Validation of the international IgA nephropathy prediction tool in a French cohort beyond 10 years after diagnosis.

INTRODUCTION: The International IgA Nephropathy Network developed a tool (IINN-PT) for predicting the risk of end-stage renal disease (ESRD) or a 50% decline in the estimated glomerular filtration rate (eGFR). We aimed to validate this tool in a French cohort with longer follow-up than previously published validation studies. METHODS: The predicted survival of patients with biopsy-proven immunoglobulin A nephropathy (IgAN) from the Saint Etienne University Hospital cohort was computed with IINN-PT models with or without ethnicity. The primary outcome was the occurrence of either ESRD or a 50% decline in eGFR. The models' performances were evaluated through c-statistics, discrimination and calibration analysis. RESULTS: There were 473 patients with biopsy-proven IgAN, with a median follow-up of 12.4 years. Models with and without ethnicity showed areas under the curve (95% confidence interval) of 0.817 (0.765; 0.869) and 0.833 (0.791; 0.875) and R2D of 0.28 and 0.29, respectively, and an excellent discrimination of groups of increasing predicted risk (P < .001). The calibration analysis was good for both models up to 15 years after diagnosis. The model without ethnicity exhibited a mathematical issue of survival function after 15 years. DISCUSSION: The IINN-PT provided good performances even after 10 years post-biopsy as showed by our study based on a cohort with a longer follow-up than previous cohorts (12.4 versus <6 years). The model without ethnicity exhibited better performances up to 15 years but became aberrant beyond this point due to a mathematical issue affecting the survival function. Our study sheds light on the usefulness of integrating ethnicity as a covariable for prediction of IgAN course.

Prognostic Value of Serum Biomarkers of Autoimmunity for Recurrence of IgA Nephropathy after Kidney Transplantation.

A prognostic biomarker for IgA nephropathy (IgAN) recurrence after renal transplant is lacking. We followed 96 consecutive first renal transplant recipients with native kidney IgAN (79 men; 92 deceased donors; mean age =48.1 years) on calcineurin inhibitor-based immunosuppression over 10 years for death, allograft failure, and clinicopathologic recurrence (CPR; clinically evident and biopsy-proven). Using time-dependent Cox regression analysis and receiver operating characteristic curves, we assessed prognostic significance of levels of galactose-deficient IgA1 (Gd-IgA1; autoantigen) and Gd-IgA1-specific IgG and IgA autoantibodies in serum obtained at time of transplant or native-kidney IgAN diagnosis (30 patients only). Overall, 13 patients died, 34 kidneys failed (17 due to CPR), and 34 patients developed CPR after a mean interval of 5.8 years. Compared with healthy controls (n=30), patients had significantly elevated serum Gd-IgA1 levels at diagnosis and transplant, but levels did not associate with any outcome. Patients also had significantly elevated levels of normalized (but not total) serum Gd-IgA1-specific IgG autoantibodies at diagnosis and transplant, and the level at transplant associated with higher risk of CPR (relative risk, 2.68; 95% confidence interval, 1.26 to 5.71; P=0.01; area under the receiver operating characteristic curve, 0.62; 95% confidence interval, 0.51 to 0.74; P=0.05). Normalized Gd-IgA1-specific IgG autoantibody level remained an independent risk factor for CPR in multivariate analysis. Serum Gd-IgA1-specific IgA autoantibody level did not change between diagnosis and transplant or predict outcome. This study emphasizes post-transplant prognostic value of normalized serum IgG antiglycan autoantibody level in patients with IgAN.

Validation of the absolute renal risk of dialysis/death in adults with IgA nephropathy secondary to Henoch-Schönlein purpura: a monocentric cohort study.

