Graziella D'Arrigo

Phosphate attenuates the anti-proteinuric effect of very low-protein diet in CKD patients

BACKGROUND High phosphate levels attenuate nephroprotection through angiotensin-converting enzyme inhibition in patients with proteinuric chronic kidney disease (CKD). Whether this phenomenon holds true for other nephroprotective interventions like very-low-protein diet (VLPD) is unknown. METHODS We tested the hypothesis that phosphate interferes with the anti-proteinuric response to VLPD in a non-randomized, sequential study in 99 proteinuric CKD patients who sequentially underwent low-protein diet (LPD; 0.6 g/kg) and VLPD (0.3 g/kg) supplemented with keto-analogues, each for periods longer than 1 year. RESULTS Serum phosphate significantly reduced during VLPD (3.2 ± 0.6 mg/dL) when compared with LPD (3.7 ± 0.6 mg/dL, P < 0.001), an effect paralleled by a substantial decline in phosphate excretion (LPD, 649 ± 180 mg/day; VLPD, 462 ± 97 mg/day; P < 0.001). The median proteinuria during LPD was 1910 mg/24 h (interquartile range: 1445-2376 mg/24 h) and reduced to 987 mg/24 h (656-1300 mg/24 h) during VLPD (P < 0.001). No significant change in the estimated glomerular filtration rate (eGFR) was observed during the two diet periods. In linear mixed models including the diagnosis of renal disease, eGFR, 24-h urine sodium and urea and other potential confounders, there was a strong interaction between serum phosphate (P = 0.04) and phosphaturia (P < 0.001) with the anti-proteinuric response to VLPD. Accordingly, 24-h proteinuria reduced modestly in patients who maintained relatively higher serum phosphate levels or relatively higher phosphaturia to be maximal in those who achieved the lowest level of serum and urine phosphate. CONCLUSION Phosphate is an important modifier of the anti-proteinuric response to VLPD. Reducing phosphate burden may decrease proteinuria and slow the progression of renal disease in CKD patients, an issue that remains to be tested in specific clinical trials.

Long-term visit-to-visit office blood pressure variability increases the risk of adverse cardiovascular outcomes in patients with chronic kidney disease

Long-term visit-to-visit blood pressure (BP) variability predicts a high risk for cardiovascular events in patients with essential hypertension. Whether long-term visit-to-visit BP variability holds the same predictive power in predialysis patients with chronic kidney disease (CKD) is unknown. Here we tested the relationship between long-term visit-to-visit office BP variability and a composite end point (death and incident cardiovascular events) in a cohort of 1618 patients with stage 2-5 CKD. Visit-to-visit systolic BP variability was significantly and independently related to baseline office, maximal, and average systolic BPs, age, glucose, estimated glomerular filtration rate, and albumin, and to the number of visits during the follow-up. Both the standard deviation of systolic BP (hazard ratio: 1.11, 95% confidence interval: 1.01-1.20) and the coefficient of variation of systolic BP (hazard ratio: 1.15, 95% confidence interval: 1.02-1.29) were significant predictors of the combined end point independent of peak and average systolic BP, cardiovascular comorbidities, Framingham risk factors, and CKD-related risk factors. Antihypertensive treatment (β-blockers and sympatholytic drugs) significantly abrogated the excess risk associated with high systolic BP variability. Thus, large visit-to-visit systolic BP variability in patients with CKD predicts a higher risk of death and nonfatal cardiovascular events independent of underlying BP levels.

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

BACKGROUND AND OBJECTIVES High serum IL-6 is a major risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patients with CKD, but it is still unknown whether the link between IL-6 and CVD in CKD is causal in nature. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a cohort of 755 patients with stages 2-5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up±SD, 31±10 months) and used the functional polymorphism (-174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal. RESULTS In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P<0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the -174 G/C polymorphism had higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95% CI, 1.15 to 4.00; P=0.02) as well as a 87% higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes. CONCLUSIONS In patients with stages 2-5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the -174 G/C polymorphism in the IL-6 gene suggests that IL-6 may be causally involved in the high CV risk in this population.

