Long-Term Renal Allograft Survival After Posttransplantation Diagnosis of Primary Hyperoxaluria

Abstract

Primary hyperoxaluria (PH) is a rare metabolic disorder with autosomal recessive inheritance characterized by excessive production and systemic deposition of oxalate. Unfortunately, the diagnosis in some patients is not made until after kidney transplantation. These grafts are nearly always lost unless the patient receives a liver transplant to correct the underlying defect in oxalate metabolism. We describe a patient who developed extensive oxalate deposition within her transplanted kidney necessitating a return to hemodialysis (HD). After treatment with pyridoxine, high-flux dialysis, and substitution of sirolimus for Cyclosporin A, she ceased dialysis and maintained stable allograft function. A 47-year-old woman was admitted for a deceased-donor kidney transplantation in 2006 with kidney failure attributed to reflux nephropathy and a history of traumatic nephrectomy during childhood. She underwent peritoneal dialysis before transitioning to HD for 3 years. Her medical history included painful peripheral neuropathy and small-joint polyarthropathy characterized by subperiosteal erosions. Surgery was uncomplicated with immediate graft function. Immunosuppression consisted of induction with basiliximab and maintenance with prednisolone, mycophenolate mofetil, and cyclosporin. Kidney biopsies performed on days 7 and 11 after transplantation, for an unexplained decline in renal function, showed changes of mild acute tubular necrosis. A further decline in kidney function on day 22 prompted another biopsy that demonstrated extensive deposition of calcium oxalate crystals with associated tubular damage (Fig. 1).FIGURE 1: Kidney biopsy at 3 weeks after transplantation showing extensive oxalate deposition. A, hematoxylin and eosin. Original magnification, ×100. B, under polarized light. Original magnification, ×400.Given the likely diagnosis of PH, daily high-flux HD, pyridoxine (1), dithiazide, magnesium and phosphate supplements, and a low-oxalate diet were commenced (2). Urinary oxalate excretion was elevated at 1.2 mM/day (normal, <0.6 mM/day). Cyclosporin was ceased given the association with hyperoxaluria and hypocitraturia, renal calcium-oxalate deposition (3), and poor kidney transplantation outcomes (4, 5). The serum creatinine stabilized at 150 μM/L after 5 weeks. Rapid and extensive deposition of oxalate within the small joints of the hand resulted in a gross deforming polyarthropathy and, within the bone marrow, led to refractory anemia. The diagnosis of type-1 hyperoxaluria was confirmed by genetic testing where a mutation in the alanine:glyoxylate aminotransferase (AGT) gene (homozygous 508A missense mutation, Gly170Arg) was identified. Subsequent family screening identified several other family members with the same AGT gene mutation. A protocol kidney biopsy at 3 months showed acute T-cell–mediated rejection (Grade IB) and persistent oxalate deposition. The rejection resolved after three doses of methylprednisolone and addition of sirolimus. Eight months after transplantation, she had a prolonged hospital admission with an ischemic toe requiring amputation, Clostridium difficile colitis, and extensive deep-vein thrombosis. A rise in serum creatinine prompted a biopsy that demonstrated T-cell–mediated rejection (Grade IA) and extensive oxalate deposition. Because of her multiple medical problems, the rejection episode was not treated. HD was recommenced and immunosuppression (prednisolone, mycophenolate mofetil, and low-dose sirolimus; levels 4–6 ng/mL) continued to preserve residual graft function and aid in oxalate clearance. While on HD, she maintained a daily urine output of 1.5 to 2 L/day. After 18 months of HD, the patient’s predialysis serum creatinine began to decline. HD was slowly weaned, and she now maintains a serum creatinine level of 175 μmol/L 5 years later. PH type 1 is caused by a deficiency of the liver-specific peroxisomal enzyme AGT, and PH type 2 is caused by a deficiency of the cytosolic/mitochondrial enzyme glyoxylate/hydroxypyruvate reductase (2). PH type 3 has only recently been described and is caused by the loss of function of the mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme (6). Clinical presentation of PH is heterogenous, often leading to delayed diagnosis. Prognosis and treatment options vary according to the type of PH (reviewed in Hoppe [7]). Liver transplantation with or without kidney transplantation is the only cure for PH type 1. Transplantation outcomes in children and adults with PH demonstrate better kidney graft survival in patients with combined liver-kidney transplantation (8, 9) than in those with kidney transplantation alone. However, in patients with PH type 1 with the homozygous G170R mutation of alanine-glyoxalate aminotransferase and who are responsive to pyridoxine treatment, kidney transplantation alone may be considered (10). Late diagnosis of PH is not uncommon, and it is important to secure the genetic mutation involved as soon as possible. Our patient has a mutation that responded to pyridoxine treatment (11). This case also illustrates that it is possible to preserve kidney allograft function in some patients with PH. Furthermore, replacing Cyclosporin A with a mammalian target of rapamycin inhibitor may reduce oxalate deposition and contribute to improved graft outcomes (12). Veena Roberts 1 Sid V. Rajakumar1 Sandra Crikis2 Karen M. Dwyer1 Prudence A. Hill3 David J. Goodman1 1Department of Nephrology St Vincent’s Hospital Melbourne Melbourne, Australia 2Department of Nephrology Western Health Fitzroy, Australia 3Department of Anatomical Pathology St Vincent’s Hospital Melbourne Melbourne, Australia