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.

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).

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.

Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathologic observations in three cases.

Renal failure insidiously developed in three patients treated with a combination of hydrochlorothiazide and triamterene five to 10 weeks after commencing therapy. All had normal renal function prior to therapy and none had preexisting renal disease. Two of the patients had eosinophilia and two had a fever. One patient was oliguric. Renal biopsy demonstrated acute interstitial nephritis histologically. Direct immunofluorescence did not disclose evidence of either immune complex or antitubular basement membrane antibody deposition. Withdrawal of the drug led to remarkable improvement with renal function returning to normal in two patients and near normal in the third. The sequence of events and the histologic findings strongly suggest that the acute interstitial nephritis was due to a drug-induced hypersensitivity reaction. Although hydrochlorothiazide appears to be the drug responsible for the reaction, certain observations suggest a possible potentiating role for triamterene.

Differences between the O-acetylated sialic acids of the epithelial mucins of human colonic tumors and normal controls: a correlative chemical and histochemical study.

Chemical analyses, together with histochemical assessments, were carried out on specimens of adenocarcinoma of the colon and histologically normal colonic epithelium (from resection margins from cases of carcinoma of the colon). In the epithelial glycoproteins of the normal tissue, both chemical and histochemical investigations indicated that the great majority of the sialic acids contained a side-chain O-acyl substituent located at position C8, whereas the side-chain substitution of the sialic acids of tumor glycoproteins was markedly reduced. Chemical analysis of the normal glycoproteins indicated that the great majority of the sialic acids were resistant to digestion with Vibrio cholerae neuraminidase, presumably due to an ester substituent at C4. The sialic acids of the tumor glycoproteins were significantly different from normal, in that they were less resistant to digestion with neuraminidase (p greater than 0.01), and therefore had a lower percentage of substitution at C4 (p greater than 0.01).

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.

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.

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.

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.

Drug-induced acute interstitial nephritis with granulomas.

To shed more light on the immunopathogenesis of drug-induced acute interstitial nephritis, a combined histologic, immunopathologic, and ultrastructural study of renal biopsy specimens from nine patients with drug-induced renal disease was performed. None of the patients had pre-existing renal disease or evidence of sarcoidosis or tuberculosis. The principal drugs included a hydrochlorothiazide-triamterene combination (Dyazide), hydrochlorothiazide, fenoprofen, and furosemide and triamterene. Renal insufficiency developed approximately four to ten weeks after initiation of drug therapy. In all cases, withdrawal of the drug(s) with or without steroid therapy resulted in restoration of normal or near-normal renal function. Histologically, all biopsy specimens showed acute interstitial nephritis characterized by an intense but patchy mononuclear cell interstitial infiltrate consisting of lymphocytes, monocytes, and plasma cells, modest numbers of eosinophils, patchy tubular atrophy, interstitial edema, and normal glomeruli. All biopsy specimens contained interstitial (and, in two cases, perivascular) non-caseating granulomas, which were numerous in one case, moderate in four cases, and rare in the remainder. Direct immunofluorescence was negative for IgG, IgM, IgA, C1q, C4, and C3 along glomerular and tubular basement membranes. Immunoperoxidase staining for lysozyme (performed in three cases) demonstrated many positive cells in the infiltrate. In two cases in which granulomas were present in prepared sections, the epithelioid and multinucleated giant cells did not stain for lysozyme. Electron microscopy of the granulomas in two cases revealed that the epithelioid and giant cells had "secretory" features characteristic of hypersensitivity granulomas. These findings provide further evidence for the participation of cell-mediated immunity in the pathogenesis of at least some cases of drug-induced acute interstitial nephritis.

Lupus glomerulonephritis with thrombotic microangiopathy.

Well-documented cases of systemic lupus erythematosus (SLE) with thrombotic microangiopathy (TMA) are rare. Renal biopsy in a 25-year-old woman with SLE who was in renal failure demonstrated proliferative lupus glomerulonephritis with arteriolar thrombosis and the arterial intimal changes of TMA. No staining of vessels for immunoglobulins or complement was found by direct immunofluorescence. Fibrillar and flocculent deposits were seen in the widened and rarefied subendothelial space in a small artery and two glomeruli, one of which also contained electron-dense deposits. The vascular findings, which are those of TMA, are distinct from the immune complex vasculopathy of SLE.

