In situ formation of subepithelial glomerular immune complexes in passive serum sickness

Epimembranous glomerular deposition of circulating immune complexes in considered to be the pathogenesis of immune complex glomerulonephritis, based on experiments in serum sickness glomerulopathy. A subepithelial localization of immune aggregates, however, was never obtained after the intravenous injection of preformed immune complexes. Recent studies on heterologous immune complex glomerulonephritis provide evidence of in situ formation of subepithelial glomerular immune complex aggregates as a second pathogenetic mechanism. We investigated the existence of a comparable mechanism in a serum sickness model of glomerulonephritis. A passive immune complex glomerulopathy involving lysozyme/antilysozyme and bovine serum albumin (BSA)/anti-BSA was used to investigate this thesis. Alternating perfusion of a kidney with antigen and antibody resulted in a granular deposition of both components along the glomerular basement membrane (GBM). The deposits of immune aggregates were localized exclusively along the epithelial side of the GBM and were still present 3 days after the perfusion. Control perfusions with preformed immune complexes or with either BSA or anti-BSA alone did not result in subepithelial deposition. Conclusion. The alternating excess of antigen and antibody in the circulation might result in in situ formation of immune complexes localized at the epithelial side of the GBM.     

Celiac disease associated with immune complex glomerulonephritis.

A patient with immune complex glomerulonephritis and celiac disease without dermatitis herpetiformis or other underlying disease associated with glomerulonephritis is presented. Antibodies to wheat proteins were found in serum and withdrawal of gluten from the diet resulted in disappearance of immune complexes from serum and resolution of both renal and intestinal disease, suggesting a dietary source of antigen. Despite extensive immunopathologic studies of the renal biopsy, neither dietary nor endogenous brush border antigens were demonstrated in glomeruli.     

Mucosal immunity in primary glomerulonephritis: II. Study of the serum IgA subclass repertoire to food and airborne antigens.

IgA specific for 7 food and 6 airborne antigens were sought in the serum of 30 adult patients with IgA mesangial nephropathy (IgA GN), 23 with membranous nephropathy (MGN), 20 with idiopathic nephrotic syndrome (INS), 11 with membranoproliferative GN (MPGN) and 22 healthy controls by means of an enzyme-linked immunoassay. The IgA subclass was determined using monoclonal antibodies. Increased levels of IgA specific for gliadin, bovine serum albumin (BSA), ovalbumin, lysozyme and alpha-lactalbumin were found in IgA GN, while increased levels of IgA to BSA, ovalbumin, lysozyme and alpha-lactalbumin were observed in MGN; IgA specific for alpha-lactalbumin were increased in INS, and MPGN patients had reduced levels of IgA to BSA and increased levels of IgA to beta-lactoglobulin and alpha-lactalbumin. These specific IgA to food antigens were restricted to the IgA1 subclass. Patients with IgA GN had significantly increased levels of IgA specific for Dermatophagoides pteronyssinus (DP) and Dactil while the MGN group showed increased levels of IgA specific for DP, feathers, Dactil and mold. INS patients had increased levels of IgA specific for DP, feathers, Dactil, mold and dog hairs, while MPGN patients had increased levels of IgA specific for feathers, Dactil, dog hairs and mold. All these specific IgA to airborne antigens were restricted to the IgA1 subclass. Patients with the four types of primary glomerulonephritis had decreased IgA specific for cat hairs which were of both the IgA1 and IgA2 subclasses. We conclude that anomalies of the IgA repertoire to environmental antigens are also encountered in primary glomerulonephritis other than IgA GN.     

Psoriasis vulgaris associated with mesangiocapillary glomerulonephritis

A patient experienced the concomitant onset of psoriasis vulgaris and mesangiocapillary glomerulonephritis (MCGN) with massive proteinuria. Laboratory examination revealed reduced glomerular filtration rate (GFR), elevated serum IgG, IgA and circulating immune complex (CIC) levels. Both diseases responded promptly to combined therapy with prednisolone, urokinase and plasma exchange. CIC and GFR were normalized with histological improvement. To our knowledge, this is the first case of glomerulonephritis, which can be related to psoriasis vulgaris through an immune mechanism.     

