Participation of complement components in glomerular deposition in IgA nephropathy

To clarify the role of complement components in glomerular deposition in IgA nephropathy, clinicopathological and immunohistological studies were performed on 299 patients (171 males and 128 females; age, 9-71 years). Glomerular IgA deposition with IgG and/or IgM was observed more frequently in patients with Clq and/or C4 than in those with only C3 deposition (P less than 0.001). Patients with glomerular deposition of Clq and/or C4 showed more severe proteinuria (1 g/24 hr less than), a lower glomerular filtration rate (GFR), a higher incidence of duplication of capillary walls and more severe proliferation of mesangial cells and an increase in mesangial matrix (P less than 0.05), as compared to those without both Clq and C4. Patients with glomerular C3 deposition had significantly lower serum CH50 levels at the time of renal biopsy (P less than 0.02) and a significantly higher incidence of sclerotic lesions (P less than 0.05). Patients with C3 deposition in the mesangium and peripheral capillaries had significantly higher serum IgA levels (P less than 0.02), a significantly higher incidence of adhesion (P less than 0.01), duplication and endocapillary proliferation (P less than 0.05) and a more severe increase in mesangial cells (P less than 0.01) than those with C3 deposition only in the mesangium. The above findings demonstrate that analysis of the complement system in glomeruli is important for the evaluation of glomerular damage, clinical findings and prognosis.     

Complement activation in IgA nephropathy

Activation of alternative complement pathway is presumed to be important pathogenically in IgA nephropathy since renal biopsies usually exhibit glomerular deposition of C3 and P (properdin). Surprisingly, little is known about plasma complement activation in this disease, and the plasma C3 and C4 concentrations are usually normal or increased. We quantitated C3 activation in 202 plasmas from 81 patients with IgA nephropathy using a sensitive new assay that detects a neoantigen [iC3b-C3d neoantigen) which appears when C3b is inactivated to iC3b, C3dg, or C3d. This assay accurately quantitates small amounts of in vivo C3 activation. The concentration of iC3b-C3d neoantigen in plasma was significantly increased, indicating C3 activation in 37% of the pediatric and 57% of the adult plasmas assayed. When data from serial determinations in the patients were analyzed, 75% of the adult and 57% of the pediatric patients had C3 activation on at least one occasion. Classical pathway activation, quantitated by C4 activation was found in 20% of the adult and 5% of the pediatric plasmas. No association was found between elevated iC3b-C3d neoantigen concentration and history of macroscopic hematuria, chronic renal insufficiency or degree of proteinuria. These studies show that complement activation can frequently be detected in the plasma of IgA nephropathy patients. However, the pathophysiologic significance of this complement activation remains to be determined.     

Effect of cyclosporine a on circulating immune complexes in IgA nephropathy

This work was undertaken to examine the effect of cyclosporine A (CyA) on the serum concentration of circulating immune complexes in 22 patients with IgA nephropathy during an infection-free period. They were randomly divided into 2 groups: 11 patients received oral cyclosporine A (5 mg/kg/day) for 12 weeks and 11 patients received placebo (0.05 ml/kg/day). A significant reduction of proteinuria was observed in patients on CyA therapy but not in those receiving placebo. IgG-circulating immune complexes (CIC) were determined by solid phase Clq enzyme immunoassay (Clq EIA) and radial immunodiffusion (RID) and IgA-CIC were determined by solid phase anti-C3 enzyme immunoassay (anti-C3 EIA) and radial immunodiffusion. There was no change in IgA-CIC measured by RID and anti-C3 EIA after 12 weeks of CyA therapy. Similarly, changes in IgG-CIC were not demonstrated with CyA therapy. No apparent decrease in IgG-CIC or IgA-CIC was observed with placebo treatment. Our study suggests that immunomodulation by CyA therapy does not affect the IgA-CIC and IgG-CIC levels in patients with IgA nephropathy.     

Elevated urinary excretion of the C5b-9 complex in membranous nephropathy.

