Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies.

BACKGROUND: Mature podocytes are growth-arrested because of the expression of cyclin-dependent kinase inhibitors. Under pathological conditions, podocytes may undergo mitosis, but not cell division. Exceptions to this rule are collapsing glomerulopathies (CGs), including HIV-associated nephropathy (HIVAN) and idiopathic CG, where podocytes undergo a dysregulation of their differentiated phenotype and proliferate. METHODS: To shed light on the mechanism underlying podocyte proliferation in CG, we analyzed the expression of the proliferation marker Ki-67, cyclins (A, D1), cyclin-dependent kinase inhibitors (p27, p57), and podocyte differentiation marker synaptopodin in eight cases of HIVAN and two cases of idiopathic CG. Normal fetal and adult kidneys served as controls. RESULTS: Both HIVAN and idiopathic CG showed a marked reduction in the expression of p27, p57, and cyclin D1 (absent in 69, 62, and 80% of all glomeruli, respectively). Cyclin A and Ki-67 were expressed in 11 and 29% of all glomeruli. Moreover, there was partial loss of synaptopodin and cyclin D1 expression in nonaffected glomeruli. CONCLUSIONS: The loss of p27 and p57 leading to expression of cyclin A may account for the activation of podocyte proliferation in CG. Furthermore, the loss of cyclin D1 from histologically normal glomeruli suggests a possible role of cyclin D1 in mediating the dysregulation of the podocyte cell cycle in CG. These novel findings offer insight into the molecular regulation of mature podocyte differentiation. Podocyte proliferation in CG provides evidence in support of a previously underestimated plasticity of mature podocytes.

Fibrous long-spacing collagen in bacillary angiomatosis.

Fibrous long-spacing (FLS) collagen is a distinct ultrastructural form of collagen present in normal tissue, various tumors, and tissues degraded by bacterial collagenases in vivo and in vitro. An association between FLS collagen and bacillary angiomatosis has not been previously described. Six cases of bacillary angiomatosis, including one autopsy case with disseminated disease, were examined ultrastructurally. In addition, Kaposi sarcoma (3), pyogenic granuloma (3), capillary hemangioma (3), and cavernous hemangioma (2) were examined for comparison. A vascular proliferation in a lymph node from a patient with AIDS (1) and a case of pulmonary capillary hemangiomatosis (1), also in an AIDS patient, were studied. Abundant FLS collagen was identified in 4 of 6 cases of bacillary angiomatosis, in close association with the organisms. FLS collagen was not seen beyond the immediate vicinity of the organisms. The FLS collagen in bacillary angiomatosis was seen in skin biopsies and in lung and skeletal muscle in the autopsy case; in the latter case, as well as in the two AIDS-associated, nonbacillary angiomatosis, non-Kaposi sarcoma vascular proliferations, there was a striking distribution of FLS collagen around small blood vessels. Occasional FLS collagen was observed in all three pyogenic granuloma. When present in pyogenic granuloma, FLS collagen was intermixed with subendothelial collagen. Abundant FLS collagen was identified in close association with the organisms of bacillary angiomatosis in four cases; this morphologic alteration was seen in skin as well as lung and skeletal muscle. An association between FLS collagen and endothelial cells in normal tissue (Descemet's membrane) and in certain vascular proliferations appears to exist.

Recurrent crescentic membranous nephropathy in two successive renal transplants: association with choroidal effusions and retinal detachment.

We report the case of a 50-year-old man in whom crescentic membranous nephropathy recurred in two successive renal transplants leading rapidly to renal failure. Deterioration of renal function was associated with choroidal effusions and retinal detachments. Multiple serologic tests were negative. High-dose steroids, cyclophosphamide, cyclosporine, plasmapheresis and OKT3 failed to arrest the deterioration of renal function.

Analysis of adhesion molecule expression by tubular epithelial cells using urine immunocytology.

On their surface, renal tubular cells present intercellular adhesion molecule-1 (ICAM-1) during acute renal allograft rejection. We propose that the extent of ICAM-1 expression by renal tubular cells can be estimated from urine immunocytology. To test this hypothesis, we obtained 52 samples of urine from 31 renal transplant recipients with either acute tubular necrosis, rejection or stable renal function. Cytocentrifuged aliquots of urinary sediment were incubated with monoclonal antibodies to ICAM-1 in an avidin-biotin-peroxidase technique. To corroborate our findings, biopsy specimens were obtained for conventional and immunohistology one hour following vascular anastomosis and during rejection episodes. The proportion of renal tubular cells that expressed ICAM-1 was low in patients with acute tubular necrosis (23.8 +/- 3.6%) and high in patients with rejection (53.1 +/- 4.4% [SEM]) (P < .001). In 11 patients who recovered from rejection, the proportion of ICAM-1-positive renal tubular cells decreased from 55.9 +/- 5.6% to 25.5 +/- 4.3% (P < .05). In two patients who initially had acute tubular necrosis and then rejected their transplants, the expression of ICAM-1 on renal tubular cells tended to increase (from 27.5 +/- 2.5% to 60.0 +/- 20.0%, P = .12). In eight patients with acute tubular necrosis who never rejected their transplants, ICAM-1 expression remained low (23.1 +/- 3.8%). Immunocytology correlated well with immunohistology and the clinical diagnosis. Our findings suggest that urine immunocytology may be useful in monitoring adhesion molecule expression by renal tubular cells.

