F. Bryson Waldo

Methylprednisolone treatment of patients with steroid-resistant nephrotic syndrome

Treatment with a combination of pulse methylprednisolone (MP) and an alkylating agent has been reported to induce long-term remission of proteinuria in patients with steroid-resistant nephrotic syndrome (SRNS). We have treated 13 patients with SRNS with a course of pulse MP. There were 8 black patients and 5 white; 10 had a biopsy diagnosis of focal segmental glomerulosclerosis (FSGS) and 3 nil lesion. Initially 5 patients responded and 2 partially responded. Of the responding patients, 5 relapsed while treated with alternate-week MP therapy. Of these relapsing patients, 3 received a second course of MP plus chlorambucil; 2 responded. The patients were observed for a mean of 47 months (range 4–64 months). When last seen only the 3 patients with a biopsy diagnosis of nil lesion were protein free. There were no complications of steroid therapy. Six patients currently have end-stage renal disease and 2 have renal insufficiency. All of the 6 patients with no response to treatment were black. These data suggest that a course of pulse MP therapy alone induces short-term remission of the nephrotic syndrome in some white patients with FSGS, but in almost no blacks. Patients who relapse may respond to retreatment, but addition of an alkylating agent does not appear to induce longterm remission in patients with FSGS.

Alternate-Day Prednisone Therapy in Children With IgA-Associated Nephritis

IgA nephropathy (IgAN) leads to renal failure in up to 30% of affected children and adults. There is currently no consensus on therapy in IgAN. Six patients with risk factors for disease progression were identified based on clinical or histologic findings. These patients were treated with alternate-day prednisone for 12 to 60 (mean, 36) months and followed for 28 to 60 (mean, 54) months. Follow-up biopsies were available in four patients. At last examination all treated patients had normal urinalysis and serum creatinine level. Follow-up biopsies showed stable or improved glomerular histology in three of four patients. One patient had a slight worsening of the interstitial disease. No steroid toxicity was observed. The outcome of these treated patients was compared with that of 15 comparable patients from another center who received no treatment and with patients from two published clinical pathology series. A normal urinalysis was found at follow-up in all treated patients, compared with one of 15 untreated patients (P = 0.003). None of the patients in the published series with comparable disease had normal urinalysis at follow-up. End-stage renal disease or renal insufficiency occurred in seven of 15 untreated and no treated patients (P = 0.19). The data strongly support the need for a prospective control trial of prednisone therapy in IgAN.

Therapy of focal and segmental glomerulosclerosis with methylprednisolone, cyclosporine A, and prednisone

Abstract. Patients with steroid-resistant focal and segmental glomerulosclerosis (FSGS) have a poor prognosis but may benefit from high-dose methylprednisolone or cyclosporine A therapy. Ten patients were treated with a protocol of methylprednisolone infusions for 8 weeks followed by a combination of cyclosporine A and alternate-day prednisone for maintenance of remission for 2 weeks. Eight of ten patients remitted the nephrotic syndrome within 8 weeks of beginning treatment. One patient remitted edema but remained proteinuric, and one did not respond. After observation for 12 – 24 months, seven patients maintained remission with normal glomerular filtration rate. One non-responder had renal insufficiency and one patient had secondary non-response and end-stage renal disease. No patients developed hypertension. One patient had the diagnosis of Hodgkin disease made after 10 months of therapy. Follow-up renal biopsy in four patients showed no evidence of progressive interstitial disease. There were no other major side effects. Steroid-resistant FSGS may be successfully treated with the described protocol. Additional studies will be needed to determine if this approach prevents progression of renal disease.

Aggressive therapy of infants with renal failure

Nine infants, who presented with renal failure within the first 3 months of life, were treated with continuous ambulatory peritoneal dialysis (CAPD). Seven infants survived to an age of 12–15 months, when they received transplants. Two patients died while on CAPD. Six infants are alive with a functioning renal allograft, at an average age of 35.5 months and an average of 22 months post-transplant. Neurological development is normal in four of the six infants tested. The mean current height of the six transplant recipients is just below 2 SD from the mean.

Therapy of focal segmental glomerulosclerosis with cyclosporine A

Six patients with biopsy-documented focal segmental glomerulosclerosis were treated with cyclosporine A (CyA) a new and potent T-cell suppressant. Dosage was adjusted to maintain trough levels between 100 and 300 ng/ml (whole blood radioimmunoassay). Patients were treated for 6 weeks or until unacceptable drug toxicity occurred. In one patient proteinuria was significantly reduced. This same individual was the only patient treated within 6 months of diagnosis. Therapy was discontinued in two patients at week 4, one because of worsening renal failure and one because of hypertension. These complications occurred despite trough CyA blood levels of less than 300 ng/ml. The results suggest that further and controlled studies of CyA are warranted in the therapy of nephrotic syndrome associated with focal segmental glomerulosclerosis, especially when used early in the course of disease. The data also suggest enhanced toxicity of CyA in patients with active nephrotic syndrome.

