A. Andrew Abraham

Apoptosis in human immunodeficiency virus-associated nephropathy

Focal segmental glomerulosclerosis associated with human immunodeficiency virus nephropathy (HIVFGS) involves glomeruli, tubules, and interstitium. Its pathogenesis is unknown, but HIV peptides may be critical in its development. Human immunodeficiency virus peptides and peptide-antibody complexes are immunomodulatory, and are associated with apoptosis in lymphoid cells. To determine whether apoptosis is present in HIVFGS, renal biopsy specimens of eight patients with HIVFGS were compared with those of 10 patients with idiopathic focal glomerulosclerosis (FGS) using the Apoptag kit (Oncor, Gaithersburg, MD), which detects single cell apoptosis in formalin-fixed tissue by staining 3 nucleosome fragments with digoxigenin-labeled nucleotides after terminal deoxynucleotidyl transferase enzyme treatment. Apoptosis was scored per glomerulus, in total renal tissue sectioned, and in tubules and interstitium per square millimeter using a computerized digital image analyzer. There was no difference between the number of apoptotic cells per glomerulus or per square millimeter of interstitium in patients with FGS and HIVFGS. There were greater numbers of tubular apoptotic cells per square millimeter (2.1 +/- 0.9 v 0.15 +/- 0.08; P = 0.03) in HIVFGS compared with idiopathic FGS. The difference between apoptotic cells per total square millimeter of renal tissue (2.8 +/- 1.2 v 0.7 +/- 0.3) approached significance (P = 0.066). Apoptosis may be associated with the pathogenesis of HIV nephropathy and may be an important determinant of the tubular disease in HIVFGS.

Macrophages in Human Immunodeficiency Virus-Associated Kidney Diseases

Human immunodeficiency virus (HIV)-associated nephropathies are characterized by renal immune cell interstitial infiltration in patients with peripheral T-cell depletion. Since interstitial inflammation may mediate cytokine-induced fibrosis, we evaluated the immune cell population in the interstitium and glomeruli in renal biopsy tissue from 10 HIV-infected patients with focal segmental glomerulosclerosis (HIVFGS), staining renal biopsy specimens for UCHL-1 (a T-cell marker), OPD4 (predominantly a T helper-cell marker), PG-M1 (a macrophage marker), and L26 (a B-cell marker), and comparing them with renal tissue specimens from patients with HIV-associated immune complex glomerulonephritis (ICD) and from uninfected patients with FGS. Five fields comprising 0.2 mm2 were examined at a magnification of x400, a total area of 1 mm2. Total immune cells were estimated as the sum of UCHL-1, L-26, and PG-M1 cells. The T helper to suppressor (H/S) ratio was estimated as OPD4/(UCHL-1 - OPD4) lymphocytes. Tubular interstitial infiltrate was variable but dense in the majority of the infected biopsies, and was mild to moderate in all uninfected cases. The proportion of interstitial macrophages was greater in biopsy specimens from patients with HIVFGS than in those with HIVICD. In contrast, there was a greater percentage of B cells in the infiltrate in HIVICD compared with HIVFGS. Although there were fewer immune cells in whole glomeruli compared with 1 mm2 interstitium, macrophages were the predominant cells in glomeruli. B lymphocytes were generally absent in glomeruli in infected tissue, a pattern similar to uninfected tissue. The blood H/S ratio in HIV-infected patients was 0.2 +/- 0.03.(ABSTRACT TRUNCATED AT 250 WORDS)

Membranoproliferative Glomerulonephritis in a Patient Treated With Interferon-α for Human Immunodeficiency Virus Infection

