ANCA-associated glomerulonephritis in the very elderly

Antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune glomerulonephritis (GN) is the most common finding in very elderly patients biopsied for acute kidney injury. Appropriate treatment strategies in this age group are currently undefined since it is unclear whether the benefits of immunosuppression exceed the risks. We retrospectively evaluated a cohort of 78 cases of biopsy-proven pauci-immune GN in individuals aged >80 years of whom 72% were p-ANCA and 20% were c-ANCA positive. The patients treated with immunosuppression had a significantly lower incidence of end-stage renal disease (ESRD) 1 year after biopsy (36%) compared with untreated patients (73%; P=0.03). Only peak serum creatinine before biopsy and the use of immunosuppression influenced progression to ESRD. There was no significant difference in the 1-year mortality rates between these groups (46 vs 64%; P=0.3). However, when follow-up was extended beyond 2 years, immunosuppression was associated with a lower risk of death (HR 0.33, 95% CI 0.11-0.97) and death or ESRD (HR 0.16, 95% CI 0.06-0.42) in multivariable models.     

ANCA-associated crescentic IgA glomerulonephritis in pregnancy

Only a few reports have documented the presence of crescentic IgA nephropathy associated with antineutrophil cytoplasmic antibodies (ANCA), suggesting an overlap that has therapeutic significance as regards the patients' response to treatment. We report a case of rapidly progressive glomerulonephritis with P-ANCA, with biopsyproven crescentic IgA glomerulonephritis in an 11-week pregnant woman who responded very well to cyclophosphamide and prednisone. Her 24-h urine protein dropped from 5400 mg/day to 516 mg/day and serum creatinine from 2.7 mg/dL to 1.4 mg/dL. To the best of our knowledge, this is the first such case reported in pregnancy. Eighteen months after her initial presentation, she has no significant clinical problems and her laboratory work-up shows stable results.     

ANCA-associated glomerulonephritis in systemic-onset juvenile idiopathic arthritis

Systemic-onset juvenile idiopathic arthritis is an inflammatory disease of unknown cause and is not commonly associated with kidney involvement. We describe 3 patients with systemic-onset juvenile idiopathic arthritis with high disease activity who developed antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis 1-6 years after the onset of systemic-onset juvenile idiopathic arthritis. Renal and systemic-onset juvenile idiopathic arthritis remission occurred in one patient under anti-interleukin 1 (anti-IL-1) treatment associated with immunosuppressive drugs. The other 2 patients developed end-stage renal disease, and one of those patients died. This report suggests that the diagnosis of ANCA-associated glomerulonephritis must be considered in patients with systemic-onset juvenile idiopathic arthritis with persistently active systemic disease who present with proteinuria. Furthermore, use of an anti-IL-1 agent might be an effective therapeutic option.     

Chances of renal recovery for dialysis-dependent ANCA-associated glomerulonephritis

In patients who have anti-neutrophil cytoplasm autoantibody (ANCA)-associated glomerulonephritis and are on dialysis at time of diagnosis, renal function is sometimes insufficiently restored by immunosuppressive treatment, which often coincides with potentially lethal adverse effects. This study investigated the clinical and histologic variables that determine the chances of dialysis independence, dialysis dependence, or death after 12 mo in these patients. Sixty-nine patients who had ANCA-associated glomerulonephritis and were dialysis dependent at diagnosis received uniform, standard immunosuppressive therapy plus either intravenous methylprednisolone or plasma exchange. Eleven clinical and histologic variables were assessed. Univariate and binary logistic regression analyses were performed. Predictive parameters were entered into a two-step binary logistic regression analysis to differentiate among the outcomes of dialysis independence, dialysis dependence, or death. The point at which the chance of therapy-related death exceeded the chance of dialysis independence was determined. The chance of recovery exceeded the chance of dying in most cases. Intravenous methylprednisolone as adjunctive therapy plus <18% normal glomeruli and severe tubular atrophy increased the chance of therapy-related death over the chance of dialysis independence. Plasma exchange treatment plus severe tubular atrophy and <2% normal glomeruli increased the chance of therapy-related death over that of dialysis independence. Even with ominous histologic findings, the chance of renal recovery exceeds the chance of therapy-related death when these patients are treated with plasma exchange as adjunctive therapy.     