IgA nephropathy databank: Development of a system for management of renal biopsy acquired data☆

T HE DEVELOPMENT of comprehensive systems for the identification and follow-up of patients with IgA nephropathy (IgAN) will better establish the importance of IgAN as a cause of end-stage renal disease (ESRD); provide a readily available resource for testing hypotheses about the pathogenesis, natural history, and possible treatment interventions for IgAN; and gain epidemiologic data about IgAN in the United States. On April 12 and 13, 1996, a group of renal pathologists and nephrologists met at the Medical Education and Research Institute in Memphis, TN, to discuss the development of a regional databank for IgAN and to reach a consensus on how renal biopsy data will be managed in that databank. The term “databank” is used instead of “registry” to emphasize the concept that the information stored in the database is meant to be accessible to all serious investigators interested in IgAN. For over 15 years, Drs Robert J. Wyatt and Bruce A. Julian, with the collaboration of many renal pathologists and nephrologists in the fourstate region of Kentucky, Tennessee, Alabama, and Mississippi, have identified many of the known cases of IgAN in the region. The IgAN databank has been established in Memphis for entry of the clinical data for these patients. At the time of this conference, 987 patients from this region had been identified, and clinical data for almost 300 (mostly from the Lexington, KY, and Memphis, TN, areas) have been entered into the IgAN databank. The database was designed using the Macintosh-based relational database, 4th Dimension (ACIUS, Cupertino, CA) and may be accessed via modem. The latest version of 4th Dimension is platform independent, allowing use by both Windows and Macintosh operating systems. The purpose of the presentations on April 12, 1996, was to develop the framework for a discussion on the development of a system for the management of renal biopsy data in the IgAN data-

Macroscopic Hematuria and Proteinuria Preceding Renal IgA Deposition in Patients With IgA Nephropathy

Although the clinical onset of IgA nephropathy is frequently impossible to define, macroscopic hematuria apparently heralds the onset of the disease in some patients. We describe the clinical course and renal histologic findings of four adults with IgA nephropathy who were diagnosed by the characteristic immunohistologic features in a second renal biopsy specimen. IgA was not detected in the initial renal biopsy specimens obtained 9 months to 4 years earlier. The first renal biopsy had been performed to evaluate macroscopic hematuria (recurrent in three patients), accompanied by pathologic proteinuria in two patients. Our observations suggest that the pathognomonic immunohistologic findings of IgA nephropathy may follow the clinical onset and raise questions about the presumed pathogenetic role of IgA in the early stages of this disease.

Zinc and copper balance in children on continuous ambulatory peritoneal dialysis

We monitored serum zinc and copper levels for 4 months in six patients treated with continuous ambulatory peritoneal dialysis (CAPD). Zinc and copper fluxes were studied during a single dialysis exchange and over a 3-day period. Routine oral trace element supplements were then discontinued for 2 months. Serum zinc levels declined but serum copper levels remained unchanged. One month after oral supplements had been restarted, serum zinc levels returned to normal and serum copper levels rose above initial values. Zinc and copper concentrations in dialysis exchange indicated that the patients absorbed zine and lost copper in significant amounts. The patients had poor dietary intakes of both minerals. These data suggest that patients treated with CAPD benefit from oral zinc supplementation.

Role of IgA in IgA nephropathy

IgA nephropathy (Berger disease) is defined by the dominant or codominant deposition of IgA in the renal mesangium. There is much evidence in vitro to suggest up-regulation of the IgA immune response in patients. Data from tonsillar and bone marrow-derived lymphocytes and from in vivo immunization studies indicate that the primary defect is an up-regulated systemic one, rather than mucosal IgA production. Several lines of evidence suggest that increased IgA production alone is inadequate to explain the pathogenesis of Berger disease. Murine models of IgA nephropathy indicate that local complement activation mediated by deposited IgG is essential for mesangial cell proliferation and subsequent renal injury. Circulating immune complexes from patients with Berger disease contain IgA and IgG within the same lattice. In vitro studies of model immune aggregates containing various mixtures of IgA and IgG indicate that the IgG is the site of complement activation and fixation. The IgA in the aggregate actually inhibits both complement activation and binding to erythrocyte complement receptor CR1. This effect of IgA may prevent effective immune complex clearance. In future studies, more emphasis should be placed on the roles of IgG and complement in the pathogenesis of IgA nephropathy.

Racial incidence of hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children and is caused by infection with verotoxin-productingEscherichai coli. There is no consensus on the relative incidence of HUS in blacks and whites. An equal racial incidence has been reported by two centers with small black populations. A series from Washington D. C. reported a low incidence in blacks. The population of Alabama is 32% black and 66% white. The Childrens Hospital of Alabama admission rate has a similar racial distribution (35% black, 65% white). A record review from 1980–1992 identified 45 patients with HUS; 43 (96%) were white and only 2 (4%) were black. Based on census data for Alabama in 1980 and 1990, this gives an average annual incidence of HUS of 0.45 per 100,000 in whites and of 0.043 per 100,000 in blacks (P<0.001, Fischers exact test). Similar results were found in the group of patients with HUS and a history of diarrhea; whites 0.39 and blacks 0.02 (P<0.001). However, in those with no history of diarrhea there was no significant racial difference: whites 0.05 and blacks 0.02. There were too few blacks to compare clinical course and outcome. We conclude that typical diarrhea-associated HUS is a relatively rare disease in blacks compared with whites. The reasons are unclear.