Development of Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody-positive Necrotizing Crescentic Glomerulonephritis in an Elderly Patient with Immunological Kidney Disease

A 78-year-old man presented with hypercalcemia and renal disease with high serum IgG4 and positive myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), exhibiting sarcoidosis-like chest findings. A renal biopsy revealed tubulointerstitial nephritis, membranous nephropathy (MN), and sub-capsular lymphoid aggregates without fulfilling the diagnostic criteria of IgG4-related disease or sarcoidosis. Steroid therapy ameliorated the serological and renal abnormalities. After 5 years, following gradual increases in the neutrophil count and upper respiratory infection (URI), necrotizing crescentic glomerulonephritis (NCGN) developed with an increased serum MPO-ANCA level. These results suggest that in the presence of MPO-ANCA in immune senescence, the persistent neutrophil increase with URI may lead to the development of NCGN.     

Membranous Glomerulonephritis Associated with Sarcoidosis*

Summary: Two patients with sarcoidosis involving pulmonary hilar lymph nodes developed the nephrotic syndrome. Renal biopsy in both cases showed membranous glomerulonephritis. In one patient, there was an associated renal vein thrombosis.     

Membranous Glomerulonephritis Associated with Sarcoidosis*

Summary: Two patients with sarcoidosis involving pulmonary hilar lymph nodes developed the nephrotic syndrome. Renal biopsy in both cases showed membranous glomerulonephritis. In one patient, there was an associated renal vein thrombosis.     

Necrotizing and Crescentic Lupus Nephritis with Antineutrophil Cytoplasmic Antibody Seropositivity

