Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function.

BACKGROUND: Long-term renal transplant function is limited primarily by a progressive scarring process loosely termed "chronic rejection, chronic allograft nephropathy, or allograft fibrosis." Although the etiology of transplant fibrosis is uncertain, several possible factors including chronic cyclosporin A (CsA) exposure may contribute to its pathogenesis. CsA stimulates renal fibrosis perhaps through the induction of the potent pro-sclerotic growth factor, transforming growth factor beta (TGFbeta). Previously, we demonstrated that, in human transplant biopsies, acute CsA toxicity but not acute tubular necrosis is associated with elevated levels of renal TGFbeta protein. We now examine whether long-term CsA treatment (>1 year) is associated with elevated levels of intra-allograft TGFbeta and whether heightened expression of TGFbeta is clinically significant. METHODS: Using immunohistochemical techniques, we determined the relative level of expression of intrarenal TGFbeta protein in transplant biopsies. We studied biopsies obtained from 40 CsA-treated patients that were diagnosed as having chronic allograft fibrosis. Biopsies were scored as having minimal or high levels of TGFbeta. RESULTS: Seventy-two percent of patients expressed high levels of intra-allograft TGFbeta. This group of patients lost renal function at an average rate of -19.5+/-17.3 ml/min/year. In contrast, patients with minimal or no TGFbeta expression experienced a decline of only -6.2+/-4.1 ml/min/year (P=0.01). CONCLUSIONS: These results suggest that the majority of CsA-treated patients with biopsy proven chronic fibrosis have elevated levels of intra-graft TGFbeta that correlates with an increased rate of decline in renal function.

Membranoproliferative glomerulonephritis with primary Sjögren's syndrome.

Glomerular involvement in primary Sjögren's syndrome is rare and only five cases of membranoproliferative glomerulonephritis have been reported. We present a case of a 31-year-old white woman with primary Sjögren's syndrome who developed nephrotic syndrome. Evaluation showed no evidence of an associated connective tissue disease. Kidney biopsy was consistent with type I membranoproliferative glomerulonephritis. The patient's nephrotic syndrome resolved spontaneously, a course that has not been reported previously in this setting.

Study of EHS type IV collagen lacking Goodpasture's epitope in glomerulonephritis in rats.

The Goodpasture's epitope has been mapped to the alpha 3 non-collagenous chain (NC1) of type (IV) collagen [alpha 3col(IV)]. We have developed a model of experimental autoimmune glomerulonephritis (EAG) in rats immunized once with collagenase solubilized GBM (csGBM). Engelbreth-Holm-Swarm (EHS) tumor contains abundant col(IV) with little or no alpha 3col(IV). To test the hypothesis that antigens related to Goodpasture epitope are required to produce EAG in our model, we immunized rats once with 40 micrograms csEHS. Positive controls immunized with csGBM developed typical EAG with GBM bound antibody, proteinuria, and glomerulonephritis. EHS rats developed circulating and bound antibody to mesangium and tubular basement membrane with minimal GBM deposits, but did not develop proteinuria or glomerulonephritis. Although circulating antibody in EHS rats bound to csGBM by ELISA, there was no binding in ELISA to M2 antigen containing the Goodpasture epitope while EAG rat's serum did bind. By Western blot with antisera to Goodpasture epitope, EHS antigen was less complex than GBM in the monomer/dimer regions and appeared to lack NC1 corresponding to alpha 3col(IV). Blotting with sera from EHS rats demonstrated reactivity to various components of GBM but not to alpha 3col(IV). EAG sera and renal eluates bound to alpha 3col(IV). EAG rats evidenced cell mediated immunity while EHS rats did not (stimulation index EHS 1.1, EAG rats 8.0).(ABSTRACT TRUNCATED AT 250 WORDS)

Juxtaglomerular body abnormalities in youth-onset diabetic subjects.

