Efficacy and Safety of Oral Supplementation with Liposomal Iron in Non-Dialysis Chronic Kidney Disease Patients with Iron Deficiency.

INTRODUCTION: Iron deficiency is common in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Oral iron supplementation is recommended in these patients, but it is associated with a higher incidence of gastrointestinal adverse reactions. Liposomal iron therapy has been proposed as a new iron formulation, improving iron bioavailability with less side effects; however, few data are available in patients with NDD-CKD. METHODS: We designed a single-arm pilot study to evaluate the efficacy of liposomal iron administered for six months in correcting iron deficiency (defined as serum ferritin < 100 ng/mL and/or transferrin saturation < 20%) in patients with NDD-CKD stages 1-5. The primary endpoints were the achievement of serum ferritin ≥ 100 ng/mL and transferrin saturation ≥ 20%. Secondary outcomes were hemoglobin (Hb) changes and the safety of liposomal iron. RESULTS: The efficacy population included 34/38 patients, who completed at least one visit after baseline. Liposomal iron increased the achievement of transferrin saturation targets from 11.8% at baseline to 50.0% at month 6 (p = 0.002), while no significant correction of serum ferritin (p = 0.214) and Hb was found (p = 0.465). When patients were stratified by anemia (Hb < 12 g/dL in women and Hb < 13 g/dL in men), a significant improvement of transferrin saturation was observed only in anemic patients (from 13.3 ± 5.8% to 20.2 ± 8.1%, p = 0.012). Hb values slightly increased at month 6 only in anemic patients (+0.60 g/dL, 95%CI -0.27 to +1.48), but not in those without anemia (+0.08 g/dL, 95%CI -0.73 to +0.88). In patients taking at least one dose of liposomal iron (safety population, n = 38), the study drug was discontinued in eight patients due to death (n = 2), a switch to intravenous iron (n = 2), and the occurrence of side effects (n = 4). CONCLUSIONS: The use of liposomal iron in patients with NDD-CKD is associated with a partial correction of transferrin saturation, with no significant effect on iron storage and Hb levels.

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. Methods: We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. Results: We included 26 RCTs with 24 387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10 g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21 g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, P < .001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1 mg/week, 95% CI -5.6 to -0.6, P = .020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. Conclusions: HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

Sex difference in cardiovascular risk in patients with chronic kidney disease: pooled analysis of four cohort studies.

BACKGROUND: Progression of chronic kidney disease (CKD) has proven to be faster in men than in women. Whether the same holds true for cardiovascular risk remains ill-defined. METHODS: We conducted a pooled analysis of 4 cohort studies from 40 nephrology clinics in Italy including patients with CKD (estimated GFR<60 ml/min/1.73m2 or higher if proteinuria > 0.15 g/day). The aim was to compare multivariable-adjusted risk (Hazard Ratio, 95% Confidence Interval) of a composite cardiovascular endpoint (cardiovascular death and non-fatal myocardial infarction, congestive heart failure, stroke, revascularization, peripheral vascular disease, and non-traumatic amputation) in women (n = 1 192) versus men (n = 1 635). RESULTS: At baseline, women had slightly higher systolic blood pressure (SBP) as compared with men (139±19 vs 138±18 mmHg, P = 0.049), lower eGFR (33.4 vs 35.7 mL/min/1.73 m2, P = 0.001) and lower urine protein excretion (0.30 g/day vs 0.45 g/day in men, P < 0.001). Women did not differ from men in age and prevalence of diabetes while having a lower prevalence of cardiovascular disease, left ventricular hypertrophy and smoking habit. During a median follow-up of 4.0 years, 517 fatal and non-fatal cardiovascular events were registered (199 in women and 318 in men). The adjusted risk of cardiovascular events was lower in women (0.73, 0.60-0.89, P = 0.002) than in men; however, the cardiovascular risk advantage of women progressively diminished as SBP (as continuous variable) increased (P for interaction = 0.021). Similar results were obtained when considering SBP categories; when compared to men, women had lower cardiovascular risk for SBP <130 mmHg (0.50, 0.31-0.80; P = 0.004) and between 130-140 mmHg (0.72, 0.53-0.99; P = 0.038), while no difference was observed for SBP>140 mmHg (0.85, 0.64-1.11; P = 0.232). CONCLUSIONS: Higher BP levels abolish the cardiovascular protection seen in female vs male patients with overt CKD. This finding supports the need for higher awareness of hypertensive burden in women with CKD.

15-year-change of phenotype and prognosis in non-dialysis CKD patients referred to a nephrology clinic.

