Emmanuel Villar

Age and comorbidity may explain the paradoxical association of an early dialysis start with poor survival

Starting patients on dialysis early has been increasing in incidence in several countries. However, some studies have questioned its utility, finding a counter-intuitive effect of increased mortality when dialysis was started at a higher estimated glomerular filtration rate (eGFR). To examine this issue in more detail we measured mortality hazard ratios associated with Modification of Diet in Renal Disease eGFR at dialysis initiation for 11,685 patients from the French REIN Registry, with sequential adjustment for a number of covariates. The eGFR was analyzed both quantitatively by 5-ml/min per 1.73 m(2) increments and by demi-decile (i.e., 5 percentiles of the distribution); the 15th demi-decile, including values around 10 ml/min per 1.73 m(2), was our reference point. The patients more likely to begin dialysis at a higher eGFR were older male patients; had diabetes, cardiovascular diseases, or low body mass index and level of albuminemia; or were started with peritoneal dialysis. During a median follow-up of 21.9 months, 3945 patients died. The 2-year crude survival decreased from 79 to 46%, with increasing eGFR from less than 5 to over 20 ml/min per 1.73 m(2). Each 5-ml/min/1.73 m(2) increase in eGFR was associated with a 40% increase in crude mortality risk, which weakened to 9%, but remained statistically significant after adjusting for the above covariates. Analysis by demi-decile showed only the highest to be at significantly higher risk. Hence we found that age and patient condition strongly determine the decision to start dialysis and may explain most of the inverse association between eGFR and survival.

Effect of Age, Gender, and Diabetes on Excess Death in End-Stage Renal Failure

Life expectancy is short in elderly individuals with end-stage renal failure (ESRF). This study aimed to compare mortality in patients with ESRF versus the general population (GP) to assess the evolution of excess mortality by age, gender, nephropathy, and dialysis modality after first dialysis. All incident adult dialysis patients from January 1,1999, to December 31, 2003, who lived in Rhône-Alpes Region (France) were included and followed up to death or December 31, 2005. Standardized mortality ratios (SMR) in comparison with GP were computed in the first to the fifth years after first dialysis. In the whole cohort (3025 incident patients), SMR decreased during these 5 yr from 7.4 to 5.2 (P = 0.002). In the 18- to 44-, 45- to 64-, 65- to 74-, 75- to 84-, and > or =85-yr-old groups, SMR decreased from 26.7 to 6.2 (P = 0.01), from 12.8 to 8.1 (P = 0.03), from 8.6 to 5.6 (P = 0.051), from 7.1 to 4.5 (P = 0.02), and from 3.5 to 1.2 (P = 0.14), respectively. Among age categories, differences were significant in the first 3 yr (P < 0.05). SMR were higher 1.5-fold in women than in men in the first 4 yr (P < 0.05). In patients with diabetic nephropathy (DN), SMR increased during the first 3 yr (P = 0.045) and were higher than in patients without DN in the second, third, and fourth years (P < 0.05). SMR were higher in the peritoneal dialysis than in the hemodialysis group in the fourth year (P < 0.01). Patients with ESRF have a high excess mortality compared with the GP. Older patients with ESRF experienced less excess mortality. ESRF cancels out womens survival advantage noted in the GP. SMR evolution in patients with DN was different from that in patients without DN.

Mycophenolate Mofetil Monotherapy in Membranous Nephropathy: A 1-Year Randomized Controlled Trial

BACKGROUND Treatment of patients with membranous glomerulonephritis (MGN) is controversial because of the lack of clear benefit of the immunosuppressive regimens on patient or renal survival. The objective of this study is to evaluate the efficacy and safety of mycophenolate mofetil (MMF) for patients with MGN. STUDY DESIGN 1-year prospective, randomized, and controlled clinical trial. SETTING & PARTICIPANTS 36 patients with biopsy-proven idiopathic MGN and nephrotic syndrome. INTERVENTION 19 patients received MMF (2 g/d) for 12 months and 17 patients were in the control group. All patients had the same conservative treatment based on renin-angiotensin blockers, statins, low-salt and low-protein diet, and diuretics in case of edema. OUTCOMES & MEASUREMENTS End points were the mean proteinuria over creatinuria ratio in mg/g throughout the study and numbers of complete and partial remissions at 1 year (month 12). Data were analyzed on an intention-to-treat analysis. RESULTS Mean proteinuria over creatinuria ratio was stable in both groups throughout the study (P = 0.1). Mean proteinuria over creatinuria ratio was 4,690 +/- 2,212 mg/g in the MMF group and 6,548 +/- 4,601 mg/g in the control group (95% confidence interval of the difference, -619 to +4,247; P = 0.1). Remission was complete in 3 patients (1 in the MMF group, 2 in the control group; P = 0.5) and partial in 11 patients (6 in the MMF group, 5 in the control group; P = 0.9). The probability of complete or partial remission did not differ between the 2 groups after 12 months (relative risk, 0.92; 95% confidence interval, 0.48 to 1.75; P = 0.7). Kidney function was stable in the 2 groups according to estimated glomerular filtration rate and serum creatinine level. LIMITATIONS The small number of patients and short follow-up prevent generalizations. CONCLUSIONS A 12-month regimen of MMF did not decrease mean proteinuria over creatinuria ratio or increase partial and complete remissions. Serious adverse effects were observed in 4 patients (20%) receiving MMF.

