Relative prognostic impact of nutrition, anaemia, bone metabolism and cardiovascular comorbidities in elderly haemodialysis patients.

BACKGROUND: The prognostic impact of nutrition and chronic kidney disease (CKD) complications has already been described in elderly haemodialysis patients but their relative weights on risk of death remain uncertain. Using structural equation models (SEMs), we aimed to model a single variable for nutrition, each CKD complication and cardiovascular comorbidities to compare their relative impact on elderly haemodialysis patients' survival. METHODS: This prospective study recruited 3165 incident haemodialysis patients ≥75 years of age from 178 French dialysis units. Using SEMs, the following variables were computed: nutritional status, anaemia, mineral and bone disorder and cardiovascular comorbidities. Systolic blood pressure was also used in the analysis. Survival analyses used Poisson models. RESULTS: The population average age was 81.9 years (median follow-up 1.51 years, 35.5% deaths). All variables were significantly associated with mortality by univariate analysis. Nutritional status was the variable most strongly associated with mortality in the multivariate analysis, with a negative prognostic impact of low nutritional markers {incidence rate ratio [IRR] 1.42 per 1 standard deviation [SD] decrement [95% confidence interval (CI) 1.32-1.53]}. The 'cardiovascular comorbidities' variable was the second variable associated with mortality [IRR 1.19 per 1 SD increment (95% CI 1.11-1.27)]. A trend towards low intact parathyroid hormone and high serum calcium and low values of systolic blood pressure were also associated with poor survival. The variable 'anaemia' was not associated with survival. CONCLUSIONS: These findings should help physicians prioritize care in elderly haemodialysis patients with CKD complications, with special focus on nutritional status.

Achievement of 2009 and 2017 Kidney Disease: Improving Global Outcomes mineral and bone targets and survival in a French cohort of chronic kidney disease Stages 4 and 5 non-dialysis patients.

BACKGROUND: The aim of the third French Phosphorus and Calcium Observatory (Photo-Graphe® 3) was to assess the achievement of international Kidney Disease: Improving Global Outcomes (KDIGO) recommendations on optimal serum phosphate, calcium and parathyroid hormone (PTH) levels and possible associations with mortality in patients with chronic kidney disease (CKD). METHODS: This was a prospective, observational study conducted with nephrologists in France who were selected using a clustering approach. Adult patients with non-dialysis Stage 4 or 5 CKD and no kidney graft history were eligible. Data about clinical events, serum biochemistry and treatment were collected every 6 months for 2.5 years and 12 months thereafter. The Kaplan-Meier method was used for survival analysis and Cox proportional hazards model for identification of factors associated with survival. RESULTS: Overall, 566 CKD Stage 4 patients (men, 56%) and 153 CKD Stage 5 patients (men, 62%) were included. In Stage 4, only 14-15% patients achieved the three main 2009 KDIGO targets during the first 2 years and 22% at 2.5 years. In Stage 5 patients, the proportion remained <6% throughout. The percentages of patients achieving the three main 2017 KDIGO targets were slightly higher at each time point. Overall, 14% of Stage 4 and 10% of Stage 5 patients died in the observation period. Only age and haemoglobin level were significantly associated with risk of all-cause mortality. CONCLUSIONS: Few CKD patients achieved KDIGO mineral targets. Increased mortality risk was linked to older age and lower haemoglobin level, but not to serum calcium, phosphate or PTH targets.

[Management of bone and mineral metabolism disorders before the dialysis stage remains still perfectible. Data from the French Phosphorus and Calcium Survey Photo-Graphe]. / La prise en charge des troubles du métabolisme minéral et osseux avant le stade de la dialyse reste encore perfectible. À partir des données de l'Observatoire national du métabolisme minéral et osseux Photo-Graphe.

Only limited data is available on the management of the chronic kidney disease-associated bone and mineral metabolism disorder (CKD-MBD) in the pre-dialysis stages of CKD in France. A better knowledge of current management habits could lead to an improvement in the implementation of international recommendations (KDIGO). The 3rd version of the French Phosphorus and Calcium Survey Photo-Graphe (Sanofi) included a cohort of CKD stages 4 and 5 patients, whose aim was to examine the prevalence of CKD-MBD and the quality of its management in patients under the care of 62 nephrologists from over 20 geographical regions in France. The study started in October 2011, i.e. one year after patient enrollment. We examined in particular the percentage of patients presenting with laboratory parameter abnormalities indicative of CKD-MBD who were not receiving adequate treatment. A total of 456 patients with CKD stage 4 and 154 with CKD stage 5 were studied. Their mean age was 72.9±14.2 years, and male/female ratio was 58/42. KDIGO targets of serum PTH for CKD stages 4 and 5 were not achieved in respectively 80 and 84% of the patients, for serum calcium in 8 and 22% and for serum phosphate in 12 and 46%. As a potential explanation, insufficient therapy was estimated to account for respectively 45 and 60% of insufficiently controlled secondary hyperparathyroidism, and for 36% of persistent hyperphosphatemia in stage 5. It should be noted that 55.5 and 57.5% of patients were receiving native vitamin D. In this national observatory, the management of CKD-MBD stages 4 and 5 appears suboptimal, especially as regards the control of secondary hyperparathyroidism, which remained untreated in nearly 50% of the patients. Hyperphosphatemia was also common and inadequately controlled in CKD stage 5. To improve the management of CKD-MBD, nephrologists need to be more aware of the importance of aiming for recommended laboratory targets and how this can be achieved.