Background and objectives: Lupus nephritis is a classic immune complex glomerulonephritis. In contrast, antineutrophil cytoplasmic antibodies are associated with necrotizing and crescentic glomerulonephritis, in the absence of significant immune deposits. Antineutrophil cytoplasmic antibodies are detected by indirect immunofluorescence in 20% of patients with systemic lupus erythematosus. We report 10 cases of necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity.Design, setting, participants, & measurements: Ten patients with systemic lupus erythematosus, antineutrophil cytoplasmic antibody positivity, and renal biopsy findings of lupus nephritis and antineutrophil cytoplasmic antibody–associated glomerulonephritis were identified. The clinical features, pathologic findings, and outcomes are described.Results: The cohort consisted of eight women and two men with a mean age of 48.4 yr. Perinuclear antineutrophil cytoplasmic antibody was detected by indirect immunofluorescence in nine patients. Four of the nine patients and the single remaining patient were found to have myeloperoxidase–antineutrophil cytoplasmic antibodies by enzyme-linked immunosorbent assay. Clinical presentation included proteinuria, hematuria, and acute renal insufficiency, with mean creatinine of 7.1 mg/dl. All biopsies exhibited prominent necrosis and crescents with absent or rare subendothelial deposits and were interpreted as lupus nephritis and antineutrophil cytoplasmic antibody–associated glomerulonephritis. All patients received cyclophosphamide and prednisone. Three patients died of infectious complications. Among the remaining seven patients, five achieved a complete or near-complete remission, one had a remission with subsequent relapse, and one had no response to therapy.Conclusion: Antineutrophil cytoplasmic antibody–associated necrotizing and crescentic glomerulonephritis may occur superimposed on lupus nephritis. In patients with lupus nephritis and biopsy findings of prominent necrosis and crescent formation in the absence of significant endocapillary proliferation or subendothelial deposits, antineutrophil cytoplasmic antibody testing by enzyme-linked immunosorbent assay is recommended.Lupus nephritis (LN) is a classic immune complex–mediated renal disease. The formation of glomerular immune deposits results in complement activation; leukocyte infiltration; cytokine release; cellular proliferation; and, in some instances, necrosis, crescent formation, and/or eventual glomerular scarring. The patterns of glomerulonephritis (GN) seen in patients with LN reflect the sites of immune complex deposition (1).Pauci-immune necrotizing and crescentic GN differs from LN in that glomerular necrosis and crescent formation occur in the absence of significant cellular proliferation and in the presence of no more than a “paucity” of glomerular immune complex deposits. Antineutrophil cytoplasmic antibodies (ANCA) are directly implicated in the pathogenesis of this form of glomerular injury and are thought to directly target cytokine-primed neutrophils that express myeloperoxidase (MPO) or proteinase 3 (PR3) at the cell surface. After activation by MPO-ANCA or PR3-ANCA, neutrophils release cytokines, toxic oxygen metabolites, and lytic proteinases, leading to endothelial damage with subsequent glomerular basement membrane rupture, necrosis, and crescent formation (2).In LN, the degree of subendothelial deposit formation roughly correlates with the degree of endocapillary proliferation, and the findings of fibrinoid necrosis and crescent formation are more commonly encountered in biopsies with extensive endocapillary proliferation. However, there are reported cases of LN in which focal segmental or diffuse glomerular necrosis or crescent formation occurs without significant subendothelial deposits (3–7). Schwartz et al. (3) described four cases of LN manifesting diffuse segmental or global endocapillary proliferation with only focal subendothelial deposits, two of which exhibited glomerular necrosis. These cases were reported before the advent of ANCA testing (3). Ferrario et al. (4) reported nine cases of focal and segmental LN, four of which were characterized by segmental glomerular necrosis without endocapillary hypercellularity. Immunofluorescence (IF) was performed in seven of the nine cases and either was negative or showed only mesangial positivity. Electron microscopy (EM) and ANCA testing were not performed. Akhtar et al. (5) and Charney et al. (6) each described two cases of LN with segmental glomerular necrosis and endocapillary hypercellularity, without subendothelial deposits. All four of the patients had negative ANCA serologies. Arahata et al. (7) described a single case of ANCA-associated necrotizing and crescentic GN in a patient with LN and scant subendothelial deposits.A major modification introduced in the 2003 International Society of Nephrology/Renal Pathology Society classification of LN was to subdivide LN IV (endocapillary or extracapillary GN involving ≥50% of glomeruli) into LN IV-S and LN IV-G, on the basis of whether the glomerular lesions were segmental (S) or global (G) in distribution (1). This change in the classification scheme was based largely on the experience of the Lupus Nephritis Collaborative Study Group, which found that patients who meet criteria for IV-S have a worse outcome than those with IV-G (8). In this study, patients with LN IV-S had more extensive fibrinoid necrosis, a lesser degree of immune complex deposition, and a worse outcome, leading the authors to suggest that the findings resembled a “pauci-immune GN” (8). Two subsequent studies have confirmed that LN IV-S is associated with more extensive glomerular necrosis and less prominent subendothelial deposit formation than LN IV-G (9,10). In both of these studies, the authors raised the possibility that a pauci-immune mechanism may be playing a role in the cases of LN IV-S that exhibit prominent necrosis in the absence of significant endocapillary proliferation or subendothelial deposits (9,10). In the study by Hill et al. (9), ANCA was proposed as a potential pathomechanism, but the prevalence of ANCA seropositivity was not studied.We previously reported three LN cases with extensive fibrinoid necrosis and crescent formation, absent or rare subendothelial deposits, and positive ANCA serologies (11,12). In these cases, the disproportionate degree of necrosis and crescent formation suggested overlapping features of LN and ANCA-associated GN. In this report, we expand our experience to 10 cases. The clinical features, renal biopsy findings, and outcomes are provided.     

Pauci-immune Crescentic Glomerulonephritis Superimposed on Diabetic Glomerulosclerosis

