Lucia Di Micco

Effects of Antiplatelet Therapy on Mortality and Cardiovascular and Bleeding Outcomes in Persons With Chronic Kidney Disease: A Systematic Review and Meta-analysis

BACKGROUND Antiplatelet agents are used to prevent cardiovascular events; however, treatment effects may differ in persons with chronic kidney disease (CKD) because atherosclerotic disease is less prevalent, whereas bleeding hazards may be increased in this population. PURPOSE To summarize the effects of antiplatelet treatment on cardiovascular events, mortality, and bleeding in persons with CKD. DATA SOURCES Embase and Cochrane databases through November 2011 without language restriction. STUDY SELECTION Randomized trials that included adults with CKD and compared antiplatelet agents with standard care, placebo, or no treatment. DATA EXTRACTION Data for populations, interventions, outcomes, and risk for bias were extracted. Quality of evidence for treatment effects on myocardial infarction, death, and bleeding was summarized by using Grading of Recommendations Assessment, Development, and Evaluation guidelines. DATA SYNTHESIS Nine trials (all post hoc subgroup analyses for CKD) involving 9969 persons who had acute coronary syndromes or were undergoing percutaneous coronary intervention and 31 trials involving 11,701 persons with stable or no cardiovascular disease were identified. Low-quality evidence has found that in persons with acute coronary syndromes, glycoprotein IIb/IIIa inhibitors or clopidogrel plus standard care compared with standard care alone had little or no effect on all-cause or cardiovascular mortality or on myocardial infarction but increased serious bleeding. Compared with placebo or no treatment in persons with stable or no cardiovascular disease, antiplatelet agents prevented myocardial infarction but had uncertain effects on mortality and increased minor bleeding according to generally low-quality evidence. LIMITATIONS Data for antiplatelet agents in persons with CKD are frequently derived from post hoc analyses of trials of broader populations. Definitions for bleeding outcomes and trial duration were heterogeneous. CONCLUSION Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards. PRIMARY FUNDING SOURCE None.

Acute Effects of Very-Low-Protein Diet on FGF23 Levels: A Randomized Study

BACKGROUND AND OBJECTIVES High levels of fibroblast growth factor 23 are associated with mortality, CKD progression, and calcification in CKD patients. The aim of this pilot study is to assess whether a very-low-protein diet (0.3 g/kg per day) with a consequent low intake of phosphorus would reduce fibroblast growth factor 23 compared with a low-protein diet (0.6 g/kg per day) in CKD patients not yet on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A prospective, randomized, controlled crossover study was performed in which 32 patients were randomized into two groups. Group A (16 patients) received a very-low-protein diet (0.3 g/kg body wt per day) supplemented with ketoanalogues during the first week and a low-protein diet during the second week, and group B (16 patients) received a low-protein diet during the first week and a very-low-protein diet during the second week. Fibroblast growth factor 23, seric, and urinary phosphate levels were measured at baseline and the end of each study period. RESULTS After only 1 week of the very-low-protein diet, reductions in fibroblast growth factor 23 levels (33.5%), serum phosphate (12%), and urinary phosphate (34%) with the very-low-protein diet compared with the low-protein diet were observed. Serum and urinary phosphate levels and protein intake were significant determinants of fibroblast growth factor 23 (95% confidence interval=1.04-1.19, 1.12-1.37, and 1.51-2.23, respectively). CONCLUSIONS A very-low-protein diet supplemented with ketoanalogues reduced fibroblast growth factor 23 levels in CKD patients not yet on dialysis.

Antiplatelet Therapy to Prevent Hemodialysis Vascular Access Failure: Systematic Review and Meta-analysis

