Raphael Borok

Focal segmental glomerular sclerosis in adults: Presentation, course, and response to treatment

The authors performed a retrospective clinicopathologic study in 81 patients with primary focal segmental glomerular sclerosis (FSGS) to determine whether they could identify clinical or histologic features at presentation that could be predictive of outcome and response to therapy. Males constituted 58% of patients, and 53% were black. At biopsy the patients were 40 +/- 17 years old; 74% were nephrotic, and renal insufficiency was present in 62%. The average time from presentation to biopsy was 16 months, and the average total follow-up was 62 months. Nephrotic patients had a significantly poorer prognosis as compared with nonnephrotic patients (5- and 10-year survivals of 76% and 57% v 92% and 92%; P < 0.05). A multivariate analysis was done on histologic and clinical features at biopsy, assessing for risk factors leading to end-stage renal disease, showing only the serum creatinine and the degree of interstitial fibrosis to have a significant correlation. Thirty nephrotic patients received prednisone, with a treatment time of 5.5 +/- 4 months and a total dose of 5.9 +/- 2.9 g per course of treatment. Fifteen of these patients (50%) achieved a remission by 3.7 +/- 2 months (10 complete remission and 5 partial remissions), with all patients responding within 9 months. Only two patients had spontaneous remissions (both partial). The 5- and 10-year survival for patients in remission were both 100% as compared with 66% and 41% (P < 0.01), respectively, for nephrotic patients not in remission. No clinical feature at presentation of biopsy was predictive of response to therapy when a multivariate analysis was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

The racial prevalence of glomerular lesions in nephrotic adults

We retrospectively evaluated the prevalence of primary glomerular lesions in adults who had a renal biopsy for nephrotic proteinuria. From July 1975 to May 1994, 340 patients undergoing renal biopsies evaluated at Rush-Presbyterian-St Lukes Medical Center had the primary glomerular lesions of minimal-change disease, focal segmental glomerular sclerosis (FSGS), membranous glomerulonephritis (MGN), membranoproliferative glomerulonephropathy, immunoglobulin A nephropathy, and immunotactoid glomerulopathy. The patients had a mean age of 43 +/- 17 years, 57% were male, and 50% were white, 36% were black, 7% were of other race, and 7% were of unknown race. The distribution of lesions for black patients was minimal-change disease 14%, FSGS 57%, MGN 24%, membranoproliferative glomerulonephritis 2%, immunoglobulin A 2%, and immunotactoid glomerulopathy 1%; for white patients, the distribution of lesions was minimal-change disease 20%, FSGS 23%, MGN 36%, membranoproliferative glomerulonephropathy 6%, immunoglobulin A 8%, and immunotactoid glomerulopathy 6%. The prevalence of FSGS was significantly greater (P < 0.0001) and that for MGN, immunoglobulin A, and immunotactoid glomerulopathy was significantly less (P < 0.05) for black patients compared with white patients. In a logistic regression analysis, race remained the only significant predictor of FSGS (P = 0.0001), with black patients four times as likely to have FSGS as white patients. The distribution of lesions among white patients was similar based on gender, age, and biopsy period. For black patients the distribution was also similar based on gender and age, but over 20 years the incidence of FSGS increased from 39% (1975 to 1984) to 64% (1985 to 1994) (P < 0.01). Thus, significant racial differences in the distribution of primary glomerular lesions exists. This has important prognostic and therapeutic implications for nephrotic adults.

Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes

Extensive apoptosis or programmed cell death (PCD) of both hematopoietic (erythroid, myeloid, megakaryocytic) and stromal cells in myelodysplastic syndromes (MDS) cancels the high birth-rate resulting in ineffective hematopoiesis and has been demonstrated as the probable basis for peripheral cytopenias in MDS by our group. It is proposed that factors present in the microenvironment are inducing apoptosis in all the cells whether stromal or parenchymal. To investigate this hypothesis further, bone marrow biopsies from 46 MDS patients and eight normal individuals were examined for the presence of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) and one cellular component, macrophages, by the use of monoclonal antibodies immunohistochemically. Results showed the presence of TNF-alpha and TGF-beta in 41/46 and 40/46 cases of MDS respectively, while only 15 cases showed the presence of GM-CSF. Further a significant direct relationship was found between the degree of TNF-alpha and the incidence of PCD (p= 0.0015). Patients who showed high PCD also had an elevated TNF-alpha level. Thus, the expression of high amounts of TNF-alpha and TGF-beta and low amounts of the viability factor GM-CSF may be responsible for the high incidence of PCD leading to ineffective hematopoiesis in MDS. Future studies will be directed at attempting to reverse the lesion in MDS by using anti-TNF-alpha drugs such as pentoxifylline.

