Zubidat, Dalia

ABSTRACT C3 glomerulonephritis (C3GN) is a rare kidney disease driven by dysregulation of the alternative complement pathway. We report two challenging cases of patients with C3GN in whom various immunosuppressant therapies have failed to achieve complete remission, prompting treatment with eculizumab, an anti-C5 humanized monoclonal antibody that inhibits the terminal complement pathway. Although transient improvement in kidney function was observed, both patients eventually experienced worsening renal parameters, with increasing proteinuria and hematuria, culminating in progression to end-stage kidney disease. Repeated kidney biopsies following eculizumab therapy demonstrated persistent, granular mesangial and capillary wall C3 (3+) staining on immunofluorescence studies, indicating ongoing complement activation upstream of the C5 blockade and the perpetuation of C3 deposits in the glomeruli. These cases underscore the limited efficacy of terminal complement inhibition in halting disease progression in C3GN.

Abstract Background and Aims Although the choice of dialysis technique is based on several factors, patient survival is undoubtedly one of the most relevant. In a context where randomization to either peritoneal dialysis (PD) or hemodialysis (HD) proved to be extremely challenging, previous meta-analyses were greatly limited due to the inclusion of historical studies. Method We performed a systematic review by searching multiple databases up to April 22nd, 2022. We included studies meeting the following criteria: adult patients (>18 years) with end-stage kidney disease on dialysis; comparison of PD versus HD; reporting mortality data via intention-to-treat analysis; initiation of dialysis after 2000; patient classification by dialysis modality at 90 days post-initiation; and ≥50 patients per group (Figs 1 and 2). The primary outcome was the association between dialysis modality (PD vs HD) and mortality assessed via hazard ratios (HR) [Fig. 3]. Subgroup analyses were conducted to explore potential sources of heterogeneity, including sex, age, diabetes, dialysis vintage, geographical location, HD access, and study cohort inclusion period [Figs 4 and 5]. Results Database search yielded 5317 citations, from which, 27 observational studies met the eligibility criteria, including 1 033 362 incident dialysis patients [Figs 1 and 2]. The pooled mortality HR for PD versus HD was 1.01 (95% CI 0.93–1.10 [Fig. 3]). Heterogeneity was substantial (I2 = 94%) and was largely explained by different baseline features of the included populations. A statistically significant subgroup effect was demonstrated for age (>65 vs.<65 years; P = 0.01), geographical location of the studies (Oceania vs. Europe vs. Asia vs. North America; P < 0.01), and HD vascular access (central venous catheter vs. arteriovenous fistula; P < 0.01, only one study included) [Figs 4 and 5]. Conclusion This meta-analysis suggests that overall PD and incentre HD likely carry equivalent survival benefits. However, differences were detected among subgroups based on age, geographic location, HD access type, but not on sex, diabetes status, dialysis vintage and study cohort inclusion period.

Abstract Background Although the choice of dialysis technique is based on several factors, patient survival is undoubtedly one of the most relevant. In a context where randomization to either peritoneal dialysis (PD) or hemodialysis (HD) proved to be extremely challenging, previous meta-analyses were greatly limited due to the inclusion of historical studies. Methods We performed a systematic review by searching multiple databases up to April 22nd, 2022. The primary outcome was the association between dialysis modality (PD vs HD) and mortality assessed via hazard ratios (HR). Subgroup analyses were conducted to explore potential sources of heterogeneity, including sex, age, diabetes, dialysis vintage, geographical location, HD access, and study cohort inclusion period. Results Database search yielded 5317 citations, from which, 27 observational studies met the eligibility criteria, including 1 033 362 incident dialysis patients. The pooled mortality HR for PD versus HD was 1.01 (95% CI 0.93–1.10). Heterogeneity was substantial ( I 2 = 94%) and was largely explained by different baseline features of the included populations. A statistically significant subgroup effect was demonstrated for age (> 65 vs.<65 years; p = 0.01), geographical location of the studies (Oceania vs. Europe vs. Asia vs. North America; p < 0.01), and HD vascular access (central venous catheter vs. arteriovenous fistula; p < 0.01, only one study included). Conclusions This meta-analysis suggests that overall PD and incentre HD likely carry equivalent survival benefits. However, differences were detected among subgroups based on age, geographic location, HD access type, but not on sex, diabetes status, dialysis vintage and study cohort inclusion period.