Transformation from tubulointerstitial nephritis to crescentic glomerulonephritis: an unusual presentation of ANCA-associated renal vasculitis

A 44-year-old man with acute renal failure and antineutrophil cytoplasmic antibodies (ANCA) positivity was described. The first renal biopsy specimen showed tubulointerstitial nephritis (TIN) with normal glomeruli. However, delayed recovery of renal function with low-dose steroid treatment for TIN prompted a second renal biopsy 1 month later; and the specimen demonstrated a dramatically different morphology, with necrotizing and crescentic glomerulonephritis. Improvement in renal function occurred, together with reduction of ANCA titers, following intensive immunosuppressive therapy. This case illustrates an unusual presentation of TIN in ANCA-associated renal vasculitis. The possible pathogenetic mechanism are discussed.     

Sjögren's syndrome with ANCA-associated crescentic extramembranous glomerulonephritis

A 49-year-old woman with a 1-year history of Sjögren's syndrome was diagnosed with cutaneous leukocytoclastic vasculitis and necrotizing crescentic membranous glomerulonephritis. Antineutrophil cytoplasmic antibodies targeting myeloperoxidase were found. She reported a transient episode of nephritis 4 years earlier. This pattern of kidney disease is not typical of Sjögren's syndrome. Methylprednisolone boluses followed by oral glucocorticoid therapy were given in combination with mycophenolate mofetil. Renal function stabilized after 2 months, and tests for anti-myeloperoxidase reverted to negative.     

Tubular osteopontin expression in patients with ANCA-associated glomerulonephritis.

OBJECTIVE: To elucidate the role of osteopontin (OPN) in monocyte recruitment in crescentic glomerulonephritis, we investigated immunohistochemical localization of OPN in the kidney and its correlation with clinical and histopathologic parameters in biopsy specimens of patients with myeloperoxidase antineutrophil cytoplasmic autoantibody- (MPO-ANCA) associated glomerulonephritis. METHODS: Twelve patients with MPO-ANCA-associated glomerulonephritis were enrolled in this study. Clinical parameters such as creatinine clearance and urinary protein excretion of each patient were obtained at the time of biopsy. Paraffin-embedded sections were used for immunohistochemical staining using the LSAB method. Five cortical interstitial fields randomly selected at original magnification x 200 were assessed using a computer-assisted color image analyzer. Tubular OPN expression was assessed as the percentage of positive area in the tubulointerstitium. Double immunofluorescent staining using antibodies against OPN and alpha(v)beta3 was performed. RESULTS: In all of the cases studied, OPN was occasionally localized within the glomeruli, and expressed slightly in proximal tubular epithelium and significantly in distal tubular epithelium. Tubular OPN expression tended to be promoted in the interstitium infiltrating by numerous monocytes/macrophages. The extent of tubular OPN expression was positively correlated with serum ANCA titers and urinary OPN concentrations. Enhanced alpha(v)beta3 expression appeared in the distal tubular epithelium expressing OPN. CONCLUSION: These results suggest that inducible expression of OPN and alpha(v)beta3 in the tubular epithelium seems to be associated with interstitial moncyte infiltration and subsequent tubulointerstitial changes in human MPO-ANCA-associated glomerulonephritis.     

Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis.

BACKGROUND: Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages. RESULTS: MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy. CONCLUSIONS: Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.     

Mast cells and tubulointerstitial fibrosis in patients with ANCA-associated glomerulonephritis

Background. To elucidate the role of mast cells (MCs) in the pathogenesis of crescentic glomerulonephritis, we investigated the immunohistochemical localization of MCs in the kidney and the correlation between MC localization and tubulointerstitial lesions in biopsy specimens and serum stem cell factor (SCF) levels in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. Methods. Thirteen patients with ANCA-associated glomerulonephritis were enrolled in this study. Clinical parameters, such as serum creatinine and urinary protein excretion, were obtained from each patient at the time of biopsy. Paraffin-embedded sections were used for immunohistochemical staining, using the labelled streptavidin bio-tin (LSAB) method. Monoclonal antibodies to human tryptase, α-smooth-muscle actin, and CD68 were used as primary antibodies. Ten cortical interstitial fields were randomly selected at an original magnification of ×400 and assessed using a computer-assisted color image analyzer. Tubulointerstitial fibrosis was assessed as the percentage of the area stained with Masson trichrome in ten cortical interstitial fields. The measurement of serum SCF levels was performed by using an enzyme-linked immunoassay. Results. In all of the control subjects, a few tryptase-positive MCs were observed in the glomeruli and interstitium. In contrast, sparse MCs were observed in the interstitium, but not in the glomeruli of diseased kidneys. The number of interstitial MCs in the tubulointerstitial lesions was positively correlated with the degree of interstitial fibrosis. Moreover, a significant positive correlation was observed between the number of interstitial MCs and the serum SCF concentration (r = 0.85; P = 0.001). Conclusions. Our findings suggest that MC infiltration induced by SCF in interstitial tissues seems to be associated with tubulointerstitial fibrosis in human ANCA-associated glomerulonephritis. Received: May 31, 2002 / Accepted: November 8, 2002 Acknowledgments The authors thank Professor Hiroshi Toma of the Department of Urology, Tokyo Women's Medical University, for donating the control tissues. We wish to thank Mr. Shigeru Horita and Mr. Tsutomu Ishizuka for their special technical assistance. This study was supported in part by Grants for Progressive Renal Diseases from the Ministry of Health of Japan and a Grant-in-Aid from the Ministry of Health, Science, Sports, and Culture of Japan. Correspondence to:S. Otsubo     