Pharyngeal flap revisions: flap elevation from a scarred posterior pharynx.

Twenty-one consecutive patients who had earlier superiorly based pharyngeal flap surgery and persistent velopharyngeal insufficiency were seen between 1976 and 1991. Patients were divided into two treatment groups, depending on the results of videofluoroscopic and nasopharyngoscopic assessment. The first group consisted of 18 patients who had bilateral port insufficiency and required a complete reconstruction of a new superiorly based pharyngeal flap that was elevated from a scarred posterior pharyngeal wall. After an average follow-up of 6.2 years, 15 patients had normal resonance, 2 patients had improvement but continued hypernasality, and 1 patient was hyponasal. The second group consisted of 3 patients who had "patch" flaps to a unilateral port insufficiency. Postoperatively, all 3 of those patients had normal resonance. Indications for the decision to "redo" or patch flaps are described.

Combined antihypertensive and lipid-lowering therapy in experimental glomerulonephritis.

We examined the interrelation between systemic hypertension, hyperlipidemia, and progressive renal injury in experimental glomerulonephritis. Induction of nephrotoxic serum nephritis in Sprague-Dawley rats led to systemic hypertension and hyperlipidemia. Four groups of rats were studied over a 16-week period: (1) untreated nephritic rats; (2) nephritic rats treated with hydralazine, reserpine, and lasix (AH); (3) nephritic rats treated with lovastatin (4 mg/kg) (Lova); and (4) nephritic rats treated with combined antihypertensive/lipid-lowering therapy (AH/Lova). Systolic blood pressure rose progressively in untreated rats (152 +/- 4 mm Hg at 16 weeks). Blood pressure was reduced by antihypertensive therapy (P < .001) (108 +/- 2 mm Hg in the AH group and 111 +/- 3 mm Hg in the AH/Lova group) but remained elevated in animals treated with lovastatin alone (P > .05) (156 +/- 3 mm Hg in the Lova group). Serum cholesterol rose progressively in untreated rats (3.70 +/- 0.85 mmol/L [143 +/- 33 mg/dL] at 16 weeks). The rise in serum cholesterol was prevented by lovastatin therapy (P < .001) (2.22 +/- 0.41 mmol/L [86 +/- 16 mg/dL] in the Lova group and 2.09 +/- 0.52 mmol/L [81 +/- 2 mg/dL] in the AH/Lova group) but not antihypertensive therapy (P > .05) (2.92 +/- 0.65 mmol/L [113 +/- 25 mg/dL] in the AH group). Proteinuria was reduced by antihypertensive therapy (P < .001) and lipid-lowering therapy (P < .05) (16-week values: 1.069 +/- 0.167 g/d in untreated rats, 0.663 +/- 0.164 g/d in the Lova group, 0.392 +/- 0.051 g/d in the AH group, and 0.176 +/- 0.035 g/d in the AH/Lova group).(ABSTRACT TRUNCATED AT 250 WORDS)

Soluble interleukin-2 receptor levels in lupus nephritis.

Soluble interleukin-2 receptor (IL-2R) levels were measured and correlated prospectively with clinical, histologic and serologic findings over a 9-month period in 62 lupus patients. Initially, 39 patients had clinical nephritis and 23 patients did not have nephritis. The 62 lupus patients has significantly higher IL-2R than 15 normal controls, most of this difference attributable to patients with nephritis. During lupus nephritis flare 9 of 10 patients showed significant elevations of IL-2R while only 6 of the 10 patients showed either elevation of anti-DNA antibody or decrease in CH50. During disease remission or stable clinical activity changes in IL-2R levels paralleled changes in anti-DNA antibody and CH50. Nephritis patients with cellular proliferative histology had significantly higher IL-2R levels than those with membranous or mesangial nephropathy. IL-2R correlated strongly with histologic activity and chronicity indices, IgG and C3 deposition whereas anti-DNA antibody and CH50 levels did not. IL-2R levels did not correlate with serum creatinine suggesting that elevations of IL-2R were not simply due to decreased clearance. These observations suggest that serum IL-2R level is a useful marker of disease activity in lupus nephritis and may serve as a helpful adjunct in management of this disorder.

