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.

Repeat renal biopsy improves the Oxford classification-based prediction of immunoglobulin A nephropathy outcome.

BACKGROUND: The prognosis of IgA nephropathy (IgAN) is very heterogeneous. Predicting the nature and the rate of the disease progression is crucial for refining patient treatment. The aim of this study was to evaluate the prognostic impact of an Oxford classification-based repeat kidney tissue evaluation to predict end-stage renal disease (ESRD). METHODS: Patients with biopsy-proven primary IgAN who underwent two renal biopsies at our centre were analyzed retrospectively. Renal biopsies were scored by two pathologists blinded to the clinical data and according to the updated Oxford classification. Cox models were generated to evaluate the prognostic impact considering the Oxford classification elementary lesions from the first (Model 1) or the second (Model 2) biopsy, adjusted on clinical data at time of reevaluation. The prognostic impacts of the dynamic evolution of each elementary lesion between biopsies were also assessed through univariate and multivariate evaluation. RESULTS: A total of 168 adult patients were included, with a median follow-up duration of 18 (range 11-24) years. The second biopsy was performed either systematically (n = 112) of for-cause (n = 56), after a median time of 5.4 years. The prognostic performances of Model 2 (second biopsy) were significantly better than Model 1 (first biopsy, analysis of deviance P < 0.0001). The dynamic changes of C and T lesions were significantly associated with the progression toward ESRD after adjustment on variables from Model 2. CONCLUSION: Both static and dynamic Oxford-based histological evaluation offered by a repeat biopsy improves the prediction of ESRD in patients with IgAN.

Evaluation of the efficacy of an interdialytic "ethanol 40% v/v - enoxaparin 1000 U/mL" lock solution to prevent tunnelled catheter infections in chronic hemodialysis patients: a multi-centre, randomized, single blind, parallel group study.

BACKGROUND: Tunnelled dialysis catheter (TC) infections are a major health complication and are associated with increased antibiotic consumption, hospital stays, health costs and mortality. Experimental data provide evidence that Ethenox, a mixture of enoxaparine 1000 U/mL in 40% v/v ethanol, could be a promising lock solution. The aim of the study is to compare an interdialytic lock solution of Ethenox with reference lock solutions, unfractionated heparin (UFH) or citrate 4% for the prevention of TCI in hemodialysis patients. METHOD: This study will monitor a multicentre, prospective, single blind, randomized, controlled, parallel group trial. The main inclusion criteria are patients > 18 years old with end-stage renal disease, treated with chronic hemodialysis/hemodiafiltration three times a week, with incident or prevalent non-impregnated internal jugular TCs inserted for at least 2 weeks and able to give informed consent. Exclusion criteria are TCI in the previous 4 weeks and anti-infective treatment for TCI in the previous 2 weeks. Patients will be randomized to receive either study treatment Ethenox in the intervention group or reference solutions in the control group, unfractionated heparin (UFH) or citrate 4% w/v according to usual practice. The primary outcome measure will be time to first TCIs assessed by an endpoint adjudication committee blinded to the study arm according to predefined criteria. Patients will receive the study treatment for up to 12 months. Intention-to-treat analysis of the primary endpoint will be performed with a marginal Cox proportional hazard model. Prospective power calculations indicate that the study will have 90% statistical power to detect a clinical significant two-fold increase in median infection-free survival if 200 patients are recruited into each arm over a period of 24 months. DISCUSSION: Firm evidence of the efficacy of the Ethenox lock in preventing TCI could be of major clinical benefit for patients. The results of this study will allow the development of new guidelines based on a high level of evidence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03083184 , date of registration March 17 2017 and European Clinical Trials Database Identifier: EudraCT 2016-A00180-51), date of registration July 11 2016.

Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy.

Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H-related genes 1 and 3 (CFHR3,1Δ) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Δ genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients' medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Δ We did not detect an association between CFHR3,1Δ and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Δ did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Δ genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.

Anti-phospholipase A2 receptor antibody levels at diagnosis predicts spontaneous remission of idiopathic membranous nephropathy.