BACKGROUND: We established earlier the absolute renal risk (ARR) of dialysis/death (D/D) in primary IgA nephropathy (IgAN) which permitted accurate prospective prediction of final prognosis. This ARR was based on the potential presence at initial diagnosis of three major, independent, and equipotent risk factors such as hypertension, quantitative proteinuria≥1 g per day, and severe pathological lesions appreciated by our local classification scoring≥8 (range 0-20). We studied the validity of this ARR concept in secondary IgAN to predict future outcome and focused on Henoch-Schönlein purpura (HSP) nephritis. METHODS: Our cohort of adults IgAN concerned 1064 patients with 101 secondary IgAN and was focused on 74 HSP (59 men) with a mean age of 38.6 at initial diagnosis and a mean follow-up of 11.8 years. Three major risk factors: hypertension, proteinuria≥1 g/d, and severe pathological lesions appreciated by our global optical score≥8 (GOS integrated all elementary histological lesions), were studied at biopsy-proven diagnosis and their presence defined the ARR scoring: 0 for none present, 3 for all present, 1 or 2 for the presence of any 1 or 2 risk factors. The primary end-point was composite with occurrence of dialysis or death before (D/D). We used classical statistics and both time-dependent Cox regression and Kaplan-Meier survival curve methods. RESULTS: The cumulative rate of D/D at 10 and 20 years post-onset was respectively 0 and 14% for ARR=0 (23 patients); 10 and 23% for ARR=1 (N=19); 27 and 33% for ARR=2 (N=24); and 81 and 100% (before 20 y) in the 8 patients with ARR=3 (P=0.0007). Prediction at time of diagnosis (time zero) of 10y cumulative rate of D/D event was 0% for ARR=0, 10% for ARR=1, 33% for ARR=2, and 100% by 8.5y for ARR=3 (P=0.0003) in this adequately treated cohort. CONCLUSION: This study clearly validates the Absolute Renal Risk of Dialysis/Death concept in a new cohort of HSP-IgAN with utility to individual management and in future clinical trials.

The podocin mutation R229Q and early recurrence (within the first year) of glomerular disease after renal transplantation.

BACKGROUND: Podocin is a key protein involved in the pathogenesis of steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis (FSGS) and is characterized by a high rate of early recurrence after renal transplantation (RTx) in children and adults. MATERIAL AND METHODS: We studied 206 RTx adult recipients: 187 with a diagnosis of glomerular nephropathy, GN (biopsy-proven in 149, clinical in 38), plus 19 with unknown diagnosis as original kidney disease (OKD), the NPHS2 gene polymorphism, G755A, and correlated with the presence of early recurrence of OKD within the first year (proteinuria over 1 g/day and graft-biopsy proven). RESULTS: The A allele podocin gene mutation frequency was 3.4% (14/412) overall - 7.1% (4/56) in FSGS as expected, but surprisingly 5.7% (6/106) in IgA nephropathy. Fifty recipients (24.3%) developed proteinuria >1 g/d, with 12 recipients demonstrating early clinico-pathological recurrence by 1 year (5.8%) with 5/28 in FSGS, 2/53 in IgAN, 2/14 in membranoproliferative GN (with 1 graft loss within the first year), 1/19 in crescentic GN, 1/19 in unknown disease, and 1/38 in clinical GN. Only 2 recurrent patients (both with FSGS) had the R229Q podocin mutation (16.7%). CONCLUSIONS: The podocin mutation R229Q may play a role in the pathogenesis of FSGS and in early recurrence after transplantation, but does not allow accurate prediction of recurrence or the associated potential for prevention.

Predicting the risk for dialysis or death in IgA nephropathy.

For the individual patient with primary IgA nephropathy (IgAN), it remains a challenge to predict long-term outcomes for patients receiving standard treatment. We studied a prospective cohort of 332 patients with biopsy-proven IgAN patients followed over an average of 13 years. We calculated an absolute renal risk (ARR) of dialysis or death by counting the number of risk factors present at diagnosis: hypertension, proteinuria ≥1 g/d, and severe pathologic lesions (global optical score, ≥8). Overall, the ARR score allowed significant risk stratification (P < 0.0001). The cumulative incidence of death or dialysis at 10 and 20 years was 2 and 4%, respectively, for ARR=0; 2 and 9% for ARR=1; 7 and 18% for ARR=2; and 29 and 64% for ARR=3, in adequately treated patients. When achieved, control of hypertension and reduction of proteinuria reduced the risk for death or dialysis. In conclusion, the absolute renal risk score, determined at diagnosis, associates with risk for dialysis or death.

Natural history of primary IgA nephropathy.

Primary IgA nephropathy (IgAN) is the most frequent type of primary glomerulonephritis worldwide. The characteristic presentation is gross hematuria at the time of an infectious episode. A renal biopsy still is mandatory for the diagnosis. The natural history of the disease is characterized by clinical and pathologic progression over time, which can vary from a few years to more than 50 years. It is possible to make a broad prediction at the time of diagnosis of the long-term (20 years) risk of progressive chronic kidney disease, and then to end-stage renal disease requiring renal replacement therapy (20-year cumulative end-stage renal disease risk range, 14%-39%). The 3 major independent risk factors are arterial hypertension, proteinuria more than 1 g/d, and severe renal histopathologic lesions including hyalinosis, crescents, or defined by histopathologic scoring systems. When any clinical risk factors are present, patients should be targeted closely by appropriate treatments in the following order: (1) precise control of hypertension, (2) control of proteinuria when persisting for greater than 1 g/d, and (3) evidence-based treatment where available for severe lesions. This is a symptomatic treatment strategy because pathogenesis and etiology still remain unclear.