Background and objectives: Pauci-immune necrotizing and crescentic glomerulonephritis (PNCGN) superimposed on diabetic glomerulosclerosis (DGS) is a rare occurrence. Only limited data on this dual glomerulopathy are available.Design, setting, participants, & measurements: Twenty-three cases of PNCGN superimposed on DGS were identified from the archives of the Renal Pathology Laboratory of Columbia University. The clinical features, pathologic findings, and outcomes are described.Results: The majority of patients were white, elderly, and had longstanding diabetes. Patients presented with acute renal failure and an active urine sediment. Antinuclear cytoplasmic autoantibody (ANCA) testing was positive by indirect immunofluorescence in 18 of 22 patients. Sixteen patients had a P-ANCA pattern, 9 of whom underwent further testing and were found to be MPO-ANCA positive by enzyme-linked immunosorbent assay. Among the two patients with C-ANCA by indirect immunofluorescence, enzyme-linked immunosorbent assay was performed in one and revealed PR3-ANCA. Eight patients had extrarenal manifestations of vasculitis, including 6 with pulmonary hemorrhage. At the time of presentation and renal biopsy, 11 patients required hemodialysis. The mean percentages of glomeruli with cellular crescents, fibrous crescents, and necrosis were 24.9, 8.4, and 12.9, respectively. Most patients were treated with cyclophosphamide and prednisone. At a mean follow-up of 14.6 mo (available in 21 patients), 8 patients had died and 8 of the remaining 13 patients had reached end-stage renal disease. Correlates of end-stage renal disease were hemodialysis at presentation and the degree of DGS.Conclusions: PNCGN may occur superimposed on DGS. The prognosis for this dual glomerulopathy is dismal despite aggressive therapy.Diabetes mellitus (DM) is the most common cause of end-stage renal disease (ESRD) in the developed world. The majority of diabetic patients who develop proteinuria and renal failure have diabetic glomerulosclerosis (DGS), which is characterized by diffuse or nodular mesangial sclerosis and thickening of glomerular and tubular basement membranes. Given the likelihood of finding DGS, most patients with DM who develop proteinuria and renal insufficiency do not undergo renal biopsy.Common indications for renal biopsy in patients with DM include sudden onset of heavy proteinuria, proteinuria in the absence of diabetic retinopathy, acute renal failure (ARF), and persistent hematuria (1). Arterionephrosclerosis, ischemic nephropathy, papillary necrosis, acute pyelonephritis, and glomerulonephritis are some of the more frequent nondiabetic conditions that occur in diabetic patients. The biopsy prevalence of nondiabetic diseases varies widely, from 6% to 81% (2), depending on the threshold of nephrologists for performing renal biopsy on diabetic patients (1,3–4).In diabetic patients, renal biopsy may reveal DGS, nondiabetic renal disease, or DGS with superimposed nondiabetic disease. Among the glomerular diseases that may occur superimposed on DGS, the most common are membranous glomerulopathy, IgA nephropathy, and acute postinfectious glomerulonephritis (1,2). Minimal change disease, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, and lupus nephritis also have been reported. Rapidly progressive glomerulonephritis is a common pattern of ARF in older patients coming to renal biopsy. Nevertheless, pauci-immune necrotizing and crescentic glomerulonephritis (PNCGN) superimposed on DGS is a rare occurrence, with only 9 cases reported in the English literature (5–12). Herein, we describe the clinical, pathologic, and outcome data of 23 patients with PNCGN superimposed on DGS.     

Hypocomplementemic Urticarial Vasculitis Syndrome With Crescentic Glomerulonephritis

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disease characterized by multiple organ system involvement, including renal disease, with low complement levels. We report the case of a 31-year-old woman who presented with nonspecific symptoms including fatigue, diarrhea, macular rash and abdominal pain with acute renal failure leading to end-stage kidney disease. Laboratory results showed hematuria, nephrotic range proteinuria, worsening creatinine and low C1q levels. Left kidney biopsy showed proliferative glomerulonephritis with crescent formation. She was treated with 6 months of intravenous cyclophosphamide, followed by 2 doses of intravenous rituximab (1 g each), thereafter maintained on mycophenolate mofetil and glucocorticoid-based therapy. She experienced a full recovery of renal function after 12 months of dialysis dependence. Hypocomplementemic urticarial vasculitis syndrome with crescentic glomerulonephritis is a rare disease with only 5 other reported cases in literature. In our case, we document a delayed but excellent renal recovery during a 2-year follow-up.     

Clinical and Immunologic Characteristics of Patients With ANCA-Associated Glomerulonephritis Combined With Membranous Nephropathy: A Retrospective Cohort Study in a Single Chinese Center

The concurrent antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) and membranous nephropathy (MN) have been increasingly documented, mainly in case studies and case series; however, the differences of clinical and pathologic characteristics as well as outcomes between ANCA-GN patients with and without MN remain unclear.The current study investigated the clinical and immunologic features of patients with combined ANCA-GN and MN in a large cohort.Twenty-seven of 223 patients had combined ANCA-GN and MN; they had significantly higher levels of initial serum creatinine, higher Birmingham Vasculitis Activity Score and poorer renal outcome than ANCA-GN patients without MN (P < 0.05). ANCA-GN patients with MN could recognize the light chain of myeloperoxidase more frequently than those without MN (P < 0.05). The prevalence of circulating anti-PLA2R antibodies and glomerular PLA2R deposits was significantly lower in patients with combined ANCA-GN and MN than that in patients with idiopathic MN (P < 0.05). Compared with the idiopathic MN patients, the patients with combined ANCA-GN and MN had significantly higher recognition frequency of immunoglobulin (Ig) G2 and IgG3, and significantly lower recognition frequency of IgG4 (P < 0.05).Patients with combined ANCA-GN and MN had distinct clinical features and a different pathogenesis of MN.     

