique de Louvain, Brussels; and Renal Unit, Cliniques St. Pierre, Ottignies, Belgium. Work done at the Cliniques Universitaires St. Luc, Brussels, Belgium. Received December 10, 2001; accepted in revised form February 22, 2002. Address reprint requests to Charles van Ypersele de Strihou, MD, PhD, Department of Nephrology, Avenue Hippocrate, 1200 Brussels, Belgium. E-mail [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4001-0029$35.00/0 doi:10.1053/ajkd.2002.33934
American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: E3
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was characterized by persistent oligoanuria (daily urine output 100 to 200 mL) until the second transplantation. Hemodialysis was continued. Renal graft ultrasound disclosed no dilation of the excretory cavities. Serial nuclear imaging studies with technetium 99m (TechneScan MAG3) showed preserved renal blood flow but altered radiotracer concentration without excretion. The diagnosis of primary nonfunction was considered. A first kidney graft biopsy specimen obtained on the 10th postoperative day showed no glomerular, vascular, or rejection lesions but tubular epithelial necrosis and numerous crystals in the tubular lumen (Fig 1A). The crystals had a polyhedral or rhomboid shape and appeared as doubly refractile under polarized light, characteristics consistent with calcium oxalate crystals. A second biopsy specimen obtained 2 months after transplantation disclosed interstitial fibrosis, tubular atrophy, and persistent calcium oxalate crystals (Fig 1B). Oxalate crystals were absent in the native kidney removed at the time of transplantation and in the graft biopsy specimen obtained just before transplantation. The renal transplant was not removed. The immunosuppressive regimen was tapered, and only prednisolone (5 mg/d) was maintained. Other baseline drugs included calcium carbonate (2,000 mg/d), ranitidine (150 mg/d), and subcutaneous enoxaparin (3,000 UI Axa/d). Administration of ascorbic acid and naftidrofuryl, interrupted at the time of first transplantation, was not resumed to avoid any increase in the oxalate burden. On December 12, 1996, a second cadaveric renal transplantation was performed. Immunosuppression included a 500-mg intravenous methylprednisolone bolus followed by oral prednisolone, 20 mg daily; mycophenolate mofetil, 500 mg twice a day; and tacrolimus, 5 mg twice a day. The patient remained oligoanuric and required continued hemodialysis. Serial scintigraphic studies and Doppler ultrasound studies excluded vascular graft thrombosis. There was no evidence of ureteral obstruction or urinary leak at ultrasonography. The first graft biopsy specimen, obtained on the 10th postoperative day, revealed extensive tubular damage and massive intratubular calcium oxalate deposition (Fig 1C). Plasma oxalate concentration, measured immediately before transplantation (enzyme oxalate oxidase method), was 890 g/dL (98.8 mol/L), well within the range observed in patients with ESRF resulting from common nephropathies (mean value, 712 ⫾ 141 g/dL [79.0 ⫾ 15.7 mol/L]) and lower than that observed in patients with ESRF related to primary hyperoxaluria (mean value, 1296 ⫾ 287 g/dL [143.9 ⫾ 31.9 mol/L]). These results were provided by the Service de Biochimie Me´dicale–CHU Pitie´ Salpe´trie`re (Paris, France). The patient remained on dialysis with the following treatment: tacrolimus, 7 mg daily; prednisolone, 5 mg daily; and ticlopidine, 250 mg twice daily. Seven months later, predialysis serum creatinine fell progressively, from 7.3 mg/dL (645 mol/L) in early September to 4.1 mg/dL (362 mol/L) on November 3, 1997, with a concomitant rise of urinary output. On November 3, 1997, creatinine clearance reached 13 mL/min (0.217 mL/s), and hemodialysis was interrupted. Six months later, in May 1998, the serum creatinine fell to 2.4 mg/dL (212 mol/L) with a creatinine clearance of 28 mL/min (0.468 mL/s). Urinary oxalate levels, measured repeatedly between February and May
CUVELIER ET AL
1998, were significantly increased, ranging from 44.8 to 60.3 mg daily (497 to 669 mol) (normal range, 10 to 45 mg [111 to 500 mol] daily). On June 4, 1998, the patient developed pneumoccocal pneumonia and septic shock. Continuous hemodiafiltration followed by hemodialysis was required until July 9, 1998. Recurrent diarrhea during the revalidation phase was investigated further. A 3-day fecal fat collection showed increased fat loss (43.8 g; normal range, 0 to 7 g/d). An abdominal ultrasound revealed pancreatic calcifications and ductal dilation. Chronic pancreatitis with fat malabsorption and secondary hyperoxaluria was diagnosed. Review of the past history disclosed no alcohol consumption but an episode of acute cephalic pancreatitis in November 1994. At that time, serum levels of amylase and lipase were increased (1,540 IU/L; normal range, 20 to 220 IU/L, and 4,476 IU/L; normal range, 14 to 220 IU/L), and on computed tomography scan, the pancreas appeared enlarged with a single fluid collection without signs of chronic pancreatitis. The patient’s mother remembered foul-smelling stools for several years and intermittent diarrhea for about 1 year. The patient was treated with calcium carbonate and lipase supplementation (Creon). In December 1999, the serum creatinine was 2.1 mg/dL (185 mol/L) with a creatinine clearance of 27 mL/min (0.451 mL/s). Oxaluria reached 40.2 mg/d (446 mol). Serum creatinine was stable in September 2001 (3.0 mg/dL [265 mol/L]).