Abnormal microalbuminuria in insulin-dependent diabetic subjects (IDDS) is significantly associated with pre-clinical nephropathy. In youth-onset IDDS declining plasma renin activity is significantly associated with improved albumin excretion, while persistently elevated renin activity is associated with continued abnormal microalbuminuria. To determine if these changes are reflected in changes in cell count in the juxtaglomerular body and if biopsy findings correlate with abnormal microalbuminuria, renal tissue of 20 IDDS (Study IDDS) ages 16 to 31 years, evaluated concurrently for plasma renin activity and microalbuminuria, were examined by light microscopy. Biopsy or autopsy specimens from 21 normal subjects and 32 IDDS (Non-Study IDDS), ages 2 to 25, were also examined. Specimens from the majority of prepubertal and all pubertal and postpubertal Non-Study IDDS and all Study IDDS independently of status of microalbuminuria had morphologic abnormalities. Normal or mesangially expanded glomeruli were found in association with expanded juxta-glomerular bodies and increased cell number, or with sclerotic bodies and decreased cell number. Sclerosis of juxtaglomerular bodies occurred independently of glomerular sclerosis. The highest percentage of glomeruli with expanded juxtaglomerular bodies and high cell count was present in specimens of Study IDDS with the most abnormal levels of microalbuminuria. T lymphocytes, noted within juxtaglomerular bodies, were present in specimens of 62% of the 52 Study and Non-Study IDDS. Abnormalities of the juxtaglomerular body are distinctive features of renal pathology in IDDS. T lymphocytes in the endocrine juxtaglomerular body suggest the presence of an autoimmune process. Confirmatory studies are necessary.

Long-term oral or intravenous aluminum administration in rabbits. I. Renal and hepatic changes.

Long-term aluminum (Al) administration was studied in rabbits using intravenous (I.V.) injections of aluminum maltol or oral aluminum citrate in drinking water along with calcium. In the intravenous study, renal and liver tissue Al levels increased and were associated with proximal renal tubular pathology and with hepatic periportal Al-positive multinucleated cells. After oral Al, renal Al levels were increased in the Al-hard water group, while hepatic Al levels were not significantly increased over controls. However, cirrhosis was found in five orally-loaded animals which received Al and/or low dietary calcium or soft water. Collectively, these findings suggest that renal accumulation of Al is causally related to nephrotoxicity; that the lack of renal changes after oral loading is due to low absorption from normal adult gastrointestinal tract and normal functioning of mature kidneys; and that the elevated liver Al levels, achieved after I.V. administration, are related to the presence of hepatic Al-containing giant cells.

Disparate urinary catecholamine patterns in secondary hypertension due to unique sequential development of pheochromocytoma and neuroblastoma.

A 43-year-old white woman had a pheochromocytoma removed from her left adrenal gland, and one year later she developed a new left upper abdominal mass that was found to be a neuroblastoma. On both occasions, urinary vanillylmandelic acid level was elevated. However, urinary norepinephrine and epinephrine levels were increased only during the pheochromocytoma episode, while the urinary homovanillic acid level was elevated only when neuroblastoma developed. Despite a high suspicion of pheochromocytoma recurrence, the urinary catecholamine profile was suggestive of neuroblastoma, which was revealed by histopathologic analysis of the tumor tissue.

A long-term intravenous model of aluminum maltol toxicity in rabbits: tissue distribution, hepatic, renal, and neuronal cytoskeletal changes associated with systemic exposure.

We studied the toxicity of an intravenously injected, water-soluble aluminum complex (aluminum maltol) in 20 young adult male New Zealand white rabbits over a period of 8 to 30 weeks. Sixteen rabbits injected with aluminum-free maltol and 15 untreated rabbits served as controls. Rabbits were injected three times per week with 75 mumol of aluminum maltol per injection, or a molar equivalent amount of maltol alone, through an indwelling jugular catheter. Liver contained the highest concentrations of aluminum among the aluminum maltol-treated rabbits, and aluminum accumulation was correlated with the appearance of periportal multinucleated giant cells in 13 of 20 rabbits. These cells stained positively for aluminum when a fluorescent (Morin) stain was applied to tissue from rabbits with a high concentration of aluminum in the liver. Proximal renal tubular necrosis or atrophy was found in 15 of 20 aluminum maltol-treated rabbits but not in maltol-treated and untreated controls. Renal tubules in rabbits with acute proximal renal necrosis stained positively for aluminum. Neurofibrillary tangles, immunoreactive with a monoclonal antibody to the 200-kDa subunit of neurofibrillary protein, were observed in the oculomotor nucleus of 3 aluminum maltol-treated rabbits (treated for 12, 20, and 29 weeks), but in none of the two groups of controls. These tangles were present in 3 of 10 aluminum-treated rabbits in which the nucleus was located. None of the 17 animals in both control groups in which the nucleus was found demonstrated tangles. A slight increase in brain tissue aluminum concentration was confirmed by an electrothermal atomic absorption spectrophotometric method. There were no specific findings in heart or lung tissue from aluminum-treated rabbits, although the aluminum content of these tissues was 10 to 20 times greater than control values. This model should be useful for investigating the effects of systemic exposure to high concentrations of solubilized aluminum.