PURPOSE: Changes over time of phenotype and prognosis in CKD patients starting nephrology care are undefined. This information is critical to correctly plan and optimize healthcare resources and clinical management in tertiary care. METHODS: We performed a long-term observational cohort study including 2,866 non-dialysis CKD patients newly referred to our nephrology clinic from 2004 to 2018. Three cohorts were constituted based on 5-year calendar intervals (2004-2008, 2009-2013, and 2014-2018). The changes over time of main demographic, clinical and laboratory characteristics were compared among the three cohorts. We also compared between cohorts the risk of renal death (combined endpoint of renal replacement therapy-RRT, or death before RRT) as well as of the single components (RRT or death). RESULTS: Across the three cohorts, we detected a significant increase in the prevalence of age ≥ 75 years (from 22.0 to 28.4%), male gender (from 53.1 to 62.1%), diabetes (from 32.6 to 39.5%), severe proteinuria ≥ 500 mg/24 h (from 46.9 to 52.4%). Mean eGFR at referral declined from 56.8 ± 27.0 to 49.6 ± 26.1 mL/min/1.73m2. Incidence of renal death significantly declined over time (5.36, 3.22 and 4.54/100 pts-year in 2004-2008, 2009-2013 and 2014-2018 cohorts, respectively). As compared with patients referred in 2004-2008, adjusted risk of renal death was lower in patients referred in 2009-2013 (HR 0.49, 95%CI 0.34-0.69) and 2014-2018 (HR 0.61, 95%CI 0.45-0.84). Similar results were obtained for RRT, while mortality did not change over time. CONCLUSIONS: In the last 15 years, phenotype of newly referred CKD patients has remarkably changed with increasing frequency of older patients and more severe disease; however, renal survival improved suggesting greater efficacy of nephrology care.

The effects of somatostatin analogues on liver volume and quality of life in polycystic liver disease: a meta-analysis of randomized controlled trials.

A clear evidence on the benefits of somatostatin analogues (SA) on liver outcome in patients affected by polycystic liver disease is still lacking. We performed a meta-analysis of RCTs and a trial sequential analysis (TSA) evaluating the effects of SA in adult patients with polycystic liver disease on change in liver volume. As secondary outcome, we evaluated the effects on quality of life as measured by SF36-questionnaire. Six RCTs were selected with an overall sample size of 332 adult patients with polycystic liver disease (mean age: 46 years). Mean liver volume at baseline was 3289 ml in SA group and 3089 ml in placebo group. Overall, unstandardized mean difference in liver volume was - 176 ml (95%CI, - 406, 54; p < 0.133). Heterogeneity was low (I2:0%, p < 0.992). However, we performed a moderator analysis and we found that a higher eGFR significantly correlates to a more pronounced effect of SA on liver volume reduction (p = 0.036). Cumulative Z-curve in TSA did not reach either significance and futility boundaries or required information size. Three RCTs have evaluated Quality of life parameters measured by SF36-QOL questionnaire for a total of 124 patients; no significant difference was found on the effect of SA on QOL parameters when compared with placebo. The present meta-analysis revealed a potential effect of SA on reduction of liver volume and quality of life parameters, but results did not reach a statistical significance. These data could be explained by the need of further studies, as demonstrated through TSA, to reach an adequate sample size to confirm the beneficial outcomes of SAs treatment.

Atherosclerotic-nephropathy: an updated narrative review.

The increased prevalence of chronic kidney disease (CKD) in elderly patients recognizes, as main cause, the long-term exposure to atherosclerosis and hypertension. Chronic ischemic damage due to critical renal arterial stenosis induces oxidative stress and intra-renal inflammation, resulting in fibrosis and microvascular remodelling, that is the histological picture of atherosclerotic renal vascular disease (ARVD). The concomitant presence of a long history of hypertension may generate intimal thickening and luminal narrowing of renal arteries and arterioles, glomerulosclerosis, interstitial fibrosis and tubular atrophy, more typically expression of hypertensive nephropathy. These complex mechanisms contribute to the development of CKD and the progression to End Stage Kidney Disease. In elderly CKD patients, the distinction among these nephropathies may be problematic; therefore, ischemic and hypertensive nephropathies can be joined in a unique clinical syndrome defined as atherosclerotic nephropathy. The availability of novel diagnostic procedures, such as intra-vascular ultrasound and BOLD-MRI, in addition to traditional imaging, have opened new scenarios, because these tools allow to identify ischemic lesions responsive to renal revascularization. Indeed, although trials have deflated the role of renal revascularization on the renal outcomes, it should be still used to avoid dialysis initiation and/or to reduce blood pressure in selected elderly patients at high risk. Nonetheless, lifestyle modifications (smoking cessation, increased physical activity), statins and antiplatelet use, as well as cautious use of renin-angiotensin system inhibitors, remain the main therapeutic approach aimed at slowing the renal damage progression. Mesenchymal stem cells and Micro-RNA are promising target of anti-fibrotic therapy, which might provide potential benefit in ARVD patients, though safety and efficacy profile in humans is unknown too.

Types of erythropoiesis-stimulating agents and risk of end-stage kidney disease and death in patients with non-dialysis chronic kidney disease.

