The safety of a low protein diet in older adults with advanced chronic kidney disease.

BACKGROUND: A low protein diet (LPD) is recommended to patients with advanced chronic kidney disease (CKD), whereas geriatric guidelines recommend a higher amount of protein. The aim of this study was to evaluate the safety of LPD treatment in older adults with advanced CKD. METHODS: The EQUAL study is a prospective, observational study, including patients ≥65 years, incident estimated glomerular filtration rate <20 ml/min/1.73m², in six European countries with follow-up up till six years. Nutritional status was assessed by 7-point subjective global assessment (SGA) every 3-6 months. Prescribed diet (gram protein/kilogram/bodyweight) was recorded on every study visit; measured protein intake was available in three countries. Time to death and decline in nutritional status (SGA decrease by ≥2 points) were analysed using marginal structural models with dynamic inverse probability of treatment and censoring weights. RESULTS: Out of 1738 adults (631 prescribed LPD at any point during follow-up) there were 1319 with repeated SGA measurements of which 267 (20%) declined in SGA ≥ 2 points and 565 (32.5%) died. There was no difference in survival or decline in nutritional status for patients prescribed LPD ≤0.8 g/kg ideal bodyweight (Odds Ratio (OR) for mortality 1.15 (95% Confidence interval (CI) 0.86-1.55) and OR for decline in SGA 1.11 (95% CI 0.74-1.66) in the adjusted models. In patients prescribed LPD <0.6 g/kg ideal bodyweight, the results were similar. There was a significant interaction with LPD and higher age >75 years, lower SGA, and higher comorbidity burden for both mortality and nutritional status decline. CONCLUSIONS: In older adults with CKD approaching end-stage kidney disease, a traditional LPD prescribed and monitored according to routine clinical practice in Europe appears to be safe.

Association of Longitudinal High-Sensitivity Troponin T With Mortality in Patients With Chronic Kidney Disease.

BACKGROUND: Cardiac troponin T (cTnT) is associated with mortality in chronic kidney disease (CKD). However, the association between longitudinal cTnT measurements and survival has not previously been assessed. OBJECTIVES: This study determined whether various parameterizations of longitudinal cTnT measurements were associated with patient survival in the older population with advanced CKD. METHODS: The EQUAL (European QUALity) study is an observational prospective cohort study that includes subjects with stage 4-5 CKD aged ≥65 years and not on dialysis. The study includes 176 participants in Sweden, where longitudinal information of cTnT was collected. The study uses joint models for longitudinal and time-to-event data to assess the longitudinal association between cTnT and survival. RESULTS: There were 927 cTnT measurements (median 6 per patient) collected over a median follow-up of 2.4 years. The overall 5-year survival was 57% (95% CI: 46%-69%). Longitudinally measured cTnT was associated with mortality risk, with every SD increase in cTnT, at any time point, associated with a 3.3-fold increase in mortality risk (HR: 3.3; 95% CI: 2.5-4.6). The slope of the cTnT trajectory was also associated with increased mortality risk (HR: 3.2; 95% CI: 2.0-6.0), as was the area under the cTnT trajectory (HR: 4.2; 95% CI: 2.6-7.2), which reflected the cumulative cTnT exposure. CONCLUSIONS: Longitudinally measured cTnT is independently associated with mortality risk in older patients with stage 4 and 5 CKD, which suggests that monitoring patients with cTnT could be a valuable tool for the identification of subjects with a high mortality risk.

Patient-Reported Measures and Lifestyle Are Associated With Deterioration in Nutritional Status in CKD Stage 4-5: The EQUAL Cohort Study.

