Denis Fouque

Low protein diets for chronic kidney disease in non diabetic adults

BACKGROUNDnFor more than fifty years, low protein diets have been proposed to patients with kidney failure. However, the effects of these diets in preventing severe kidney failure and the need for maintenance dialysis have not been resolved.nnnOBJECTIVESnTo determine the efficacy of low protein diets in delaying the need to start maintenance dialysis.nnnSEARCH STRATEGYnCochrane Renal Group studies register, the Cochrane Central Register of Controlled studies, MEDLINE, and EMBASE. Congress abstracts (American Society of Nephrology since 1990, European Dialysis Transplant Association since 1985, International Society of Nephrology since 1987). Direct contacts with investigators.nnnSELECTION CRITERIAnRandomised studies comparing two different levels of protein intake in adult patients suffering from moderate to severe kidney failure, followed for at least one year.nnnDATA COLLECTION AND ANALYSISnTwo authors independently selected studies and extracted data. Statistical analyses were performed using the random effects model and the results expressed as risk ratio (RR) for dichotomous outcomes with 95% confidence intervals (CI). Collection of the number of renal deaths defined as the need for starting dialysis, the death of a patient or a kidney transplant during the study.nnnMAIN RESULTSnTen studies were identified from over 40 studies. A total of 2000 patients were analysed, 1002 had received reduced protein intake and 998 a higher protein intake. There were 281 renal deaths recorded, 113 in the low protein diet and 168 in the higher protein diet group (RR 0.68, 95% CI 0.55 to 0.84, P = 0.0002). To avoid one renal death, 2 to 56 patients need to be treated with a low protein diet during one year.nnnAUTHORS CONCLUSIONSnReducing protein intake in patients with chronic kidney disease reduces the occurrence of renal death by 32% as compared with higher or unrestricted protein intake. The optimal level of protein intake cannot be confirmed from these studies.

Probiotics and chronic kidney disease

Probiotics are the focus of a thorough investigation as a natural biotreatment due to their various health-promoting effects and inherent ability to fight specific diseases including chronic kidney disease (CKD). Indeed, intestinal microbiota has recently emerged as an important player in the progression and complications of CKD. Because many of the multifactorial physiological functions of probiotics are highly strain specific, preselection of appropriate probiotic strains based on their expression of functional biomarkers is critical. The interest in developing new research initiatives on probiotics in CKD have increased over the last decade with the goal of fully exploring their therapeutic potentials. The efficacy of probiotics to decrease uremic toxin production and to improve renal function has been investigated in in vitro models and in various animal and human CKD studies. However to date, the quality of intervention trials investigating this novel CKD therapy is still lacking. This review outlines potential mechanisms of action and efficacy of probiotics as a new CKD management tool, with a particular emphasis on uremic toxin production and inflammation.

Impact of hypovitaminosis D and alfacalcidol therapy on survival of hemodialysis patients: results from the French ARNOS study.

Background: In chronic kidney disease and dialysis patients, vitamin D deficiency is associated with mortality. In some observational studies, calcitriol analogue therapy was associated with a better survival rate in hemodialysis (HD) patients. The aim of this study was to determine the relationship between serum 25-hydroxyvitamin D (25-OHD) levels and alfacalcidol therapy with HD patients’ outcomes. Methods: We measured baseline 25-OHD levels using a cross-sectional analysis in 648 HD prevalent patients from the regional ARNOS French cohort. A 42-month survival analysis was applied according to serum 25-OHD level and calcitriol analogue therapy. Results: The prevalence of 25-OHD insufficiency <30 ng/ml was high (73%), with only 22% taking native vitamin D supplementation. A baseline 25-OHD level above the median value (18 ng/ml) was associated with lower all-cause mortality [hazard ratio (HR), 0.73 (0.5–0.96); p = 0.02] after adjustment for age, gender, dialysis vintage, calcemia, phosphatemia, cardiovascular disease, and diabetes. Only in monovariate analysis was low-dose oral alfacalcidol therapy associated with a better survival rate in patients with and without 25-OHD deficiency [HR, 0.7 (0.5–0.92); p = 0.05]. Conclusions: Our study shows that, among prevalent HD patients, low 25-OHD levels affect mortality. Alfacalcidol therapy, especially in small doses, may provide compensation, but this needs to be further confirmed using prospective controlled studies comparing native and active vitamin D compounds.