Multiphasic effects of blood pressure on survival in hemodialysis patients.

Dialysis patients exhibit an inverse, L- or U-shaped association between blood pressure and mortality risk, in contrast to the linear association in the general population. We prospectively studied 9333 hemodialysis patients in France, aiming to analyze associations between predialysis systolic, diastolic, and pulse pressure with all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular endpoints for a median follow-up of 548 days. Blood pressure components were tested against outcomes in time-varying covariate linear and fractional polynomial Cox models. Changes throughout follow-up were analyzed with a joint model including both the time-varying covariate of sequential blood pressure and its slope over time. A U-shaped association of systolic blood pressure was found with all-cause mortality and of both systolic and diastolic blood pressure with cardiovascular mortality. There was an L-shaped association of diastolic blood pressure with all-cause mortality. The lowest hazard ratio of all-cause mortality was observed for a systolic blood pressure of 165 mm Hg, and of cardiovascular mortality for systolic/diastolic pressures of 157/90 mm Hg, substantially higher than currently recommended values for the general population. The 95% lower confidence interval was approximately 135/70 mm Hg. We found no significant correlation for either systolic, diastolic, or pulse pressure with myocardial infarction or nontraumatic amputations, but there were significant positive associations between systolic and pulse pressure with stroke (per 10-mm Hg increase: hazard ratios 1.15, 95% confidence interval 1.07 and 1.23; and 1.20, 1.11 and 1.31, respectively). Thus, whereas high pre-dialysis blood pressure is associated with stroke risk, low pre-dialysis blood pressure may be both harmful and a proxy for comorbid conditions leading to premature death.

Low parathyroid hormone status induced by high dialysate calcium is an independent risk factor for cardiovascular death in hemodialysis patients.

Here we studied a possible association between low parathyroid hormone (PTH) status and mortality in incident patients undergoing hemodialysis . A total of 1983 patients were included at baseline and prospectively followed for 24 months. Patients were classified according to their Kidney Disease: Improving Global Outcomes PTH status at baseline and at 12 months, and mortality evaluated at 12 to 24 months using adjusted Cox analysis. Factors potentially involved in PTH status variability between baseline and 12 months were analyzed. A decrease in serum PTH from normal or high to low values between baseline and 12 months was associated with significantly increased cardiovascular mortality at 12 to 24 months (hazard ratio, 2.03; 95% confidence interval, 1.22-3.36). For patients with high or normal baseline PTH levels, the main independent factor at 6 months for a decrease to low PTH levels at 12 months was high dialysate calcium (1.75 mmol/L), whereas prescription of non-calcium-based phosphate binders was associated with a lower risk of PTH decrease. In the high cardiovascular (CV) mortality risk subgroup of patients who acquired a low PTH status at 12 months, the main independent factor at 12 months associated with significant 12- to 24-month CV mortality was high dialysate calcium (odds ratio, 5.44; 95% CI, 2.52-11.75). Thus, patients with a serum PTH decrease to low values after 1 year of hemodialysis treatment are at high risk of short-term CV death. High dialysate calcium was an important contributor to PTH oversuppression, and continued use was associated with increased CV mortality.

[Changes in mineral and bone disorder management in a French cohort of hemodialysis patients between 2008 and 2012: The National Bone and Mineral Metabolism observatory (Photo-Graphe 2 and 3)]. / Évolution de la prise en charge des troubles minéraux et osseux des patients hémodialysés en France entre 2008 et 2012 : Observatoire national du métabolisme minéral et osseux.