DISCUSSION
The present case is unique in two ways: first, early graft failure resulting from massive intratubular calcium oxalate precipitation in the absence of primary oxalosis in two successive grafts; second, a late unexpected graft function improvement after 11 months. The adequate graft blood flow and the absence of urologic complications despite postoperative oligoanuria led twice to a putative diagnosis of post-transplant acute tubular necrosis, the most common cause of delayed graft function in cadaveric transplant recipients.1 Transplant biopsy specimens performed 10 days after each transplantation displayed a unique picture, however, reminiscent of acute oxalate nephropathy: severe tubular epithelial necrosis with widespread intratubular calcium oxalate deposits. To our knowledge, this is the first report of immediate post-transplant graft failure attributed to acute oxalate nephropathy outside primary oxalosis. An extensive review of the literature revealed a similar case, reported in a veterinary journal.3 A cat, given two renal allografts, 14 days apart, for nonhyperoxaluric chronic renal failure, developed oxalate nephrosis in both allografts. The cause of the extensive calcium oxalate deposition was not identified.
RECURRENT GRAFT FAILURE AND ENTERIC HYPEROXALURIA
Fig 1. (A) Extensive oxalate crystal deposition in tubular lumen observed under half-polarized light in a biopsy specimen obtained 10 days after the first transplantation. (H&E, original magnification ⴛ 310.) (B) Biopsy specimen obtained 2 months after the first transplantation shows oxalate crystals occupying the lumen of atrophic tubules surrounded by interstitial fibrosis. (H&E, original magnification ⴛ 310.) (C) Recurrent crystal deposition in the tubular lumen in a biopsy specimen obtained 10 days after the second transplantation. (H&E, original magnification ⴛ 310.)
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In our patient, the recurrence of the same unusual picture in two successive grafts suggested not only a causal relationship between the massive deposition of calcium oxalate crystals and the transplants’ failure, but also the existence of a patient-related underlying disorder (ie, an abnormality of the oxalate metabolism). In humans, oxalic acid is either absorbed from the gastrointestinal tract or generated as an end product of the metabolism of glycine and ascorbic acid. Its only route of elimination is the kidney, with daily urinary oxalate excretion ranging from 10 to 45 mg.4 Hyperoxaluria, defined as a 24hour urinary oxalate excretion exceeding the 10to 45-mg range,5 may result in urolithiasis, nephrocalcinosis, progressive renal failure, and, rarely, acute renal failure secondary to massive intrarenal deposition of calcium oxalate.4 Hyperoxaluria is either inborn (primary hyperoxaluria) or acquired (secondary hyperoxaluria) as a consequence of increased oxalate production from exogenous precursors or from enhanced intestinal oxalate absorption. Primary oxalosis, a rare autosomal recessive disease, was excluded in our patient on clinical grounds. No calcium oxalate deposits were present in the native kidney removed at the time of first transplantation. Among the causes of secondary hyperoxaluria, accidental massive exposure to oxalate precursors was ruled out: ethylene glycol poisoning,6 star fruit ingestion,7 methoxyflurane anesthesia,8 or parenteral administration of large doses of naftidrofuryl or ascorbic acid.9-11 Serum oxalate levels increase in chronic renal failure as a result of impaired renal clearance, and significant oxalate retention occurs when the glomerular filtration rate falls to less than 20 mL/min/1.73 m2.12 Serum oxalate levels remain elevated despite the removal of oxalate during dialysis,13,14 a finding confirmed in our patient on maintenance hemodialysis for about 5 years. Before his first transplantation, the patient had been given ascorbic acid and naftidrofuryl, both oxalate precursors likely to augment the oxalate burden.15-18 As a result of oxalate retention, the newly grafted kidney excretes large amounts of oxalate during the first 24 to 48 hours after transplantation and returns serum oxalate to normal levels.19 A transient oxalate supersaturation and precipitation within the renal tubules may occur. It is unlikely that the additional burden