Survival advantage of hemodialysis relative to peritoneal dialysis in patients with end-stage renal disease and congestive heart failure

Peritoneal dialysis (PD) has been proposed as a therapeutic option for patients with end-stage renal disease and associated congestive heart failure (CHF). Here, we compare mortality risks in these patients by dialysis modality by including all patients who started planned chronic dialysis with associated congestive heart failure and were prospectively enrolled in the French REIN Registry. Survival was compared between 933 PD and 3468 hemodialysis (HD) patients using a Kaplan-Meier model, Cox regression, and propensity score analysis. The patients were followed from their first dialysis session and stratified by modality at day 90 or last modality if death occurred prior. There was a significant difference in the median survival time of 20.4 months in the PD group and 36.7 months in the HD group (hazard ratio, 1.55). After correction for confounders, the adjusted hazard ratio for death in PD compared to the HD patients remained significant at 1.48. Subgroup analyses showed that the results were not changed with regard to the New York Heart Association stage, age strata, or estimated glomerular filtration rate strata at first renal replacement therapy. The use of propensity score did not change results (adjusted hazard ratio, 1.55). Thus, mortality risk was higher with PD than with HD among incident patients with end-stage renal disease and congestive heart failure. These results may help guide clinical decisions and also highlight the need for randomized clinical trials.

A new approach for measuring gender disparity in access to renal transplantation waiting lists.

Background Gender inequity in access to renal transplantation waiting lists, in favor of men, has long since been demonstrated in a number of studies. Discrepancies between the results of the available studies might be explained by different analytical approaches or different national contexts. In this study we analyzed French end-stage renal disease registry data using a novel model to determine whether the female gender is associated with a lower probability of being listed on the transplant waiting list or with a longer time from dialysis start until registration, or both. Methods The effect of gender on access to the national renal transplantation waiting list was assessed in 9497 men and 5386 women aged 18 to 74 years who started dialysis between 2002 and 2009. We used a semiparametric regression cure model adjusted for age, work status, and 11 comorbidities or disabilities. Results Women were younger and less likely to work or have associated comorbidities. At the study endpoint, 33.8% of the men and 34.1% of the women were placed on the renal transplantation waiting list. After taking potential confounders into account, our model shows that women demonstrated a lower probability of being registered on the national transplant waiting list (odds ratio=0.69; 95% confidence interval, 0.62–0.78) and a longer time from dialysis start to registration (hazard ratio=0.89; 95% confidence interval, 0.84–0.95) than men. This disparity affects predominantly older women who do not work or have diabetes and is more pronounced in some geographic areas. Conclusions These poorly understood gender-based inequities require further consideration.

Trends in the epidemiology and care of diabetes mellitus-related end-stage renal disease in France, 2007–2011

Aims/hypothesisThe aim was to study geographic variations and recent trends in the incidence of end-stage renal disease (ESRD) by diabetes status and type, and in patient condition and modalities of care at initiation of renal replacement therapy.MethodsData from the French population-based dialysis and transplantation registry of all ESRD patients were used to study geographic variations in 5,857 patients without diabetes mellitus, 227 with type 1 diabetes mellitus, and 3,410 with type 2. Trends in incidence and patient care from 2007 to 2011 were estimated.ResultsAge- and sex-adjusted incidence rates were higher in the overseas territories than in continental France for ESRD unrelated to diabetes and related to type 2 diabetes, but quite similar for type 1 diabetes-related ESRD. ESRD incidence decreased significantly over time for patients with type 1 diabetes (−10% annually) and not significantly for non-diabetic patients (0.2%), but increased significantly for patients with type 2 diabetes (+7% annually until 2009 and seemingly stabilised thereafter). In type 2 diabetes, the net change in the absolute number was +21%, of which +3% can be attributed to population ageing, +2% to population growth and +16% to the residual effect of the disease. Patients with type 2 diabetes more often started dialysis as an emergency (32%) than those with type 1 (20%) or no diabetes.Conclusions/interpretationThe major impact of diabetes on ESRD incidence is due to type 2 diabetes mellitus. Our data demonstrate the need to reinforce strategies for optimal management of patients with diabetes to improve prevention, or delay the onset, of diabetic nephropathy, ESRD and cardiovascular comorbidities, and to reduce the rate of emergency dialysis.

