Claude G. Biava

Recurrent focal glomerulosclerosis: Natural history and response to therapy

PURPOSE Recurrent focal glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. PATIENTS AND METHODS We reviewed all the charts of patients with biospy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, post-transplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. RESULTS FGS recurred in 25 allografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. CONCLUSIONS FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

Membranous Nephropathy: Predictors of Terminal Renal Failure

By univariate analysis of patients with membraneous nephropathy, terminal renal failure was associated with male sex, a large amount of proteinuria, low serum albumin concentration, low creatinine clearance rate, high serum creatinine concentration, and high systolic blood pressure, but was not associated with age or prednisone treatment. In a multivariate life table analysis that controlled for all these factors simultaneously, the risk of developing terminal renal failure was significantly independently associated only with sex, serum albumin concentration, and prednisone treatment, being higher in men, lower in those treated with prednisone, and inversely related to serum albumin. Except for the minimal electron-dense deposition, the electron microscopic findings had no predictive value.

The clinical course of IgA-nephropathy and Henoch-Schönlein purpura following renal transplantation.

Recurrence of IgA-nephropathy and Henoch-Schönlein purpura is a common finding after renal transplantation. From 1970 to 1984, 1788 transplants were performed at our center. 13 patients had IgA-nephropathy and 3 patients had Henoch-Schönlein purpura. No patient with Henoch-Schönlein purpura had a proved recurrence. Six patients with IgA-nephropathy had a recurrence of IgA disease in the allograft within 3 to 8 months of transplantation. Three patients with a recurrence have retained their kidneys with stable renal function (follow-up of 1.7-2.7 years). Two of these patients lost their graft from severe rejection. One patient, who received an HLA-identical transplant, lost the graft from recurrent IgA disease associated with crescenteric glomerulonephritis. We found no difference in the prevalence of HLA-B 35 among the IgA patients compared with our total transplant population. IgA patients who received living related transplants had a higher recurrence rate of IgA in their allograft when compared with recipients of cadaveric kidneys (83% vs. 14%). Some caution is recommended in using related donors, especially HLA-identical siblings in patients with renal failure secondary to IgA-nephropathy.

The testicular morphology of individuals exposed to dibromochloropropane

Abstract Testicular biopsies from 10 individuals with histories of exposure to 1,2-dibromo-3-chloropropane (DBCP) were studied by light and electron microscopy. In seven subjects, spermatogenic activity was either significantly decreased or absent. There appeared to be a correlation between the diminution in spermatogenesis and the duration of industrial exposure to the agent.

Membranous nephropathy: its relative benignity in women.

By means of renal biopsy and light, immunofluorescence, and electron microscopy, a diagnosis of membranous nephropathy (MN) was made in 100 patients. The nephrotic syndrome was present in 83 of these patients. 65 of the patients were men and 35 were women. The average period of follow-up was 99.8 months. As judged by the incidence of death and of improvement or complete healing, the women fared better than the men, whether given high-dose alternate-day prednisone therapy or not. The incidence of improvement or complete healing in the patients given prednisone was higher than the reported for patients who were not given corticosteroids. We have shown that occurrence of MN is more frequent in women than men and the course of MN is more benign in women than in men; alternate-day prednisone therapy appears to be beneficial in patients with MN.

A test of the carcinogenicity of enflurane, isoflurane, halothane, methoxyflurane, and nitrous oxide in mice.

We exposed Swiss ICR mice for 2-hour periods to 1/32, 1/8 and/or 1/2 MAC enflurane, halothane, isoflurane, methoxyflurane, or N2O both in utero during the last 1/2 of pregnancy (4 exposures at 2-day intervals) and after delivery (24 exposures at 2-to-3-day intervals). Anesthetics were delivered in air or in O2. Thus, 1973 mice were exposed and examined after 15 months of life for the development of neoplastic lesions. Neoplastic lesions (principally pulmonary adenomas, lymphomas, hepatocyte lesions, liver vascular lesions) were found in all treatment and control sets. There was no indication that a specific anesthetic or anesthetic dose was carcinogenic. Our results do not confirm the suggestion that isoflurane is a hepatocarcinogen, nor do our data suggest that. the modern inhaled anesthetics pose a significant threat of carcinogenicity.

Crescentic glomerulonephritis associated with nonrenal malignancies.