BACKGROUND Hemodialysis vascular access failure occurs often and increases morbidity for people on hemodialysis therapy. Antiplatelet agents may prevent hemodialysis vascular access failure, but potentially may be hazardous in people with end-stage kidney disease who have impaired hemostasis. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials. SETTING & POPULATION Adults on long-term hemodialysis therapy. SELECTION CRITERIA Trials evaluating hemodialysis vascular access outcomes identified by searches in Cochrane CENTRAL and Renal Group Trial Registers and Embase, without language restriction. INTERVENTION Antiplatelet therapy. OUTCOMES Hemodialysis vascular access failure (thrombosis or loss of patency), failure to attain vascular access suitable for dialysis, need for intervention to attain patency or assist maturation, major bleeding, minor bleeding, and antiplatelet treatment withdrawal. Treatment effects were summarized as RRs with 95% CIs using random-effects meta-analysis. RESULTS 21 eligible trials (4,826 participants) comparing antiplatelet treatment with placebo or no treatment were included. 12 trials (3,118 participants) started antiplatelet therapy around the time of dialysis vascular access surgery and continued treatment for approximately 6 months. Antiplatelet treatment reduced fistula failure (thrombosis or loss of patency) by one-half (6 trials, 1,222 participants; RR, 0.49; 95% CI, 0.30-0.81) but had uncertain effects on graft patency and attaining fistula or graft function suitable for dialysis. Overall, antiplatelet treatment had uncertain effects on major bleeding. LIMITATIONS Unclear or high risk of bias in most trials and few trial data, particularly for antiplatelet effects on graft function and vascular access suitability for dialysis. CONCLUSIONS Antiplatelet treatment protects fistula from thrombosis or loss of patency, but has little or no effect on graft patency and uncertain effects on vascular access maturation for dialysis and major bleeding. Interventions that demonstrably improve vascular access suitability for dialysis are needed.

Blood pressure variability and outcomes in chronic kidney disease

BACKGROUND We investigated the effects of visit-to-visit systolic blood pressure variability (SBPV) on both mortality and dialysis inception in a cohort of chronic kidney disease (CKD) patients not requiring dialysis therapy. Furthermore, we also explored the carry-over effect of visit-to-visit SBPV on mortality after dialysis initiation. METHODS We conducted a longitudinal retrospective, observational, multi-centre study in three tertiary care nephrology outpatient clinics. All the ambulatory CKD patients admitted to the outpatient clinics from 1 January 2004 to 31 December 2005 were screened for study eligibility. We selected all consecutive patients older than 18 years of age with a mean estimated glomerular filtration rate of <60 mL/min/m(2), free from cardiovascular disease. SBPV was defined as the ratio of the SD to the mean SBP of five values recorded during a run-in phase of 4-5 months. Data on dialysis inception and mortality were recorded through 31 December 2010. RESULTS Overall, we selected a cohort of 374 elderly (median age: 79 years) subjects. A total of 232 (62%) and 103 (29%) patients were male and had diabetes, respectively. A significant association between SBPV and the risk of death but not of CKD progression to dialysis was noted at univariate and after multivariable adjustments (hazard ratio for all-cause mortality per 1% increase in SBPV: 1.05; 95% confidence interval: 1.02-1.09; P = 0.001). Notably, no lethal event was recorded after dialysis initiation. CONCLUSIONS Current findings suggest that SBPV may be of use for risk stratification in CKD patients.

Effect of a Low- Versus Moderate-Protein Diet on Progression of CKD: Follow-up of a Randomized Controlled Trial

BACKGROUND Whether low-protein-diet (LPD) as opposed to moderate-protein-diet (MPD) regimens improve the long-term survival of patients with chronic kidney disease (CKD) or induce protein-caloric malnutrition is unknown. STUDY DESIGN Intention-to-treat analysis of follow-up data from a randomized controlled trial. SETTING & PARTICIPANTS 423 patients with CKD (stages 4-5) were randomly assigned between January 1999 and January 2003 and followed up until December 2006 or death. The first phase of follow up was from January 1999 to June 2004; additional follow-up was from July 2004 to December 2006. INTERVENTION LPD versus MPD (protein intake, 0.55 vs 0.80 g/kg/d). OUTCOMES Protein-caloric malnutrition (defined as the occurrence of 1 of the following: loss of body weight > 5% in 1 month or 7.5% in 3 months or body mass index < 20 kg/m(2) with serum albumin level < 3.2 g/dL and normal C-reactive protein level [<0.5 mg/dL]), dialysis, death, or the composite outcome of dialysis and death. RESULTS Baseline mean age was 61 years, estimated glomerular filtration rate was 16 mL/min/1.73 m(2), proteinuria had protein excretion of 1.67 g/d, body mass index was 27.1 kg/m(2), protein intake was 0.95 g/kg/d, and there were 57% men. Duration of follow-up was 32 months (median, 30 months; 25th-75th percentiles, 21-39). Average protein intakes were 0.73 +/- 0.04 g/kg/d for the LPD and 0.9 +/- 0.06 g/kg/d for the MPD. 3 patients (0.7%) met criteria for protein-caloric malnutrition. 48 patients died (11%), 83 initiated dialysis therapy (20%), and 113 (27%) reached the composite outcome. In unadjusted Cox survival analyses, effects of the LPD on these outcomes were 1.01 (95% CI, 0.57-1.79), 0.96 (95% CI, 0.62-1.48), and 0.98 (95% CI, 0.68-1.42), respectively. LIMITATIONS Low event rates for dialysis therapy initiation and death. CONCLUSIONS Most patients, who were regularly followed up in CKD clinics, were acceptably adherent to the prescribed dietary protein intake restrictions; the LPD and MPD did not lead to protein wasting; and the LPD did not decrease the risk of death or dialysis therapy initiation compared with the MPD.