In experimental membranous nephropathy, antibody binding to glomerular epithelial cell membrane antigens results in complement activation and formation of complement C5b-9 membrane attack complexes in glomeruli. During active disease, the C5b-9 complexes are shed into the urine. To test the hypothesis that a similar mechanism might be operative in human membranous nephropathy, we measured urinary excretion of C5b-9 and C5 in 146 proteinuric patients with biopsy-proven glomerular diseases or diabetes mellitus. Urinary excretion of C5b-9 relative to C5 excretion was higher in 40 patients with membranous nephropathy than in 106 patients with proteinuria due to non-membranous glomerulonephritis when analyzed by covariance analysis (P less than 0.0002). Urinary C5b-9 excretion was higher in membranous nephropathy than in membranoproliferative glomerulonephritis (N = 13, P less than 0.05), minimal change-focal sclerosis (N = 33, P less than 0.001), mesangial proliferative glomerulonephritis (N = 9, P less than 0.02) and IgA nephropathy (N = 7, P less than 0.025). Urinary C5b-9 excretion was also higher in patients with lupus nephritis (N = 18, P less than 0.02) compared to those with non-membranous glomerulonephritis. The lupus patients with the highest excretion had clinical or pathological features of membranous nephropathy. Nine patients with membranous nephropathy and elevated urinary C5b-9 excretion had a shorter duration of disease (P less than 0.05), lower serum creatinine levels (P less than 0.05) and more proteinuria (P less than 0.02) than the 31 membranous nephropathy patients with normal values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced glomerular prostaglandin formation in experimental membranous nephropathy

To determine whether the induction of immune-mediated glomerular injury influences the formation of cyclooxygenase products by glomerular cells, we determined prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) (as the stable metabolite of TXA2) formation in isolated glomeruli of rats with passive Heymann nephritis (PHN). PHN is a model of membranous nephropathy mediated by antibody and complement independent of inflammatory cells. Five days following induction of PHN by injection of heterologous antibody to rat proximal tubular brush border antigen (Fx1A) rats developed proteinuria 36.5 +/- 34 (controls 3.8 +/- 1 mg/day). Treatment with cobra venom factor, which depleted complement C3 levels to less than 10% of baseline, prevented the development of proteinuria (6.9 +/- 2 mg/day). The development of subepithelial, glomerular immune-complex deposits and proteinuria was associated with a significant stimulation of glomerular PGE2 (87%) and TXB2 (183%) formation. This increment in glomerular prostanoid biosynthesis was significantly inhibited (PGE2 increased 22%, TXB2 increased 75%) in animals that were complement depleted with cobra venom factor. Cobra venom factor had no effect on glomerular prostanoid formation in normal rats. In additional experiments we tested the hypothesis that TXA2 may contribute to mediation of proteinuria in PHN. We utilized a thromboxane synthetase inhibitor UK38485. UK38485 reduced glomerular TXB2 formation by 80% without influencing glomerular deposition of 125I-labeled antibody, and did not alter levels of urine protein excretion in rats with PHN (control 42 +/- 21, UK 38485, 39 +/- 24 mg/day, P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined glomerular deposition of polymeric rat IgA and IgG aggravates renal inflammation

BACKGROUND: IgA nephropathy (IgAN) is characterized by deposition in the glomerular mesangium of IgA together with C3, C5b-9, and properdin. IgG deposition as a risk factor in IgAN was recently confirmed by a long-term follow-up of patients with IgAN. We previously reported on an acute model of IgA-mediated glomerular inflammation in Wistar rats. METHODS: To investigate the effect of the combination of IgA and IgG on glomerular injury, Wistar rats were injected with a minimum dose of rat IgG in the presence or absence of a subnephritogenic dose of polymeric rat IgA. Subsequently, glomerular complement activation, influx of inflammatory cells, proteinuria, and hematuria were assessed. RESULTS: Administration of IgG to the rats resulted in maximal proteinuria of 20.3 +/- 12.1 mg/24 h on day 2 and an absence of overt glomerular inflammation. Administration of polymeric rat IgA antibodies to rats resulted in hematuria with a moderate mesangial complement deposition. In the combination group, however, glomerular deposition of C5b-9 was dramatically increased. This was accompanied by increased proteinuria as compared with rats receiving IgA or IgG antibody injections alone on day 7. Microhematuria occurred in rats receiving either polymeric rat IgA or IgG alone or the combination. While both rat IgG and polymeric IgA induced minor mesangial cell (MC) proliferation and MC lysis, the combination resulted in a pronounced, significant increased percentage of aneurysm formation on day 7 after injection. CONCLUSIONS: We conclude that in this model of IgA-induced glomerulopathy, a selective, complement-dependent glomerular inflammation is induced in Wistar rats by glomerular codeposition of rat isotypic monoclonal antibodies.     

