Recurrent and de novo diabetic nephropathy in renal allografts.

BACKGROUND: Histologic findings of diabetic nephropathy (DN) are observed in allografts of patients with pretransplant (PreTx) diabetes mellitus (DM) and in patients who develop DM posttransplant (PostTx). Patients with allograft biopsies (Bx) were retrospectively studied to determine the incidence of recurrent and de novo DN and to ascertain what, if any, risk factors predispose to histologic DN in either patient population. METHODS: From the renal transplant services at four hospitals from 1992 to 2000, the authors identified all patients with PreTxDM and PostTxDM (n=81). Those with renal biopsies performed >/=18 months PostTx were classified according to the presence or absence of histologic DN (Bx-positive, n=23; Bx-negative, n=35). Patients were then subdivided into four categories-recurrent DN (n=16), de novo DN (n=7), no recurrent DN (n=27), and no de novo DN (n=8)-for analyses. RESULTS: Among these 58 patients, 74.1% had PreTx and 25.9% had PostTx diabetes. Of those with histologic DN, 69.6% were recurrent DN and 30.4% were de novo DN, making de novo DN at least as likely to develop as recurrent DN. After the onset of diabetes in the de novo population, the time to development of histologic DN was similar in the recurrent and the de novo patients (6.68+/-3.86 years vs. 5.90+/-3.13 years, P=0.66) and more rapid than previously reported. Apart from a more frequent family history of hypertension in patients with allograft DN compared with those without allograft DN, known risk factors for the development of native DN did not significantly differ among patients in the four cohorts. Proposed risk factors related to transplantation did not correlate with the development of recurrent or de novo DN. CONCLUSION: Among patients with histologic DN, de novo DN occurred at least as frequently as recurrent DN, and the time to onset of histologically apparent DN was more rapid than previously reported. Neither the usual clinical predictors of DN nor clinical variables related to transplantation clearly distinguished the group with DN from the group without it, potentially implicating novel mechanisms in its pathogenesis.

Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome.

Apparent mineralocorticoid excess (AME) syndrome is a rare inherited disorder caused by 11beta-hydroxysteroid dehydrogenase (11-HSD 2) isozyme deficiency in the kidney. This enzyme is responsible for oxidizing cortisol to its inactive metabolite cortisone. An elevated tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF) to tetrahydrocortisone (THE) ratio in the urine is pathognomonic of AME syndrome. Clinical features include hypertension, hypokalemia, alkalosis, reduced plasma renin activity (PRA), low aldosterone levels, and occasionally nephrocalcinosis. Here we describe a 13-year-old boy who presented with severe hypertension, hypokalemia, low PRA and aldosterone levels, and elevated THF plus aTHF/THE ratio in the urine consistent with a diagnosis of AME syndrome. On ultrasound examination, he had severe nephrocalcinosis, and bilateral renal cysts. Renal cysts have not been previously reported in AME syndrome. The development of nephrocalcinosis and renal cysts may be associated with chronic long-standing hypokalemia. An early diagnosis and treatment of AME syndrome could help to prevent these sequelae, and to preserve renal function.

Recent advances in the understanding and management of primary vesicoureteral reflux and reflux nephropathy.

Vesicoureteral reflux and reflux nephropathy continue to be active areas of clinical investigation. There is conclusive evidence that vesicoureteral reflux is inherited. Prenatal diagnosis offers the opportunity for early recognition and intervention that may reduce the incidence of complications of vesicoureteral reflux such as pyelonephritis episodes and the development of reflux nephropathy.

Nephronophthisis associated with Ellis-van Creveld syndrome.

Ellis-van Creveld (EvC) and Jeune's asphyxiating thoracic dystrophy (ATD) are related disorders characterized by narrow thoracic cage and short-limbed dwarfism. Some patients have overlapping features of both ATD and EvC, indicating that these syndromes may be a part of a disease spectrum. Nephronophthisis has been occasionally reported in patients with ATD, but not with EvC syndrome. We report a patient who was diagnosed with EvC syndrome at birth. He developed hypertension at 5 months of age and gradually progressive renal failure, requiring renal transplantation at 8 years. Histopathological findings in the nephrectomy specimen were indicative of nephronophthisis. The association of nephronophthisis in a patient with EvC syndrome has not been reported previously. This association further supports the hypothesis that ATD and EvC syndromes are related and represent a spectrum of disorders.

Protracted, gross hematuria in sickle cell trait: response to multiple doses of 1-desamino-8-D-arginine vasopressin.

Gross and microscopic hematuria are well-known complications in patients with sickle cell hemoglobinopathy. Most of these episodes of gross hematuria are self limiting, but rarely may be severe and persistent requiring definitive intervention. Before subjecting these patients to surgical management such as partial or total nephrectomy, several medical therapies of variable benefit have been suggested. We report a patient with sickle cell trait who experienced severe, intractable gross hematuria for 5 months and showed a dramatic response to multiple doses of 1-desamino-8-D-arginine vasopressin (DDAVP) infusion. The remarkable response observed in this patient suggests that treatment with DDAVP infusion may be considered in patients with unremitting gross hematuria associated with sickle cell trait.

