Eric Alamartine

Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses.

To clarify the risk factors for chronic renal failure in idiopathic IgA glomerulonephritis (IgA-GN), we performed a dual study on 282 patients using both standard univariate statistical methods and the multivariate regression model of Cox. During a follow-up ranging from 1 to 36 years, with a mean of 8 years, 18% of the patients (50/282) had gone into chronic renal failure (CRF), with 18 of them in end-stage renal disease (ESRD) (6%). The univariate comparison of patients with CRF versus patients without CRF showed multiple risk factors: mainly arterial hypertension, an amount of proteinuria, nephrotic syndrome, a high level of serum IgA, presence of HLA-B35 antigen, and the intensity of most pathological lesions on light microscopy. The actuarial survival rate for a normal renal function (serum creatinine less than 135 mumol/L [1.5 mg/dL]) was 84% at 10 years and 64% at 20 years. The multivariate study allowed the isolation of only four risk factors with a significant effect on survival rate. These were the amount of proteinuria, the global optical score on first renal biopsy, the presence of an initial hypertension, and the presence of the HLA-B35 antigen. From these results, the probability of renal survival for individual patients may be calculated and a high-risk subgroup defined. Our data confirm the greater usefulness of multivariate over univariate statistical analyses in finding risk factors for CRF in IgA-GN.

Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis

Experimental evidence suggests a role for obesity in the formation and progression of some glomerular lesions, but data for human glomerulonephritis are lacking. In a cohort of 162 incident patients with biopsy-proven immunoglobulin A (IgA) nephropathy, we assessed whether the presence of an elevated body mass index (BMI >/= 25 kg/m(2)) at the time of the first renal biopsy (RB1) correlated with clinical data at RB1 (24-hour proteinuria, arterial hypertension, and renal function), pathological data (global optical score [GOS] with detailed pathological indices), and clinical progression to both arterial hypertension and chronic renal failure (CRF). In both univariate and multivariate analyses, the presence of an elevated BMI at RB1 was significantly associated with the severity of pathological renal lesions (GOS and vascular, tubular, and interstitial indices). Hypertension-free survival was significantly less in overweight patients (P: < 0.0001) compared with those with normal weight. In a Cox regression analysis for hypertension-free survival including 24-hour proteinuria greater than 1 g, GOS, and metabolic parameters, only elevated BMI and GOS were independent factors for the development of arterial hypertension. CRF-free survival was also significantly less in patients with an excessive BMI. In a multivariate Cox regression analysis for CRF-free survival, hypertension, GOS, and BMI at RB1 were independent risk factors for CRF. In IgA nephropathy, excessive body weight and/or BMI are underestimated predictive factors for the development of arterial hypertension and, ultimately, CRF.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression

Background. The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. Methods. This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1–2 mg/kg per day. Results. At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P =0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P =0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P =0.009), leukopenia (37.3% vs. 9.5%, P <0.001), fever (25.2% vs. 10.1%, P =0.001), herpes simplex (17.9% vs. 5.7%, P =0.001), and thrombocytopenia (11.3% vs. 3.2%, P =0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). Conclusion. Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

The Use of the Oxford Classification of IgA Nephropathy to Predict Renal Survival

BACKGROUND AND OBJECTIVES A new classification for IgA nephropathy was recently proposed, namely the Oxford classification. It established specific pathologic features that predict the risk of progression of renal disease. This classification needs validation in different patient populations. We propose a retrospective study to evaluate the predictive value of the Oxford classification on renal survival defined by doubling creatinine or end-stage renal disease in patients with IgA nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We included 183 patients with primary IgA nephropathy diagnosed between 1994 and 2005. Mean follow-up time was 77 months. Doubling creatinine occurred in 20% of the patients, and end-stage renal disease occurred in 16%. The biopsies were revisited to apply the Oxford classification. The influence of pathologic features on renal survival was analyzed in univariate and multivariate models. RESULTS In univariate time-dependent analyses, tubular atrophy/interstitial fibrosis, segmental glomerulosclerosis, and endocapillary hypercellularity strongly impacted doubling creatinine or end-stage renal disease. On the contrary, mesangial hypercellularity was not associated with renal outcome. In the multivariate model, only estimated GFR at baseline was a risk factor, pathologic lesions having no independent influence. CONCLUSIONS We confirm the usefulness of the Oxford classification to establish the renal prognosis of patients with IgA nephropathy, although renal function at baseline seems to be of a greater importance than pathologic lesions.

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.

Post-Transplantation Lymphoproliferative Disorder After Kidney Transplantation: Report of a Nationwide French Registry and the Development of a New Prognostic Score

PURPOSE Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a French nationwide population of adult kidney recipients over 10 years. PATIENTS AND METHODS A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses. RESULTS Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 μmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients. CONCLUSION This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.