Background: The diagnostic role of circulating anti-phospholipase A2 receptor antibodies (anti-PLA2R Abs) is now well recognized in idiopathic membranous nephropathy (iMN). These Abs could also be interesting as predictors of clinical outcome. In this study, we explored the prognostic value of anti-PLA2R Abs measured in a cohort of iMN patients, with a special focus on their ability to detect patients achieving spontaneous remission. Methods: All adult patients with biopsy-proven iMN diagnosed between 1978 and 2007 were retrospectively screened in our centre. Using a validated enzyme-linked immunosorbent assay, levels of anti-PLA2R Abs were measured from serum samples obtained at the time of renal biopsy and stored at -80°C until processing. Clinical data on disease activity, treatments and outcomes were collected by reviewing patients' medical records. The association between anti-PLA2R Ab titres and clinical activity/outcome was assessed by Cox proportional hazard and Kaplan-Meier methods. Results: In this retrospective study, 68 patients were included in the final analysis (median follow-up of 81 months). No significant association was found between anti-PLA2R Ab titres at diagnosis with baseline proteinuria, baseline estimated glomerular filtration rate or chronic kidney disease progression. Spontaneous remission was observed in 22% of patients. Ab titres were significantly and gradually correlated in a dose-response manner with the likelihood of spontaneous remission. Conclusions: While Ab titres measured at diagnosis were not found to predict the activity of iMN, evaluation of anti-PLA2R Ab titres might prove useful in the early identification of patients likely to achieve spontaneous remission.

Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.

Large cohort studies suggest that high convective volumes associated with online hemodiafiltration may reduce the risk of mortality/morbidity compared to optimal high-flux hemodialysis. By contrast, intradialytic tolerance is not well studied. The aim of the FRENCHIE (French Convective versus Hemodialysis in Elderly) study was to compare high-flux hemodialysis and online hemodiafiltration in terms of intradialytic tolerance. In this prospective, open-label randomized controlled trial, 381 elderly chronic hemodialysis patients (over age 65) were randomly assigned in a one-to-one ratio to either high-flux hemodialysis or online hemodiafiltration. The primary outcome was intradialytic tolerance (day 30-day 120). Secondary outcomes included health-related quality of life, cardiovascular risk biomarkers, morbidity, and mortality. During the observational period for intradialytic tolerance, 85% and 84% of patients in high-flux hemodialysis and online hemodiafiltration arms, respectively, experienced at least one adverse event without significant difference between groups. As exploratory analysis, intradialytic tolerance was also studied, considering the sessions as a statistical unit according to treatment actually received. Over a total of 11,981 sessions, 2,935 were complicated by the occurrence of at least one adverse event, with a significantly lower occurrence in online hemodiafiltration with fewer episodes of intradialytic symptomatic hypotension and muscle cramps. By contrast, health-related quality of life, morbidity, and mortality were not different in both groups. An improvement in the control of metabolic bone disease biomarkers and ß2-microglobulin level without change in serum albumin concentration was observed with online hemodiafiltration. Thus, overall outcomes favor online hemodiafiltration over high-flux hemodialysis in the elderly.

Identifying Hemodialysis Patients With the Highest Risk of Staphylococcus aureus Endogenous Infection Through a Simple Nasal Sampling Algorithm.

In contrast to Staphylococcus aureus intermittent nasal carriers, persistent ones have the highest risk of infection. This study reports the usefulness of a simple nasal sampling algorithm to identify the S. aureus nasal carriage state of hemodialysis patients (HPs) and their subsequent risk of infection.From a cohort of 85 HPs, 76 were screened for S. aureus nasal carriage once a week during a 10-week period. The S. aureus nasal load was quantified by using either culture on chromogenic medium or fully automated real-time polymerase chain reaction assay. Molecular typing was used to compare strains from carriage and infection.The algorithm based on quantitative cultures was able to determine the status of S. aureus nasal carriage with a sensitivity of 95.8%, a specificity of 94.2%, a positive predictive value of 88.5%, and a negative predictive value of 98.0%. Of note, the determination of the S. aureus carriage state was obtained on the first nasal sample for all the 76 HPs, but 1 (98.7%). The algorithm based on quantitative polymerase chain reaction assay directly from the specimen yielded similar performances. During the 1-year follow-up after the last sampling episode, HPs classified as persistent nasal carriers with the algorithm were found to have a higher risk of S. aureus infection than those classified as nonpersistent carriers (P < 0.05), especially for infections of endogenous origin (P < 0.001).This simple algorithm is reliable for determining the S. aureus nasal carriage status in clinical practice and could contribute to characterize at an early stage of take-up patients with the highest risk of S. aureus infection.

[Survey among French dialysis practitioners about the screening and decolonization of nasal Staphylococcus aureus carriage in dialysis patients]. / Enquête auprès des néphrologues français sur les pratiques de dépistage et de décolonisation du portage nasal de Staphylococcus aureus des patients dialysés chroniques.

Staphylococcus aureus nasal carriage is frequent in dialysis patients and is associated with an increased risk of staphylococcal infections in this population. Data from the literature showed that decolonization of S. aureus nasal carriers in hemodialysis and peritoneal dialysis reduce S. aureus catheter-related infections. During the last national congress of nephrology, a survey was conducted among volunteer dialysis physicians to evaluate their practice about screening and decolonization of S. aureus nasal carriage among their patients. Only 30 participants (45.5% [30/66]) declared to screen S. aureus nasal carriage in patients of hemodialysis and 59.6% (31/52) in peritoneal dialysis. Participants declared to decolonize their patients before insertion of a vascular catheter in 55.8% of cases. This small study would need to be completed by a national survey.