A comparative immunologic study of IgA nephropathy

A conglutinin binding assay has been used to detect circulating immune complexes (CIC) containing IgA, IgG, or IgM in sera from patients with IgA nephropathy. IgA class CIC were detected in 40.7% of patient. IgG class CIC were detected only in patients with glomercular IgG deposits. IgM class CIC were detected more often in patients with glomerular IgM deposits than in patients without glomerular IgM deposits. These results demonstrate an association between the immunoglobulin in CIC and those in glomerular deposits. CIC were not detected in sera from most patients with IgA nephropathy by a Clq binding assay, however, since this assay does not detect IgA class CIC. Immunoelectronmicroscopic studies of IgA nephropathy have shown that C3 deposits are localized to the same areas as IgA deposits. In conclusion, we suggest that mesangial IgA deposits are composed of immune complexes and may be derived from CIC.     

Polymorphs infiltrate glomeruli in mesangial IgA glomerulonephritis

During episodes of macroscopic hematuria, patients with IgA nephropathy commonly have polymorphonuclear neutrophils (PMNs) as well as fibrin and mononuclear cells in glomerular capillaries. We quantitated PMN and macrophage infiltration in glomeruli of 54 patients with IgA nephropathy in whom renal biopsies were obtained within 30 days of macroscopic hematuria. Control biopsies (N = 22) were from patients with IgA nephropathy and urinary erythrocyte counts below 50,000/ml. PMN monocyte/macrophages were quantitated using the monoclonal antibodies FMC10 and HAM56, respectively. In patients with heavy hematuria, 45.9 +/- 3.4% (mean +/- SE) of glomeruli were positive for PMNs (control 10.5 +/- 2.8%, P = 0.001) with a mean PMN count/glomerulus of 1.10 +/- 0.20 (control 0.13 +/- 0.03, P = less than 0.001). 65.6 +/- 9.7%. Of the glomeruli were positive for monocytes in the heavy hematuria group (control 40.0 +/- 8.4, P less than 0.05) with the mean monocyte count per glomerulus being 1.6 +/- 0.2 (control 0.6 +/- 0.1, P less than 0.01). We conclude that, in the acute phase of mesangial IgA nephropathy, PMN and monocytes are present and presumably participate in glomerular injury.     

Evaluating the clinical course and prognostic factors of posttransplantation immunoglobulin A nephropathy

INTRODUCTION: Previous reports have suggested that posttransplantation immunoglobulin (Ig) A nephropathy displays a relatively benign course, hardly ever affecting graft function. However, more recent studies with longer follow-up have shown that posttransplantation IgA nephropathy may be a significant contributor to graft loss. Additionally, there may be other clinical or pathological factors that affect long-term graft outcome. We retrospectively analyzed 30 kidney transplant recipients with biopsy-proven IgA nephropathy in their allografts to determine the clinical course and prognostic factors in posttransplantation IgA nephropathy. The median duration of follow-up was 36 months (range, 1 month-17 years). The median onset of IgA nephropathy was 33.6 months posttransplantation (range, 5 days-103 months). The most common presentation was an abnormal urine examination (96.6%). Fifteen (50%) displayed microscopic hematuria with proteinuria more than 1 g/d. Fifteen patients (50%) lost their grafts at a median time of 24 months after the onset of disease (range, 1-93 months). Allograft loss was associated with a high serum creatinine level at the time of diagnosis (3.68 +/- 2.23 vs 1.79 +/- 0.34 mg/dL; P = .006), a greater level of proteinuria at the time of diagnosis (2.43 +/- 0.76 vs 1.29 +/- 1.07 g/d; P = .003), and more than 50% extracapillary proliferation (P = .05). Fibrinoid necrosis on allograft pathology impacted 1-year allograft survival (P = .025). CONCLUSION: Posttransplantation IgA nephropathy worsens allograft outcomes among patients with increased serum creatinine level or significant proteinuria at presentation or significant glomerular inflammation and/or tubulointerstitial damage.     