Rapidly progressive glomerulonephritis in IgA/IgG cryoglobulinemia

Mixed IgA/IgG cryoglobulins were found in the serum of a 48-year-old man suffering from rapidly progressive glomerulonephritis (RPGN) with crescent formation. The type-II cryoglobulins were composed of monoclonal IgA1-kappa and polyclonal IgG, with the IgA possessing antibody activity against the IgG. The RPGN was of the immune complex type with granular deposits of IgA, IgG, and C3 on immunofluorescence microscopy and preponderant subendothelial deposits on electron microscopy. Occluding protein thrombi could be demonstrated in several glomerular capillary loops. Removal of the cryoglobulins from the patient's serum by plasmapheresis and immunosuppression was paralleled by a remarkable improvement in renal function with fall of serum creatinine values from 13.6 mg/dl (1,202.2 mumol/l) to 2.8 mg/dl (247.5 mumol/l), a resolution of the glomerular lesions, and clinical improvement as well. Our observations suggest that the crescentic glomerulonephritis may be due to an immune complex-like deposition of the cryoproteins. We conclude that crescentic glomerulonephritis in IgA/IgG cryoglobulinemia has to be considered as an autoimmune form of RPGN.     

Effect of thrombocytopenia on the onset of immune complex glomerulonephritis.

The effect of platelets on the development of immune complex glomerulonephritis (GN) was examined using bovine serum albumin (BSA) GN with platelet depletion. To clarify the role of platelets in the initial stage of BSA GN, thrombocytopenia was induced before BSA infusion. In 18 New Zealand white rabbits, BSA was intravenously injected twice after the presensitization. Eight of these BSA GN rabbits were injected daily with goat anti-rabbit platelet antiserum to induce thrombocytopenia, and platelet counts were maintained below 5 x 10(4)/microliters throughout the experiment. In the thrombocytopenic group, the degree of proteinuria was significantly decreased compared to the control group. Glomerular polymorphonuclear leukocyte infiltration, mononuclear cell proliferation, exudation and glomerular enlargement were significantly suppressed in the thrombocytopenic group. The results suggest that platelets may be quite important in the initiation and development of immune complex GN.     

Acute Postinfectious Crescentic Glomerulonephritis: Clinicopathologic Presentation and Risk Factors

Background: Glomerular crescent formation is a feature of the most severe forms of human glomerulonephritis. The postinfectious form of rapidly progressive glomerulonephritis with crescents is a form of immune complex glomerulonephritis which seem to have a better prognosis. A relatively poorer prognosis for crescentic postinfectious glomerulonephritis in South Africa has been reported. In the present study, we have tried to determine the mode of presentation, and the prognostic factors for renal and patient outcome for cases with postinfectious crescentic glomerulonephritis (CGN). Methods:Between 1990 and 2000 a total number of 128 patients with CGN were managed at our center, among them 23 cases were diagnosed as postinfectious CGN. They were followed-up for a mean period of 40.1 ± 28.9 months. Among them 12 were males and 11 were females. The median age was 12.35 years (range 4–55 years). The median serum creatinine at presentation was 7.24 mg/dl (range 1.3–14.5 mg/dl). We studied the clinical, laboratory and histopathological data ^.of our cases and their impact on the renal and patient outcome. Results:By univariate study the risk factors for renal dysfunction were the age, hypertension, and nephrotic range proteinuria during the follow-up period. By multivariate analysis only the, hypertension, and presence of nephrotic range proteinuria during the follow-up period were the significant risk factors. The risk factors that significantly affected patient mortality were hypertension and serum creatinine at last follow-up. Conclusion: postinfectious CGN is a severe form of glomerulonephritis that usually presents with rapidly progressive renal failure. The persistence of hypertension and nephrotic range proteinuria during the follow-up are major bad prognostic predictors for renal dysfunction.     

Effect of the immunosuppressive agent, ciclosporin, on experimental immune complex glomerulonephritis in rats.