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resulting from the previous intake of ascorbic acid and naftidrofuryl was instrumental in the graft failure because the same picture with oxalate crystals in the tubular lumen recurred in the second allograft despite the withdrawal of both medications. The serum oxalate concentration measured before the first transplantation was within the range observed in hemodialyzed patients with ESRF not related to primary oxalosis. Overabsorption of oxalate and hyperoxaluria (enteric hyperoxaluria) have been reported in association with a variety of gastrointestinal disorders, such as Crohn’s disease, celiac sprue, intestinal lymphangiectasia, pancreatic insufficiency, extensive ileal resection, and jejunoileal bypass surgery for obesity.20-25 These conditions share a fat malabsorption with steatorrhea. In the absence of weight loss, abdominal pain, or diarrhea, no investigations had been undertaken in our patient before the onset of recurrent diarrhea in June 1998. A diagnosis of chronic pancreatitis with fat malabsorption and increased oxaluria was then made on the basis of steatorrhea, pancreatic calcifications with ductal dilation, and slightly but consistently elevated urinary oxalate levels. The episode of acute pancreatitis 4 years earlier further supported the diagnosis. The repeated graft failure likely resulted from an undiagnosed enteric hyperoxaluria caused by chronic pancreatitis with steatorrhea. Renal transplantation is not contraindicated in patients with enteric hyperoxaluria. Two such cases have been reported. The first patient with short-bowel syndrome maintained stable renal function 10 months after a successful cadaveric graft transplantation; the transplant biopsy specimen showed no evidence of recurrent oxalosis.26 The second patient, with ESRF after extensive small bowel resection, maintained good renal function 7 years after a successful transplantation despite persistent hyperoxaluria.27 In both cases, measures were taken to reduce hyperoxaluria and prevent graft oxalosis, including a diet low in oxalate and fat, oral calcium supplements to bind oxalate in the intestinal lumen, high fluid intake, and inhibitors of crystallization such as magnesium and citrate to prevent tubular precipitation of the filtered oxalate. Patients with enteric hyperoxaluria also might benefit from the additional measures advocated in patients with primary oxalosis: high-efficiency daily dialysis for
RECURRENT GRAFT FAILURE AND ENTERIC HYPEROXALURIA
5 to 7 days before transplantation with the intent to remove as much oxalate as possible, extreme post-transplantation urinary dilution, and early intensive post-transplantation dialysis.28 The late improvement of allograft function, 11 months after the second transplantation, is of interest. We previously reported the spontaneous recovery of renal function in a kidney transplant recipient who had developed an acute oxalate nephropathy after a parenteral overdose of naftidrofuryl.9 Renal function recovery from acute oxalate nephropathy is not unusual. Outside transplantation, several cases of spontaneous acute renal dysfunction were observed in association with enteric hyperoxaluria, most frequently in the setting of intestinal bypass operations for obesity.20,24 It was proposed that widespread intratubular precipitation of calcium oxalate led to tubular obstruction and damage but was followed by the subsequent dissolution of the crystals and the recovery of renal function. The outcome is not always as good, however: ESRF or limited recovery was reported in several other cases,21,23 perhaps as a result of the severity and the extent of the renal damage, the inability to resorb the calcium oxalate salts from the renal parenchyma, and a continuing oxalate deposition. Before concluding an unfavorable outcome, it would be wise to keep our patient’s history in mind and adopt a conservative course of action. In conclusion, this is the first description of a patient with ESRF not related to primary oxalosis who developed acute oxalate nephropathy in two renal allografts, 7 months apart, most probably secondary to enteric hyperoxaluria. This observation highlights the fact that in the presence of oxalate nephropathy or hyperoxaluria, intensive investigations are needed to uncover and treat the cause of hyperoxaluria, even in the absence of overt symptoms. Recovery from oxalate-induced graft failure may be slow and require an attentive patience from the attending physicians. REFERENCES 1. McKay DB, Milford EL, Tolkoff-Rubin NE: Clinical aspects of renal transplantation, in Brenner BM, Rector FC (eds): The Kidney. Philadelphia, PA, Saunders, 2000, pp 2542-2590 2. Hricik DE, Zarconi J, Schulak JA: Influence of lowdose cyclosporine on the outcome of treatment with OKT3