Complement Receptor (CR1) and IgG or IgA on Erythrocytes and in Circulating Immune Complexes in Patients with Glomerulonephritis

This study reports the quantitative analysis of complement receptor(CR1) molecules on erythrocyte surface, the amount of immunoglobulin-containingmaterial (IgG-IC and IgA1-IM) on the erythrocyte surface, andthe concentrations of circulating immune complexes (IgG-CICand IgA-CIC); also reported are the HLA phenotypes of 44 patientsaffected by various forms of glomerulonephritis (including 20primary IgA nephropathy, 11 membranous glomerulonephritis, 9lupus nephritis and 4 renal vasculitis). Erythrocyte CR1 molecules were found to be decreased (P<0.02)and erythrocyte IgG-IC were less than in controls (P<0.025)in lupus nephritis patients, whereas IgG-CIC were significantlygreater (P<0.02). In patients affected by primary IgA nephropathy, mean erythrocyteCR1 concentrations were significantly decreased (P<0.02).Patients with impaired renal function had mean erythrocyte CR1values significantly greater than those with normal renal function(P<0.002). Immunoglobulin-containing material on the erythrocytesurface was not significantly increased, whereas the serum concentrationsof both IgA-CIC and IgG-CIC were significantly increased (P<0.02). In membranous nephropathy erythrocyte CR1 molecules were quantitativelysimilar to control data and no increase in CIC was observed.Conversely, erythrocyte IgG-IC were significantly increased(P<0.01). No significant relationship among erythrocyte CR1 molecules,erythrocyte surface-associated immunoglobulins, CIC, and HLAphenotype was observed in any patient group.     

Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy.

We have measured complement activation markers, C3dg and C5b-9 in plasma and urine from patients with idiopathic membranous nephropathy and IgA nephropathy. There was no significant difference in levels of plasma C5b-9 between the patient groups. However, high plasma concentrations of C3dg were associated significantly with IgA nephropathy with 45% of patients having levels over 25 U/ml (P less than 0.001). High concentrations of urinary C3dg and C5b-9 were associated significantly with membranous nephropathy (43% and 43% of the patient group, respectively) compared to patients with IgA nephropathy (10% and 0%, respectively, P less than 0.001). In a retrospective analysis of 31 patients with membranous nephropathy, 66% of patients with high initial urinary C5b-9 showed an unstable clinical course compared to 18% of patients with initially absent or low C5b-9 (P less than 0.001). We suggest that high urinary C5b-9 identifies those patients with a membranous lesion which retains an active immunological component contributing to the pathology of progressive glomerular damage.     

C6 depletion reduces proteinuria in experimental nephropathy induced by a nonglomerular antigen.

The role of the complement membrane attack complex, C5b-9, in mediating glomerular injury has been well defined in models of membranous nephropathy induced by antibody to endogenous glomerular epithelial cell membrane antigens. The effect of selective C6 depletion (to prevent C5b-9 formation) on morphologic characteristics and proteinuria in a model of in situ subepithelial immune complex nephritis induced by an exogenous cationized antigen (human immunoglobulin G (IgG)) followed by rabbit antibody to human IgG was studied. Selective C6 depletion was achieved by repeated administration of a goat antibody to rat C6. Other groups were treated with cobra venom factor to induce generalized complement depletion and with sublethal irradiation to deplete circulating leukocytes. In C6-depleted rats, C6 levels were reduced to less than 3% of baseline throughout the 2 days of the study compared with over 100% in controls. At 4 h after disease induction, glomerular deposition of antigen and antibody were similar in C6D and control groups by immunofluorescence and by direct measurement of glomerular deposition of radiolabeled antigen and antibody (cationized 131I human IgG, 9.1 +/- 0.1 micrograms/38,000 glomeruli in C6D versus 9.8 +/- 0.9 in controls; P = was not significant; rabbit 125I-labeled anti-human IgG, 104 +/- 10 ng in C6D versus 80 +/- 9 ng in controls; P = was not significant). Circulating C3 levels and glomerular C3 deposition were also similar in C6D and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of indomethacin on glomerular permselectivity and hemodynamics in nephrotoxic serum nephritis