Methylprednisolone therapy for acute crescentic rapidly progressive glomerulonephritis.

In the last 10 years we have evaluated 63 patients with acute crescentic rapidly progressive glomerulonephritis (AC-RPGN), 46 of whom received pulse methylprednisolone (PM). The groups consisted of patients with no immune deposits, immune complexes, vasculitis, and antiglomerular basement membrane (anti-GBM) disease. Seventy-nine percent of non-anti-GBM patients improved versus 25% of unpulsed, p less than 0.005; 70% stopped dialysis (D) versus none of unpulsed, p less than 0.009; creatinine decreased from 8.6 before to 2.7 mg/dl after PM, p less than 0.05. Percent crescents and oligoanuria did not influence PM results, but did with conventional therapy (prednisone, cytotoxics, anticoagulants, supportive treatment). Seventeen percent of anti-GBM patients improved, none stopped D. In anti-GBM patients, serum creatinine less than 6 mg/dl was associated with a favorable response to PM, p = 0.045. Twenty-one percent of responding patients lost function at 19.8 months. The long-term response for non-anti-GBM patients was 62%. Patients with low chronicity on biopsy had shorter duration of disease (p = 0.006) and 92% initial, 85% long-term improvement; those with high chronicity had an immediate 71%, and 36% long-term response rate, p less than 0.02. Thus, PM is effective and appears superior to conventional therapy in treatment of non-anti-GBM AC-RPGN.

Clinical identification of nondiabetic renal disease in diabetic patients with type I and type II disease presenting with renal dysfunction.

A retrospective study was done on 109 diabetic patients who had renal biopsies during 1974-1984 to determine factors identifying nondiabetic renal disease in patients with diabetes mellitus presenting with renal dysfunction. Six of 49 (12%) patients with type I and 17 of 60 (28%) with type II diabetes mellitus had other renal diseases, with or without diabetic glomerulosclerosis. Multivariate predictors of other renal disease in type I diabetes mellitus were duration less than 5 years (p less than 0.001), absence of proteinuria (p less than 0.001), and absence of neuropathy (p less than 0.05). In type II diabetes mellitus these were late age of onset (p less than 0.001), absence of neuropathy (p less than 0.05), and Caucasian race (p less than 0.005). Some patients with other diseases appeared to respond to therapy directed at their nondiabetic glomerulosclerosis disease. We emphasize the need to distinguish between the subgroup of diabetic patients with nondiabetic renal disease from the majority who have diabetic glomerulosclerosis alone. The latter group should be spared the discomforts, risks, and costs of a renal biopsy.

T-cells and macrophages in rapidly progressive glomerulonephritis: clinicopathologic correlations.

We phenotyped with monoclonal antibodies (MAb) the cellular infiltrates in kidneys of patients with rapidly progressive glomerulonephritis (RPGN) responsive (R) or nonresponsive (NR) to pulse methylprednisolone therapy (PM)-eight anti-GBM, six no immune deposits, three immune complex, two vasculitis, and one proliferative GN. There were glomerular, periglomerular, crescentic, and interstitial T and T-cell subsets. Few interstitial and no glomerular B and NK cells were observed. TH cells were much more common than TS. Phenotypes were quantitatively evaluated in 221 nephritic and 32 control glomeruli. T and/or TH cells were positively correlated with M phi, r = 0.30 to 0.74, P less than 0.05 to 0.0005. Although differences in phenotypes were observed, these differences were insufficient to distinguish between subtypes. Analysis of R and NR revealed no relationship to percent crescents, entry serum creatinine, oliguria, or need for dialysis. NR was related to presence of anti-GBM disease, P = 0.001, as was ability to stop dialysis, 0 of 7 GBM versus 9 of 10 other, P less than 0.001. Mild infiltrates of lymphocytes and M phi correlated with R, P less than or equal to 0.02. R had fewer numbers of TH and M phi in glomeruli, P = 0.0001, in crescents, P less than 0.02, and total TH and M phi compared to NR, P less than 0.001. Crescentic and total TH/S ratios were lower in NR than R, P less than 0.05. These findings demonstrate that components of the cell-mediated immune (CMI) system are present by MAb analysis, that subtypes cannot be differentiated by CMI constitution, and R to PM is related to intensity and composition of CMI involvement. Independence of the CMI system relative to anti-GBM disease remains to be clarified.