Effect of the immunosuppressive agent, ciclosporin (CS), on bovine serum albumin (BSA) nephritis in rats was evaluated. Eight weeks after immunization, 19 male Wistar rats received a daily intravenous dose of BSA (2 mg). Two weeks later, 11 rats received BSA and an oral dose of CS (10 mg/kg), and 8 rats received only BSA for 2 weeks. Urinary protein was measured weekly and serum anti-BSA antibody was measured by passive hemagglutination biweekly. The animals were killed at the 12th experimental week and blood samples and kidney specimens were obtained. BUN and serum creatinine were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. Urinary protein excretion was significantly less in CS-treated rats than in nontreated controls at the 2nd week after treatment (5.3 +/- 1.3 vs. 25.6 +/- 10.3 mg/day, p less than 0.05). Anti-BSA antibody titers were lower in treated rats than in controls at the 2nd week after the treatment. There were no significant differences in the levels of BUN and serum creatinine between two groups. Glomerular hypercellularity and mesangial widening were milder in treated rats than in controls, and glomerular deposition of BSA was less intense in treated rats than in controls. These results suggest that CS suppressed the antibody production and the development of glomerular changes in rats with immune complex glomerulonephritis.     

Experimental studies on factors causing acute serum sickness glomerulonephritis of immune complex origin

In acute serum sickness glomerulonephritis induced in rabbits by large doses of BSA, the relationship of the host's immunological status and the severity of renal histological changes was studied. It was found that good antibody producers developed more severe renal lesions. The higher avidity of antibodies enhances the inflammatory effect of immune complexes. Kidney is favoured for deposition of immune complexes especially in the case of chronic immune complex formation in the presence of antigen excess. Diminished phagocytic function of leukocytes (probably decreased immune complex saturating capacity) may also contribute to the severity of renal histological alterations.     

Risk factors in idiopathic renal vasculitis and glomerulonephritis

In this retrospective study, we analyzed clinical laboratory, and pathologic variables to determine their value in predicting survival and survival free of renal failure for 170 consecutive patients with idiopathic renal vasculitis and glomerulonephritis evaluated during a 15 year period. Of the 170 patients, 108 had focal segmental necrotizing glomerulonephritis alone (FSNGN), 33 had FSNGN and small-artery vasculitis, and 29 had FSNGN and medium-sized artery vasculitis. Considerable overlap of clinical, laboratory, and pathologic findings existed among the three groups. Overall patient survival was 81% at one year, 61% at five years, and 44% at ten years, significantly less than expected survival. Overall survival free of renal failure, by definition, was lower than patient survival. There were no differences among these three groups in patient survival or survival free of renal failure. Multivariate analysis identified leukocytosis and serum creatinine level as independent predictors of patient survival and survival free of renal failure. In addition, univariate analysis identified age and hypertension as significant risk factors but did not add independent predictive value for these two end points. In patients with serum creatinine levels less than 4 mg/dl, the effect of increasing levels of leukocyte count was significantly associated with poorer outcomes for both patient survival (P = 0.006) and survival free of renal failure (P = 0.024). Outcomes for these two end points were worse for patients with lower serum creatinine levels (less than 4.0 mg/dl) and high leukocyte counts (greater than 16,000/mm3) than for those with serum creatinine levels greater than or equal to 4.0 mg/dl.     

Membranoproliferative glomerulonephritis in a patient with X-linked agammaglobulinemia

Immune complex and complement systems play an important role in membranoproliferative glomerulonephritis (MPGN). X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by severe hypogammaglobulinemia. We report the case of an XLA patient who developed MPGN during an intravenous immunoglobulin (IVIG) treatment. In this patient, the serum IgG level was maintained at more than 400 mg/dl of regular IVIG administration (2.5 g/dose/month). The patient presented with microscopic hematuria, proteinuria (U-pro/Cr: 4.0–4.2) and low serum complement levels (C3: 57.8 mg/dl) 3 years after IVIG treatment and was diagnosed histopathologically as having MPGN type III. Both hematuria and proteinuria significantly improved, and the serum complement level returned to a normal level following methylprednisolone pulse therapy. To our knowledge, this is the first case report of MPGN associated with XLA. Although it is unclear how MPGN occurred in this XLA patient, we suggest that residual humoral immunity in the patient could be associated with the development of MPGN.     