A randomized prospective study comparing low-dose OKT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients

Abstract Acute steroid‐resistant rejection episodes in kidney allograft recipients require treatment with antilymphocyte antibodies. Monoclonal anti‐CD3 and polyclonal antilymphocyte antibodies have been widely used but seldom compared. Recent data have suggested that these antibodies could be used at reduced doses without jeopardizing their efficacy. In this study, we randomized renal transplant recipients who encountered a first acute steroid‐resistant rejection episode to low‐dose ATG or low‐dose OKT3 treatment. Sixty patients were enrolled in the study. They received prophylactic immunosuppression with cyclosporin, azathioprine, and prednisolone. Treatment of biopsy‐proven rejection consisted of a 10–day course of either ATG (n= 31) or OKT3 (n= 29). The total ATG dose was 484 ± 110 mg, i.e., 0.75 mg/kg per day. The total OKT3 dose was 32 ± 4 mg, i. e., 0.05 mg/kg per day. We compared reversion of rejection, side effects, immunodepression, and graft function. Reversion of rejection was similar in the two groups, although we noted a trend in favor of ATG. Results were 3% vs 10% early graft failures, 13% vs 23% overall graft failures, 28% vs 38% 3‐month actuarial incidence of rebound rejection, and 89% vs 81% 1‐year graft survival rate in the ATG and OKT3 groups, respectively. Tolerance was worse in the OKT3 group due to the first‐dose syndrome. Infections and cancers occurred with the same frequency. ATG resulted in a deeper and longer decrease in peripheral lymphocyte subsets. Graft function was similar in the two groups. We conclude that low‐dose ATG and low‐dose OKT3 are equally effective in reversing steroid‐resistant acute rejection. Tolerance was better with ATG, which also gave a more potent and longlasting immunodepression. The use of reduced doses of ATG and OKT3 did not appear to lessen their efficacy.

Significant Risk Factors for Occurrence of Cancer After Renal Transplantation: A Single Center Cohort Study of 1265 Cases

Occurrence of cancer after renal transplantation remains a major problem, and the second cause of death. We performed a retrospective analysis of first cancer, first skin cancer, and first organ cancer (including posttransplant lymphoproliferative disease [PTLD]) among 1265 cases from 1979 to 2006. The occurrence of cancer was clearly a time-dependent event justifiying the use of Kaplan-Meier survival and Cox regression methods. The 10-year cumulative incidences of first cancer, first skin cancer, and first organ cancer were 24.6%, 14.5%, and 14.5%, respectively. Recipient age was a major, independent risk factor for the 3 endpoints with a 6% increased relative risk for each year increment (P < .0001). Female gender was also a major, independent risk factor, but only for skin cancer (P = .0002). We could not demonstrate any difference between the immunosuppressive drugs used for induction or maintenance therapy, especially between antithymocyte globulin (ATG) vs anti-CD25, cyclosporine vs tacrolimus, and azathioprine vs mycophenolate mofetil. Large cohorts are needed with strict stratifications for recipient age and gender to detect any difference, if any, among the drugs.

Cystatin C-based equations in renal transplantation: moving toward a better glomerular filtration rate prediction?

Creatinine-based glomerular filtration rate (GFR) estimators perform poorly in renal transplant recipients. Cystatin C might be a better alternative to serum creatinine in assessing renal graft function. We compared several cystatin C-based equations with the modification diet renal disease (MDRD) equation in 120 adult renal transplant recipients for whom the GFR was measured by the gold standard inulin clearance. Mean inulin-measured GFR was 52.6 mL/min/1.73 m2 (range, 13–119). The Hoek, Rule, Le Bricon, and Filler cystatin C-based formulas showed significantly better performances (accuracy 30% of 82%, 81%, 78%, and 71%), than the MDRD equation (58%, Mac Nemar test, P<0.01). Sensitivity to detect a GFR below 60 mL/min/1.73 m2 was significantly higher for the Hoek and the Rule equations (0.95, 95% CI 0.91–1) than for the MDRD equation (0.76, 95% CI 0.67–0.85). These data confirm that cystatin C as a GFR marker offers significant advantages over creatinine in renal transplantation.

MDRD versus CKD-EPI equation to estimate glomerular filtration rate in kidney transplant recipients.

Background The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-based equation was developed to address the systematic underestimation of the glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease (MDRD) Study equation in patients with a relatively well-preserved kidney function. The performance of the new equation for kidney transplant recipients is discussed. Methods We analyzed the performances of the CKD-EPI equation in comparison with the MDRD Study equation in 825 stable kidney transplant recipients. Bias, precision, and accuracy within 30% of true GFR were determined. GFR was measured by urinary clearance of inulin (n=488) and plasma clearance of 51Cr-EDTA (n=337). Results Mean measured GFR (mGFR) was 50±19 mL/min/1.73 m2. On the whole cohort, bias was significantly lower for MDRD Study equation compared with CKD-EPI creatinine. This superiority translates into a better accuracy (80% and 74% for the MDRD and CKD-EPI creatinine, respectively). The best performance of the MDRD Study equation is confirmed both in the subgroups of patients with mGFR <60 mL/min/1.73 m2 and between 60 and 90 mL/min/1.73 m2. For mGFR >90 mL/min/1.73 m2, there were no significant differences between the two equations in terms of performance. Conclusions The CKD-EPI creatinine equation does not offer a better GFR prediction in renal transplant patients compared with the MDRD Study equation, even in the earlier CKD stages.