The present study was undertaken to determine the effects of prostaglandin synthesis inhibition on glomerular hemodynamics in nephrotoxic serum nephritis and to elucidate the mechanisms by which prostaglandin synthesis inhibition reduces proteinuria in nephritic rats. Dextran sieving studies were performed before and after intravenous administration of indomethacin to control rats and to nephritic rats with heavy proteinuria. Indomethacin did not significantly alter mean arterial pressure, glomerular filtration rate or proteinuria in control rats nor were significant changes in dextran sieving observed. By contrast, in nephritic rats indomethacin significantly reduced glomerular filtration rate (2.58 +/- 0.50 vs. 1.39 +/- 0.27 ml/min, P less than 0.001), proteinuria (0.198 +/- 0.079 vs. 0.048 +/- 0.019 mg/min, P less than 0.05) and filtration rate-corrected proteinuria (0.059 +/- 0.033 vs. 0.031 +/- 0.013 mg/ml GFR, P less than 0.05). The fractional clearance of neutral dextrans with molecular radii exceeding 42 A were elevated above control values in nephritic rats (P less than 0.05). After administration of indomethacin, the fractional clearance of neutral dextrans uniformly declined toward control values and remained elevated only for molecular radii exceeding 54 A. Assessment of glomerular hemodynamics in nephritic rats before and after indomethacin showed significant declines in single nephron filtration rate (31.5 +/- 3.0 vs. 21.2 +/- 2.5 nl/min, P less than 0.02), glomerular plasma flow rate (99.5 +/- 6.7 vs. 68.5 +/- 7.8 nl/min, P less than 0.05) and glomerular ultrafiltration coefficient (0.0430 +/- 0.0033 vs. 0.0339 +/- 0.0032 nl.sec-1.mm Hg-1, p less than 0.05). Indomethacin did not significantly change these parameters in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complement activation products in the urine from proteinuric patients

The presence of plasma proteins in the tubular lumen has variety of adverse effects on the tubular cells. Among various plasma proteins filtered through glomerular barrier, complement has been proven as the possible candidate inducing tubulointerstitial injury. To study the role of intratubular complement activation in proteinuric patients, complement activation products (CAP) at C3 level (iC3b and Bb) and C9 level (membrane attack complex) were measured in both plasma and urine of patients with minimal change nephrotic syndrome (MCNS), focal glomerular sclerosis, IgA nephropathy, membranous nephropathy, and diabetic nephropathy. For evaluation of the effect of metabolic acidosis on the intratubular complement activation, urinary CAP were measured before and after sodium bicarbonate administration in patients with renal insufficiency. The following results were obtained: (1) Patients with focal glomerular sclerosis and diabetic nephropathy showed the highest level of urinary CAP excretion rate (unit/creatinine), while MCNS revealed no increase. (2) Patients with membranous nephropathy showed a unique finding, i.e., isolated increase of membrane attack complex excretion. (3) There was no significant correlation between urine and plasma levels of CAP. (4) Except for MCNS patients, the urinary excretion rate of CAP significantly increased when the level of proteinuria exceeded the nephrotic range, and it was significantly correlated with the serum creatinine level. (5) Urinary CAP excretion rate significantly decreased 2 wk after sodium bicarbonate administration without affecting the level of proteinuria or plasma CAP. These results suggest that the degree of intratubular complement activation correlates with the level of proteinuria, type of glomerular disease, impairment of renal function, and metabolic acidosis.     

Mononuclear cell activation and decreased renal function in IgA nephropathy with crescents

Our previous immunohistologic studies with monoclonal antibodies (mAb) showed that glomerular and interstitial accumulations of mononuclear cells (MNC) were common features of many types of proliferative glomerulonephritis, especially crescentic glomerulonephritis. The current study examined a series of patients with crescentic IgA disease, since IgA disease in general has a highly variable course and the presence of crescents is one indicator of likely progression to end-stage renal failure. We compared the intraglomerular and interstitial infiltrates within biopsies from patients with crescentic IgA nephropathy (N = 5) versus those with noncrescentic IgA (N = 18), or normal controls (N = 10). Few leucocytes were found within glomeruli of normal (2.4 +/- 0.7 cells/glomerular cross section) (mean +/- SEM) or noncrescentic IgA disease biopsies (3.8 +/- 0.7), and no activated MNC bearing receptors for interleukin-2 (IL-2R) were detected. By contrast, in crescentic IgA disease, glomerular leucocytes were increased (5.1 +/- 0.6, P less than 0.01), due to increased monocyte (3.1 +/- 0.9, P less than 0.01) and T cell (1.4 +/- 0.4, P less than 0.01) infiltration, and IL-2R + MNC were then observed (1.2 +/- 0.5, P less than 0.05). Studies of interstitial cells showed small numbers of leucocytes within normal kidneys (101 +/- 16/mm2). Biopsies from noncrescentic IgA disease showed a fivefold increase in interstitial MNC infiltration (total leucocytes 565 +/- 105/mm2, P less than 0.01), due to an influx of T cells (283 +/- 59/mm2, P less than 0.01) and monocytes (120 +/- 32/mm2, P less than 0.01), and including a mean of 20% IL-2R+ MNC (114 +/- 29/mm2, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Remission of proteinuria improves prognosis in IgA nephropathy