ABSTRACT Background The impact of sex in the clinical presentation and outcomes of patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) has not been studied, particularly in patients with severe kidney involvement at presentation (eGFR &lt; 15 ml/min/1.73 m2). Methods A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and eGFR&lt;15 ml/min/1.73 m2 or end-stage kidney disease (ESKD) at presentation. Clinical presentation and renal outcomes were analyzed according to sex. Results We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR &lt; 15 ml/min/1.7 3m2 at the time of diagnosis: 78 (47%) were females and 88 (53%) were males. Hypertension was more frequently present in males (85.2% vs 70.5%, P = .022). Median serum creatinine (SCr) was higher in males when compared with females [5.2 (IQR 4.2–7.4) vs 3.6 (IQR 2.8–5.1) mg/dl, P &lt; .001]. Males started dialysis within 4 weeks more frequently than female (p = .003) although the median percentage of crescents was similar between groups (35.7% in males versus 36.4% in females, P = .0873). However, the rate of dialysis initiation or progression to ESKD in the first 12 months was not different between males (15, 62.5%) versus females (29, 61.7%) at 12 months. By multivariable logistic regression, factors related with dialysis initiation within the first 4 weeks in our cohort were SCr, alveolar hemorrhage, and PR3-ANCA adjusted for sex. Conclusion In our cohort, male patients presented with higher serum creatinine (SCr), and dialysis was started within the first 4 weeks more frequently (53.4% vs 30.7%). There were no differences in outcomes of kidney recovery, overall dialysis rates, and progression to ESKD within 12 months in patients with AAV-GN and eGFR &lt; 15 ml/min/1.73 m2 between groups.

Abstract Background and Aims Biological sex has been associated to a more rapid rate of chronic kidney disease progression (ie, speed of kidney function loss) in male than female [1]. Testosterone can increase oxidative stress, activate the renin angiotensin system, and aggravate renal fibrosis, whereas estrogens inhibit these pathological processes in the diseased kidney [2]. Several factors such as lower disease awareness and surveillance rates as well as disparities in health-care access result in late initiation or lack of kidney replacement therapy among females [3-5]. The impact of sex in the clinical presentation and outcomes of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) with glomerulonephritis (AAV-GN) has not been studied, particularly in patients with severe kidney involvement at presentation (eGFR&lt;15 mL/min/1.73 m2). Method A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and eGFR&lt;15 ml/min/1.73 m2 or ESKD at presentation. Clinical presentation and outcomes (renal recovery, dialysis at presentation, and ESKD) were analyzed according with sex. Results We analyzed 166 patients with biopsy proven active AAV-GN and eGFR &lt;15 mL/min/1.73 m2 at the time of diagnosis (Fig. 1): 78 (47%) were females and 88 (53%) were males. Arterial hypertension was more frequently present in males (85.2% vs. 70.5%, p = 0.022). Median serum creatinine (SCr) was higher in males when compared with females (5.2 [IQR 4.2-7.4] vs. 3.6 [IQR 2.8-5.1] mg/dL, p &lt; 0.001) but there were no differences in eGFR at presentation. When analyzing only the 71 (24 females and 47 males) patients that started dialysis within 4 weeks, infections at 12 months were more common in females (75.0% vs. 36.2%, p = 0.017). The rate of dialysis initiation or progression to ESKD was not different between males (15, 62.5%) versus females (29, 61.7%) being on dialysis at 12 months. By multivariable logistic regression, factors related with dialysis initiation within 4 weeks in our cohort were SCr (OR1.478, [95% CI 1.231-1.776], p &lt; 0.001), alveolar hemorrhage (OR 2.726, [95% CI 1.099-6.763], p = 0.031) and PR3-ANCA (OR3.155, [95% CI 1.485-6.702], p = 0.003) adjusted to sex). Patients who remained on dialysis at 12 months more often had higher SCr at diagnosis (IRR 1.098 [95% CI, 1.026–1.175], p = 0.007), severe chronicity changes on kidney biopsies (IRR 2.469 [95% CI,1.205–5.061], p = 0.014), higher chronicity score (IRR 1.178 [95%CI, 1.062-1.308], p = 0.002) and lower hemoglobin (IRR 0.824 [95%CI, 0.683-0.994], p = 0.043). Minimal chronicity changes were protective for the achievement of this endpoint (IRR 0.228 [95% CI, 0.070-0.741], p = 0.014). Multivariable Cox regression showed that patients with higher SCr at diagnosis and moderate/severe chronicity changes on biopsy were at higher risk to evolve to ESKD at 12 months compared to patients with lower chronicity grades, even when adjusted to sex. Conclusion In our cohort, male patients presented with higher SCr, and dialysis was started within 4 weeks more frequently. However, this did not result in different outcomes in terms of kidney recovery, overall dialysis rates, and progression to ESKD in patients with AAV-GN and eGFR&lt;15 mL/min/1.73 m2 between groups.