Successful Treatment of Membranous Glomerulonephritis with Rituximab in Calcineurin Inhibitor-Dependent Patients

Background and objectives: Calcineurin inhibitors (CNIs) induce remission of proteinuria in most nephrotic patients with membranous glomerulonephropathy (MGN). However, 60% of patients become treatment dependent and are at risk of chronic nephrotoxicity. The aim of this study was to evaluate the efficacy of rituximab in patients with long-term dependence on CNIs.Design, setting, participants, and measurements: Thirteen patients with MGN, normal renal function, and proven dependence on CNIs, despite previous treatment with other immunosuppressant drugs, received a single trial of four weekly doses of rituximab (375 mg/m²). Outcome measures were the percentage of patients with CNI withdrawal and no evidence of relapse and the percentage of patients with complete or partial remission 30 mo after CNI withdrawal.Results: After rituximab, proteinuria decreased significantly (2.5 ± 0,76 basal versus 0.85 ± 0.17 at 6 mo; P = .0003). CNIs and other immunosuppressant drugs could be withdrawn in all patients with no evidence of relapse. After CNI withdrawal, GFR increased significantly (90.3 ± 15 basal to 106.4 ± 20 at 3 mo with a mean increase of 15.3% [range 0–20]). Three patients suffered a relapse of nephrotic proteinuria 19, 23, and 28 mo after rituximab treatment; all were successfully treated with a second course of rituximab. At 30 mo, all patients were in remission.Conclusions: In patients with MGN with long-term CNI dependence, rituximab can be an effective tool to overcome dependence on CNI, thus avoiding the risk of nephrotoxicity related to the chronic exposure to these drugs.Membranous glomerulonephropathy (MGN) is the most frequent cause of nephrotic syndrome in adults. There is general agreement that patients with persistent nephrotic syndrome are at risk of developing progressive renal insufficiency (1–4). In these patients, prospective randomized clinical trials have demonstrated that the calcineurin inhibitors (CNIs) cyclosporine (5,6) and tacrolimus (7) induce complete or partial remission of proteinuria in more than 70% of patients. However, more than 60% of patients treated with CNI suffer subsequent relapses or become treatment dependent (5–8) and need prolonged therapy to maintain remission, which exposes them to the nephrotoxic effects of this drugs. Consequently, for these patients, there is a need for the development of new treatment strategies aimed at reducing the risk of chronic nephrotoxicity. MGN is an antibody-mediated disease induced by deposits of immunoglobulins and complement components on the subepithelial layer of the glomerular capillary wall (9). This immune deposition promotes injury to the glomerular filtering barrier, proteinuria, and eventual renal failure (10). Infiltration of CD-20+ cells has also been demonstrated in renal biopsies of patients with MGN (11). Results in experimental MGN have shown that the inhibition of B cell function is associated with beneficial effects on proteinuria, (12) and human studies clearly demonstrated that the inhibition of B cells with alkylating agents induces remission of the nephrotic syndrome (13). The availability of monoclonal antibodies targeted to the cell surface antigen CD-20 of B cells permits an analysis of the effect of more selective and specific B cell inhibition in the outcome of several antibody-mediated diseases in clinical studies (14). In recent years, observational studies have shown that the administration of the anti-CD20 monoclonal antibody rituximab can reduce urinary protein excretion and preserve renal function in patients with MGN and persistent nephrotic syndrome (15–19).This pilot observational study was conducted in patients with MGN with normal renal function, who experienced long-term dependence on CNI despite previous treatment with high-dose immunoglobulins and mycophenolate mofetil. The study aim was to evaluate whether a single course of rituximab could allow either dose reduction or withdrawal of CNI.     