Cationic antigens in poststreptococcal glomerulonephritis

Antigen charge is an important factor in the pathogenesis of experimental immune complex glomerulonephritis. Its potential role in man was investigated in post-streptococcal glomerulonephritis, a disease where the causative agent is known. Cationic, extracellular streptococcal antigens were detected in 8 of 18 renal biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). The antigen was found mainly in earlier biopsies in which both IgG and IgM were present. Patients' sera taken at the time of biopsy contained antibody to cationic, streptococcal antigens. Cationic moieties are known to have affinity for the glomerular basement membrane and it is possible that the type of antigen described here initiates APSGN via in situ immune complex formation.     

Failure of heparin to affect two types of experimental glomerulonephritis in rabbits.

Anticoagulation has been reported to ameliorate antiglomerular basement membrane glomerulonephritis (anti-GBM-GN) while its effect on chronic immune complex glomerulonephritis (IC-GN) as studied in the NZB mouse is unclear. Chronic serum sickness IC-GN was induced in rabbits by injecting bovine serum albumin (BSA) daily. Anti-GBM-GN was induced by i.v. injection of a known amount of heterologous anti-GBM antibody. Heparin was administered beginning at two to six weeks after the first BSA injections or before the administration of anti-GBM antibody, on various schedules from 5000 U every 12 hr to 8000 U every 8 hr. With this dosage the partial thromboplastin time remained greater than 1-1/2 to 2-1/2 times the control at the time of the subsequent heparin injection. Heparinized and nonheparinized groups were matched according to duration of disease, maximum anti-BSA concentrations or anti-GBM antibody dosage--and no significant differences were found in proteinuria; severity of the glomerular histologic lesions; or immunofluorescence patterns of immunoglobulin G (IgG), third component of complement (C3), BSA or fibrinogen-related antigen(s) (FRA). Crescent formation was not prevented. This study shows that heparin in the maximum permissible dosage is ineffective in preventing glomerular FRA deposition or altering the progression of experimental IC-GN or anti-GBM-GN in rabbits.     

Decrease in cell proliferation by an matrix metalloproteinase inhibitor,doxycycline, in a model of immune‐complex nephritis

Aim: Renal expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) contribute to the development of tubulointerstitial fibrosis characteristic of progressive forms of primary glomerulonephritis (GN). The aim of this study was to investigate the therapeutic effect of MMP inhibitor, doxycycline, administration in an experimental rat model of immune‐complex nephritis (ICN). Methods: The induction of immune‐complex glomerulonephritis was carried out by the administration of an i.v. dose of 2 mg bovine serum albumin (BSA) daily for 28 days after 8 weeks of s.c. immunization with 1 mg of BSA in complete Freund's adjuvant. Doxycycline (30 mg/kg) was given daily (in groups 2 and 4) by gavage for 28 days. Results: Animals treated with doxycycline showed significant reduction in glomerular area and cell proliferation than non‐treated controls. Glomerular deposition of immunoglobulin (Ig)G and C3 was less intense in treated rats than non‐treated controls. Although not statistically significant, interstitial inflammation was less intense in treated rats than non‐treated controls. Glomerular expression of MMP‐9 by immunoflourescence was significantly inhibited in the treated group. In addition pro‐MMP‐2 on gelatin zymography was importantly suppressed by doxycycline in ICN. Conclusion: Doxycycline, in addition to its antibiotic property, may, following further investigation, provide a possible survival benefit in proliferative glomerulonephritis.     

Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal study.