Physical Performance and Clinical Outcomes in Dialysis Patients: A Secondary Analysis of the Excite Trial

Background/Aims: Scarce physical activity predicts shorter survival in dialysis patients. However, the relationship between physical (motor) fitness and clinical outcomes has never been tested in these patients. Methods: We tested the predictive power of an established metric of motor fitness, the Six-Minute Walking Test (6MWT), for death, cardiovascular events and hospitalization in 296 dialysis patients who took part in the trial EXCITE (ClinicalTrials.gov Identifier: NCT01255969). Results: During follow up 69 patients died, 90 had fatal and non-fatal cardiovascular events, 159 were hospitalized and 182 patients had the composite outcome. In multivariate Cox models - including the study allocation arm and classical and non-classical risk factors - an increase of 20 walked metres during the 6MWT was associated to a 6% reduction of the risk for the composite end-point (P=0.001) and a similar relationship existed between the 6MWT, mortality (P<0.001) and hospitalizations (P=0.03). A similar trend was observed for cardiovascular events but this relationship did not reach statistical significance (P=0.09). Conclusions: Poor physical performance predicts a high risk of mortality, cardiovascular events and hospitalizations in dialysis patients. Future studies, including phase-2 EXCITE, will assess whether improving motor fitness may translate into better clinical outcomes in this high risk population.

Renal Biopsy in 2015--From Epidemiology to Evidence-Based Indications.

Background: Although the number of patients reaching end-stage kidney disease without a biopsy-proven diagnosis is increasing, the utility of renal biopsy is still an object of debate. We analyzed epidemiological data and the main indications for renal biopsy with a systematic, evidence-based review at current literature. Summary: There is a high discrepancy observed in biopsy rates and in the epidemiology of glomerular diseases worldwide, related to the different time frame of the analyzed reports, lack of data collection, the different reference source population and the heterogeneity of indications. The evidence-based analysis of indications showed that renal biopsy should be crucial in adults with nephrotic syndrome or urinary abnormalities as coexistent hematuria and proteinuria and in corticosteroid resistant-children with severe proteinuria. The knowledge of renal histology can change the clinical management in patients with acute kidney injury significantly, after the exclusion of pre-renal or obstructive causes of kidney damage. Scarce evidence indicates that renal biopsy can be useful in patients with advanced chronic kidney disease and its use should always be considered after weighing the benefits and potential risks. Renal biopsy should be crucial in patients with renal involvement due to systemic disease. In patients with diabetes with atypical features, renal biopsy may be fundamental to diagnose an unexpected parenchymal disease mislabeled as diabetic nephropathy. Finally, in elderly patients, the indications and the risks are not different from those in the general population. Key Message: Renal biopsy still remains a concrete approach for managing a substantial percentage of renal diseases.

Body mass index trend in haemodialysis patients: The shift of nutritional disorders in two Italian regions

BACKGROUND In the USA, the increase in the prevalence of obesity in the general population has been accompanied by a marked increase in the prevalence and incidence of obesity in the dialysis population. However, secular trends of body mass index (BMI) have not been investigated in European renal registries. METHODS We investigated the secular trend of BMI across 18 years (1994-2011) in two haemodialysis (HD) registries (Calabria in southern Italy and Emilia in northern Italy) on a total of 16 201 prevalent HD patients and in a series of 3559 incident HD patients. We compared trends in BMI for HD patients with those in the background general population of the same regions. RESULTS The average BMI rose from 23.5 kg/m(2) in 1994 to 25.5 (+8.5%) in 2011 in the Calabria registry and from 23.7 in 1998 to 25.4 (+7.1%) in 2011 in the Emilia registry (P < 0.001). The proportion of obese patients (i.e. with BMI >30 kg/m(2)) rose from 6 to 14% in Calabria and from 6 to 16% in Emilia (P < 0.001). These patterns were fully confirmed in incident patients and were mirrored by a substantial decline in the prevalence of underweight-normal and underweight (P < 0.001) patients. Of note, the steepness of the increase in BMI in haemodialysis patients was 3.7 times more pronounced than that in the coeval, age- and sex-matched general population of Calabria and Emilia. CONCLUSIONS In two regional haemodialysis registries in Italy a steady increase in overweight and obese patients is observed. These patterns are more pronounced than those found in the general population. If further confirmed in other European haemodialysis cohorts, these findings may have relevant public health implications.

Validity of Vascular Calcification as a Screening Tool and as a Surrogate End Point in Clinical Research

On a world scale, in 2013, there have been >17 million cardiovascular deaths, one half of which attributable to ischemic heart disease.1 More than 50% of cases of ischemic heart disease deaths presenting as sudden cardiac death have no history of symptoms heralding the critical event,2 and most myocardial infarctions occur in low or moderate risk subjects (ie, in the largest segment of the general population). On a life-time scale, the risk of myocardial infarction at the age of 40 years is 1 in 2 men and 1 in 3 in women.3 These figures underline the potential relevance of timely screening and treatment of individuals at risk of cardiovascular disease. The Framingham Risk Score or the recently developed risk calculator, which informs the American College of Cardiology/American Heart Association cholesterol guideline,4 the HeartScore,5 or the QRISK calculator,6 are center pieces of current policies for cardiovascular risk assessment and for lipid-lowering treatment. Because in these calculators age is the most informative risk factor for the prediction of cardiovascular events,7 these instruments have limited precision for the prediction of coronary atherosclerosis at individual level particularly in young subjects who have a low absolute risk for cardiovascular disease events.8 Novel biomarkers measurable in plasma or serum have been intensively investigated to refine risk prediction in individuals at low or moderate risk, but the gain in prediction power by these biomarkers is just of modest degree.9 Imaging biomarkers provide an estimate of the atherosclerotic burden in critical areas of the arterial system like the coronary circulation and may provide an integrated measure of life time exposure to risk factors. Among imaging markers of atherosclerosis assessment of vascular calcification, in particular of coronary calcification, is considered as the most valuable one because it outperforms other imaging …