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 glomerulonephritis associated with remote visceral infection.

The biopsies of 8 patients with diffuse proliferative glomerulonephritis associated with remote visceral infection (GN-RVI) were evaluated by histochemistry and electron microscopy for the presence and extent of intraglomerular monocytic infiltration. The sites of infection were cardiac valves (2 cases), ventriculoatrial shunts (2 cases), lungs (2 cases), blood (1 case) and retroperitoneal space (1 case). Seven of the patients had an elevated serum creatinine (1.5-6.5 mg/dl) and all had proteinuria, hematuria and an active urinary sediment. Histochemical investigation using the alpha-naphthyl acetate stain for nonspecific esterase (NSE) was conducted in 7 of the biopsies and showed relatively numerous intraglomerular monocytes in 5 cases. Electron microscopy demonstrated conspicuous monocytic infiltration of glomeruli in the 1 biopsy in which histochemistry was not done and in the 5 cases with high NSE indices (mean number of NSE + cells/glomerulus). The mean NSE index for the group was 4.5 (+/- 3.1) (range = 0.6-10.0). This was compared to the mean NSE indices for other types of diffuse proliferative glomerulonephritis (GN) - GN associated with mixed essential cryoglobulinemia (GN-CRY) (4 cases), membranoproliferative GN, type I (MPGN) (18 cases), post-infectious GN (PIGN) (9 cases) and diffuse lupus GN (GN-SLE) (35 cases). The NSE index for GN-RVI was less than that of GN-CRY (9.1 +/- 5.8) but greater than those of PIGN (3.5 +/- 2.5), GN-SLE (2.6 +/- 2.3) and MPGN (1.3 +/- 1.3). The differences between the GN-RVI index and those of GN-CRY, PIGN and GN-SLE were not significant but the difference between GN-RVI and MPGN was (p less than 0.01, Student's test).

Membranoproliferative glomerulonephritis type 1: comparison of natural history in children and adults.

Clinical, laboratory and pathological data on 46 patients (29 children and 17 adult) with Type 1 membranoproliferative glomerulonephritis (MPGN) were reviewed in order to compare the natural history of the disease in two age groups. The nephrotic syndrome was the most common presenting clinical feature in both age groups. Established renal failure at time of biopsy was seen in adult males only. All the adults males, but none of the women, were either dead or in renal failure after a mean duration of diseases of 17.7 months. In contrast 43% of the children (both sexes) were in renal failure after a mean duration of disease of 51.6 months. Statistical analysis disclosed that only up to 48 months was there a significant difference in survival between the two age groups (P less than .01). Beyond this time the difference was not statistically significant. The difference in behaviour of MPGN in the two age groups is similar to that observed in other glomerulonephropathies.

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.

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)

Histogenesis of glomerular crescents. Immunohistochemical demonstration of cytokeratin in crescent cells.

Recent studies have suggested that crescents are primarily of monocytic origin and that epithelial cells are a minor factor in their composition. Frozen sections of renal biopsies from 11 cases of crescentic glomerulonephritis (CGN) and 5 controls (2 acute interstitial nephritis, 1 focal glomerulosclerosis, 1 benign recurrent hematuria, 1 normal kidney) were stained for intracellular cytokeratin (CK) with a mouse monoclonal anti-CK antiserum (PKK1) and nonspecific esterase (NSE) activity. Indirect immunofluorescence with PKK1 antiserum showed that in all biopsies there was positive staining of collecting duct and proximal and distal tubular epithelium but no reactions in blood vessels or interstitium. In control case glomeruli there was no staining of the tuft, including the visceral epithelium. In all cases some parietal epithelium was CK-positive. In 4 CGN biopsies the majority of the crescents showed cytoplasmic staining for CK in more than 50% of the crescent cells. In 2 cases most crescents contained between 10-50% CK-positive cells, whereas in 5 biopsies little or no CK was present in the majority of crescents. In all but one CGN case the majority of crescents contained fewer than 30% NSE-positive cells (monocytes). Electron microscopy demonstrated intermediate filaments in many crescent cells and scattered desmosomes within crescents. The results indicate that epithelial cells, probably of parietal epithelial origin, contribute significantly to crescent formation.

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.