Long-term cyclosporine A treatment of steroid-resistant and steroid-dependent nephrotic syndrome.

Eighteen patients with steroid-resistant nephrotic syndrome (SRNS) and steroid-dependent nephrotic syndrome (SDNS) were treated with cyclosporine A (CyA) (6 mg/kg/d) for 2 to 29 months. CyA levels were monitored monthly and plasma levels by Abbott TDX (Therapeutic Drug Analyzer System) fluorescence polarization immunoassay were maintained at 100 to 150 ng/mL. The corticosteroid dosage administered at the time CyA therapy was initiated was variable and was continued following CyA therapy. Six of these patients (all with SDNS and minimal change nephrotic syndrome [MCNS]) had been treated with one or more courses of cytotoxic drug therapy, and all had clinical evidence of corticosteroid toxicity after receiving corticosteroid therapy for 26 to 120 months. The corticosteroid dosage was reduced by slow tapering and was ultimately discontinued in six patients. These patients were maintained on CyA monotherapy for 7 to 21 months at a dose of 3.2 to 6.7 mg/kg/d. Following 11 to 29 months of CyA therapy, seven patients underwent an elective renal biopsy, which showed nephrotoxicity in all seven. This led to discontinuation of CyA in four patients. Following discontinuation of CyA monotherapy, all four patients relapsed within 2 to 4 months. CyA therapy did not achieve a remission in 10 patients with SRNS regardless of the presence of focal segmental glomerulosclerosis (FSGS) or MCNS on renal biopsy. In conclusion, CyA has limited effectiveness in patients with SDNS who manifest corticosteroid toxicity; however, CyA should be used cautiously because of the potential for CyA nephrotoxicity and the failure to obtain a sustained remission following discontinuation of CyA monotherapy. CyA dependence is substituted for corticosteroid dependence.

Improved cadaveric renal transplant outcome in children.

We analyzed the results of 165 pediatric cadaver renal transplants performed at the University of California at Los Angeles to identify the factors which are linked to improved allograft survival. Both univariate life-table analysis and the Cox proportional hazard model were used. The use of a sequential immunosuppressive regimen (P less than 0.001) and kidneys from donors of more than 6 years of age (P less than 0.001) were found to be the factors having the most influence on primary graft survival. The sequential regimen was the only factor favorably influencing retransplants. With sequential therapy 1- and 2-year actuarial graft survival rates were 94% and 91% in primary transplants, and 82% and 70% in retransplants. Medication noncompliance exerted a large negative effect on transplant outcome. Of 70 recipients who had been on cyclosporine for at least 6 months, 50% evidenced noncompliance. Sixty-four percent of adolescents were noncompliant. Thirteen percent of the recipients lost their graft because of noncompliance. We conclude that good results can be obtained with cadaver renal transplants in children with a sequential immunosuppressive regimen and the use of kidneys from adolescent and adult donors. Noncompliance is a great barrier to long-term success in pediatric transplantation.

Induction of membranous nephropathy in rabbits by administration of an exogenous cationic antigen.

We examined the role of antigenic electrical charge as a determinant of glomerular immune complex localization in the rabbit. Serum sickness nephritis was induced in groups of New Zealand white rabbits by daily 25-mg intravenous injections of bovine serum albumin (BSA) chemically modified to be cationic (pI > 9.5) or more anionic (pI, 3.5-4.6); an additional group received unmodified native BSA (pI, 4.5-5.1). Factors known to influence immune complex localization, e.g., molecular size of the administered antigen and resulting circulating immune complexes, immunogenicity, and disappearance time from the circulation were examined and found to be similar for both anionic and cationic BSA. Charge modification did increase the nonimmune clearance of cationic and anionic BSA compared with native BSA. Injected cationic BSA was shown in paired label experiments to bind directly to glomeruli compared with native BSA. The renal lesion produced by cationic BSA was markedly different from that found in rabbits given anionic or native BSA. Animals receiving cationic BSA uniformly developed generalized diffuse granular capillary wall deposits of IgG, C3, and BSA detected after 2 wk of injections and increasing until death at 6 wk. Qualitatively similar deposits were produced by the administration of low doses of cationic BSA of only 1 or 10 mg/d. In contrast, the injection of both anionic and native BSA resulted in mesangial deposits at 2 and 4 wk with capillary wall deposits appearing by 6 wk. Ultrastructural examination of animals receiving cationic BSA revealed pure, extensive formation of dense deposits along the lamina rara externa of the glomerular basement membrane whereas such deposits were absent or rare in animals injected with the anionic or native BSA. Albuminuria was significantly greater at 6 wk in the groups receiving cationic BSA with a mean of 280 mg/24 h compared with 53 mg/24 h in the combined groups injected with anionic or native BSA. Blood urea nitrogen values were similar in all groups at 2 and 4 wk but higher in the animals receiving cationic BSA at 6 wk. These experiments describe the reproducible induction of epimembranous immune deposits by administration of an exogenous cationic antigen. They suggest that antigenic charge can play an important role in the pathogenesis of membranous nephropathy by permitting direct glomerular binding of an antigen and predisposing to in situ immune complex formation.