Alex B. Magil

Monocytes/macrophages in renal allograft rejection

Monocytes/macrophages (MO) have long been recognized to be involved in renal allograft rejection. Monocytes/macrophages have been detected in the glomerular, vascular, and tubulointerstitial compartments during rejection. The recent demonstration that peritubular capillary deposition of complement split factor C4d, a marker for antibody-mediated rejection, is associated with relatively marked MO infiltration of the allograft during acute rejection is a significant development in our understanding of the role of the MO in rejection. High levels of MO in rejecting allografts have been associated with severe rejection, and glomerular MO infiltration in particular has been shown to be an indicator of poor graft outcome.

Tubulointerstitial lesions in human membranous glomerulonephritis: relationship to proteinuria.

Recent studies in experimental glomerular disease suggest that proteinuria may be involved in the pathogenesis of accompanying tubulointerstitial (TI) lesions. To investigate whether there is a relationship between proteinuria and TI damage in membranous glomerulonephritis, 78 biopsy specimens with no or mild vascular disease and 10% or less obsolete glomeruli were examined and evaluated quantitatively. Extent of TI damage was represented by the TI index (TII) obtained for each biopsy specimen by dividing the morphometrically measured area of cortical damage by the total cortical area and multiplying the result by 1,000. The TII increased with stage of glomerular disease, but only the difference between stages 3 and 1 was significant (P < 0.016). The TII showed significant individual correlation with 24-hour urinary protein (r = 0.435, P < 0.0001), serum albumin (r = -0.327, P = 0.0045), and percent of glomeruli with visceral epithelial cell protein absorption droplets (r = 0.419, P = 0.0001), but not with age, serum creatinine, or percent obsolete glomeruli. With multivariate analysis TII correlated significantly with urinary protein (r = 0.286, P = 0.0146) and percent glomeruli with visceral epithelial cell protein droplets (r = 0.304, P = 0.0058). The results are consistent with the hypothesis that proteinuria is involved in the development of TI injury in glomerular disease.

Idiopathic nodular glomerulosclerosis

Idiopathic nodular glomerulosclerosis is an unusual entity with light microscopic and ultrastructural features similar to those of nodular diabetic glomerulosclerosis but without evidence of abnormal glucose metabolism. We report 2 patients whose renal biopsies showed nodular glomerulosclerosis with afferent and efferent arteriolosclerosis, glomerular basement membrane thickening, focal mesangiolysis and capillary microaneurysm formation, and who had no evidence of abnormal glucose metabolism or other features of diabetes mellitus. Review of the literature shows that, of the 27 reported cases of idiopathic nodular glomerulosclerosis (not including the 2 cases reported herein), 11 showed evidence of abnormal glucose metabolism or were frankly diabetic. Of the remaining 16 cases with normal serum blood glucose measurements, 3 had diabetic retinopathy and 1 had a delayed insulin response curve. The cause and pathogenesis of the glomerular nodules are discussed, and it is suggested that arteriolar stenosis and glomerular ischemia may be involved in the development these lesions.

Childhood IgM nephropathy: comparison with minimal change disease.

The distinctiveness of IgM nephropathy (IgMN) as a clinicopathologic entity is controversial. Twenty-seven children (16 males, 11 females) with IgMN as defined immunohistochemically by diffuse mesangial staining of glomeruli for IgM were compared to a group of 63 children (40 males, 23 females) with minimal change disease (MCD). While mesangial expansion was significantly greater in IgMN than in MCD (p = 0.0014), there were no significant differences between the two groups with respect to the other biopsy factors. IgMN showed a significantly higher incidence of hypertension at presentation. More than 90% of patients in both groups presented with the nephrotic syndrome which in most initially responded to prednisone. Frequently relapsing/steroid-dependent nephrotic syndrome was the most common indication for biopsy in both groups. Approximately 60% of patients from both groups received cytotoxic therapy. Eight percent of IgMN and 7% of MCD patients failed to respond to therapy. Relapse rates and mean dose of prednisone at relapse were very similar in both groups prior to biopsy. Relapse rates diminished significantly after treatment in the postbiopsy interval, but mean dose of prednisone at relapse did not change appreciably over time. None of the patients developed renal failure or hypertension in the follow-up period. At last visit 23% of IgMN and 27% of MCD had proteinuria. The results indicate that IgMN and MCD are indistinguishable clinically in children who are biopsied for the nephrotic syndrome.