Immunoglobulin light chain nephropathies.

Excessive monoclonal light chain production and excretion may result in a variety of renal diseases which may collectively or individually be referred to as light chain nephropathy. Kappa light chains are more likely to produce tubular dysfunction and nodular nonamyloidotic glomerulosclerosis, while lambda light chains are more likely to be involved in the development of amyloidosis. The physicochemical reasons for this segregation are poorly understood. Affected patients may present with minor tubular dysfunctions, acute or chronic renal failure, mild proteinuria, or severe nephrotic syndrome. Underlying each is a dyscrasia of plasma cells or frank multiple myeloma with excessive production of monoclonal light chains. Electron microscopy and immunofluorescence studies of renal biopsies have been critical in defining these nephropathies and continue to be essential in establishing the diagnosis.

Progression of membranous nephropathy to acute crescentic rapidly progressive glomerulonephritis and response to pulse methylprednisolone.

There have been only sporadic reports of membranous nephropathy (MN) evolving into acute crescentic rapidly progressive glomerulonephritis (AC-RPGN). A patient with MN developed acute oliguric renal failure with a serum creatinine (SCr) of 8.4 mg/dl after 5 years of normal renal function. Biopsy now revealed epithelial crescent formation superimposed on MN. Pulse methylprednisolone resulted in significant improvement in renal function, with a SCr of 2.2 mg/dl at 6 months. No other favorable outcomes occurred in the 4 previous case reports of MN evolving into RPGN. AC-RPGN should be considered a treatable etiology of acute renal failure in the setting of MN.

Ultrastructural studies of experimental autoimmune glomerulonephritis in normal and bursectomized chickens.

Immunizations of chickens with bovine glomerular basement membrane (GBM) results in the development of experimental autoimmune glomerulonephritis (EAG). Animals lacking antibody to GBM develop nephritis comparable to those with antibody. The present study examined the ultrastructural lesions of EAG. Normal and bursectomized (Bsx) chickens were immunized with complete Freund's adjuvant (CFA) or CFA-GBM. We studied 3 CFA controls, 5 CFA-Bsx controls, 5 GBM immunized, 4 Bsx-GBM immunized antibody positive birds, and 6 Bsx-GBM immunized birds with no antibody. Ultrastructure of control animals was consistent with previous descriptions in chickens. In nephritic GBM-immunized animals the proliferative glomerulonephritis was associated with an increase in resident mesangial (type I) cells identified by small regularly shaped nuclei with coarsely clumped chromatin and scanty cytoplasm. (p less than 0.05). Glomerulonephritis was also associated with the occurrence of type II cells characterized by an irregular folded lobulated nucleus, finely granular chromatin, abundant cytoplasm, and dense granules and vacuoles in the cytoplasm with an appearance similar to macrophages. The presence of type II cells was highly associated with the development of glomerulonephritis, p less than 0.05. The increase in type II cells was observed in animals with and without antibody along the GBM. A third type of cell was also observed in intimate contact with type II cells and had the morphology of a lymphocyte. The lymphocytoid cells were only seen in nephritic animals. Bsx was associated with trabeculation and lucencies of the GBM not found in normal birds, p less than 0.05. EAG in chickens occurs regardless of the presence or absence of GBM-bound anti-GBM antibody. Other studies have shown that the disease can be transferred by specifically sensitized lymphocytes, but not by antibody. The present ultrastructural findings provide further evidence for the role of cell mediated immunity in the pathogenesis of this model of EAG in chickens.

Isolated xanthomatosis of the small bowel.