INTRODUCTION: Chronic kidney disease progressively induces a disorder of mineral and bone metabolism (CKD-MBD) which also leads to cardiovascular abnormalities. Previous studies showed that only few hemodialysis patients had serum calcium, phosphate and parathyroid hormone levels within the K/DOQI (Kidney-Disease Outcomes Quality Initiative) targets of 2003. Our aim was to identify the impact of different therapeutic strategies and that of the KDIGO (Kidney-Disease: Improving Global Outcomes) targets of 2009 on the control of CKD-MBD. PATIENTS AND METHODS: The French calcium and phosphate observatory monitors the mineral metabolism of patients with CKD at the local, regional and national level every six months. We compared the data recorded in June 2008 (n=1914 patients) with those collected in October 2012 (n=2481) for patients aged 18 years or more, who started hemodialysis therapy within the last 12 months. RESULTS: As compared with 2008, in 2012 fewer patients had hyperphosphatemia (55.1 % versus 64.7 %), hypocalcemia (35.5 % versus 40.3 %) and hyperparathyroidism (9.8 % versus 10.1 %) according to the KDIGO guideline, and more had hypophosphatemia (9.6 % versus 6.5 %), hypercalcemia (3.9 % versus 2.2 %) and hypoparathyroidism (31.5 % versus 25.8 %) (P<0.001, P<0.001 and P=0.002 respectively for differences in serum phosphate, calcium and PTH levels). Mean (± standard deviation [SD]) serum 25 OH vitamin D levels increased by 1.6-fold, from 48.3±42.6 nmol/L in 2008 to 76.6±45.8 nmol/L in 2012. Between 2008 and 2012, the prescription of native vitamin D derivatives and sevelamer (HCl or carbonate) increased whereas that of cinacalcet, lanthanum carbonate, calcium-chelating agents and active vitamin D derivatives decreased. CONCLUSION: Despite a slight improvement of biochemical CKD-MBD parameters in the observation period only few patients reached the three KDIGO targets (11.5 % in 2012 versus 11.1 % in 2008).

Control of mineral metabolism and bone disease in haemodialysis patients: which optimal targets?

BACKGROUND: There is a high drug treatment burden on patients receiving long-term dialysis therapy. Abnormalities of calcium and phosphate metabolism are associated with increased mortality, and attempts to correct these disturbances may improve survival. METHODS: We prospectively evaluated the targets of the currently used Kidney Disease: Improving Global Outcomes (KDIGO) guidelines in 8377 prevalent patients receiving intermittent haemodialysis therapy in France from July 2007 to December 2009. RESULTS: Adjusted Cox analyses showed that only one among six targets was predictive of mortality, i.e. a serum intact parathyroid hormone (iPTH) <130 pg/mL. A continuous risk analysis using fractional polynomials showed a 10% increase in hazard ratio (HR) for mortality for a serum phosphate <0.71 (2.2) and >1.98 (6.14) mmol/L (mg/dL), a non-corrected serum calcium <1.59 (6.37) and >2.41 (9.66) mmol/L (mg/dL) and a serum iPTH <100 and >1090 pg/mL. CONCLUSION: The findings of our observational study confirm the existence of a grey zone, in which precise biochemical targets are difficult to define, with the exception of avoiding extreme values. Given the absence of intervention trials proving the clinical usefulness of phosphorus control, and pending the results of large clinical trials on the effect of optimal PTH and calcium control on hard outcomes, the present findings may help to refine future recommendations for the treatment of chronic haemodialysis patients.

Mineral and bone disease pattern in elderly haemodialysis patients.

BACKGROUND: Although 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. METHODS: We 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. RESULTS: Elderly 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. CONCLUSION: In 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.

[Mineral and bone status in French maintenance hemodialysis patients: a comparison of June 2005 and June 2008]. / Evolution de la prise en charge de la maladie osseuse et minérale des patients hémodialysés en France entre juin 2005 et juin 2008.

INTRODUCTION: Because of the high associated morbi-mortality, phosphate and calcium disorders remain a major therapeutic challenge for nephrologists. Previous studies showed that only few patients had serum calcium, phosphate and parathyroid hormone within Kidney-Disease Outcomes Quality Initiative (K/DOQI) targets. PATIENTS AND METHODS: The French calcium and phosphate observatory monitors mineral metabolism at local, regional and national level and its follow-up every six months since 2005. More than 200 nephrologists collected more than 9000 patients' data. We compared the results recorded in June 2005 with those collected in June 2008. RESULTS: As compared with June 2005, in June 2008 fewer patients were hypercalcemic according to the K/DOQI targets (-26.2%, p<0.001) and hyperphosphatemic (-16.5%, p<0.001), more patients were hypocalcemic (+45.5%, p<0.001) and hypophosphatemic (+8.8%, p<0.02). A greater number of patients had elevated serum PTH above 300ng/l (+17.6%, p<0.001) and fewer had a PTH lower than 150ng/l (-25.4%, p<0.001). Serum 25OH vitamin D level was 21.7+/-20.0microg/l in June 2008. Overall, 10.5% of patients met all three K/DOQI targets, an improvement compared with June 2005 (6.8%, p<0.001). Between 2005 and 2008, cinacalcet, lanthane carbonate and native vitamin D derivatives prescription increased whereas calcium-based phosphate binders, sevelamer-HCL and active vitamin D derivatives decreased. CONCLUSION: Despite a significant improvement between 2005 and 2008, only few patients reach the three K/DOQI targets (10.5%) in 2008. The prospective biannual follow-up during three years will allow us to identify the impact of different treatments on calcium and phosphate metabolic control and patient's survival.