Proteinuria has been shown to be an adverse prognostic factor in IgA nephropathy. The benefit of achieving a partial remission of proteinuria, however, has not been well described. We studied 542 patients with biopsy-proven primary IgA nephropathy in the Toronto Glomerulonephritis Registry and found that glomerular filtration rate (GFR) declined at -0.38 +/- 0.61 ml/min per 1.73 m2/mo overall, with 30% of subjects reaching end-stage renal disease. Multivariate analysis revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline. Among the 171 patients with <1 g/d of sustained proteinuria, the rate of decline was 90% slower than the mean rate. The rate of decline increased with the amount of proteinuria, such that those with sustained proteinuria >3 g/d (n = 121) lost renal function 25-fold faster than those with <1 g/d. Patients who presented with > or =3 g/d who achieved a partial remission (<1 g/d) had a similar course to patients who had < or =1 g/d throughout, and fared far better than patients who never achieved remission. These results underscore the relationship between proteinuria and prognosis in IgA nephropathy and establish the importance of remission.     

Studies on circulating immune complexes. II: Circulating immune complexes in primary IgA nephropathy and membranoproliferative glomerulonephritis

A study of circulating immune complexes (CIC) was undertaken in 25 patients with primary IgA nephropathy and 13 patients with membranoproliferative glomerulonephritis (MPGN). Clinically, the 25 patients with IgA nephropathy were divided into two groups: the latent type, characterized by chance proteinuria and/or hematuria; and the acute onset type, revealing acute nephritic syndrome. Both the IgG class of CIC (IgG-IC) and the IgA class of CIC (IgA-IC) were measured by conglutinin binding enzyme immunoassay (C-assay). IgG-IC were found to be positive in 32% of the patients with IgA nephropathy, and in 77% of those with MPGN. IgA-IC were positive in 72% of the patients with IgA nephropathy, and in 54% of those with MPGN. Concerning the acute onset type of IgA nephropathy, IgG-IC and IgA-IC were found in 71% and 86% of the patients, respectively, which was more frequent than in the latent type group. Simultaneous presence of IgA-IC and glomerular IgA deposits detected by an immunofluorescence study was noted in 75% of the patients with IgA nephropathy. On the other hand, 78% of the patients with MPGN revealed IgG-IC and glomerular IgG deposits simultaneously. Thus, IgG-IC and IgA-IC appear to play important roles in the pathogenesis of MPGN and IgA nephropathy, respectively.     