Superoxide dismutase: enhanced small intestinal preservation.

Injury from oxygen free radicals has been suggested to be of greater significance in the preservation of small intestine than of other organs. To determine if using the free radical scavenger, superoxide dismutase (SOD), with University of Wisconsin (UW) solution would improve preservation of small intestine, acute and chronic studies were conducted. Thirty-centimeter segments of small intestine from Lewis rats were flushed with and stored in Collins, UW, or SOD-modified (8000 U/ml) UW solution at 4 degrees C for 18 hr. For the acute study, small intestine segments were subsequently reperfused using support rats. The support rats in the UW/SOD group also received SOD (1750 U, iv) at the onset of reperfusion of small intestine. After 2 hr of reperfusion, maltose absorption and weight gain of small intestine were determined. For the chronic study, small intestine segments were transplanted as isografts. SOD (1750 U, iv) was also given to recipients prior to reperfusion of grafts in the UW/SOD group. Long-term effects were determined by recipient survival for at least 17 days. Results showed the small intestine in the UW/SOD group had the best recovery of mucosal absorption (256 +/- 39 versus 202 +/- 21 in the Collins group, P less than 0.01), the least percentage weight gain (19 +/- 3% versus 25 +/- 5% in the UW group and 38 +/- 5% in the Collins group, P less than 0.01), and the best 17-day survival rate (9/12 versus 2/9 in the UW group, P less than 0.025, and 0/8 in the Collins group, P less than 0.01) among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of long-term normalization of serum complement levels on the course of lupus nephritis.

PURPOSE: We compared the long-term outcome of patients with lupus nephritis in whom normalization of complement levels (CH50) was sustained by adjustment of immunosuppressive therapy to those patients with persistently low complement levels despite similar immunosuppression in whom therapy was adjusted solely on the basis of clinical disease activity. PATIENTS AND METHODS: Thirty-nine female patients with lupus nephritis recruited from 1972 to 1979 were prospectively studied (mean follow-up, 116.7 +/- 11 months). Entry criteria included initial renal biopsy, low CH50, and elevated anti-DNA antibody levels. A second biopsy was performed in 24 patients after an interval of 40.6 +/- 5 months. Treatment was started with prednisone (1 mg/kg/day). Azathioprine at a dose of 1.5 to 2.0 mg/kg/day was added if complement was not normalized by prednisone alone. Twenty-five of 39 patients had normal complement levels within six months (Group 1), and immunosuppressive therapy was tapered but continuously readjusted to the lowest dosage that preserved normal CH50 and maintained clinical remission. Eight of these 25 patients subsequently became persistently hypocomplementemic due to inadequate drug intake (Group 1B), whereas the complement levels continued to be controlled in the other 17 patients (Group 1A). Despite similar therapy, the remaining 14 patients did not achieve normalization of complement within the initial six months of therapy, and therefore future treatment decisions were based solely on clinical symptoms (Group 2). Renal pathologic lesions were classified according to World Health Organization criteria and a semi-quantitative chronicity index. RESULTS: During the first six months, there were no significant differences in clinical or histologic features between patients in whom complement levels were controlled and patients in whom complement levels were not controlled. After a mean observation period of 10 years, however, patients with consistent normalization of complement (Group 1A) did much better than patients with only short-term complement control (Group 1B) or persistent hypocomplementemia (Group 2). Both groups with low complement levels had a similar outcome with significantly worse kidney and patient survival. Life-table analysis demonstrated that the differences in outcome between complement-controlled and complement-uncontrolled groups became apparent only after five or more years of follow-up. Patients with a low chronicity score on initial biopsy whose complement level was controlled did uniformly well with no renal failure or death. (ABSTRACT TRUNCATED AT 400 WORDS)

Angiotropic large cell lymphoma (intravascular malignant lymphomatosis) of the kidney: presentation as minimal change disease.

We report the first case of angiotropic large-cell lymphoma (intravascular malignant lymphomatosis) presenting as minimal change disease (MCD) and diagnosed by renal biopsy. Neoplastic lymphoid cells were disseminated throughout the glomerular capillary bed and were associated with diffuse foot process effacement. The tumor had the immunophenotype of a B cell lymphoma (reactive with LCA and L-26 and unreactive with FVIII-R-Ag, Leu-M-1, alpha-1-antichymotrypsin, lysozyme, UCHL-1, Leu-22, kappa, and lambda). The temporal association between the onset of lymphoma and MCD, and the failure of the nephrotic syndrome to respond to immunosuppressive therapy support a role for lymphoma in the pathogenesis of MCD in this patient.

Effects of dietary electrolyte supplementation on gentamicin nephrotoxicity.