[Position statements regarding usage of biosimilars of Epoetins. Position paper of the Société de néphrologie, Société francophone de dialyse, and Société de néphrologie pédiatrique]. / Recommandations d'utilisation des biosimilaires de l'érythropoïétine (EPO). Propositions de la Société de néphrologie, de la Société francophone de dialyse et de la Société de néphrologie pédiatrique.

The European patents for epoetin alpha recently expired. Biosimilars (i.e. "a medicine which is similar to a biological medicine that has already been authorized" [EMEA 2007]) of epoetins have thus been released on the market in Europe. Because of the complexity of the processes that are required to produce medicinal products containing biotechnology-derived proteins as active substances and to characterize the physicochemical properties of these compounds, the guidelines that have been developed for generic drugs cannot be used for approval of biosimilar products. The EMEA guidelines do not answer all questions that have been raised for the development of biosimilars, and in some cases, decisions will have to be taken at a national level. This is why the Society of Nephrology (Société de néphrologie), the French-speaking Society of Dialysis (Société francophone de dialyse) and the Pediatric Society of Nephrology (Société de néphrologie pédiatrique) established guidelines for the usage of biosimilar epoetins concerning approval, identification, substitution of an innovator drug, post-marketing surveillance, extension of indication and pharmacovigilance plan.

Regional variations of low-density lipoprotein oxidizability in hemodialysis patients may explain discrepancies in interventional therapy on oxidative profile.

BACKGROUND/AIMS: This study aimed at evaluating oxidative stress (OS) markers (i) in a cross-sectional study of hemodialysis (HD) patients to investigate potential regional effects of these markers and (ii) in a prospective crossover study to evaluate vitamin E-coated membrane (VE) effects. METHODS: At baseline, OS parameters including low-density lipoprotein (LDL) oxidizability were measured in HD patients from five dialysis facilities. Patients were then randomly assigned to two treatment groups: group I patients (n = 33) switching to VE, and group II patients (n = 29) still using reference polysulfone (PS) membrane. After 3 months, patients were switched from VE to PS and vice versa for 6 months. The same OS parameters were measured after each period. RESULTS: At baseline, the cross-sectional analysis of LDL oxidizability showed a regional effect. By contrast, the crossover study did not show beneficial effects of VE on this parameter. CONCLUSION: Regional variations of LDL oxidizability in HD patients exist and may explain discrepancies in interventional therapy on OS.

Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet.

Protein-restricted diets are prescribed in patients with chronic renal failure (CRF) to alleviate uremic symptoms and to slow the progression of CRF. The potential deleterious effects of protein restriction on nutritional status and clinical outcome of patients with CRF have raised concern. In this study, data were collected from 1985 to 1998 on 239 consecutive patients (age 50.2 +/- 15.6 yr) with advanced CRF (GFR 13.1 +/- 4.8 ml/min) to whom a supplemented very low protein diet (SVLPD) providing 0.3 g protein, 35 kcal, and 5 to 7 mg of inorganic phosphorus per kg per day was administered for a mean duration of 29.6 +/- 25.1 mo. The diet was supplemented with essential amino acids and ketoanalogs, calcium carbonate, iron, and multivitamins. During SVLPD, protein intake decreased from 0.85 +/- 0.23 to 0.43 +/- 0.11 g/kg per d, and body mass index and serum albumin concentration remained unchanged overall. Fourteen patients died during SVLPD; death was unrelated to nutritional parameters. Hemodialysis was initiated after SVLPD in 165 patients at a mean GFR of 5.8 +/-1.5 ml/min. During an average of 54 mo on hemodialysis, mortality was low (2.4% after 1 yr) and correlated to age only, not to nutritional parameters observed at the end of SVLPD. Similar results were obtained in 66 transplanted patients (12 were not dialyzed before transplantation). SVLPD can be safely used in patients with CRF without adverse effects on the clinical and nutritional status of the patients. Due to the preservation of nutritional status and the correction of uremic symptoms, the initiation of dialysis was deferred in these patients. The outcome of patients on renal replacement therapy is not affected by prior treatment with SVLPD during the predialysis phase of CRF.