OBJECTIVE: The aim of this study was to explore the changes in nutritional status before dialysis initiation and to identify modifiable risk factors of nutritional status decline in older adults with advanced renal disease. DESIGN AND METHODS: The European Quality Study on treatment in advanced chronic kidney disease (EQUAL) is a prospective, observational cohort study involving six European countries. We included 1,103 adults >65 years with incident estimated glomerular filtration rate <20 mL/min/1.73 m2 not on dialysis, attending nephrology care. Nutritional status was assessed with the 7-point Subjective Global Assessment tool (7-p SGA), patient-reported outcomes with RAND-36 and the Dialysis Symptom Index. Logistic regression was used to estimate the associations between potential risk factors and SGA decline. RESULTS: The majority of the patients had a normal nutritional status at baseline, 28% were moderately malnourished (SGA ≤5). Overall, mean SGA decreased by -0.18 points/year, (95% confidence interval -0.21; -0.14). More than one-third of the study participants (34.9%) deteriorated in nutritional status (1 point decline in SGA) and 10.9% had a severe decline in SGA (≥2 points). The proportion of patients with low SGA (≤5) increased every 6 months. Those who dropped in SGA also declined in estimated glomerular filtration rate and mental health score. Every 10 points decrease in physical function score increased the odds of decline in SGA by 23%. Lower physical function score at baseline, gastrointestinal symptoms, and smoking were risk factors for impaired nutritional status. There was an interaction between diabetes and physical function on SGA decline. CONCLUSIONS: Nutritional status deteriorated in more than one-third of the study participants during the first year of follow-up. Lower patient-reported physical function, more gastrointestinal symptoms, and current smoking were associated with decline in nutritional status.

Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients.

Background People with reduced glomerular filtration rate (GFR) often have elevated cardiac troponin T (cTnT) levels. It remains unclear how cTnT levels develop over time in those with chronic kidney disease (CKD). The aim of this study was to prospectively study the association between cTnT and GFR over time in older advanced-stage CKD patients not on dialysis. Methods and Results The EQUAL (European Quality Study) study is an observational prospective cohort study in stage 4 to 5 CKD patients aged ≥65 years not on dialysis (incident estimated GFR, <20 mL/min/1.73 m²). The EQUAL cohort used for the purpose of this study includes 171 patients followed in Sweden between April 2012 and December 2018. We used linear mixed models, adjusted for important groups of confounders, to investigate the effect of both measured GFR and estimated GFR on high-sensitivity cTnT (hs-cTnT) trajectory over 4 years. Almost all patients had at least 1 hs-cTnT measurement elevated above the 99th percentile of the general reference population (≤14 ng/L). On average, hs-cTnT increased by 16%/year (95% CI, 13-19; P<0.0001). Each 15 mL/min/1.73 m2 lower mean estimated GFR was associated with a 23% (95% CI, 14-31; P<0.0001) higher baseline hs-cTnT and 9% (95% CI, 5-13%; P<0.0001) steeper increase in hs-cTnT. The effect of estimated GFR on hs-cTnT trajectory was somewhat lower than a previous myocardial infarction (15%), but higher than presence of diabetes mellitus (4%) and male sex (5%). Conclusions In CKD patients, hs-cTnT increases over time as renal function decreases. Lower CKD stage (each 15 mL/min/1.73 m2 lower) is independently associated with a steeper hs-cTnT increase over time in the same range as other established cardiovascular risk factors.

Acute effects of haemodialysis on circulating microparticles.

BACKGROUND: Microparticles (MPs) are small cell membrane-derived vesicles regarded as both biomarkers and mediators of biological effects. Elevated levels of MPs have previously been associated with endothelial dysfunction and predict cardiovascular death in patients with end-stage renal disease. The objective of this study was to measure change in MP concentrations in contemporary haemodialysis (HD). METHODS: Blood was sampled from 20 consecutive HD patients before and 1 h into the HD session. MPs were measured by flow cytometry and phenotyped based on surface markers. RESULTS: Concentrations of platelet (CD41+) (P = 0.039), endothelial (CD62E+) (P = 0.004) and monocyte-derived MPs (CD14+) (P < 0.001) significantly increased during HD. Similarly, endothelial- (P = 0.007) and monocyte-derived MPs (P = 0.001) expressing tissue factor (TF) significantly increased as well as MPs expressing Klotho (P = 0.003) and receptor for advanced glycation end products (RAGE) (P = 0.009). Furthermore, MPs expressing platelet activation markers P-selectin (P = 0.009) and CD40L (P = 0.045) also significantly increased. The increase of endothelial (P = 0.034), monocyte (P = 0.014) and RAGE+ MPs (P = 0.032) as well as TF+ platelet-derived MPs (P = 0.043) was significantly higher in patients treated with low-flux compared with high-flux dialysers. CONCLUSION: Dialysis triggers release of MPs of various origins with marked differences between high-flux and low-flux dialysers. The MPs carry surface molecules that could possibly influence coagulation, inflammation, oxidative stress and endothelial dysfunction. The clinical impact of these findings remains to be established in future studies.