Nodular Regenerative Hyperplasia of the Liver Associated with Idiopathic Membranous Glomerulonephritis

Nodular regenerative hyperplasia of the liver was found in a 67-yr-old man who had been suffering from nephrotic syndrome for years. Main clinical symptoms and signs were edema, proteinuria, hypertension, and abnormal studies of electrocardiogram. His renal disease had been relatively well controlled by administration of corticosteroids, but he died suddenly on March 12, 1986. Autopsy revealed fresh and old myocardial infarct and membranous glomerulonephritis. The liver weighed 1530 g and showed a diffuse nodular configuration except for in the area of Zahn's red infarct. Fibrosis was minimal in most areas, and each nodule was circumscribed by compressed atrophic parenchyma. However, this case was unusual compared to most cases of nodular regenerative hyperplasia because there was prominent fibrosis in the perihilar portion. Paucity of interlobular arterial branches was confirmed by a crude morphometry. We describe herein this somewhat unusual nodular regenerative hyperplasia case with some discussion concerning the histogenesis.     

M2 Macrophage Infiltrates in the Early Stages of ANCA-Associated Pauci-Immune Necrotizing GN

Background and objectives

This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci-immune necrotizing GN and the primary effector cells mediating initial capillary injury.

Design, setting, participants, & measurements

Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007–2012), were studied. Neutrophils and CD68⁺, CD163⁺, CD3⁺, CD56⁺, and CD20⁺ cells were scored in paraffin sections counterstained with periodic acid–Schiff. Electron microscopy was performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN (n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls.

Results

Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3–25) normal-appearing glomeruli, a mean of 2 (range=1–5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1–11) glomeruli with cellular crescents. CD68⁺ and CD163⁺ macrophages predominated at sites of fibrinoid necrosis in pauci-immune necrotizing GN, exceeding the quantity of neutrophils and T cells (mean scores [SD]=2.5 [0.7] and 2.2 [0.75] versus 0.6 [0.5] and 0.1 [0.3], respectively; P<0.001). B and natural killer cells were rare. Normal-appearing glomeruli in pauci-immune necrotizing GN had significantly more CD68⁺ and CD163⁺ macrophages than the controls (CD68⁺, 0.9 [0.3] versus 0.4 [0.3]; CD163⁺, 1 [0.4] versus 0.4 [0.3]; P<0.001). The quantity of other glomerular infiltrates did not differ from controls. The serum creatinine level at biopsy correlated with the glomerular CD68 and neutrophil scores (r=0.74 and r=0.71, respectively; P=0.001) but did not correlate with the extent of fibrinoid necrosis (r=0.36). Macrophages were localized at minute perforations and attenuations of the capillary basement membrane by electron microscopy.

Conclusions

Early pauci-immune necrotizing GN is characterized by a selective localization of CD163⁺ M2 macrophages at sites of glomerular fibrinoid necrosis and in normal-appearing glomeruli. These observations indicate that alternatively activated macrophages are positioned as potential effectors of glomerular injury in the early stages of pauci-immune necrotizing GN and may be potential targets for therapeutic intervention.     

Pathogenesis and Diagnosis of Otitis Media with ANCA-Associated Vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is histologically characterized by systemic necrotizing vasculitis and is clinically classified into two phases, systemic or localized. Recently, otologi- cal symptoms such as otitis media and hearing loss, not previously often associated with AAV, have been reported in AAV cases. In these cases we propose a diagnosis of otitis media with AAV (OMAAV). The ANCA titer is important for the diagnosis of OMAAV, and in most cases rapid progressive hearing loss is observed as localized AAV. Peripheral facial nerve palsy or hypertrophic pachymeningitis are coupled with 25% of cases and 18% of cases respectively. Proteinase 3-ANCA (PR3-ANCA) positive otitis media causes granulomatous formation or middle ear effusion in the middle ear, on the other hand myeloperoxidase-ANCA (MPO-ANCA) positive otitis media predominantly presents as otitis media with effusion. The early diagnosed case and the sensorineural hearing loss not progressed deaf could be recovered by the immunosuppressive therapy. Delayed diagnosis of AAV occasionally leads to progression to the irreversible phase; therefore, diagnosis at the early-localized stage is important for treating AAV. In this review, we discuss the current understanding of this newly proposed concept of OMAAV.     