Diffuse Proliferative Lupus Glomerulonephritis: DETERMINATION OF PROGNOSTIC SIGNIFICANCE OF CLINICAL, LABORATORY AND PATHOLOGIC FACTORS

Clinical, laboratory and pathological factors in 35 females with diffuse proliferative lupus glomerulonephritis were analyzed to determine the prognostic significance of the individual variables. The clinical and laboratory variables were age, serum creatinine (Cr), serum C3, serum C4 and proteinuria at the time of biopsy while the biopsy ones included intraglomerular monocytic infiltration (NSE index), total glomerular deposits, extent of subendothelial deposits, extent of extraglomerular deposits, tubulo-interstitial inflammation, relative tubulo-interstitial volume and total pathologic score. Standard morphometric and counting procedures were used to determine the levels of all pathologic variables but pathologic score and extra glomerular deposits where grading estimates were done. Survival curves were determined by the life table method. Logrank and chi-square tests were used to establish levels of statistical significance. Seven patients developed established renal failure (Cr greater than or equal to 2.0 on two or more occasions at least 3 months apart) and nine showed significant deterioration of renal function (decrease in CrCl of 25% or more in between biopsy and last follow-up visit or an increase in serum Cr of 0.4 mg/dl or more over the follow-up period). The 5-year renal survival rate (absence of established renal failure) for the whole group was 77%. Serum Cr (p less than .005) and extent of extraglomerular deposits (p less than .025) were shown to be significant prognostic factors for renal survival. Of the seven patients who developed renal failure none had an NSE index greater than 3.0 and one had a C3 greater than or equal to 45 mg/dl. Statistically these factors were weak prognostic indicators (0.5 less than p less than .1). Multivariate analysis demonstrated that the extraglomerular deposit factor contributed significant additional prognostic information to that provided by Cr. Although not important as a prognostic factor on its own, the NSE index significantly improved the prognostic performance of serum Cr. The product of the NSE index and serum C3 proved to be a strong prognostic factor (p less than .005).

Tubulointerstitial lesions in young zucker rats

Zucker (Z) rats spontaneously develop proteinuria and focal glomerulosclerosis (FGS), but little is known about tubulointerstitial (TI) changes in the early stages of their disease. Thirteen male Z rats (9 obese, 4 lean) were examined at 75 (n = 6) and 120 (n = 7) days of age. Twenty-four-hour urinary protein excretion (UPr), percent of glomeruli with FGS, proportion of cortex and outer stripe occupied by vimentin (V)-positive (+) tubules (a marker of tubular damage) and the number of OX4+ (Ia+), OX42+(monocyte/macrophage), OX19+(pan T cell), OX8+(T cytotoxic cell), and OX22+(B cell) cells in both normal areas and around V+ tubules were assessed at each age. Mean UPr was 34.2 +/- 18.5 mg/day at 75 days and 183.6 +/- 129.9 mg/day at 120 days. FGS was only observed in 1% to 3% of glomeruli in five 120-day-old obese rats. All rats showed varying degrees of focal TI injury histologically. V+ tubules were observed in 12 rats, and the proportion of cortex and outer stripe occupied by V+ tubules varied from 0.1% to 7.7%. The extent of TI damage was greater at 120 days (3.7% +/- 2.9%) than at 75 days (0.5% +/- 0.5%). There was a 2- to 12-fold increase in the number of OX4+, OX42+, OX19+, and OX8+ cells in areas around V+ tubules, with OX4+ and OX42+ cells predominating.(ABSTRACT TRUNCATED AT 250 WORDS)

Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a recently described entity that is only rarely associated with a hematological or lymphoproliferative malignancy. We describe the cases of two men with preexisting chronic lymphocytic leukemia (CLL) who developed endocapillary proliferative glomerulonephritis with nonorganized monoclonal IgG(1) deposits. One biopsy also showed CLL infiltration of the cortex. Both patients were treated with rituximab in addition to cyclophosphamide in one case and fludarabine in the other with significant improvement of their renal disease and CLL. This report provides additional evidence to support the use of rituximab in the therapy of CLL-associated PGNMID.