Angiotensin II infusion ameliorates the early phase of a mesangioproliferative glomerulonephritis

BACKGROUND: Inhibition of the renin-angiotensin system slows the progression of chronic renal disease. METHODS: To test whether angiotensin II (Ang II) infusion aggravates or ameliorates an acute glomerulonephritis, the peptide was infused (200 ng/min by osmotic minipump) in rats with an anti-thymocyte antibody-induced glomerulonephritis (ATS). RESULTS: Ang II significantly increased blood pressure. Following injection of the antibody, similar glomerular binding of rabbit IgG and rat complement C3 was detected in ATS and Ang II+ATS rats, indicating no differences in delivery and binding of the antibody. Ang II infusion, however, induced a significant reduction in glomerular monocyte infiltration, cell proliferation and matrix expansion in nephritic rats compared to rats with nephritis without Ang II. The antiproliferative effect of Ang II was inhibited by the Ang II type 1 (AT1) receptor blocker irbesartan, but not by the AT2 receptor blocker PD 123319, indicating that this effect was likely transduced by AT1 receptors. Norepinephrine infusion (600 ng/min) produced a similar degree of hypertension, but did not affect glomerular proliferation in nephritic rats. Ang II induced the glomerular expression of the cell cycle inhibitor p27KIP1 and of transforming growth factor-beta (TGF-beta) and inhibited expression of monocyte chemotactic protein 1 (MCP-1). CONCLUSION: Ang II surprisingly ameliorates glomerular monocyte infiltration, proliferation and matrix expansion in ATS nephritis. Ang II-mediated induction of cyclin kinase inhibitors and TGF-beta may contribute to the protection of the glomerulus from inflammatory injury by inducing cell cycle arrest and attenuating activation of local and recruited cells. Alternatively, Ang II might protect the kidney at least in part by less inflow of disease activators due to reduction of renal blood flow. Therefore, activation of the renin-angiotensin system may have protective effects in certain pathophysiological situations.     

Two autopsy cases of ANCA-associated glomerulonephritis manifested after contrast medium use

[Case 1]: An 81-year old man was referred to our hospital with dyspnea and bloody sputum. Computed tomography with contrast medium for the evaluation of metastasis of urinary bladder carcinoma had been performed 4 months previously. On admission, his serum creatinine and potassium were 15.3 mg/dl and 6.9 mEq/l, respectively. His chest X ray revealed cardiomegaly, butterfly shadow and interstitial change, indicating congestive heart failure and interstitial pneumonia. His electrocardiogram showed that he was on the brink of cardiac arrest due to hyperkalemia. Mechanical ventilation and hemodialysis were initiated. Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) was highly positive(321 EU), leading to the diagnosis of MPO-ANCA-associated rapidly progressive glomerulonephritis (RPGN) with interstitial pneumonia. Treatment with pulse methylprednisolone was not effective and he died. Autopsy findings showed crescentic glomerulonephritis, alveolar hemorrhage and interstitial pneumonia with honeycomb formation. [Case 2]: A 73-year old man was referred to our hospital with rapid deterioration of his renal function. He had received a cardiac catheter examination 3 weeks previously. On admission, his serum creatinine was 4.5 mg/dl. His chest X ray showed cardiomegaly and interstitial change. Renal biopsy findings showed crescentic formation in the glomeruli. Moreover, MPO-ANCA was 494 EU, leading to the diagnosis of MPO-ANCA-associated RPGN with interstitial pneumonia. Treatment with pulse methylprednisolone and cyclophosphamide was not effective and he died. Autopsy findings revealed crescentic glomerulonephritis and interstitial pneumonia with honeycomb formation. Here we described two cases of ANCA-associated RPGN complicated by microscopic polyantitis and interstitial pneumonia after the use of contrast medium. The relation between ANCA-associated RPGN and the contrast medium was unclear. However, in the case of rapid deterioration of renal function, MPO-ANCA should be measured even after the use of contrast medium. The complication of lung diseases, especially interstitial pneumonia, should be investigated simultaneously.