Prevalence and Risk of Protein-Energy Wasting Assessed by Subjective Global Assessment in Older Adults With Advanced Chronic Kidney Disease: Results From the EQUAL Study.

OBJECTIVES: Prevalence and risk factors for protein-energy wasting (PEW) are poorly studied in the nondialysis, older population with advanced chronic kidney disease (CKD). Our aim was to evaluate the prevalence of PEW in advanced stage CKD patients aged greater than 65 years. Furthermore, we aimed to describe risk factors for PEW in the overall study population and among obese individuals. DESIGN: Prospective observational cohort study. METHODS: The EQUAL study, a European Quality Study on treatment in advanced chronic kidney disease, is a multicenter prospective observational cohort study in six European countries. We included patients aged ≥65 years with incident glomerular filtration rate <20mL/min/1.73m2 not on dialysis attending nephrology care. PEW was assessed by 7-point Subjective Global Assessment (7-p SGA). RESULTS: In general, the study cohort (n = 1,334) was overweight (mean body mass index [BMI] 28.4 kg/m2). The majority of the patients had a normal nutritional status (SGA 6-7), 26% had moderate PEW (SGA 3-5), and less than 1% had severe PEW (SGA 1-2). Muscle wasting and loss of fat tissue were the most frequent alterations according to the SGA subscales, especially in those aged >80 years. The prevalence of PEW was higher among women, increased with age, and was higher in those with depression/dementia. PEW was the most common in those with underweight (BMI <22 kg/m2), 55% or normal weight (BMI 22-25 kg/m2), 40%. In obese individuals (BMI >30 kg/m2), 25% were diagnosed with protein wasting. Risk factors for SGA ≤5 in obese people were similar to those for the overall study population. CONCLUSION: This European multicenter study shows that the prevalence of PEW is high in patients with advanced CKD aged >65 years. The risk of PEW increases substantially with age and is commonly characterized by muscle wasting. Our study suggests that focus on nutrition should start early in the follow-up of older adults with CKD.

Effects of lipid-lowering treatment on circulating microparticles in patients with diabetes mellitus and chronic kidney disease.

BACKGROUND: Elevated levels of circulating microparticles (MPs) may contribute to the high cardiovascular risk in diabetes mellitus (DM) and chronic kidney disease (CKD). Therefore, we investigated the effects of lipid-lowering treatment (LLT) with simvastatin alone (S) or with ezetimibe (S+E) on MPs in DM patients with or without CKD. METHODS: After a placebo run-in period, 18 DM patients with an estimated glomerular filtration rate (eGFR) of 15-59 mL/min (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were treated with S and S+E in a randomized, double-blind, crossover study. MPs from platelets, monocytes and endothelial cells (PMPs, MMPs and EMPs), and their expression of phosphatidylserine (PS), P-selectin, CD40 ligand (CD40L) and tissue factor (TF) were measured by flow cytometry. RESULTS: At baseline, all types of MPs, except TF-positive MMPs, were elevated in DM-CKD compared with DM-only patients. All MPs, regardless of origin and phenotype, were inversely correlated with eGFR. S reduced the expression of P-selectin, TF and CD40L on PMPs and of TF on MMPs in both patient groups. S+E had no further effect. S also reduced total PS-positive procoagulant MPs, PMPs and MMPs in DM-CKD but not in DM-only patients. CONCLUSIONS: DM patients with CKD stages 3-4 had elevated PMPs, EMPs and MMPs compared with DM patients with normal GFR. Simvastatin reduced procoagulant MPs, MMPs and PMPs in DM-CKD patients, suggesting a beneficial reduction of hypercoagulability in this high-risk patient group. Differences between DM-CKD and DM-only patients were counteracted by LLT.

Systematic conversion to generic tacrolimus in stable kidney transplant recipients.