The Impact of Type 2 Diabetes on Mortality in End-Stage Renal Disease Patients Differs between Genders

Background/Aims: In diabetics with end-stage renal disease (ESRD), risk of death has been reported to be non-constant after the first dialysis, and different outcomes have been observed between genders. We assessed the impact of type 2 diabetes (T2DM) on mortality in dialysis regarding its differential effect by gender using time-dependent analyses. Methods: All T2DM and non-diabetic (no-DM) patients who started dialysis in two renal units in Lyon, France, between January 1, 1995, and December 31, 2007, were included. In multivariate analyses, the Cox model and Shoenfeld residual approach were used to assess the effect of T2DM on dialysis mortality by gender. Results: We included 235 T2DM (males: 57.9%) and 480 no-DM (males: 65.6%) patients. In males, the adjusted hazard ratio (aHR) for death in T2DM versus no-DM was 0.83 (p = 0.20) and was constant over time after the first renal replacement therapy (RRT) (p = 0.88). In females, aHR for death in T2DM versus no-DM patients was not constant over time (p = 0.002). It was 0.64 (p = 0.13) within the first year after the first RRT and 2.10 (p = 0.002) after the first year. Evolutions with time of these aHR by gender were significantly different (p = 0.009). Conclusions: T2DM was associated with death only in females. This association was not constant over time after the first dialysis.

Anemia normalization in patients with type 2 diabetes and chronic kidney disease: results of the NEPHRODIAB2 randomized trial

STATEMENTS OF THE PROBLEM Correction of anemia in type 2 diabetes (T2DM) patients with chronic kidney disease stages 3-4 may slow the decline of kidney function but may increase cardiovascular risk through higher hematocrit. The NEPHRODIAB2 study was designed to assess efficacy and safety of complete hemoglobin (Hb) normalization in these patients. METHODS We randomly assigned 89 T2DM patients with an estimated glomerular filtration rate (eGFR; abbreviated 175 Modification of Diet in Renal Disease formula) of 25 to 60 ml/min per 1.73 m(2) and moderate anemia (Hb, 100-129 g/l) to a target Hb value in subnormal range (110-129g/l, group 1, n=43) or normal range (130-149 g/l, group 2, n=46). The primary end point was eGFR decline after 2 years of follow-up. Secondary end points included iron and erythropoietin dosage, quality of life (Medical Outcomes Study 36-item Short-Form Health Survey scores) and adverse events. RESULTS Six months after randomization, the mean Hb levels were <120 g/l in group 1 and >130 g/l in group 2 (P<.05 at 6, 12, 18 and 24 months). Blood pressure, 24-h proteinuria and HbA1c did not differ during follow-up (P>.05). Two-year declines in eGFR were -8.7±12.2 in group 1 and -5.1±7.8 ml/min per 1.73 m(2) in group 2 (P=.29). Mean weekly use of erythropoietin was 7.8±11.6 μg in group 1 and 30.1±33.6 μg in group 2 (P<.0001). There was no significant difference regarding Medical Outcomes Study 36-item Short-Form Health Survey score change or adverse event occurrence. CONCLUSIONS In this trial, normalization of Hb level in T2DM patients with chronic kidney disease was safe but did not significantly slow renal function decline and increased treatment cost due to erythropoietin use.

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

Background The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. Methods 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. Results 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model. Conclusions Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Evaluation and determinants of underprescription of erythropoiesis stimulating agents in pre-dialysis patients with anaemia.

Background: Inadequate anaemia correction (haemoglobin (Hb) <11 g/dl without receiving an erythropoiesis-stimulating agent (ESA) is common in pre-dialysis patients, but little is known about its determinants. We used data from the French end-stage renal disease (ESRD) registry to investigate these determinants and the patients’ anaemia status 1 year after starting dialysis. Methods: Pre-dialysis anaemia care was studied in 6,271 incident ESRD patients from 13 regions, who were first treated between 2003 and 2005. Data included pre-dialysis Hb measure and ESA use, patient’s condition and modalities of dialysis initiation. Anaemia status at 1 year was studied in 925 patients from four regions who started dialysis in 2003 and 2004, were still on dialysis one year later, and had completed the annual registry data form. Results: Overall, 34.7% of the patients had inadequate pre-dialysis anaemia correction, with variations across regions from 21.1 to 43.2%. Inadequate anaemia correction decreased from 38.0% in 2003 to 33.2% in 2005. It was less likely in patients with diabetic or polycystic kidney disease and more likely in those with malignancy, unplanned haemodialysis, and low glomerular filtration rate or low serum albumin at dialysis initiation. One year after starting dialysis, inadequate correction concerned only 2.6% of the patients. Hb level had risen from 10.3 g/dl in pre-dialysis to 11.7 g/dl, but remained lower in those with inadequate pre-dialysis correction. Conclusion: Despite improvement over time, inadequate correction with ESAs remains high in pre-dialysis patients in contrast with those on dialysis. As the timing of dialysis initiation is uncertain, continuous management of anaemia is requested.