Serum cystatin C is a determinant of central pressure augmentation index measured by oscillometric method in renal transplant recipients.

BACKGROUND: Serum cystatin C (ScysC) may help predicting cardiovascular outcome not only through its ability to detect renal dysfunction but also through its potential connection to others factors that are directly related to cardiovascular diseases. We explored the potential association of ScysC with arterial stiffness--a major contributor to cardiovascular disease--in renal transplant recipients (RTR). METHODS: Traditional and non-traditional cardio-vascular risk factors were collected from 215 stable RTR whom arterial stiffness was evaluated by the measure of the augmentation index of central pressure (AIx) determined by the arteriograph device. Serum creatinine and ScysC were measured the same day using standardized methods. Association between ScysC and AIx was examined in univariate and multivariate linear regression analysis. RESULTS: In univariate analysis, ScysC was strongly associated with AIx. This relationship was not confounded by age, gender, length of time spent on dialysis and transplantation vintage. Adjustment on the level of GFR estimated by the MDRD Study equation attenuated but did not abolish the association between ScysC and AIx. CONCLUSIONS: In conclusion, ScysC is an independent predictor of AIx in RTR. Our data suggest that arterial stiffness may partially mediate the association between ScysC and cardiovascular risk in renal transplantation.

Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis.

Heparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standard-of-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standard-of-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.

[Telemedicine: an unfruitful experience of tele-expertise in nephrology]. / Télémédecine : une expérience infructueuse de télé-expertise en néphrologie.

INTRODUCTION: We developed a new system of medical tele-expertise to improve detection and care of chronic renal failure by way of a better communication between general practitioners and specialists. It has been known for long that the incidence of chronic renal failure is increasing while cost of its treatment is very high. Unfortunately, late referral of patients with kidney diseases remains around 30%. Our goal was to help physicians to get access to nephrologists, hence to improve the cure of renal diseases. An early treatment of nephropathies may avoid the evolution to the stage of dialysis. METHODS: We created a website with the technical support of the firm Unimedecine. It allowed a secure and fast exchange of medical data, all about the case of a one patient. RESULTS: General practitioners seemed enthusiastic, but at the end, only a few of them did use the website. The number of connexion remained low throughout a 3-year experience. Questions were about advices but no progressive nephropathy was discovered. The cost of the website was a prohibitive 75 000 euros for 3 years. Therefore, we had no choice that to close the experience. DISCUSSION: Telemedicine needs juridical rules and specific finances to work on a long run.

Long-term kinetic of T-lymphocyte subsets in kidney-transplant recipients: influence of anti-T-cell antibodies and association with posttransplant malignancies.

A low CD4 lymphocyte count has been associated with skin and nonskin cancers in kidney transplant recipients (KTR) and might be a useful prediction tool. We analyzed the serial measurements of CD4 and CD8 lymphocytes to study the influence of immunosuppressants and look for a possible predictive value of lymphocyte count for the occurrence of cancer. In 250 successive KTR, blood lymphocytes were labeled for CD4 and CD8 count, prior transplantation, at month 3 and 6 and each year thereafter, throughout a 10-year observation period. The kinetics of lymphocyte subsets were compared in regard to treatments, cancer and confounding factors. ATG were responsible of an early and long lasting impairment in CD4 cells. Patients with a cancer and especially those with multiple tumors, presented with less CD4 cells throughout the observation period, but ATG were not directly associated to the occurrence of tumors. An early low CD4 count was of poor predictive value for the occurrence of cancer.

Predicting glomerular filtration rate in kidney transplantation: are the K/DOQI guidelines applicable?

The kidney disease outcomes quality initiative (K/DOQI) guidelines introduced a classification of chronic kidney disease (CKD) based on the level of kidney function. In order to predict the glomerular filtration rate (GFR), they specifically recommended the use of the modification of diet in renal disease (MDRD) study and Cockcroft-Gault (C-G) equations. Since the performance of these estimates has been questioned, we sought to determine whether these recommendations might be applicable in renal transplantation. Following the K/DOQI methodology, we compared the GFR estimated by the MDRD and C-G equations with 476 inulin clearances performed in 284 renal transplant recipients. Even though the MDRD equations provided a better prediction than C-G formula, none of them reached the level of accuracy required by the K/DOQI standards. At least, 25% of the calculated GFR gave a prediction beyond 30% of the corresponding inulin clearance value. In addition, when classified according to their predicted GFR, less than two-thirds of the transplant patients turned out to be assigned to the correct stage of CKD. We conclude that, in renal transplantation, the predictive performance of both C-G and MDRD study equations appears to be particularly impaired and may potentially compromise the validity of the K/DOQI guidelines if implemented in their current form.