BACKGROUND: Ghrelin is a newly detected orexigenic gastric hormone that stimulates food intake. Increased levels of ghrelin are often found in disease states associated with wasting. Wasting is a common phenomenon in end-stage renal disease (ESRD) patients in whom elevated ghrelin levels have been reported. However, no data are available on the relationship between body composition and plasma ghrelin levels in this patient group. METHODS: The study population consisted of 108 (71 males) ESRD patients aged 53+/-12 years. Body composition, nutritional status (subjective global assessment), estimated protein intake (nPNA), plasma ghrelin, plasma insulin and serum leptin were evaluated close to the start of dialysis treatment. Twelve healthy subjects (nine males, 44+/-6 years) served as the control group. A longitudinal evaluation of changes in plasma ghrelin and body composition was performed in 52 of the patients after 12 months of dialysis treatment. RESULTS: Markedly elevated plasma ghrelin levels (843+/-485 vs 443+/-302 pg/ml; P<0.01) were observed in ESRD patients compared with controls. Basal plasma ghrelin levels correlated significantly with plasma insulin (R = -0.32; P<0.05), body mass index (R = -0.24; P<0.05), log serum leptin levels (R = -0.23; P<0.05) and truncal fat mass (R = -0.25; P<0.05). The longitudinal analysis of body composition demonstrated that whereas fat mass increased (23.7+/-8.6 to 25.3+/-9.9 kg; P<0.05) and plasma ghrelin levels decreased (855+/-429 to 693+/-408 pg/ml; P<0.05) significantly in peritoneal dialysis patients, no significant changes in either body composition or plasma ghrelin levels were found in patients treated by haemodialysis. CONCLUSION: Markedly elevated plasma ghrelin levels are found in advanced renal failure and correlate with fat mass, plasma insulin and serum leptin levels. Changes in plasma ghrelin during 12 months of peritoneal dialysis treatment are associated with changes in body composition.     

Effects of a selective thromboxane A2 synthetase inhibitor on immune complex glomerulonephritis

It has been reported that agents which block the prostaglandin system inhibit the development of glomerulonephritis. However, the mechanisms of these effects are not clear. We studied the effect of a selective thromboxane A2 (TxA2) synthetase inhibitor, 1-benzylimidazole (BIm), on the immune complex glomerulonephritis produced by bovine serum albumin (BSA) in New Zealand white rabbits. As the BSA nephritis developed, there was no change of creatinine (Cr), serum urea nitrogen (SUN), or creatinine clearance (Ccr), but urinary protein excretion increased almost 3-fold. Coagulation and fibrinolytic studies suggested a hypercoagulable state and increased fibrinolytic activity. Platelet aggregation showed the reduction of maximum aggregation induced by ADP and collagen. Histological examination by light microscopy, immunofluorescence, and electron microscopy revealed glomerular polymorphonuclear leukocyte (PMN) infiltration, mononuclear cell (MON) proliferation, and fibrin deposition. In 70% of the rabbits, IgG and C3 deposits were seen by immunofluorescence mainly in mesangial areas. The administration of BIm to BSA nephritis had no effects on Cr, SUN or Ccr, but it significantly lessened the proteinuria. The study of coagulation and fibrinolytic activity suggested a less hypercoagulable state, and more efficient fibrinolysis occurred than in the group without BIm. BIm tended to normalize platelet aggregation. It also lessened the histological PMN infiltration (p less than 0.05), MON proliferation (p less than 0.01), and fibrin deposition (p less than 0.05). These data suggest that TxA2 may play an important pathogenetic role in the development and progression of glomerulonephritis.     

Sequential occurrence of IgA nephropathy and Henoch-Schönlein purpura: support for common pathogenesis

We report a patient who developed Henoch-Schönlein purpura (HSP) 13 years after he presented with IgA nephropathy (IgAN). In both HSP and IgAN renal biopsy most commonly reveals focal proliferative glomerulonephritis on light microscopy and immunofluorescence displays mesangial IgA deposits. In addition, patients with HSP or IgAN have elevated serum IgA levels, circulating IgA immune complexes, IgA-bearing lymphocytes, immunoglobulin-producing cells, and binding of IgG to glomerular components of similar molecular weight. The occurrence of both diseases in the same patient or the same families and the presence of immune abnormalities compatible with HSP or IgAN in relatives of patients with these diseases suggest a common pathogenesis.     