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for acute renal allograft rejection. Transplantation 47:272277, 1989 3. Gregory CR, Olander HJ, Kochin EJ, Gourley IM, Cousyn D, Levy J: Oxalate nephrosis and renal sclerosis after renal transplantation in a cat. Vet Surg 22:221-224, 1993 4. Williams HE: Oxalic acid and the hyperoxaluric syndromes. Kidney Int 13:410-417, 1978 5. Wandzilak TR, Williams HE: The hyperoxaluric syndromes. Endocrinol Metab Clin 19:851-867, 1990 6. Parry MG, Wallach R: Ethylene glycol poisoning. Am J Med 57:143-150, 1974 7. Chien-Liang C, Hua-Chang F, Kang-Ju C, Jyh-Seng W, Hsiao-Min C: Acute oxalate nephropathy after the ingestion of star fruit. Am J Kidney Dis 37:418-422, 2001 8. Frascino JA, Vanamee P, Rose PP: Renal oxalosis and azotemia after methoxyflurane anaesthesia. N Engl J Med 283:676-679, 1970 9. Cuvelier C, Goffin E, Cosyns JP, et al: Acute renal failure due to naftidrofuryl oxalate (Praxilene) overdose in a kidney transplant recipient. Nephrol Dial Transplant 10:17561758, 1995 10. Wong K, Thomson C, Bailer RR, McDiarmid S, Gardner J: Acute oxalate nephropathy after massive intravenous dose of vitamin C. Aust N Z J Med 24:410-411, 1994 11. Alkhunaizi AM, Chan L: Secondary oxalosis: A cause of delayed recovery of renal function in the setting of acute renal failure. J. Am Soc Nephrol 7:2320-2326, 1996 12. Morgan SH, Purkiss P, Watts RWE, Mansell MA: Oxalate dynamics in chronic renal failure. Nephron 46:253257, 1987 13. Ramsay AG, Reed RG: Oxalate removal by hemodialysis in end-stage renal disease. Am J Kidney Dis 4:123127, 1984 14. Mydlik M, Derzsiova K: Renal replacement therapy and secondary hyperoxalemia in chronic renal failure. Kidney Int 59:S-304-S-307, 2001 (suppl 78) 15. Thompson CS, Weinman EJ: The significance of oxalate in renal failure. Am J Kidney Dis 4:97-100, 1984 16. Shah GM, Ross EA, Sabo A, Pichon M, Reynolds RD, Bhagavan H: Effects of ascorbic acid and pyridoxine supplementation on oxalate metabolism in peritoneal dialysis patients. Am J Kidney Dis 20:42-49, 1992 17. Ono K: Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clin Nephrol 26:239-243, 1986 18. Moesch C, Charmes JP, Bouthier F, Leroux-Robert C: Calcium oxalate crystalluria in elderly patients and treatment with naftidrofuryl oxalate. Age Ageing 24:464-467, 1995 19. Worcester EM, Fellner SK, Nakagawa Y, Coe FL: Effect of renal transplantation on serum oxalate and urinary oxalate excretion. Nephron 67:414-418, 1994 20. Mandell I, Krauss E, Millan JC: Oxalate-induced acute renal failure in Crohn’s disease. Am J Med 69:628631, 1980 21. McDonald GB, Earnest DL, Admirand WH: Hyperoxaluria correlates with fat malabsorption in patients with sprue. Gut 18:561-566, 1977 22. Allen A, Clutterbuck E, Maidment G, Thompson E,
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Watts R, Pusey C: Enteric hyperoxaluria and renal failure associated with lymphangiectasia. Nephrol Dial Transplant 12:802-806, 1997 23. Wharton R, D’Agati V, Magun AM, Whitlock R, Kunis L, Appel GB: Acute deterioration of renal function associated with enteric hyperoxaluria. Clin Nephrol 34:116121, 1990 24. Ehlers SM, Posalaky Z, Strate RG, Quattlebaum FW: Acute reversible renal failure following jejunoileal bypass for morbid obesity: A clinical and pathological (EM) study of a case. Surgery 82:629-634, 1977
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25. Dobbins JW: Oxalate and intestinal disease. J Clin Gastroenterol 1:165-169, 1979 26. Roberts RA, Sketris IS, MacDonald AS, Belitsky P: Renal transplantation in secondary oxalosis. Transplantation 45:985-986, 1987 27. Kitsler H, Peter T, Thiel G, Brunner FP: Seven-year survival of renal transplant for oxalate nephropathy due to short-bowel syndrome. Nephrol Dial Transplant 10:14661469, 1995 28. Scheinman JI: Primary hyperoxaluria: Therapeutic strategies for the 90s. Kidney Int 40:389-399, 1991