High estimated pulmonary artery systolic pressure predicts adverse cardiovascular outcomes in stage 2-4 chronic kidney disease

High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2-4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04-1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03-1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68-4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05-2.91). High ePASP is relatively common in patients with stage 2-4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials.

Resistin and all-cause and cardiovascular mortality: effect modification by adiponectin in end-stage kidney disease patients

BACKGROUND Resistin is a major adipose tissue cytokine implicated in insulin resistance, inflammation and vascular damage. This cytokine is raised in patients with end-stage kidney disease (ESKD) but the relationship between resistin and major clinical outcomes has not been investigated in this population. METHODS We studied the mutual relationship between resistin and the two major adipokines (adiponectin and leptin) and the interaction between resistin and adiponectin (ADPN) and all-cause and cardiovascular (CV) mortality in a cohort of 231 haemodialysis patients followed up for 57 ± 44 months. RESULTS Plasma resistin was substantially raised in ESKD patients when compared with healthy subjects (P < 0.001). On univariate analysis, resistin was related inversely to ADPN (r = -0.14, P = 0.04) and directly to C-reactive protein (r = 0.15, P = 0.03), but was largely independent of leptin (r = 0.08, P = 0.24) and the HOMA-IR index (r = -0.04, P = 0.51). During the follow-up, 165 patients died (96 for CV causes). On both univariate (all-cause mortality: P = 0.004; CV mortality P < 0.001) and multivariate (all-cause mortality: P = 0.01; CV mortality P < 0.001) Cox regression analyses, the effect of resistin on study outcomes was closely dependent on ADPN levels. There was a consistent excess risk for all-cause (P = 0.002) and CV mortality (P = 0.003) by plasma resistin (20 ng/mL) in patients in the first ADPN tertile, but no risk excess for these outcomes was apparent in patients in the third tertile. CONCLUSION This study indicates that resistin predicts death and fatal CV events depending on plasma ADPN levels. These findings underscore the importance of the interaction among adipokines for the prediction of adverse clinical outcomes in ESKD.

Renal biopsy in patients with diabetes: a pooled meta-analysis of 48 studies

Background. The utility of renal biopsy in patients with diabetes is highly debated. Diabetics with rapidly worsening renal disease are often ‘clinically’ labelled as having diabetic nephropathy (DN), whereas, in many cases, they are rather developing a non-diabetic renal disease (NDRD) or mixed forms (DN + NDRD). Methods. We performed a systematic search for studies on patients with diabetes with data on the frequency of DN, NDRD and mixed forms, and assessed the positive predictive values (PPVs) and odds ratios (ORs) for such diagnoses by meta-analysing single-study prevalence. Possible factors explaining heterogeneity among the different diagnoses were explored by meta-regression. Results. In the 48 included studies (n = 4876), the prevalence of DN, NDRD and mixed forms ranged from 6.5 to 94%, 3 to 82.9% and 4 to 45.5% of the overall diagnoses, respectively. IgA nephropathy was the most common NDRD (3–59%). PPVs for DN, NDRD and mixed forms were 50.1% [95% confidence interval (CI): 44.7–55.2], 36.9% (95% CI: 32.3–41.8) and 19.7% (95% CI: 16.3–23.6), respectively. The PPV when combining NDRD and mixed forms was 49.2% (95% CI: 43.8–54.5). Meta-regression identified systolic pressure, HbA1c, diabetes duration and retinopathy as factors explaining heterogeneity for NDRD, creatinine and glomerular filtration rate for mixed forms and only serum creatinine for DN. ORs of DN versus NDRD and mixed forms were 1.71 (95% CI: 1.54–1.91) and 4.1 (95% CI: 3.43–4.80), respectively. Conclusions. NDRD are highly prevalent in patients with diabetes. Clinical judgment alone can lead to wrong diagnoses and delay the establishment of adequate therapies. Risk stratification according to individual factors is needed for selecting patients who might benefit from biopsy.