Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake.

AIMS/HYPOTHESIS: In early type 1 diabetes mellitus, renal salt handling is dysregulated, so that the glomerular filtration rate becomes inversely proportional to salt intake. The salt paradox occurs in both humans and rats and, with low salt intake, results in diabetic hyperfiltration. We tested whether increased salt intake could reduce the susceptibility to injury of non-clipped kidneys in diabetic rats with pre-existing Goldblatt hypertension. METHODS: Male Long-Evans rats were made hypertensive and half were then made diabetic. Blood glucose was maintained at ~20-25 mmol/l by insulin implants. One half of each received only the salt in normal chow (1% by weight) and the other half received added salt in drinking water to equal 2.7% by weight of food intake. Weekly 24 h blood pressure records were acquired by telemetry during the 4-month experiment. RESULTS: Systolic blood pressure was not affected by diabetes or increased salt intake, alone or together. Autoregulation was highly efficient in the non-clipped kidney of both intact and diabetic rats. Histological examination showed minor injury in the clipped kidney, which did not differ among groups. The non-clipped kidney showed extensive pressure-dependent glomerular and vascular injury in both intact and diabetic rats. CONCLUSIONS/INTERPRETATION: The relationship between pressure and injury was shifted toward lower blood pressure in diabetic rats, indicating that diabetes increased the susceptibility of the kidney to injury despite preservation of autoregulation. The increased susceptibility was not affected by high salt intake in the diabetic rats, thus disproving the hypothesis.

Renal failure due to T-cell mediated lymphocytic vasculitis: an unusual complication of B-cell chronic lymphocytic leukemia.

Vasculitis is an uncommon paraneoplastic syndrome, and acute renal failure is an unusual presentation of leukemia. We report a case of B-cell chronic lymphocytic leukemia that presented with acute renal failure caused by biopsy-proven lymphocytic vasculitis that subsequently was shown to be T-cell-mediated and systemic at autopsy.

Heavy chain deposition disease: recurrence in a renal transplant and report of IgG(2) 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.

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.

Intraglomerular monocyte infiltration and immune deposits in diffuse lupus glomerulonephritis.

Previous studies have suggested that separately, glomerular monocyte (MO) infiltration and persistent glomerular immune deposits have opposite prognostic implications in lupus nephritis (LN). To see whether these pathological variables are inversely related, 37 renal biopsy specimens from 37 patients with diffuse proliferative LN were assessed histologically for activity index, chronicity index, and mean glomerular deposit score per biopsy (deposit index [DI]); the latter was determined semiquantitatively on a scale of 0 to 4.0. Frozen sections were double immunolabeled for immunoglobulin G (IgG) and CD68, a marker for MOs. For each glomerulus in each biopsy specimen, the number of CD68+ cells was counted and the amount of IgG scored semiquantitatively on a scale of 0 to 4.0. For each biopsy specimen, the mean number of MOs per glomerular cross-section (MO index [MOI]) was calculated. Linear regression analysis showed a moderately strong inverse correlation between individual glomerular IgG deposit score and individual glomerular MO count (r = -0.447; P < 0.0001), a weaker but significant inverse correlation between DI and MOI (r = -0.350; P = 0.0389), and a positive correlation between the DI determined histologically in each case and the corresponding DI scored on the immunolabeled sections (r = 0.534; P = 0.0105). The results indicate that the amount of glomerular deposit and the extent of glomerular MO infiltration are inversely related in LN.

Interstitial foam cells and oxidized lipoprotein in human glomerular disease.