Renal injury in DOCA-salt hypertensive C5-sufficient and C5-deficient mice

We induced hypertension by uninephrectomy and treatment with desoxycorticosterone (DOCA) and 1% NaCl in the drinking water in congenic mice that differ in the single gene locus responsible for the presence or absence of the complement component C5 and compared them to uninephrectomized normotensive (no DOCA-NaCl) mice. In contrast to C5-sufficient (C5S) mice. C5-deficient (C5D) mice can neither generate C5a nor assemble C5b-9. After four weeks of treatment, DOCA-C5S and -C5D mice developed similar degrees of hypertension; mice receiving no DOCA remained normotensive. Only hypertensive mice developed glomerular injury. Hypertensive DOCA-C5D mice developed more glomerular capillary loop dilatation and larger glomerular capillary tuft volumes than DOCA-C5S mice (1.0 +/- 0.1 vs. 0.7 +/- 0.03 X 10(6) microns 3, respectively, P less than 0.05). However, DOCA-C5S mice, compared to DOCA-C5D mice, had significantly more glomerular cell proliferation (64.5 +/- 2 vs. 42 +/- 3 nuclei/glomerulus), cell necrosis (injury score 22 +/- 1 vs. 17 +/- 1), extracapillary proliferation (26 +/- 4 vs. 2.5 +/- 2% of glomeruli) and proteinuria (5.9 +/- 0.8 vs. 3.7 +/- 0.5 mg/24 hr; all P less than 0.05). By immunofluorescence microscopy both DOCA-C5S and -C5D had mesangial C3 deposits but only DOCA-C5S mice had C9 deposits. After 16 weeks of DOCA-NaCl C5S mice, in comparison to C5D mice, had more severe glomerulosclerosis (injury score 50 +/- 6 vs. 12 +/- 4), proteinuria (16.6 +/- 0.1 vs. 9 +/- 0.1 mg/24 hr), and renal insufficiency (serum creatinine 0.25 vs. 0.15 mg/dl), all P less than 0.05. These changes occurred despite levels of hypertension that were similar in DOCA-NaCl C5S and C5D throughout the whole study period. We conclude that C5a and/or C5b-9 may play an important role in hypertensive glomerular injury. Moreover, these studies demonstrate that differences in host responses may determine target organ susceptibility to similar injurious mechanisms.     

Phosphate restriction reduces proteinuria of the uninephrectomized, diabetic rat

Proteinuria is the clinical hallmark of diabetic nephropathy and the harbinger of progressive renal disease. Therefore, the present study was designed to examine the effect of phosphate restriction on the proteinuria of streptozotocin-induced diabetes mellitus in the rat. Uninephrectomy was performed in experimental and control groups to worsen the degree of diabetic nephropathy. Proteinuria was prevented in Sprague-Dawley rats treated with the intestinal phosphate binder, dihydroxyaluminum aminoacetate (DHAAA) (24.75 +/- 20.35 mg/d at 3 months v control, 77.45 +/- 44.72 mg/d, P less than 0.001); an effect that was independent of protein and caloric intake, plasma albumin and lipids, severity of diabetes, mean arterial pressures, cardiac output, and renal calcium accumulation. The effect of DHAAA on protein excretion and glomerular hemodynamics was examined in similarly prepared Munich-Wistar rats; these rats did not tolerate long-term studies. Three weeks of DHAAA again caused a consistent fall in proteinuria (5.98 +/- 7.28 v 34.94 +/- 24.28 mg/d) and in transmembrane hydraulic pressure difference (41.1 +/- 1.2 v 46.4 +/- 2.8 mm Hg, P less than 0.005). In conclusion, phosphate restriction significantly decreases the proteinuria of Sprague-Dawley and Munich-Wistar uninephrectomized rats with streptozotocin-induced diabetes mellitus. Micropuncture of Munich-Wistar rats suggests that a reduction of intraglomerular pressure may be at least partially responsible for such an effect.     

Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat

Intravenous administration of heterologous anti-rat thymocyte serum (ATS), which reacts with a Thy-1-like antigen present on rat glomerular mesangial cells, caused lytic (1 hr to 2 days), hypercellular (4 to 14 days), and sclerotic (2 to 3 months) mesangial lesions in Lewis rats. The normal control of 48.6 +/- 7.9 (mean +/- SD) glomerular nuclei on histologic section decreased significantly (P less than 0.001) to 39.8 +/- 6.1, 37.4 +/- 6.0, and 38.9 +/- 6.8 at one hour, four hours and two days after ATS administration, respectively. Thereafter glomerular nuclei increased to 54.7 +/- 11.5 (P less than 0.05) at four days, 62.5 +/- 9.6 (P less than 0.001) at one week and 64.1 +/- 14.2 (P less than 0.001) at two weeks, and normalized (P greater than 0.05) to 49.4 +/- 8.9 at one month and 50.6 +/- 9.0 at three months. By electron microscopy, glomerular damage in the lytic stage was restricted to mesangial cells and was manifested as hydropic degeneration or lysis. Rabbit IgG and rat C3 were found in the mesangium one hour after injection; they decreased at two days and were negligible at four days. By paired label isotope study, 11.6 micrograms of antibody bound per 7.6 X 10(4) glomeruli at one hour was needed to induce mesangial cell degeneration. No or only minimal changes in proteinuria and in serum creatinine were observed with the dosage used in this rat strain.(ABSTRACT TRUNCATED AT 250 WORDS)