Primary focal segmental glomerular sclerosis in adults: Prognostic value of histologic variants

Primary focal segmental glomerular sclerosis (FSGS) is a clinicopathologic syndrome in which variable amounts of proteinuria are associated with the renal biopsy finding of segmental glomerular scarring in some, but not all, of the glomeruli. Additional histologic features have been described in FSGS, including the position of the scar relative to the vascular and tubular pole of the glomerulus, foam cells, hyalinosis, mesangial deposits of immunoglobulin M, diffuse mesangial hypercellularity, glomerular visceral epithelial cell hyperplasia and hypertrophy, and the extent of associated interstitial fibrosis and tubular atrophy. We performed a retrospective study on 81 patients with biopsy-proven, primary FSGS to determine whether any of the histologic features of FSGS correlated with renal function at the time of biopsy and the incidence of end-stage renal disease at follow-up. Sixty patients were nephrotic and 21 had nonnephrotic proteinuria. Only the degree of interstitial fibrosis correlated with the initial serum creatinine (r = 0.536) and none of the histologic features predicted the presence of nephrotic-range proteinuria at the time of biopsy. Segmental scars involved 21% +/- 14% of the glomeruli per biopsy specimen, but their position within the glomerulus was uniform in only 13% of the cases. Diffuse mesangial hypercellularity was present in 17% of the biopsy specimens, and glomerular epithelial cell lesions were present in 57% of the biopsy specimens. Multivariate analysis showed that only the degree of interstitial fibrosis predicted end-stage renal disease in all 81 patients and in the 60 patients with nephrotic-range proteinuria. The current data do not support different therapeutic approaches in primary FSGS based on histologic subtypes.

Successful establishment of long-term bone marrow cultures in 103 patients with myelodysplastic syndromes.

We used bone marrow biopsies instead of mononuclear cells to maintain long-term cultures from 103 patients belonging to all five sub-categories of myelodysplastic syndromes (MDS), as well as 12 normal controls. By week 4, 30-50% confluency was reached and could be maintained for up to 12 weeks with 100% confluency. The four prominent cells were fibroblasts, macrophages, endothelial cells and adipocytes. Immunohistochemical and electron microscopic studies provided lineage confirmation. Normal hematopoiesis was well supported by MDS stroma. Neither the FAB nor cytogenetics was co-related with the potency of growth. MDS stroma appears to be both morphologically and functionally normal.

Pilot Study of Pentoxifylline and Ciprofloxacin with or without Dexamenthasone Produces Encouraging Results in Myelodysplastic Syndromes

Forty-three patients with myelodysplastic syndromes (MDS) were treated with a combination of pentoxifylline and ciprofloxacin (PC) with the addition of dexamethasone (PCD) in 18 patients who failed to respond to PC. There were 15 females and 28 males, and the median age was 67 years. A total of 18 patients either showed a hematopoietic improvement, a partial or complete cytogenetic response or a combination of both for an overall response rate of 42%. Seven PC only patients responded, four showing hematologic improvement, two cytogenetic responses and one patient showing a combined response. This 16% response rate to PC was increased to 61% by the addition of dexamethasone with 11/18 patients showing a response. Four of the 7 patients who responded initially to PC were given dexamethasone after at least 12 weeks of PC therapy, and only 1 showed a further improvement in response. Thus, we conclude that the combination of PCD provides an encouraging novel approach to treating MDS. The mechanism of action is probably related to the suppression of a veriety of cytokines which in turn attenuate the excessive intramedullary apoptotic death of hematopoetic cells in MDS, an observation which has been speculated to be the basis of the paradox of variable cytopenias despite cellular marrows in MDS. Larger numbers of patients need to be treated and followed for longer periods to determine the true efficacy of this therapy, especially the nature and duration of the cytogenetic responses.