Foam cells (FCs) have been detected in the cortical interstitium of some patients with glomerular disease. Whether they have a significant role in tubulointerstitial injury and disease progression is uncertain. Renal biopsy specimens from 13 patients with glomerular disease (6 with Alport's syndrome, 5 with focal glomerulosclerosis, 2 with membranoproliferative glomerulonephritis, Type 1) showing interstitial FCs were investigated by histochemical means for neutral lipid (oil red O stain); immunohistochemical means for monocytes/macrophages (CD68), apolipoproteins (Apo) A-I, B, and E, and oxidized low-density lipoprotein (LDL); and by electron microscopic examination. FCs were positive for neutral lipid, CD68, and oxidized lipoprotein but did not stain for Apo B. In four specimens, there was a weak FC reaction for Apo E alone and in one case for both Apo E and Apo A-I. Focal interstitial staining was observed for both Apo B and E but not for Apo A-I. There was focal staining of tubular epithelial cytoplasm for neutral lipid in all of the specimens, for Apo E in five of seven specimens, for oxidized lipoprotein in case, and for Apo A-I in three cases. Electron microscopic analysis showed that the FC contained numerous clear cytoplasmic vacuoles that were not membrane-bound and that were generally associated with increased numbers of collagen fibrils and basement membrane-like extracellular matrix and frequently with aggregates of extracellular lipid-like particles embedded in extracellular matrix. The findings are analogous to those in atherosclerosis and suggest a role for FCs and oxidized lipoprotein in the pathogenesis of interstitial injury in some cases of glomerular disease.

Thrombotic microangiopathy associated with cryoglobulinemic membranoproliferative glomerulonephritis and hepatitis C.

Cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) and increased incidence of vascular thromboses are complications of hepatitis C virus (HCV) infection. This report describes the clinical, laboratory, and renal biopsy findings in two HCV-positive patients with cryoglobulinemic MPGN and thrombotic microangiopathy (TMA). Testing for circulating antiphospholipid antibodies, which are detected in a significant proportion of patients with HCV, was negative in the one case in which it was done. This article discusses the possible cause of the TMA in these two cases.

Osteopontin in chronic puromycin aminonucleoside nephrosis.

Increased expression of osteopontin (OPN) associated with interstitial monocyte infiltration has been demonstrated in the early phase of a variety of experimental renal diseases. Whether these changes occur in the chronic phase of progressive glomerular disease is unknown. Chronic puromycin aminonucleoside nephrosis (PAN) was induced in 16 rats by the injection of a single bolus of PA into the internal jugular vein, which results in a triphasic disease characterized by minimal glomerular change and marked proteinuria, peaking at about 10 to 14 d and subsiding by 28 d, followed by a quiescent 4-wk period of no or minimal proteinuria and then the development of progressive focal glomerulosclerosis (FGS) and increasing proteinuria. Fifteen rats injected similarly with normal saline served as controls. At 11 d after injection, PA rats demonstrated significantly greater urinary protein excretion (P = 0.0107), cortical tubular OPN expression (P = 0.0086), and intraglomerular (P = 0.0009) and interstitial (P = 0.0212) monocyte infiltration than did the controls. At 42 d, no significant differences between the two groups with respect to the above parameters were detected. At 98 d, PA rats had FGS and showed a definite trend to increased proteinuria, cortical tubular OPN, and intraglomerular monocyte infiltration. Although the cortical interstitial monocyte count was not elevated in PA rats compared with controls, there were significantly more monocytes around OPN-positive cortical tubules than around OPN-negative ones (P = 0.0011). Cortical tubular OPN expression correlated well with urinary protein excretion (r = 0.932, P < 0.0001), cortical tubular proliferating cell nuclear antigen (r = 0.796, P < 0.0001), and intraglomerular monocyte count (r = 0.552, P = 0.0013). The results are consistent with a monocyte chemoattractant role for OPN and suggest that OPN is upregulated in the chronic phase of PAN and that this increase in expression is a result of glomerular events.

Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case.

Seven cases of nonamyloid heavy chain (gamma chain) deposition disease have been previously reported. We describe one case of a 79-year-old woman presenting with proteinuria and microscopic hematuria whose renal biopsy showed nodular glomerulosclerosis with deposition of gamma3 heavy chains and complement in the glomeruli and tubular basement membranes with no associated light chain deposition. The patient did not have multiple myeloma. This case is unique in that in all previously reported cases of heavy chain deposition disease the gamma chain subtype has been either gamma1 or gamma4.