Abstract Background and Aims A significant number of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, eGFR&lt;15mL/min/1.73m2) despite advances in remission-induction treatment. Method A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and ESKD at presentation. Renal recovery, dialysis discontinuation and maintenance in ESKD after standard remission-induction, with or without the use of PLEX were compared. Results We analyzed 166 patients with biopsy proven active kidney involvement and eGFR &lt;15mL/min/1.73m2 at the time of AAV-GN diagnosis. Patients received glucocorticoids with CYC (n = 84) or with RTX (n = 72) for remission-induction, and 49 also received PLEX. The predictors for renal recovery were erythrocyte sedimentation rate, SCr at diagnosis and minimal or mild chronicity changes. We analyzed 71 patients who started dialysis with or without PLEX within 4 weeks from AAV-GN diagnosis. The predictors for dialysis discontinuation were minimal chronicity changes in kidney biopsy at the time of diagnosis (OR 6.138, [95%CI 1.389-27.118],p = 0.017) and focal glomerular involvement (OR 5.017,[95%CI 1.287-19.567],p = 0.020). Predictors for maintenance in ESKD at 12 months included higher serum creatinine (SCr) at the time of diagnosis (IRR 1.086, [95%CI 1.005-1.173],p = 0.037), moderate (IRR 3.797,[95%CI 1.090-13.225],p = 0.036), or severe chronicity changes in kidney biopsy (IRR 5.883,[95%CI 1.542–22.439],p = 0.009). Conclusion In our cohort, kidney recovery, dialysis discontinuation, and maintenance of ESKD in patients with AAV-GN and eGFR&lt;15mL/min/1.73m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

Background The optimal strategy for remission-maintenance therapy in patients with myeloperoxidase-ANCA (MPO-ANCA)–associated vasculitis is not established. Defining parameters to guide maintenance therapy is required. Methods This was a retrospective cohort study of all patients with MPO-ANCA–associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis) and GN followed at the Mayo Clinic between 1996 and 2015. Relapse rate, MPO-ANCA status, and remission-maintenance therapies were reviewed. Logistic regression models, Kaplan–Meier method, and Cox proportional hazards regression models were applied. Results We analyzed 159 patients with active MPO-ANCA–associated vasculitis with GN. Sixty-six (42%) patients had at least one relapse, and 52 (33%) relapsed before 60 months. Patients with MPO-ANCA who became persistently negative did not relapse (hazard ratio [HR], 0.03; 95% confidence interval [95% CI], 0.002 to 0.431; P =0.01). The reappearance of MPO-ANCA was associated with a higher risk of relapse (HR, 1.91; 95% CI, 1.109 to 3.293; P =0.02). Immunosuppression was withdrawn in 80 (50%) patients, and this was less likely in those who received cyclophosphamide for remission induction or in patients with persistently positive MPO-ANCA (odds ratio [OR], 0.44; 95% CI, 0.228 to 0.861; P =0.02 and OR, 0.42; 95% CI, 0.213 to 0.820; P =0.01, respectively). Relapse frequency was not different between patients with persistently positive MPO-ANCA and patients with MPO-ANCA reappearance (44% versus 39%, P =0.49), irrespective of remission-maintenance treatment. Ear, nose, and throat involvement (OR, 6.10; 95% CI, 1.280 to 29.010; P =0.02) and MPO-ANCA reappearance (OR, 9.25; 95% CI, 3.126 to 27.361; P <0.001) were independently associated with relapse after treatment withdrawal. Conclusions Patients persistently MPO-ANCA negative are at low risk for relapse even without remission-maintenance therapy. Persistence or subsequent reappearance of MPO-ANCA is associated with a higher risk of relapse. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN06460622.mp3

Key Points Asymptomatic pyuria is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene and cystic growth. The eGFR decline occurred after detection of asymptomatic pyuria without significant changes in the rate of total kidney volume growth. This study supports the use of asymptomatic pyuria as an enriching prognostic biomarker to predict faster disease progression. Background Autosomal dominant polycystic kidney disease (ADPKD) has phenotypic variability only partially explained by established biomarkers that do not readily assess pathologically important factors of inflammation and kidney fibrosis. We evaluated asymptomatic pyuria (AP), a surrogate marker of inflammation, as a biomarker for disease progression. Methods We performed a retrospective cohort study of adult patients with ADPKD. Patients were divided into AP and no pyuria (NP) groups. We evaluated the effect of pyuria on kidney function and kidney volume. Longitudinal models evaluating kidney function and kidney volume rate of change with respect to incidences of AP were created. Results There were 687 included patients (347 AP, 340 NP). The AP group had more women (65% versus 49%). Median ages at kidney failure were 86 and 80 years in the NP and AP groups (log rank, P =0.49), respectively, for patients in Mayo Imaging Class (MIC) 1A–1B as compared with 59 and 55 years for patients in MIC 1C–1D–1E (log rank, P =0.02), respectively. Compared with the NP group, the rate of kidney function (ml/min per 1.73 m 2 per year) decline shifted significantly after detection of AP in the models, including all patients (−1.48; P <0.001), patients in MIC 1A–1B (−1.79; P <0.001), patients in MIC 1C–1D–1E (−1.18; P <0.001), and patients with PKD1 (−1.04; P <0.001). Models evaluating kidney volume rate of growth showed no change after incidence of AP as compared with the NP group. Conclusions AP is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene, cystic burden, and cystic growth. These results support AP as an enriching prognostic biomarker for the rate of disease progression.