Several renal pathologic entities have been reported to be associated with human immunodeficiency virus (HIV) infection. The most common is focal glomerulosclerosis, but several different types of glomerulonephritis have been observed in patients with HIV infection and the acquired immunodeficiency syndrome. The mechanisms involved in the pathogenesis of the kidney disease remain obscure. We studied an HIV-infected patient treated with interferon-alpha who had developed proteinuria and membranoproliferative glomerulonephritis to determine whether the renal disease was associated with HIV infection or with chemotherapy. Circulating HIV antibodies were assessed by enzyme-linked immunosorbent assay; circulating immune complexes (CICs) were measured by C1q assay and isolated by polyethylene glycol precipitation, then subjected to gel electrophoresis and immunochemical analysis. Renal biopsy tissue underwent acid elution, and the eluates were analyzed similarly. In addition the eluted antibody and the antibody from the CIC were assessed by immunodiffusion with eluate and immune complex antigens. A single CIC was detected, which was composed of an immunoglobulin G antibody complexed to a 26-kd protein antigen that was shown to be interferon-alpha. Eluate from the renal biopsy tissue demonstrated identical material, which cross-reacted with the components of the isolated CIC. Immune complex renal diseases, such as membranoproliferative glomerulonephritis, may be related to biologic response modifying agents in patients with HIV infection. The relative roles of their biologic response modification and the disordered immunoregulation seen in such patients in the pathogenesis of the renal disease is unclear. Renal biopsy is necessary to assess the etiology of the renal disease in HIV-infected patients.

Diabetic glomerulopathy in the SHR/N-corpulent rat: role of dietary carbohydrate in a model of NIDDM

SummaryWe evaluated the course of diabetes and nephropathy in the SHR/N-cp (corpulent) rat characterized by genetic obesity, non-insulin-dependent diabetes (NIDDM), and hypertension, and examined whether the nephropathy in this model is influenced by the type of carbohydrate intake. Two groups of obese and lean SHR/N-cp rats were fed diets containing 54 % carbohydrate, as either sucrose or starch for 3 months (group I) and 9 months (group II). After 3 months on either diet, group I obese rats had higher 2-h response serum glucose levels and urinary glucose excretion than lean rats. Sucrose feeding was associated with greater proteinuria and a higher percentage of abnormal glomeruli in obese rats. Morphometric evaluation of glomeruli (by computerized image analysis) showed greater mean renal corpuscular volume and mesangial fraction in obese than in lean rats fed similar diets. Mean renal corpuscular volume and mesangial fraction were also greater in sucrose-fed obese rats than in starch-fed obese rats. After 9 months, group II obese rats had substantial reductions in serum and urine glucose levels but they were still hyperinsulinaemic and showed more proteinuria than lean rats and a higher percentage of sclerotic glomeruli compared with group I obese rats. At this time, mean mesangial fraction but not renal corpuscular volume was still higher in obese than in lean rats. In group I obese rats, a significant correlation was found between mesangial fraction and urinary protein excretion (r= 0.67,p<0.05). In group II obese rats, renal corpuscular volume was correlated with percentage of glomerular sclerosis (r=0.60,p<0.05). Thus, obese SHR/N-cp rats develop persistent proteinuria and glomerulopathy marked by glomerular enlargement, increased mesangial matrix, and progressive glomerular sclerosis. Sucrose feeding accentuates mesangial expansion and glomerulosclerosis in obese rats. [Diabetologia (1995) 38: 31–38]

Serological studies of a case of fatal craniofacial mucormycosis.

Counter-immunoelectrophoresis and indirect immunofluorescence tests were used in a fatal case of craniofacial mucormycosis.The indirect immunofluorescent test was rapid and more sensitive than counter-immunoelectrophoresis and provided estimation of serum antifungal antibodies (IgA, IgG and IgM).The high serum IgA titer (comparable to IgM) found in this case of acute infection suggests a role of IgA antibodies which needs further investigation.

Ultrastructural changes in skeletal muscles of rats treated neonatally with 6-mercaptopurine.

The purpose of this study was to characterize the ultrastructural changes in the muscles of 2- and 6-month-old rats that were injected with 6-mercaptopurine monohydrate (6-MP) at 2 mg base/kg sc daily from 2 to 22 days of age. The earliest, usually subsarcolemmal alterations, were disorganization of fibrils at the Z-bands with excessive Z-band-like material and loss of myofibrils. In the most extensive lesions, the entire fiber was involved, with vacuoles within the disorganized fibrils. The peripheral nerves and vessels were unremarkable. Thus 6-MP-induced changes appear to be primarily myogenic in origin.