A case of xanthomatosis of the small bowel is described. Beginning with the proximal jejunum, an 85-cm segment of small bowel was distorted by regularly spaced nodular accumulations of lipid-laden macrophages that expanded the submucosa and muscularis and extended to the serosal surface. The conditions often associated with xanthomatosis were not found in this patient.

Congo red-negative amyloidosis-like glomerulopathy.

Three cases of amyloidosis-like glomerulopathy are presented in which renal amyloidosis was initially diagnosed on the basis of ultrastructural findings, despite negative Congo red staining. The histologic and immunofluorescence findings and, on careful examination, ultrastructural features of this amyloidosis-like glomerulopathy all serve to distinguish it from true amyloidosis. The clinical behavior suggests that it is a primary glomerulopathy since, with time, no other systems become involved.

Iatrogenic renal disease.

PIP: This chapter reviews some of the more important and common types of iatrogenic renal diseases. Modern developments in diagnostic methods and therapeutic modalities have been accompanied by an increasing frequency and variety of iatrogenic diseases including those of the kidneys. Among these renal diseases is the combination of microangiopathic hemolytic anemia and acute renal failure, commonly called hemolytic-uremic syndrome (HUS). Renal pathology is characteristic. Small artieries and arterioles show occlusive intimal proliferation with trapping of red cells and red cell fragments within a myxoid stroma. The vessel may develop segmental necrosis or occlusive thrombosis resulting in secondary ischemic contraction or necrosis of glomeruli. Glomeruli may be affected by the primary vasculopathy as well. The syndrome is rare in adults but has been described in postpartum women and several cases of HUS have been reported in women taking oral contraceptives. The incidence is unknown but the small number of reported cases suggests the complication is rare since the syndrome is dramatic and unlikely to escape attention. The pathogenesis of HUS is unknown, but endothelial injury is a central feature. Whether this is caused by fibrin deposition or whether fibrin deposition develops after endothelial injury is unknown. In one study of 17 children with HUS, all had an inhibitor of glomerular fibrinolysis in their serum. The prevalence of thrombotic complications in women taking oral contraceptives is well known but the mechanism is not known.^ieng

Bladder polyp and heavy proteinuria in a patient with Hodgkin's disease in remission.

A 21-year-old man who developed heavy proteinuria 8 years after remission of Hodgkin's disease treated with MOPP chemotherapy and radiation therapy is reported. Evidence of Hodgkin's disease could not be documented, and minimal changes were revealed by renal biopsy. Proteinuria persisted for 20 months and was followed by dysuria and the discovery of an inflammatory polyp of the bladder. The proteinuria decreased 1 month after excision of the polyp, and disappeared during the following year. Rather than indicating relapse of lymphoma, proteinuria in this patient resulted from a lesion not previously associated with Hodgkin's disease, but possibly resulting from long-term effects of therapy.

Early onset of clinical diabetic nephropathy in children--a new subgroup?

The onset of fixed proteinuria and hypertension in insulin-dependent diabetic is generally associated with eventual renal insufficiency due to diabetic nephropathy or with a superimposed glomerulopathy. We report three adolescents with normal renal function who developed fixed proteinuria and hypertension after only 7 to 11 years of insulin-dependent diabetes mellitus. Blood pressure ranged from 130/95 to 165/104 mmHg, urinary protein excretion was 1.31 to 1.37 g/24 hours, and creatinine clearance ranged from 98-133 ml/min/1.73 m2. Renal biopsy revealed changes consistent only with diabetic glomerulosclerosis. Follow-up evaluation for 11 months to 3 1/2 years revealed blood pressure reductions to 125/78-140/85 mmHg as a result of antihypertensive medications. Creatinine clearance increased by 12-20% and urinary protein excretion remained unchanged. We conclude that these patients may represent an unusual subgroup of insulin-dependent diabetics with early development of clinical and pathological diabetic nephropathy in the face of normal renal function.

Cold-reacting IgM antibody-induced renal allograft failure. Similarity to hyperacute rejection.

Hyperacute rejection of renal allografts is usually mediated by IgG antibody, but recent studies indicate that cold-reacting IgM alloantibodies are also associated with immediate malfunction of renal allografts. We report 2 cases of cold-reacting IgM-mediated allograft malfunction in which immediate posttransplant biopsies resembled hyperacute rejection. This reaction can probably be prevented by warming the kidney just before transplantation.