The effects of electrolyte supplementation via drinking solutions on gentamicin-induced nephrotoxicity were studied in rats. Four groups of animals were injected with gentamicin, 120 mg/kg daily for 5 days and were studied 2-4 days after the last injection. Electrolyte supplements were begun before the gentamicin injections and were continued throughout the study. The drinking solutions were tap water, NaCl, NaCl + KCl, or NaHCO3 + KHCO3 + diamox. At the end of the study, blood urea nitrogen (BUN) and serum creatinine were markedly increased only in the group receiving tap water. Nevertheless, 24 hour creatinine clearance in awake rats and inulin clearance in anesthetized rats were found to be severely reduced in all gentamicin-treated animals. However, the rats receiving NaHCO3 + KHCO3 + diamox had significantly higher creatinine clearance than all other experimental groups. Proximal intratubular free-flow pressure, measured by micropuncture, and internal proximal diameters were significantly increased above normal controls in all groups, but were least abnormal in the rats receiving HCO3- and diamox. Semiquantitative histologic evaluation revealed significantly less tubular necrosis and cast formation in this group than in all the other experimental groups. The observations suggest that dietary sodium, potassium, and chloride supplements, even accompanied by large fluid intake, provide relatively little protection against gentamicin nephrotoxicity. In contrast, HCO3- and diamox supplements resulted in significant, albeit incomplete, protection of GFR and renal histology.

Evidence against increased glomerular pressure initiating diabetic nephropathy.

Studies were carried out to determine whether exaggerated glomerular hydraulic pressure (PG) initiates the development of glomerular pathology and proteinuria in insulin-dependent diabetic rats. Normotensive (WKY) and hypertensive rats (SHR) were made diabetic by streptozotocin injection. One group of SHR diabetic rats was treated with antihypertensive drugs to reduce blood pressure. One week after onset of diabetes, micropuncture determinations of PG, measured by stopped-flow technique, revealed that PG was higher in WKY diabetics than in non-diabetic WKY controls, and that PG was even higher in SHR diabetics (P less than 0.05). Similarly prepared groups of animals were followed for six months, approximately one fifth to one third of the expected life span of these rats. Tail systolic blood-pressure measurements documented continuous severe systolic-hypertension in SHR diabetics, normal pressure in the WKY diabetics and hypotension in the SHR diabetics treated continuously with antihypertensive drugs. Urinary protein excretion, measured monthly, was statistically the same in all groups, with no evidence of a progressive rise in the SHR diabetics. PG measured in two rats from each group after four months of diabetes was similar to values found after one week of diabetes. Semiquantitative histologic scoring of glomerular mesangial expansion after six months of diabetes failed to demonstrate any significant difference between the normotensive WKY diabetics and the hypertensive SHR diabetics. These observations suggest that elevated PG does not in itself initiate glomerular pathology or proteinuria in diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrent membranoproliferative glomerulonephritis type 1 in successive renal transplants.

We report a man who developed renal failure due to membranoproliferative glomerulonephritis (MPGN) type 1 which recurred in two cadaveric kidney transplants. This is the third such case in the literature. Nephrotic syndrome developed within 1 month following transplantation and histologic evidence of disease recurrence was documented in both kidneys 2 months after transplantation. Both grafts failed within 18 months. Factors which determine disease recurrence remain obscure.

The value of needle renal allograft biopsy. III. A prospective study.

Previous studies of the value of percutaneous renal transplant biopsy have been retrospective. We prospectively studied whether biopsy affected patient management. Thirty-five patients with elevated serum creatinine level underwent 44 biopsies in situations in which the diagnosis was in doubt. At the time of biopsy, all clinical and laboratory data were reviewed, and a proposed treatment plan was outlined. Biopsy results were available within 24 hours. We evaluated whether biopsy influenced treatment. Other than hematuria (less than 24 hours), there were no complications. Nine biopsy specimens (20.5%) were inadequate for evaluation. Forty-six percent of adequate biopsy specimens (36% of total biopsy specimens) influenced patient management. Adequate biopsy specimens resulted in a change in treatment in 10 of 19 patients receiving prednisone and azathioprine and 6 of 16 receiving prednisone and cyclosporine. The remaining biopsy specimens, although not changing management confirmed the treatment plan in ambiguous clinical situations. We conclude that percutaneous biopsy is an important aid in patient management.

Symptomatic sarcoidosis of the stomach.

A patient is presented here who had gastric sarcoidosis which was initially diagnosed as Menetrier's disease. The English medical literature comprises 19 cases with symptomatic gastric sarcoidosis, and these are reviewed. The clinical, roentgenographic, and endoscopic findings in gastric sarcoidosis are quite variable, but of the symptomatic patients, 75% present with pain and 25% with bleeding; surgery is required in 50% of patients, while of those treated with corticosteroids, 66% improve symptomatically. Endoscopic biopsies are accurate and essential in establishing the diagnosis.