MYOFIBROBLAST: A PROGNOSTIC MARKER AND TARGET CELL IN PROGRESSIVE RENAL DISEASE

Myofibroblasts play an important role in many tissue injuries, and particularly in renal disease. The myofibroblast differentiation is an early event in the development of fibrosis. Myofibroblast-like cells express smooth muscle (SM) cytoskeletal markers (α-SM actin in particular) and participate actively in the production of extracellular matrix. Identification of early risk factors, particularly histological criteria, could be useful to identify patients at risk of progressive renal failure and needing a treatment. The evaluation of myofibroblast differentiation in renal tissue may reflect the intensity of tissue injury, predict long term outcome of chronic renal disease and help physicians to select therapeutic choices. More than a disease activity indicator, myofibroblasts appear to be a pivotal target for future therapies in progressive renal disease.

Mineral and bone disease pattern in elderly haemodialysis patients

BACKGROUNDnAlthough many studies have recently addressed the mineral and bone disorder of chronic kidney disease (CKD-MBD), only limited information is available for elderly dialysis patients.nnnMETHODSnWe prospectively collected serum phosphorus, calcium, parathyroid hormone (PTH), 25(OH) vitamin D, albumin, C-reactive protein, protein intake and CKD-MBD treatments in 9169 maintenance haemodialysis patients in France in June 2008. We then compared biological and treatment patterns in 3403 patients aged 75 or over to their younger counterparts.nnnRESULTSnElderly patients exhibited lower serum phosphorus and parathyroid hormone concentrations (-8 and -18%, respectively) but slightly higher corrected serum calcium levels (+2%) compared to patients aged below 75 years. Elderly patients had higher mean C-reactive protein, lower serum albumin levels and reduced protein intake. Calcium and non-calcium phosphate binders as well as cinacalcet usage and dosage were significantly reduced in elderly patients, with a trend towards lower active vitamin D derivatives usage. Elderly patients were better controlled according to the Kidney Disease Outcome Quality Initiative (K/DOQI) targets compared to patients aged below 75.nnnCONCLUSIONnIn this large 2008 cohort of elderly haemodialysis patients, it appears easier to control serum parameters of CKD-MBD as compared to younger dialysis patients. A better control of serum phosphorus was observed, with less phosphate binder and reduced cinacalcet dosage.

Low protein diets for chronic renal failure in non diabetic adults

BACKGROUNDnFor more than fifty years, low protein diets have been proposed to patients with kidney failure. However, the effects of these diets in preventing severe renal failure and the need for maintenance dialysis have not been resolved.nnnOBJECTIVESnTo determine the efficacy of low protein diets in delaying the need to start maintenance dialysis.nnnSEARCH STRATEGYnMedline and Embase search from January 1966 through to June 1999. Congress abstracts (American Society of Nephrology since 1990, European Dialysis Transplant Association since 1985, International Society of Nephrology since 1987). Direct contacts with investigators.nnnSELECTION CRITERIAnRandomised trials comparing two different levels of protein intake in adult patients suffering from moderate to severe renal failure, followed for at least one year. Diabetic nephropathy patients were excluded.nnnDATA COLLECTION AND ANALYSISnSeven trials were selected from over 40 studies since 1975. A total of 1494 patients were analysed, 753 had received reduced protein intake and 741 a higher protein intake. Collection of the number of renal deaths defined as the need for starting dialysis, the death of a patient or a kidney transplant during the trial.nnnMAIN RESULTSnTwo hundred and forty two renal deaths were recorded, 101 in the low protein diet and 141 in the higher protein diet group, giving an odds ratio of 0.62 with a 95% confidence interval of 0.46 to 0.83 (p=0.006). To avoid one renal death, four to 56 patients need to be treated with a low protein diet during one year.nnnREVIEWERS CONCLUSIONSnReducing protein intake in patients with chronic renal failure reduces the occurrence of renal death by about 40% as compared with higher or unrestricted protein intake. The optimal level of protein intake cannot be confirmed from these studies.

Clinical management of the uraemic syndrome in chronic kidney disease

The clinical picture of the uraemic syndrome is a complex amalgam of accelerated ageing and organ dysfunction, which progress in parallel to chronic kidney disease. The uraemic syndrome is associated with cardiovascular disease, metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and endocrine dysfunction. In this Review, we summarise specific, modern management options for the uraemic syndrome in chronic kidney disease. Although large randomised controlled trials are scarce, based on data from randomised controlled trials and observational studies, as well as pathophysiological reasoning, a therapeutic algorithm can be developed for this complex and multifactorial condition, with interventions targeting several modifiable factors simultaneously.

Calcium carbonate, but not sevelamer, is associated with better outcomes in hemodialysis patients: results from the French ARNOS study.