BACKGROUND: Tacrolimus (Prograf®) is a key drug in the immunosuppressive treatment of renal transplant patients. Since the expiration of the patent for Prograf®, generic preparations have been approved in Europe as bioequivalence has been shown in healthy volunteers. However, few studies have investigated whether patients can be successfully converted from Prograf® to generic tacrolimus. Tacrolimus drug costs are by far the largest single item in the total drug expenditure for patients with renal disease in the Stockholm area. Considerable reductions in drug costs could be achieved if generic tacrolimus were to be used. The aim of this quality assurance study was to evaluate whether a switch from Prograf® to generic tacrolimus (Tacrolimus Sandoz®) could be safely performed in renal transplant patients. It further aimed to investigate changes of renal function (measured in estimated glomerular filtration rate, eGFR), need for dose changes and to calculate potential drug cost savings as a result of the conversion. METHODS: We planned to recruit at least 50 patients. Plasma creatinine levels and trough concentrations of tacrolimus were collected from patients with renal transplants at three occasions during treatment with Prograf® and three times after conversion to Tacrolimus Sandoz®. The eGFR was calculated before and after the conversion. RESULTS: Sixty-three of 67 enrolled patients (69% males, age 28-80 years) are included in this analysis. The ratio of mean trough concentrations of tacrolimus after comparison with before conversion was 1.02 (90% confidence interval 0.95-1.09). Fourteen patients experienced a change in tacrolimus levels >20% compared with baseline, no patients changed >20% in eGFR. The drug cost saving per daily dose was 33.40 SEK (∼€3.60, -23%). CONCLUSIONS: Stable kidney transplant patients treated with Prograf® can be converted to Tacrolimus Sandoz® if trough concentrations of tacrolimus and plasma creatinine levels are closely monitored. The conversion brought savings, despite costs for extra monitoring.

Lipid-lowering treatment and inflammatory mediators in diabetes and chronic kidney disease.

BACKGROUND: Inflammation may contribute to the high cardiovascular risk in diabetes mellitus (DM) and chronic kidney disease (CKD). Monocyte chemoattractant protein-1 (MCP-1) facilitates the recruitment of monocytes into atherosclerotic lesions and is involved in diabetic nephropathy. Interferon gamma (IFNγ) is important in atherosclerosis and increases the synthesis of chemokines including MCP-1. Lipid-lowering treatment (LLT) with statins may have anti-inflammatory effects, and ezetimibe cotreatment provides additional cholesterol lowering. METHODS: After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S+E) were compared in a randomized, double-blind, cross-over study on inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min × 1·73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR > 75 mL/min (DM only) were included. RESULTS: At baseline, monocyte chemoattractant protein 1 (MCP-1) (P = 0·03), IFNγ (P = 0·02), tumour necrosis factor-α (TNFα) (P < 0·01) and soluble vascular adhesion molecule (sVCAM) (P = 0·001) levels were elevated in DM-CKD compared with DM-only patients. LLT with S and S+E reduced MCP-1 levels (P < 0·01 by anova) and IFNγ levels (P < 0·01) in DM-CKD patients but not in DM-only patients. Reductions were most pronounced with the combination treatment. CONCLUSIONS: DM patients with CKD stages 3-4 had increased inflammatory activity compared with DM patients with normal GFR. Lipid-lowering treatment decreased the levels of MCP-1 and IFNγ in DM patients with concomitant CKD, which may be beneficial with regard to the progression of both atherosclerosis and diabetic nephropathy.

Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial.

BACKGROUND: Diabetes mellitus (DM) is associated with hyperreactive platelets and increased platelet-leukocyte aggregation (PLA), but the impact of concomitant chronic kidney disease (CKD) has been much less studied. Lipid-lowering treatment (LLT) may have favorable effects on platelet activation and inflammation. The objective of this mechanistic study was to investigate the impact of CKD on platelet function and inflammatory parameters in patients with DM and the effects of LLT. METHODS: After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S + E) were compared in a randomized, double-blind, cross-over study on platelet reactivity, PLA formation and inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min × 1.73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were included. RESULTS: PLAs were elevated at baseline in DM-CKD compared with DM-only (P = 0.04). S + E reduced PLAs among total leukocytes and neutrophils in DM-CKD patients (P = 0.01 for both) but not in the DM-only group. Platelet reactivity did not differ between patient groups or with LLT. Plasma levels of sCD40L (P < 0.001), elastase (P < 0.01) and von Willebrand factor (VWF) (P < 0.001) were elevated in DM-CKD compared with DM-only. S + E reduced sCD40L in DM-CKD patients (P = 0.01), but LLT did not influence VWF or elastase. CONCLUSIONS: DM patients with CKD stages 3-4 had increased PLA and inflammatory activity compared with DM patients with normal GFR. Simvastatin + ezetimbe decreased PLAs and plasma sCD40L in DM patients with concomitant CKD. Clinical Trial registration http://www.clinicaltrials.gov. Identifier NCT01035320.