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.

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice.

Phosphatidylinositol 3-kinase (PI3K) has emerged as a critical component of multiple immune system intracellular signalling pathways. The levels and relative ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P(2)) and phosphatidylinositol (3,4,5) trisphosphate (PIP(3)), are regulated by inositol phosphatases such as Pten and SHIP. Interestingly, mice heterozygous for Pten, a 3'-inositol phosphatase, develop a progressive lymphoproliferative syndrome with autoimmune features. Given the importance of PIP(3) species in regulating immune responses, we hypothesized that heterozygosity for the 5'-inositol phosphatase SHIP might exacerbate the autoimmune phenotype of Pten(+/-) mice. In keeping with this, mice heterozygous for both Pten and SHIP developed lymphoproliferation, hypergammaglobulinaemia, autoantibody titres and renal pathology that were more severe than that of Pten(+/-) mice. These results suggest that the relative levels of phosphatidylinositol phosphatases are likely critical to immune system homeostasis and they also highlight the potential for gene dosage effects in regulating susceptibility and/or severity of autoimmunity.

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.

Steroid-responsive pleuropericarditis and livedo reticularis in an unusual case of adult-onset primary hyperoxaluria.

We present a case of a 54-year-old woman with rapidly progressive renal failure of uncertain origin, who developed pleuropericarditis and livedo reticularis 6 weeks after initiation of hemodialysis (HD). The presentation with acute renal failure, the development of serositis, and the dramatic clinical response to empiric steroid therapy initially suggested the diagnosis of a systemic inflammatory disorder or vasculitis. Renal biopsy, performed 3 days after presentation, suggested crystal deposition disease, and subsequent investigations, using both dialysate oxalate concentrations and liver biopsy, led to the diagnosis of primary hyperoxaluria (PH). We discuss this atypical adult presentation of PH and propose a role for the use of steroids in the management of the acute inflammatory symptoms of oxalosis. We also briefly discuss the current medical management of patients with PH, including transplantation.

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.

Uptake and metabolism of lipoprotein-X in mesangial cells.

Progressive glomerulosclerosis is a major complication in patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. The lack of LCAT activity results in the accumulation of an abnormal lipoprotein, lipoprotein-X (Lp-X), in the plasma of these patients. Lipoprotein-X contains high levels of unesterified cholesterol and phosphatidylcholine. Lp-X may play a role in the accumulation of lipids in the kidney, which in turn may lead to glomerulosclerosis. The objective of this study is to examine the uptake and metabolism of Lp-X by rat mesangial cells. Our results suggest that Lp-X is taken up by mesangial cells and that the lipids in Lp-X are metabolized. Lysosomes containing unesterified cholesterol and phosphatidylcholine, in a molar ratio similar to Lp-X, were synthesized to investigate the roles individual apolipoproteins (apo CI, II, III and E) play in the uptake of Lp-X. Both apo CI and CIII inhibited its uptake while apo CII (1.5 fold) and E (4 fold) stimulated the uptake of Lp-X. Very low density lipoprotein (VLDL) and low density lipoprotein (LDL) inhibited Lp-X uptake by mesangial cells. However, at higher concentrations of high density lipoprotein (HDL), the uptake of Lp-X was stimulated. Proteoglycans have an important role in regulating the uptake of Lp-X, while cytoskeleton-dependent phagocytosis and the scavenger receptor do not appear to be involved.

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.

Inhibition of progression of chronic puromycin aminonucleoside nephrosis by probucol, an antioxidant.

Oxidants have been shown to be involved in the initiation of chronic puromycin aminonucleoside nephrosis in rats, but it is uncertain whether they have a role in the progression of this disease. Rats given a single internal jugular venous bolus of puromycin aminonucleoside (PA) develop early nephrotic syndrome that subsides after about 28 days followed by a 4-wk period of minimal proteinuria and then the development of focal glomerulosclerosis and increasing proteinuria. Fifty-two rats on a high-cholesterol diet were divided into four groups. Two groups of 16 animals each received a single internal jugular venous bolus of PA. One of these groups was started on the dietary antioxidant, probucol (1% wt/wt), 4 days after the PA injection and continued on it until termination. The remaining rats were given an internal jugular venous injection of an equivolume of normal saline. Five of these animals were also started on dietary probucol 4 days after the saline injection. At 11 days postinjection all animals given PA, whether on probucol or not, developed marked proteinuria with histologically minimal glomerular change and significant increases in intraglomerular monocyte and proliferating cell nuclear antigen counts. Forty-two days after PA injection all PA-injected rats had minimal urinary protein injection and no glomerular changes. At 98 days postinjection rats given PA without probucol developed focal glomerulosclerosis and significant proteinuria compared with PA-injected rats on probucol and those injected with saline (P < 0.05). The probucol-fed PA-injected rats showed no glomerular disease and their urinary protein excretion rates were very similar to those of the saline controls. The results indicate that probucol inhibits the progression of chronic puromycin aminonucleoside nephrosis and are consistent with the suggestion that oxidants are involved in the progression of this entity.

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)

Remission of nephrotic syndrome of HBV-associated membranous glomerulopathy following treatment with interferon.

We report a 26-year-old homosexual man who developed membranous glomerulopathy with nephrotic syndrome secondary to hepatitis B virus infection and HBe antigenemia. Aminotransferase levels were minimally abnormal, and a liver biopsy showed mild chronic 'persistent' hepatitis. He was initially treated for 4 weeks with human lymphoblastoid alpha-interferon by subcutaneous injection without effect. A second 4-week course of interferon in combination with acyclovir also failed to eradicate HBeAg from the circulation or to reduce the proteinuria. Four years later, he developed new symptomatic hepatitis, with plasma aminotransferases elevated to 200-300 IU/l for more than 4 months. Treatment with interferon was again initiated, and by the 4th month of therapy, he had seroconverted to anti-e status, and cleared the HBeAg from circulation. At the same time, proteinuria significantly dropped from an average of 7 g/day to less than 0.5 g/day. Four years after completion of interferon treatment, he became HBsAg negative and anti-HBsAg reactive while remaining persistently HBeAg negative and anti-HBe positive. He has been free of edema, with normal renal and hepatic function, and his 24-hour protein excretion was less than 0.12 g/day.

Simultaneous development of diffuse immunoblastic lymphoma in recipients of renal transplants from a single cadaver donor: transmission of Epstein-Barr virus and triggering by OKT3.

Rapidly progressive diffuse immunoblastic lymphoma is an uncommon but devastating complication of organ transplantation that typically occurs early in the postoperative period. The fulminant course is characterized by progressive encephalopathy and coagulopathy, with malignant B-cell infiltration in the graft and other sites. Both de novo infection with Epstein-Barr virus (EBV) and treatment with the monoclonal antibody OKT3 have been implicated in the development of this disorder. We report two patients who received renal transplants from the same cadaver donor, with transmission of EBV from the same source, in whom treatment with OKT3 for acute rejection triggered the simultaneous development of fulminant and fatal B-cell immunoblastic lymphoma. We suggest that antilymphocyte agents be used with caution in EBV-seronegative graft recipients who receive a transplant from an EBV-seropositive donor to minimize the risk of this lethal complication.

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.