Low-protein diets for chronic kidney disease patients: the Italian experience

BackgroundNutritional treatment has always represented a major feature of CKD management. Over the decades, the use of nutritional treatment in CKD patients has been marked by several goals. The first of these include the attainment of metabolic and fluid control together with the prevention and correction of signs, symptoms and complications of advanced CKD. The aim of this first stage is the prevention of malnutrition and a delay in the commencement of dialysis. Subsequently, nutritional manipulations have also been applied in association with other therapeutic interventions in an attempt to control several cardiovascular risk factors associated with CKD and to improve the patients overall outcome. Over time and in reference to multiple aims, the modalities of nutritional treatment have been focused not only on protein intake but also on other nutrients.DiscussionThis paper describes the pathophysiological basis and rationale of nutritional treatment in CKD and also provides a report on extensive experience in the field of renal diets in Italy, with special attention given to approaches in clinical practice and management.SummaryItalian nephrologists have a longstanding tradition in implementing low protein diets in the treatment of CKD patients, with the principle objective of alleviating uremic symptoms, improving nutritional status and also a possibility of slowing down the progression of CKD or delaying the start of dialysis. A renewed interest in this field is based on the aim of implementing a wider nutritional therapy other than only reducing the protein intake, paying careful attention to factors such as energy intake, the quality of proteins and phosphate and sodium intakes, making today’s low-protein diet program much more ambitious than previous. The motivation was the reduction in progression of renal insufficiency through reduction of proteinuria, a better control of blood pressure values and also through correction of metabolic acidosis. One major goal of the flexible and innovative Italian approach to the low-protein diet in CKD patients is the improvement of patient adherence, a crucial factor in the successful implementation of a low-protein diet program.

Setting dialysis start at 6.0 ml/min/1.73 m2 eGFR—a study on safety, quality of life and economic impact

BACKGROUND End-stage renal disease care requires enormous economic resources. A timely dialysis start could reduce the costs of the renal replacement therapy (RRT). Our aim was to measure the time to dialysis in CKD patients, with an estimated glomerular filtration rate (eGFR) <or=11.0 ml/min/1.73 m(2) (MDRD derived), and to evaluate the safety, economic impact and the quality of life (QoL). METHODS In a prospective, observational study, 70 consecutive CKD patients, stage 5, were screened and 30 patients were selected and followed up monthly, for 24 months or until the start of RRT, set at an eGFR = 6.0 ml/min/ 1.73 m(2) or at the occurrence of pre-defined urgent criteria. The SF-36 questionnaire to evaluate the QoL was performed at the first and the last visit. RESULTS The median time to the start of dialysis was 11.8 (25th and 75th: 5.5-17.3) months. Only seven patients urgently started dialysis, after 8 months (25th and 75th: 4.8-20). The mean monthly cost of care was euro 1146 +/- 917 per patient. The QoL was similar to that of the general population and did not change at the last assessment. Discussion. This is the first study evaluating the economic impact of intensive conservative management of CKD stage 5 to postpone start of dialysis in tertiary care. This strategy allows us to safely gain a significant amount of time free from dialysis, with good QoL and major savings in the costs of nations dialysis budget. The present results, however, are applicable only to low comorbidity patients referred to nephrology care and may not be generalized to all patients starting RRT.