[Rash and nephrotic syndrome: consider syphilis]. / Eruption et syndrome néphrotique, penser à la syphilis.

INTRODUCTION: Kidney disease is among the clinical manifestations of secondary syphilis, as this case report shows. OBSERVATION: During serologically confirmed secondary syphilis, a 63-year-old man developed a nephrotic syndrome diagnosed after biopsy as membranous nephropathy. DISCUSSION: Membranous nephropathy is an immunological complication of secondary syphilis. Recovery usually follows treatment. It is often associated with signs that may erroneously suggest connective tissue disease.

G protein beta3 subunit C825T polymorphism in primary IgA nephropathy.

BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism has been associated with increased signal transduction, increased activity of the kidney Na+/H+ exchanger, and also with late-onset essential hypertension. Hypertension is a strong independent risk factor for progression in IgA nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989 to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to 303 local Caucasian controls matched for the male predominance (214 males). The technique used was a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers, followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2% in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015). The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97; P= 0.05). This data indicated that this polymorphism had a significant but mild influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In contrast, we could not demonstrate any significant and sustained difference in the clinical presentation and evolution of the homozygous TT patients compared to non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The progression to arterial hypertension or to chronic renal failure or to end-stage renal failure (ESRF) was not significantly different. In addition, multivariate Cox regression analysis excluded a significant independent role of C825T polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgAN, but played no significant role in the progression of the disease.

Assessing renal graft function in clinical trials: can tests predicting glomerular filtration rate substitute for a reference method?

BACKGROUND: In clinical trials, comparison of renal graft function needs a rigorous determination of glomerular filtration rate (GFR). Since reference methods to measure GFR cannot be easily implemented, a number of tests predicting GFR are usually used. However, little is known about their validity in renal transplant patients. We aimed to compare the performances of six GFR tests with inulin clearance in this population. METHODS: Five hundred consecutive inulin clearances performed in 294 renal transplant recipients with stable renal function were retrospectively selected. For each of them, we computed six estimates: the 24-hour creatinine clearance, the Cockcroft-Gault, Walser, Jelliffe, Nankivell, and Levey formulas. Their respective performance was assessed by correlation (simple linear regression), accuracy (dispersion of true error), and agreement (Bland and Altman method). RESULTS: Each GFR test closely correlated with inulin clearance (P < 0.0001). Comparisons between pairs of GFR tests did not show any significant difference in accuracy between the Levey, Jelliffe, and Walser formulas. Conversely, each of these formulas demonstrated a significant lower dispersion (P < 0.005) than the others. Nevertheless, all GFR tests displayed considerable lack of agreement with limits of agreement over 40 mL/min/1.73 m2 apart. The proportion of predicted GFR differing from inulin clearance by +/- 10 mL/min/1.73 m2, ranged from 34% for the Jelliffe formula to 53% for the Nankivell's one. CONCLUSION: None of these formulas seems to be able to safely substitute for inulin clearance. In clinical trials, renal graft function should be preferably assessed using a reference method of GFR measurement.

Contrast medium-induced acute renal failure and cholesterol embolism after radiological procedures: incidence, risk factors, and compliance with recommendations.

BACKGROUND: After radiological procedures, the incidence of acute renal failure varies greatly, and cholesterol embolism may not always be recognized. Little, if anything, is known about whether recommendations for the prevention of either complication are correctly implemented. METHODS: We performed a prospective epidemiological study in a large population (n=809) of consecutive inpatients in a university hospital. The patients were monitored for risk factors, ongoing medications, and details of preventive measures and of radiological procedures. Contrast nephropathy was defined as a 25% rise in serum creatinine. Cholesterol embolism was defined by the presence of two typical signs. We analyzed the incidence, risk factors, and prevention of contrast nephropathy and cholesterol embolism. RESULTS: The most frequent procedure that our patients underwent was cardiac angiography (50%). The incidence of contrast nephropathy was 7%. We confirmed the classical risk factors (diabetes, dose of contrast medium, and renal insufficiency) and added potentially nephrotoxic medications as an independent risk factor. Fluid therapy, commonly proposed in high-risk patients, was adequately carried out in only 12% of patients. The incidence of cholesterol embolism was 4%, with 10% renal involvement. Arteriosclerosis and renal insufficiency were risk factors, but anticoagulation therapy was not. CONCLUSION: Adequate fluid therapy and discontinuation of nephrotoxic medications should be more systematically implemented in the prevention of contrast nephropathy. Recognition of cholesterol embolism is crucial.