Hypercholesterolemia and glomerular diseases in urinary screening of school children

 Although hypercholesterolemia frequently accompanies nephrotic syndrome, high serum total cholesterol (TC) levels are occasionally seen in children with non-nephrotic glomerular diseases. However, little is known of the significance, if any, of these elevated serum TC levels in non-nephrotic glomerular diseases. During the past 5 years, a total of 256,179 school children received yearly urinary screening at school for renal diseases and 1,702 children (0.66% of the total, although 174 children dropped out) had proteinuria and/or hematuria. Using the data obtained from the 1,528 children, we studied whether there is any association between serum TC levels and the presence of glomerular diseases. The detection rate of glomerular diseases (IgA nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerular sclerosis, etc.) in the subjects with high serum TC levels (≥200 mg/dl) was significantly higher (16 of 161, 9.94%, P<0.001) than in those with normal serum TC levels (<200 mg/dl) (10 of 1,367, 0.73%). There were no significant differences in serum albumin and blood urea nitrogen levels between the two groups. We conclude that children with chance proteinuria and/or hematuria may be at higher risk for glomerulonephritis of various types when they have unexplained hypercholesterolemia, and that measurement of serum cholesterol levels may be useful in urinary screening for renal diseases. Received: 21 August 1997 / Revised: 16 July 1998 / Accepted: 20 July 1998     

Renal involvement induced by human parvovirus B19 infection

In an attempt to clarify the renal involvement induced by human parvovirus B19 (HPB19) infection, we investigated 6 adult patients with transient urinary abnormalities followed by erythema infectiosum. All patients had HPB19-specific IgM antibody and showed mild proteinuria of 0.2-1.2 g/day with or without microscopic hematuria. In 5 patients a decrease of complement was present, and in 2 the circulating immune complex levels were elevated. All patients showed mild or moderate endocapillary proliferation with leukocytic infiltrates in glomeruli and leukocytic infiltrates with edema around interlobular arteries and arterioles. Immunofluorescence microscopy revealed C3c deposits with immunoglobulins along the glomerular capillary walls and in the walls of small arteries and arterioles. Electron microscopic studies showed swelling of the endothelial cells and small electron-dense deposits in mesangium (in all 6 patients) and subendothelium (in 5 of 6 patients). However, HPB19 VP1 and VP2 capsid antigens were not demonstrated in the glomerulus or the vascular wall in any patient. These findings suggest that the renal lesions caused by an immune complex mediated phenomenon would be closely correlated with the HPB19 infection, although the precise mechanism is not entirely clear, and that in adults HPB19 should be thought of as a possible cause of acute postinfectious glomerulonephritis.     

Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine

Patients with anemia and patients with chronic kidney disease have elevated risks for cardiovascular disease. Available studies have been too small to provide details about the relationship or to provide for extensive covariate control. In a large insurance database with linked laboratory values, records of women with serum creatinine >1.2 mg/dl and men with serum creatinine >1.4 mg/dl, identified from July 2000 through June 2003, were sought, and the insurance claims searches for hospitalizations that were associated with myocardial infarction, coronary revascularization, unstable angina, stroke, or congestive heart failure. New onset of dialysis also was sought. Multivariate Poisson regression was used to estimate rate ratios for these events at various hemoglobin (Hb) levels, with adjustment for patient characteristics and previous event history. Among 88,657 patients with high serum creatinine, the risk for hospitalization with myocardial infarction was two to five times higher in anemic (Hb <12 g/dl) patients than in people with Hb from 12.0 to 12.9 g/dl. A similar but less dramatic pattern of higher incidence of coronary revascularization was observed with lower Hb levels. Risks for hospitalization with congestive heart failure declined regularly with increasing Hb levels from a doubling of risk at Hb <10 g/dl to a 61% decrease at 15 g/dl, both relative to 12.0 to 12.9 g/dl. The risk for progression to dialysis was only slightly elevated (7 to 34%) in anemic patients. Anemia raises the risk for cardiovascular disease in patients with elevated serum creatinine.