A review of 80 patients with the renal biopsy diagnosis of idiopathic glomerulonephritis with extracapillary proliferation (crescentic GN) disclosed 7 cases with a coexistent nonrenal malignancy; 6 carcinomas and 1 lymphoma. In a control group of 80 patients with the renal biopsy diagnosis of minimal change or focal segmental glomerulosclerosis, only 1 case of coexistent malignancy was found (chi-square = 4.74, p less than 0.05). All of the malignancies occurred in patients older than 40 years of age and the prevalence of malignancy in patients with crescentic GN over the age of 40 was 20%. Light microscopy, immunofluorescence, and electron microscopy revealed fibrin deposition in all cases and no evidence of anti-GBM or immune complex disease. 3 patients experienced a rapidly progressive course while renal function improved in 4 patients following treatment of the underlying malignancy. The pathogenic mechanisms leading to crescentic GN in patients with malignancy are unknown; however, the high prevalence of malignancy in crescentic GN patients older than 40 along with the improvement during the treatment of the underlying malignancy suggests an etiological relationship.

De novo and recurrent membranous glomerulopathy following kidney transplantation.

Membranous glomerulopathy, de novo or recurrent, in the allograft kidney is a recognized, albeit uncommon, clinical entity. We examined the records of 936 renal allograft recipients in a seven and one-half year period. De novo membranous glomerulopathy developed in six patients. The mean onset of nephrotic-range proteinuria after transplantation was at 18.1 months (with a range of from 4 to 30 months). De novo membranous glomerulopathy did not adversely affect graft survival. Twenty-five patients were transplanted for end-stage renal disease caused by membranous glomerulopathy. The rate of recurrence of membranous glomerulopathy in patients who did not lose their allograft to rejection in the immediate posttransplant period was 7%. Additional prednisone therapy to the standard immunosuppressive protocol did not appear to be beneficial. One patient, who developed a recurrence of the original lesion, received an HLA-identical kidney. Onset of nephrotic-range proteinuria occurred four weeks post-transplant. Recurrent membranous glomerulopathy has been reported in five other patients. In the two recipients of living related allografts nephrotic-range proteinuria developed within two weeks of the transplant. Patients with end-stage renal disease caused by membranous glomerulopathy who receive a living related allograft, especially one that is HLA-identical, may be at a higher risk for morbidity and for early recurrence. We recommend caution in the use of a living related transplant for patients with end-stage renal disease caused by membranous glomerulopathy.

Inability of cyclosporine to completely prevent the recurrence of focal glomerulosclerosis after kidney transplantation

From January 1984 through July 1986, 15 patients with biopsy-proven focal glomerulosclerosis (FGS) underwent kidney transplantation. Following transplantation, all patients were immunosuppressed with cyclosporine and prednisone. There were 8 men and 7 women with a mean age of 33 years (range, 16-47 years). Five patients (33%) had recurrence of FGS. Two patients had received kidneys from HLA identical siblings, and 3 patients were transplanted with cadaveric kidneys. In 4 out of 5 patients, the recurrence of FGS occurred within 3 months of transplantation. Of the 2 graft losses in this group, one was from recurrence of FGS. Ten patients followed for a mean of 25 months did not develop recurrence of FGS. No graft loss occurred in this group. Three patients with end-stage renal disease of unknown etiology were found to have FGS in the renal allograft and were presumed to have recurrence of FGS. All 3 patients developed the nephrotic syndrome following transplantation, and 1 patient has had progressive renal failure. Cyclosporine did not prevent the recurrence or the clinical manifestations of FGS following kidney transplantation. Additional studies are needed to determine if cyclosporine is effective in certain subgroups of patients with FGS.

Comparative toxicities of enflurane, fluroxene and nitrous oxide at subanaesthetic concentrations in laboratory animals

SummaryWe compared the toxicities of subanaesthetic concentrations of fluroxene, enflurane and nitrous oxide in mice, rats and guinea pigs which were in an active growth phase. Fluroxene produced a greater mortality and decrement in weight gain than enflurane and nitrous oxide despite administration of far lower concentrations. Enflurane, 0.1 MAC, resulted in a detrimental effect on weight and early mortality in mice but not in rats or guinea pigs. Nitrous oxide, 0.1 MAC, resulted in only a minor effect on weight gain in guinea pigs and an increased incidence of focal inflammatory liver changes in mice. No consistent injury to any organs other than liver or kidney were found.RésuméNous avons comparé la toxicité de concentrations sub-anesthésiques de Fluroxène, ďEnflurane et de Protoxyde ďAzote chez des souris, des rats et des cobayes en croissance. La mortalité et le ralentissement de la croissance sont plus marqués chez les animaux exposés au Fluroxène que chez ceux exposés à ľEnflurane ou au Protoxyde ďAzote, même si le Fluroxène est administré à de beaucoup plus basses concentrations.A 0.1 MAC, ľEnflurane amène une perte de poids et augmente la mortalité précoce chez la souris, mais non chez le rat et le cobaye. Le Protoxyde ďAzote à 0.1 MAC modifiait peu la courbe de poids du cobaye, mais chez la souris, il augmentait ľincidence de modifications inflammatoires hépatiques. Aucun autre organe que le rein et le foie n’a semblé touché.