Among patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, plasma exchange did not reduce the incidence of death or end-stage kidney disease. A reduced-dose regimen of oral ...glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD.
Pregnancy is increasingly undertaken in patients with chronic kidney disease (CKD) and, conversely, CKD is increasingly diagnosed in pregnancy: up to 3 % of pregnancies are estimated to be ...complicated by CKD. The heterogeneity of CKD (accounting for stage, hypertension and proteinuria) and the rarity of several kidney diseases make risk assessment difficult and therapeutic strategies are often based upon scattered experiences and small series. In this setting, the aim of this position statement of the
Kidney and Pregnancy Study Group of the Italian Society of Nephrology
is to review the literature, and discuss the experience in the clinical management of CKD in pregnancy. CKD is associated with an increased risk for adverse pregnancy-related outcomes since its early stage, also in the absence of hypertension and proteinuria, thus supporting the need for a multidisciplinary follow-up in all CKD patients. CKD stage, hypertension and proteinuria are interrelated, but they are also independent risk factors for adverse pregnancy-related outcomes. Among the different kidney diseases, patients with glomerulonephritis and immunologic diseases are at higher risk of developing or increasing proteinuria and hypertension, a picture often difficult to differentiate from preeclampsia. The risk is higher in active immunologic diseases, and in those cases that are detected or flare up during pregnancy. Referral to tertiary care centres for multidisciplinary follow-up and tailored approaches are warranted. The risk of maternal death is, almost exclusively, reported in systemic lupus erythematosus and vasculitis, which share with diabetic nephropathy an increased risk for perinatal death of the babies. Conversely, patients with kidney malformation, autosomal-dominant polycystic kidney disease, stone disease, and previous upper urinary tract infections are at higher risk for urinary tract infections, in turn associated with prematurity. No risk for malformations other than those related to familiar urinary tract malformations is reported in CKD patients, with the possible exception of diabetic nephropathy. Risks of worsening of the renal function are differently reported, but are higher in advanced CKD. Strict follow-up is needed, also to identify the best balance between maternal and foetal risks. The need for further multicentre studies is underlined.
Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is ...recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes.
We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease.
This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab.
Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated.
Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m
or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis.
Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician.
The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial.
The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13;
= 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08;
= 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93;
= 0.016).
Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections.
A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis.
This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study.
This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389.
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener's), ...microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.
Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol ...acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.
Background Prognostic criteria to inform women with moderate to severe renal insufficiency who wish to bear children are not well established. Study Design Longitudinal multicenter cohort study. ...Settings & Participants Nondiabetic white women with pregnancies proceeded beyond the 20th week and estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 (<1 mL/s/1.73 m2 ) before conception. Predictors Baseline GFR and proteinuria (exposure); other clinical characteristics at conception (covariates). Outcomes & Measurements Difference in GFR decreases before conception versus after delivery (mixed linear models); low birth weight (<2,500 g), and maternal renal survival (logistic and Cox regressions). Results 49 women were studied. Mean serum creatinine and GFR at conception were 2.1 ± 1 (SD) mg/dL (186 ± 88 μmol/L) and 35 ± 12 mL/min/1.73 m2 (0.58 ± 0.2 mL/s/1.73 m2 ), respectively. Overall mean GFR after delivery was less than before conception (30 ± 13.8 versus 35 ± 12.2 mL/min/1.73 m2 0.50 ± 0.23 versus 0.58 ± 0.20 mL/s/1.73 m2 ; P < 0.001), but the rate of GFR decrease did not change (0.55 ± 0.8 versus 0.50 ± 0.3 mL/min/mo 0.0092 ± 0.013 versus 0.0083 ± 0.005 mL/s/mo; P = 0.661). Independent of potential confounders, the combined presence of baseline GFR less than 40 mL/min/m2 (<0.67 mL/s/m2 ) and proteinuria with protein greater than 1 g/d, but not either factor alone, predicted faster GFR loss after delivery compared with before conception (1.17 ± 1.23 versus 0.55 ± 0.39 mL/min/mo; difference, 0.62 mL/min/mo; 95% confidence interval CI, 0.27 to 0.96 mL/min/mo 0.020 ± 0.021 versus 0.0092 ± 0.007 mL/s/mo; difference, 0.10 mL/s/mo; 95% CI, 0.005 to 0.016 mL/s/mo). The presence of both risk factors, but not either alone, also predicted shorter time to dialysis therapy or GFR halving (N = 20; hazard ratio, 5.2; 95% CI, 1.7 to 15.9) and low birth weight (N = 29; odds ratio, 5.1; 95% CI, 1.03 to 25.6). Limitations Generalizability to other settings; study power. Conclusion In women with renal insufficiency, the presence of both GFR less than 40 mL/min/1.73 m2 (<0.67 mL/s/m2 ) and proteinuria with protein greater than 1 g/d before conception predicts poor maternal and fetal outcomes.
Background Whether pregnancy impacts on the long-term outcome of immunoglobulin A (IgA) nephropathy is unknown. This study aims to compare the long-term outcome of kidney disease in women with IgA ...nephropathy and preserved kidney function who did and did not become pregnant. Study Design Multicenter longitudinal cohort study. Setting & Participants Women of childbearing age with biopsy-proven IgA nephropathy, serum creatinine level ≤1.2 mg/dL at diagnosis, and minimum follow-up of 5 years after biopsy recruited from 35 nephrology centers participating in a national collaborative study group of pregnancy and kidney disease sponsored by the Italian Society of Nephrology. Predictors Pregnancy, treated as a time-dependent variable; baseline proteinuria; hypertension; and kidney biopsy histologic characteristics. Outcome & Measures Rate of change in estimated creatinine clearance, change in proteinuria, and new-onset hypertension. Results 245 patients were enrolled. Of these, 223 women (136 and 87 in the pregnancy and nonpregnancy groups, respectively) had serum creatinine levels ≤1.2 mg/dL at diagnosis. Baseline data (including age, estimated creatinine clearance, prevalence of hypertension, and histologic grade of kidney damage) were similar between groups with the exception of proteinuria (protein excretion, 1.33 vs 0.95 g/d in the pregnancy vs nonpregnancy groups, respectively; P = 0.03). Kidney function decreased 1.31 mL/min/y (95% CI, 0.99-1.63) during a median follow-up of 10 years (range, 5-31 years) and did not differ between groups. Baseline proteinuria predicted a faster decrease, but did not modify the effect of pregnancy. Pregnancy did not affect changes in proteinuria over time or risk of new-onset hypertension. Limitations Unrecognized or unmeasured factors associated with the decision of becoming pregnant might have influenced results. Conclusions Pregnancy does not seem to affect the long-term outcome of kidney disease in women with IgA nephropathy and preserved kidney function.
Abstract
Background
Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease ...progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome.
Methods
We screened patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction <50% over a 6-month period preceding diagnosis. Data regarding patient features and response to treatment were retrieved.
Results
Of 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years interquartile range (IQR) 64–78 and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15–35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670–2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden’s classification, 6/28 biopsies (21%) were ‘focal’, 1/28 (4%) ‘crescentic’, 9/28 (32%) ‘mixed’ and 12/28 (43%) ‘sclerotic’. At last follow-up (median 32 months, IQR 12–52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT.
Conclusions
AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.
Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil ...cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once.
We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association.
Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths.
The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified.
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