A favorable survival effect of phosphate binders (PBs) on incident hemodialysis (HD) patients was recently reported, but no definitive advantages of calcium‐based or noncalcium‐based PBs have been demonstrated. The aim of this study was to assess the impact of the prescription of PBs using calcium carbonate (CaCO3) or sevelamer HCl (SV) on survival. Baseline PB prescription was recorded using a cross‐sectional analysis of prevalent HD patients from the regional Association Régionale des Néphrologues OStéodystrophie French cohort. A prospective 42‐month survival analysis study was performed. In July 2005, 1347 HD patients were included. CaCO3, SV, and mixed PBs were prescribed in 55%, 42%, and 24% of cases, respectively, and 26% were not prescribed PBs. Using a Cox proportional model adjusted for several parameters, CaCO3 use was found to be associated with less mortality (HR, 0.64 [0.4–0.78]), but not in the case of SV use (HR, 1.13 [0.92–1.3]). SV prescription was associated with higher mortality than CaCO3 (HR, 1.46 [1.1–1.9]). CaCO3, but not sevelamer prescription, is associated with a favorable effect on survival in a French HD population. This novel result can be partly accounted for by the differences in mineral metabolism disorder management that exist between randomized controlled trials and “real life” conditions.

Association between very low PTH levels and poor survival rates in haemodialysis patients: results from the French ARNOS cohort.

Introduction: A very low parathyroid hormone (PTH) level (VLPL) is associated with an increased risk of adynamic bone disease, vascular calcification, and mortality in haemodialysis (HD) patients. The aim of the study was to assess the frequency, the associated factors, and the prognosis of non-surgical VLPL in a cohort of prevalent HD patients. Methods: In July 2005, a cross-sectional study was performed on the French ARNOS cohort in 1,348 prevalent HD patients from 24 dialysis centres in the Rhône-Alpes area. Patients with a baseline intact PTH level <50 pg/ml (VLPL, Group 1) and ≧50 pg/ml (Group 2) were compared and a 42-month survival analysis was performed. Patients with prevalent or incident parathyroidectomy were excluded. Results: We studied 1,138 prevalent HD patients. As compared to patients of Group 2 (n = 1,019), patients with VLPL (Group 1, n = 119) had lower serum albumin levels (34.5 ± 5 vs. 36.4 ± 5 g/l, p < 0.0001), less protein intake (nPCR 0.99 ± 0.28 vs. 1.1 ± 0.28 g/kg/day, p = 0.01), higher calcaemia (2.30 ± 0.2 vs. 2.26 ± 0.2 mmol/l, p = 0.01) and were more frequently treated with calcium carbonate (67 vs. 54%, p < 0.001). Patients with VLPL had a higher mortality rate (HR: 1.4 (1.07–1.8), p = 0.006) after adjustment for age, gender, diabetes, and dialysis vintage. The odds ratios of mortality for patients with VLPL remained higher in all calcaemia and serum albumin quartiles. Only 3/119 patients in Group 1 did not receive any PTH-lowering therapies (i.e. calcium carbonate (67%), alfacalcidol (38%), cinacalcet (10.1%), and dialysate calcium ≧1.5 mmol/l (94%)). Conclusion: In this observational French cohort, VLPL was observed in 10% of prevalent HD patients and was associated with poor survival rates. An inadequate therapeutic strategy could be responsible for this observation. The real consequences of this iatrogenic adynamic bone disease remain hypothetical, but it may be related to the risk of developing vascular calcification. It is hypothesized that a more adequate strategy, using fewer PTH-lowering therapies in cases of VLPL, may help in improving the poor prognosis.

The systemic nature of CKD

The accurate definition and staging of chronic kidney disease (CKD) is one of the major achievements of modern nephrology. Intensive research is now being undertaken to unravel the risk factors and pathophysiologic underpinnings of this disease. In particular, the relationships between the kidney and other organs have been comprehensively investigated in experimental and clinical studies in the last two decades. Owing to technological and analytical limitations, these links have been studied with a reductionist approach focusing on two organs at a time, such as the heart and the kidney or the bone and the kidney. Here, we discuss studies that highlight the complex and systemic nature of CKD. Energy balance, innate immunity and neuroendocrine signalling are highly integrated biological phenomena. The diseased kidney disrupts such integration and generates a high-risk phenotype with a clinical profile encompassing inflammation, protein–energy wasting, altered function of the autonomic and central nervous systems and cardiopulmonary, vascular and bone diseases. A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can be targeted for CKD prevention and therapy.