Very Low-Protein Diet (VLPD) Reduces Metabolic Acidosis in Subjects with Chronic Kidney Disease: The “Nutritional Light Signal” of the Renal Acid Load

Background: Metabolic acidosis is a common complication of chronic kidney disease; current guidelines recommend treatment with alkali if bicarbonate levels are lower than 22 mMol/L. In fact, recent studies have shown that an early administration of alkali reduces progression of CKD. The aim of the study is to evaluate the effect of fruit and vegetables to reduce the acid load in CKD. Methods: We conducted a case-control study in 146 patients who received sodium bicarbonate. Of these, 54 patients assumed very low-protein diet (VLPD) and 92 were controls (ratio 1:2). We calculated every three months the potential renal acid load (PRAL) and the net endogenous acid production (NEAP), inversely correlated with serum bicarbonate levels and representing the non-volatile acid load derived from nutrition. Un-paired T-test and Chi-square test were used to assess differences between study groups at baseline and study completion. Two-tailed probability values ≤0.05 were considered statistically significant. Results: At baseline, there were no statistical differences between the two groups regarding systolic blood pressure (SBP), diastolic blood pressure (DBP), protein and phosphate intake, urinary sodium, potassium, phosphate and urea nitrogen, NEAP, and PRAL. VLPD patients showed at 6 and 12 months a significant reduction of SBP (p < 0.0001), DBP (p < 0.001), plasma urea (p < 0.0001) protein intake (p < 0.0001), calcemia (p < 0.0001), phosphatemia (p < 0.0001), phosphate intake (p < 0.0001), urinary sodium (p < 0.0001), urinary potassium (p < 0.002), and urinary phosphate (p < 0.0001). NEAP and PRAL were significantly reduced in VLPD during follow-up. Conclusion: VLPD reduces intake of acids; nutritional therapy of CKD, that has always taken into consideration a lower protein, salt, and phosphate intake, should be adopted to correct metabolic acidosis, an important target in the treatment of CKD patients. We provide useful indications regarding acid load of food and drinks—the “acid load dietary traffic light”.

Urine Creatinine Excretion and Clinical Outcomes in CKD

BACKGROUND AND OBJECTIVES Twenty-four-hour urine creatinine excretion is a reliable approximation of muscle mass. Whether changes in urine creatinine predict clinical outcomes in persons with CKD is unknown. This work studied the relationship between urine creatinine and patient and renal survival in people with CKD not requiring renal replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This longitudinal cohort study included incident stages 3-5 CKD patients referred to the renal clinic at the University Federico II in Naples between January of 1995 and December of 2005. Clinical data and urine creatinine were updated at each visit. Main outcomes were all-cause mortality and kidney failure requiring dialysis. RESULTS This study enrolled 525 individuals and followed them for a median of 6 years (range of 4 months to 15 years). Urine creatinine excretion declined by 16 mg/d per year (95% confidence interval, 14 to 19) in participants with CKD stages 3a, 3b, and 4, and it remained stable in participants with stage 5 CKD. Per each 20 mg/d decline in urine creatinine, mortality increased by 3% (adjusted hazard ratio, 1.03; 95% confidence interval, 1.01 to 1.05), and the risk of initiating dialysis increased by 2% (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01 to 1.03). These associations were independent of body mass index and GFR. CONCLUSIONS In persons with CKD stages 3 and 4, urine creatinine declines at a rate of 16 mg/d per year. Lower urine creatinine excretion predicts greater risk of kidney failure and patient mortality.

Daily dialysis reduces pulse wave velocity in chronic hemodialysis patients

Pulse wave velocity (PWV) is a predictor of morbidity and mortality in patients with end-stage renal disease (ESRD). Dialysis patients show cyclic changes in PWV related to their hydration status and blood pressure. Our aim is to assess the impact of daily dialysis on PWV. We performed a randomized crossover study of 60 patients who underwent standard hemodialysis (HD) three times per week for at least 6 months. Patients were classified into three groups according to their PWV values before (pre-) and after (post-) HD, with a cutoff value of 12 m s−1, as follows: the low–low (LL) group had normal pre-HD and post-HD PWV; the high–low (HL) group had high pre-HD PWV and normal post-HD PWV; and the high–high (HH) group had high pre- and post-HD PWV. All patients continued standard HD for 2 weeks. A total of 10 patients from each group were randomly assigned to continue standard HD for 1 week and then underwent daily dialysis for 1 week. The remaining 10 patients underwent daily dialysis for 1 week and then underwent standard HD for 1 week. PWV values were measured before and 1 h after each dialysis session. With daily dialysis treatment, 2 of 20 patients (10%) moved from the PWV–HH group to the PWV–HL group, whereas 18 of 20 patients (90%) moved from the PWV–HL group to the PWV–LL group (P=0.030). Daily dialysis reduces PWV in the ESRD patients. As PWV is a strong predictor of mortality in ESRD and has cyclic variations in patients who are on standard HD, we believe that daily dialysis may be used in patients with high PWV levels to reduce their mortality risk.