Prognostic Factors and Long-Term Outcome with ANCA-Associated Kidney Vasculitis in Childhood

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Comparison of Ultrastructural Features Between Patients with Mercury-associated Membranous Nephropathy and Idiopathic Membranous Nephropathy

BackgroundProlonged exposure to mercury can cause membranous nephropathy. Mercury-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) have similar clinical manifestations, making misdiagnoses likely. We compared the clinicopathological and ultrastructural features of M-MN and I-MN.MethodsWe retrospectively analyzed the clinicopathological data of 13 M-MN patients and 13 I-MN patients. Electron micrographs of glomerular capillaries were taken, and foot process width (FPW) and the number of foot processes per 10 μm glomerular basement membrane (GBM) were calculated. The presence and location of electron-dense deposits were recorded.ResultsCompared with I-MN patients, M-MN patients were younger (38.7 ± 8.5 versus 45.8 ± 5.7 years, P = 0.020), achieved complete remission more quickly (9.0 ± 6.1 versus 20.3 ± 9.8 months, P = 0.004), and had a lower relapse rate (0 versus 45.5%, P = 0.014). Patients with M-MN also had lower FPW (974.3 [interquartile range or IQR, 791.2–1504.4] nm versus 2370.6 [IQR, 2219.4–2559.1] nm, P = 0.001), more foot processes per 10 μm GBM (8.1 [IQR, 5.2–10.0] versus 3.3 [IQR, 3.1–3.5], P = 0.001), and a higher rate of mesangial electron-dense deposits (41.7% versus 0, P = 0.015). A cut-off FPW of <1654 nm differentiated M-MN from I-MN with high sensitivity (92.3%) and specificity (83.3%).ConclusionsFoot process effacement was less severe in M-MN than in I-MN. In patients with mercury toxic exposure, MN with less severe foot processes effacement suggested mercury could be the cause. Better prognosis in patients with M-MN may be associated with minor podocyte damage.     

肾小球膜性病变——重金属肾损害

报道1例中年女性患者因存在神经系统、消化系统和肾脏损害的临床表现,经肾活检证实形态学改变符合肾小球膜性病变;但无论肾活检形态改变特点还是临床表现均提示存在引起肾脏病变的继发病因。最终,经临床和实验室检查证实患者肾脏病变与汞中毒相关。     

Predictors of Treatment Outcomes in ANCA-Associated Vasculitis with Severe Kidney Failure

Background and objectives

In ANCA-associated GN, severe renal dysfunction portends a poor prognosis for renal recovery and patient survival. This study evaluated the prognostic factors affecting renal and patient outcomes in patients presenting with severe kidney failure to guide immunosuppressive therapy.

Design, setting, participants, & measurements

This study retrospectively evaluated clinical and histopathologic characteristics of 155 patients who underwent biopsy between October 1985 and February 2011 (median eGFR at presentation, 7.1 ml/min per 1.73 m²; 87% required hemodialysis), all treated with immunosuppressive medications. Three outcomes of interest were measured: patient survival, renal survival, and treatment response (defined as dialysis-free survival without active vasculitis by 4 months after biopsy). Competing risk, Cox, and logistic regression analyses were conducted for each outcome measure.

Results

Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died. In a competing risk analysis, estimated cumulative incidence rates of ESRD and disease-related mortality were 26% and 17% at 1 year and 32% and 28% at 5 years, respectively. Cyclophosphamide therapy and treatment response by 4 months were independently associated with patient and renal survival, adjusting for the percentage of normal glomeruli, histopathologic chronicity index score, and baseline clinical characteristics. Only 5% of patients still dialysis dependent at 4 months subsequently recovered renal function. Low chronicity index score (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 1.04 to 1.30, per unit decrease) and baseline eGFR>10 ml/min per 1.73 m² (OR, 2.77; 95% CI, 1.09 to 7.01) were significantly associated with treatment response by 4 months. Among cyclophosphamide-treated patients, the likelihood of treatment response was >14% even with highest chronicity index score and eGFR<10 ml/min per 1.73 m².

Conclusions

Although low baseline renal function and severe renal scarring are associated with lower treatment response rate, no “futility” threshold could be identified. Conversely, continued immunosuppressive therapy beyond 4 months is unlikely to benefit patients who remain dialysis dependent.