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Successful Renal Transplantation in a Patient with Congenital Generalized Lipodystrophy: A Case Report

Year: 2004

Type: article

Abstract: This report documents what we believe to be the first successful case of renal transplantation in a patient with total lipodystrophy, a rare disorder of lipid metabolism. EC, a 47-year-old female, presented to our center with congenital generalized lipodystrophy and renal failure. She originally presented as a ‘case for diagnosis’ at age 8 months, as previously documented in the literature (1). Associated with her primary diagnosis were insulin-resistant diabetes mellitus, hypertriglyceridemia, steatohepatitis, and episodes of pancreatitis. Atypical for persons with congenital lipodystrophy, she had five term pregnancies and one miscarriage. She developed chronic renal failure at age 42, and progressed with nephrotic range proteinuria to end-stage renal disease at age 45. A renal biopsy was not performed. She was begun on hemodialysis at age 45, which was complicated by uremic pericarditis and GI bleeding. Upon evaluation for renal transplantation she had hematuria, and 10 g of protein on a 24-h urine collection. ANA was negative. Serum complements were not obtained. On physical exam, there was a comprehensive absence of adipose tissue, acromegaloid features, hepatomegaly and a systolic ejection cardiac murmur. Laboratory studies demonstrated a serum creatinine of 11 mg/dL, BUN 127 mg/dL, and fasting lipid panel with total cholesterol 213 mg/dL, triglycerides 1000 mg/dL, HDL 33 mg/dL, and LDL 178 mg/dL. The c-peptide was markedly elevated to 30.7 ng/mL, indicative of profound insulin resistance combined with renal failure. Owing to cholelithiasis and a history of pancreatitis, she underwent a pretransplant cholecystectomy and a liver biopsy, which revealed steatohepatitis, with mild steatosis, minimal inflammatory infiltrate and perisinusoidal fibrosis. Before transplantation, the patient's lipids were aggressively controlled with an HMG co-A reductase inhibitor, fenofibrate as well as omega-3 fatty acid supplements (fish oil) and high doses of insulin (>200 units daily). Just before transplantation, her hemoglobin A1C was 5.9%, her fasting glucose was less than 130, and her triglycerides were reduced to less than 300 mg/dL. In June 2001, the patient underwent a living-related renal transplant from her haploidentical brother. The transplant was technically uneventful with the exception of a strikingly barren retroperitoneum void of adipose tissue. It is also notable that despite a long-standing history of severe hyperlipidemia, her iliac vessels were grossly uninvolved with atherosclerotic disease. She received preoperative thymoglobulin, methylprednisolone and mycophenolate mofetil, and was maintained postoperatively on tacrolimus, mycophenolate and prednisone. She recovered without complication. At 3 months postoperatively, her creatinine clearance was 98cc/min/1.73 m2 and urine protein excretion 243 mg. Her prednisone was poorly tolerated and was withdrawn owing to aggressive periorbital adipose deposition, edema and a 10-kg weight gain at 6 months post transplantation. This resolved upon steroid withdrawal, although discontinuation of steroids did not have a substantive effect on her overall metabolic condition and her weight stabilized approximately 7 kg greater than her pretransplant weight. At 1 year, her transplant biopsy showed no evidence of rejection, lipid deposition or recurrent disease (Figure 1). Her serum creatinine at that time was 1.0 mg/dL, and her urinalysis revealed no protein by dipstick or cellular elements. A 24-h urine collection demonstrated a creatinine clearance of 103 cc/min/1.73 m2 and absence of significant proteinuria. Photomicrograph of a renal allograft biopsy taken 1 year after renal transplantation in the described patient with congenital generalized lipodystrophy. The biopsy has normal architecture and no evidence of allograft rejection or lipid accumulation. This biopsy was obtained before the patient was placed on leptin therapy. Fourteen months following transplantation, EC was entered into a NIH protocol to evaluate the efficacy of recombinant leptin on the progression of lipodystrophy. On entry her microalbumin excretion was 37 mg/day. She was treated with 0.08 mg/kg/day subcutaneously of recombinant leptin. This was temporally associated with an 8-kg weight loss and stabilized with increased dietary intake at her pretransplant weight. Within 4 months, her insulin requirement had dropped substantially (200 units daily to 80 units daily). After 8 months, she was euglycemic and off all exogenous insulin. After 12 months, she maintained normal lipids without fenofibrate or fish oil. Her creatinine clearance and total protein excretion were similar to levels seen at 1 year and her urine microalbumin excretion had fallen to 9.9 mg/day. A total complement activity (CH50) was normal at 121 CAE units with C3 and C4 levels stable and within normal limits (97 and 21 mg/dL, respectively). She currently maintains control of her diabetes and lipids with leptin alone. Her current serum creatinine is 1.0 mg/dL with normal CH50, C3 and C4, and normal microalbumin excretion of 12.1 mg/day. Lipodystrophy is a rare and heterogeneous disorder characterized by the absence of adipose tissue. The most common form of lipodystrophy is partial lipodystrophy. First described in the literature in 1885 by Wier-Mitchell, partial lipodystrophy involves localized body parts, typically the face and upper half of the trunk (2). Generalized lipodystrophy, first described by Lawrence in 1946, occurs less frequently, and involves the complete absence of subcutaneous adipose tissue (3). It can be characterized as either congenital or acquired, and is slightly more common in women than in men (4). Congenital generalized lipodystrophy is inherited in an autosomal recessive manner, and is typically first diagnosed during infancy by the absence of subcutaneous fat. The acquired form is thought to follow an undefined illness or infection (5). There are many metabolic and systemic illnesses associated with both partial and generalized lipodystrophy. Most are a result of defective lipid metabolism. These include severe insulin resistance, renal failure, hypertriglyceridemia, hepatic steatosis, and pancreatitis (6). The etiologic basis for the renal disease in our patient with congenital generalized lipodystrophy is unknown, but was characterized by nephrotic range proteinuria. Although not generally recognized, proteinuric forms of renal disease appear to be a feature of both congenital and acquired forms of complete lipodystrophy (E. Javor, in preparation, 2003). There are only three case reports of renal disease associated with these disorders (7-9). In contrast, membranoproliferative glomerulonephritis (MPGN) is well known to be associated with acquired partial lipodystrophy. Patients with partial lipodystrophy typically present with MPGN II, including renal insufficiency in the presence of low serum C3 levels and prominent C3 nephritic factor (10). Up to 90% of patients with partial lipodystrophy are thought to develop MPGN type I or II, with greater than 50% progressing to renal failure (11, 12). A review of the literature found only four cases of renal transplantation among patients with all forms of lipodystrophy (8,13-15). Three of these cases involved patients with partial lipodystrophy, and the results were mixed. The remaining report addressed the case of congenital generalized lipodystrophy and documented an unsuccessful attempt at renal transplantation. These studies were all performed before the advent of modern lipid-lowering therapeutics. The first documented report of attempted renal transplantation in a patient with partial lipodystrophy involved a 25-year-old male with MPGN II, who in 1979 underwent transplantation. The graft was lost to early acute rejection. This patient underwent retransplantation nearly 15 years later and at a 5 years' follow up had good renal function (13). Schmidt et al. reported a second case of a patient with partial lipodystrophy who underwent two consecutive renal transplantations. The first was rejected, with evidence of recurrent intramembranous disease within 7 months. The second allograft had stable function at 22 months despite evidence, once again, of recurrent intramembranous disease (14). Chopra et al. described a patient from India with partial lipodystrophy transplanted for MPGN II. A successful transplant without evidence of recurrent disease was documented at 20 months (15). Casali et al. reported the only documented case in the literature of congenital generalized lipodystrophy and renal transplantation. One month after transplantation in 1978 there were massive lipid deposits in the renal tubules with necrosis and hemorrhage. The patient expired 2 months later from pulmonary sepsis (8). This report raised the speculation that the uncontrolled lipid deposits were to be expected in the generalized form of this disease and thus represented a non–immunological barrier to transplantation. Leptin is a hormone produced primarily in adipose tissue which signals adequate nutrition (16). Normally, leptin curbs appetite (17) and stimulates oxidation of fat (18). As patients with generalized lipodystrophy lack significant adipose tissue, they are consequently deficient in leptin. Fat therefore accumulates in ectopic areas such as muscle and liver, leading to diseases such as diabetes (19) and steatohepatitis (20). Replacing leptin reverses the abnormal fat deposition and subsequent metabolic abnormalities in these patients (21). Despite the success of leptin therapy in our patients with lipodystrophy, to date it remains an investigational drug. Therefore, we were hesitant to initiate leptin therapy immediately post-transplant. Fourteen months after demonstrating a successful renal transplant and continuing aggressive management of her diabetes and hyperlipidemia, we started EC on leptin therapy. Treatment with leptin has resulted in dramatic improvement in glycemic control (HbA1c 6.5% off antidiabetic medications) and normalization of her lipid profile (triglycerides 103 mg/dL off antilipid treatments). Based on our experience, and the marked improvement in pharmacological agents for the control of hyperlipidemia, we feel that renal transplantation is not only possible, but should be considered for patients with end-stage renal disease associated with all forms of lipodystrophy. Aggressive perioperative glucose and lipid management as well as improvements made in immunosuppresion since the Casali case (8) are contributory to the success of this surgery. The advent of leptin as a systemic therapy for this disorder will also likely improve the outcome of patients suffering from this disease. This case, viewed in conjunction with the successful results of Chopra (15) with a partial lipodystrophy patient, demonstrates that selected patients with end-stage renal disease and lipodystrophy may enjoy success following kidney transplantation.

Source: American Journal of Transplantation

DOI: 10.1111/j.1600-6143.2004.00358.x