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.

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.

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)

Oxidized low-density lipoprotein in experimental focal glomerulosclerosis.

Oxidized low-density lipoproteins (Ox-LDL) have been shown to be involved in the pathogenesis of atherosclerosis. Because of the similarities between atherosclerosis and focal glomerulosclerosis, a study was performed to demonstrate whether Ox-LDL could be detected in the glomeruli in experimental FGS. FGS was induced in 12 rats on a 4% cholesterol-1% choline diet by seven injections of puromycin aminonucleoside over a 10 week period. Eight rats on a normal diet served as controls. Fourteen weeks after the start of the experiment all rats were sacrificed. The test animals showed marked hypercholesterolemia and proteinuria. About 20% of glomeruli in test animals showed FGS and variable amounts of glomerular lipid were demonstrated. Immunohistochemical staining using five specific monoclonal antibodies against various forms of Ox-LDL showed positive staining of a variable number of glomeruli in the test rats. The staining pattern appeared to be intracellular. Staining with ED1 showed significantly increased numbers of intraglomerular monocytes in the test rats (test vs. control 2.4 +/- 1.1 vs. 0.4 +/- 0.1 monocytes per glomerulus, P < 0.0001). Control animals showed no segmental sclerosis, no glomerular lipid, and no staining for Ox-LDL. Lipid analysis of isolated glomeruli showed increased cholesterol, increased arachidonic acid and decreased eicosapentaenoic acid in test animals compared to controls. The findings suggest a role for Ox-LDL in the pathogenesis of experimental FGS and support the hypothesis that FGS is analogous to atherosclerosis.

Focal glomerulosclerosis in idiopathic membranous glomerulonephritis.

The significance of the finding of focal glomerulosclerosis (FGS) in idiopathic membranous glomerulonephritis (MGN) is uncertain. Twenty-seven patients with mixed FGS and MGN (MGN-FGS) were compared to 25 patients with MGN alone (generally matched for age, sex and stage of glomerular lesion) with respect to pathology, presenting clinical and laboratory features, and course of disease. Biopsies from the MGN-FGS patients showed significantly more extensive tubulointerstitial disease (P less than 0.001) than did those with MGN alone. At the time of biopsy, the MGN-FGS group had a significantly higher proportion of patients with hypertension (P = 0.006) and microhematuria (P = 0.006), a marginally higher percentage of patients with the nephrotic syndrome (P = 0.051), and a greater mean 24-hour urinary protein excretion (P = 0.004). A similar proportion of patients in each group were treated with either prednisone alone or prednisone with an immunosuppressive. Forty-eight percent of MGN-FGS patients and 13% of the MGN patients developed established renal failure in the follow-up period (P = 0.008). The renal survival rate for the MGN-FGS group was significantly lower at 24 months (0.61 vs. 0.93, P less than 0.05), 60 months (0.48 vs. 0.88, P less than 0.025), and over the entire follow-up period (P less than 0.05). The results indicate that FGS in MGN is associated with a significantly poorer prognosis than MGN without this lesion.

Intraglomerular foam cells and human focal glomerulosclerosis.

Experimental evidence suggests a pathogenetic role for lipids in focal glomerulosclerosis (FGS) analogous to atherosclerosis. As foam cells (FC) are an important factor in atherosclerosis, a retrospective comparative study was done to evaluate the significance of intraglomerular FC in human FGS. Glomerular FC infiltration was evaluated in 115 biopsies of FGS, 120 biopsies of membranous glomerulonephritis (MGN) and 50 biopsies of minimal-change disease (MCD). Selected clinical and laboratory data collected at about the time of biopsy were reviewed. The proportion of biopsies showing glomerular FC was much higher in FGS (70%) than in either MGN (12%) or MCD (0%) p less than 0.001. The mean percent (+/- SD) of glomeruli with FC per biopsy was significantly greater in FGS (7.9 +/- 9.9) than in MGN (2.0 +/- 7.8; p less than 0.0001). Of the 14 MGN biopsies with FC, 13 showed superimposed FGS. Mean serum total cholesterol and triglyceride were not significantly higher in FGS than in either MGN or MCD. The results demonstrate a close association of glomerular FC infiltration with FGS.