Heavy chain deposition disease: Recurrence in a renal transplant and report of IgG2 subtype

Heavy chain deposition disease (HCDD) is a rare entity characterized by tissue deposition of monoclonal heavy chains without light chains. Previous reports of HCDD include gamma(1)-, gamma(3)-, gamma(4)-, and alpha-heavy chain subtypes. Renal transplantation for HCDD has not been previously reported. We report a case of gamma(2)-HCDD in a 67-year-old patient who presented with proteinuria, hematuria, and renal insufficiency and progressed to end-stage renal failure after 6 months. The second case involves a 26-year-old woman who had a renal transplant for HCDD and recurrent gamma(1)-HCDD in the transplant. Neither patient had myeloma. The complete spectrum of gamma-HCDD subtypes has now been reported. Further data are required to make conclusive statements about the true recurrence rate of HCDD in renal transplants.

Focal proliferative lupus nephritis: A clinicopathologic study using the W.H.O. classification

Focal proliferative lupus glomerulonephritis has traditionally been considered to be more benign than the diffuse form. A recent study of lupus nephritis using the W.H.O. classification demonstrated no difference in 4-year survival between those with focal and those with diffuse disease. Because of this development, a comparative clinicopathologic study of 15 patients with focal proliferative lupus glomerulonephritis was done using the W.H.O. classification. Generally, patients with focal proliferative lupus glomerulonephritis presented with milder renal disease with respect to proteinuria and renal insufficiency. Involvement of the central nervous system was more prominent in focal proliferative lupus glomerulonephritis. Therapy for both types of disease was similar. Mean duration of renal disease was 48 months for focal and 50.7 months for diffuse disease. Three patients with focal proliferative lupus glomerulonephritis and two with diffuse proliferative lupus glomerulonephritis were dead at the end of the follow-up period. Established renal failure was present in one patient with focal disease and two with diffuse disease. Deterioration of renal function was noted in two patients with focal proliferative lupus glomerulonephritis and five with diffuse proliferative lupus glomerulonephritis at the end of the follow-up period. No statistically significant differences in cumulative five-year survival rates (focal = 0.751; diffuse = 0.858), cumulative five-year renal survival rates (focal = 1.00; diffuse = 0.846), deterioration of renal function and quantitative proteinuria at the end of the follow-up period were noted. although qualitatively milder, the focal form of renal disease followed a course similar to that of the diffuse type.

Monocytes and macrophages in focal glomerulosclerosis in Zucker rats.

It has been recently suggested that focal glomerulosclerosis (FGS) is analogous to atherosclerosis. Obese Zucker (OZ) rats spontaneously develop hyperlipidemia, proteinuria and FGS. To evaluate the role of the monocyte (MO) and its derivatives in the pathogenesis of the lesion, 30 OZ rats and 15 lean littermates (LZ) were followed for up to 240 days of age. At 75, 120 and 240 days of age, groups of 10 OZ and 5 LZ were assessed with respect to serum total and free cholesterol (TC and FC), triglyceride, lipoprotein electrophoresis, renal histology, histochemistry and immunohistochemistry. All serum lipids were raised at 75 days in OZ rats and increased progressively at 120 and 240 days. The early lesions of FGS were first demonstrated in OZ at 120 days with more advanced lesions at 240 days. FGS was seen in LZ only at 240 days when their serum lipids were raised. Intraglomerular MO infiltration was significantly higher in OZ than in LZ at all time periods (p less than 0.01) and greater in glomeruli with FGS lesions than in those without (p less than 0.01 and 120 days and p less than 0.05 at 240 days). Staining for ED1 and Ia antigens with monoclonal antibodies demonstrated increasing numbers of intraglomerular ED1+ and Ia+ cells with increasing age and extent of FGS. The findings suggest a role for intraglomerular macrophages in the pathogenesis of FGS in OZ.