Ideas in pathology. Focal and segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FGS) is an important cause of the nephrotic syndrome and renal failure in children and adults. This review will present a detailed description of the pathological and clinical features of FGS and discuss in depth the modern concepts of its pathogenesis, which recent studies indicate is multifactorial and analogous to that of atherosclerosis.

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.

Macrophage origin of the multinucleated cells of myeloma cast nephropathy.

The histogenesis of the multinucleated cells that characterize myeloma cast nephropathy ("myeloma kidney") has long been a subject of debate. Recent studies have implicated monocyte/macrophage-derived cells rather than tubular epithelial cells as the progenitors of these multinucleated cells. In this study a panel of antibodies including one with high specificity for macrophages was used to study four cases of myeloma cast nephropathy. The authors' findings extend previous observations of others to confirm the macrophage origin of the multinucleated cells in this form of renal injury.

Monocytes and focal glomerulosclerosis.

It has been suggested that focal glomerulosclerosis (FGS) is analogous to atherosclerosis. Because monocytes and their derivatives are involved in the latter, these cells may be involved in the development of the former. To investigate this possibility a combined histochemical and ultrastructural study of FGS was done. Sections from 13 biopsies showing FGS were stained for either nonspecific esterase or lysozyme to detect monocytes and their derivatives. These include foam cells (lipid-containing macrophages) in which there was positive cytoplasmic staining for both nonspecific esterase and lysozyme. Twenty-one of 29 glomeruli (72%) with segmental sclerotic lesions contained monocytes and/or foam cells, whereas only 18 of 251 glomeruli (7%) without the lesions demonstrated these cells (p less than 0.0001). The mean number of monocytes and/or foam cells in segmentally sclerotic glomeruli was 2.0 +/- 1.7 compared with 0.2 +/- 0.3 for uninvolved glomeruli (p less than 0.01). In glomeruli with sclerotic lesions foam cells predominated over monocytes. Neutral lipid was observed focally and segmentally in 29 of 35 biopsies with FGS. Electron microscopy in 23 biopsies consistently demonstrated intracapillary cells with monocytic features but few foam cells in very early lesions characterized by epithelial cell changes but no or minor glomerular tuft alterations. With progression, the relative number of monocytes declined but foam cells were observed more frequently. These results suggest that monocytes and their derivatives are involved in the development of FGS.

Effect of magnesium diet in gentamicin-induced acute renal failure in rats.

Clearance experiments were conducted with metabolic cages to determine the effect of dietary magnesium on gentamicin nephrotoxicity. Three groups of male Wistar rats were given low, medium- or high-magnesium diets. Following baseline clearances, gentamicin was administered by intramuscular injection (20 mg/kg). Additional clearances were performed 6 and 11 days after gentamicin administration. 24-hour clearances were also taken 8 days after gentamicin withdrawal. The present experiments demonstrated that high magnesium intake protected the kidney against injury induced by gentamicin. This reduction in nephrotoxicity was probably due to competition of binding between magnesium and gentamicin to the renal membrane. Histological examinations were also done in these animals. The results showed that the most severe changes were seen in rats receiving a low-magnesium diet. Rats given a high-magnesium diet showed the least toxic changes while rats receiving a medium-magnesium diet showed changes of intermediate severity. These observations complemented the results obtained from 24-hour clearances and indicate the protective effect of dietary magnesium on the development of acute renal failure following administration of gentamicin.