BACKGROUND: Despite the widespread use of erythropoiesis-stimulating agents (ESAs) to treat anaemia, the risk of adverse outcomes associated with the use of different types of ESAs in non-dialysis chronic kidney disease (CKD) is poorly investigated. METHODS: From a pooled cohort of four observational studies, we selected CKD patients receiving short-acting (epoetin α/ß; n = 299) or long-acting ESAs (darbepoetin and methoxy polyethylene glycol-epoetin ß; n = 403). The primary composite endpoint was end-stage kidney disease (ESKD; dialysis or transplantation) or all-cause death. Multivariable Cox models were used to estimate the relative risk of the primary endpoint between short- and long-acting ESA users. RESULTS: During follow-up [median 3.6 years (interquartile range 2.1-6.3)], the primary endpoint was registered in 401 patients [166 (72%) in the short-acting ESA group and 235 (58%) in the long-acting ESA group]. In the highest tertile of short-acting ESA dose, the adjusted risk of primary endpoint was 2-fold higher {hazard ratio [HR] 2.07 [95% confidence interval (CI) 1.37-3.12]} than in the lowest tertile, whereas it did not change across tertiles of dose for long-acting ESA patients. Furthermore, the comparison of ESA type in each tertile of ESA dose disclosed a significant difference only in the highest tertile, where the risk of the primary endpoint was significantly higher in patients receiving short-acting ESAs [HR 1.56 (95% CI 1.09-2.24); P = 0.016]. Results were confirmed when ESA dose was analysed as continuous variable with a significant difference in the primary endpoint between short- and long-acting ESAs for doses >105 IU/kg/week. CONCLUSIONS: Among non-dialysis CKD patients, the use of a short-acting ESA may be associated with an increased risk of ESKD or death versus long-acting ESAs when higher ESA doses are prescribed.

The Role of Prognostic and Predictive Biomarkers for Assessing Cardiovascular Risk in Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) is currently defined as the presence of proteinuria and/or an eGFR < 60 mL/min/1.73m2 on the basis of the renal diagnosis. The global dimension of CKD is relevant, since its prevalence and incidence have doubled in the past three decades worldwide. A major complication that occurs in CKD patients is the development of cardiovascular (CV) disease, being the incidence rate of fatal/nonfatal CV events similar to the rate of ESKD in CKD. Moreover, CKD is a multifactorial disease where multiple mechanisms contribute to the individual prognosis. The correct development of novel biomarkers of CV risk may help clinicians to ameliorate the management of CKD patients. Biomarkers of CV risk in CKD patients are classifiable as prognostic, which help to improve CV risk prediction regardless of treatment, and predictive, which allow the selection of individuals who are likely to respond to a specific treatment. Several prognostic (cystatin C, cardiac troponins, markers of inflammation, and fibrosis) and predictive (genes, metalloproteinases, and complex classifiers) biomarkers have been developed. Despite previous biomarkers providing information on the pathophysiological mechanisms of CV risk in CKD beyond proteinuria and eGFR, only a minority have been adopted in clinical use. This mainly depends on heterogeneous results and lack of validation of biomarkers. The purpose of this review is to present an update on the already assessed biomarkers of CV risk in CKD and examine the strategies for a correct development of biomarkers in clinical practice. Development of both predictive and prognostic biomarkers is an important task for nephrologists. Predictive biomarkers are useful for designing novel clinical trials (enrichment design) and for better understanding of the variability in response to the current available treatments for CV risk. Prognostic biomarkers could help to improve risk stratification and anticipate diagnosis of CV disease, such as heart failure and coronary heart disease.

Renal resistive index in chronic kidney disease patients: Possible determinants and risk profile.

BACKGROUND: High ultrasound renal resistive index (RI) predicts poor cardiorenal outcomes in chronic kidney disease (CKD) and has recently emerged as a marker of nephroprotective drugs response. Thus, having a risk profile of CKD patients with abnormal RI may be relevant for the clinicians. METHODS: Consecutive patients referred to our non-dialysis CKD clinic from 01/01/2016 to 01/12/2016, were evaluated by clinical and ultrasound analysis. Inclusion criteria were age >18 years and presence of CKD defined as estimated glomerular filtration rate (eGFR)<60 mL/min/1.73m2 and/or proteinuria>0.150g/24h. Renal artery stenosis, solitary kidney, acute kidney injury were the main exclusion criteria. RI value was the mean of three measures in segmental arteries in each kidney. Univariate analysis was performed to evaluate associations between continuous RI and clinical variables. Multivariate linear regression analysis, based on stepwise method with an elimination criterion of p<0.10, was used to assess the independent correlates of RI as continuous variable. RESULTS: We studied 73 patients (69.9% men). Mean RI was 0.67±0.09. Frequencies of diabetes and cardiovascular disease (CVD) were 19.2% and 20.6% and median eGFR 54.1 [30.0-84.6] mL/min/1.73m2. From low (<0.65) to intermediate (0.65-0.70) to high (>0.70) RI categories, eGFR and haemoglobin levels were decreased while diabetes, cardiovascular disease (CVD), phosphate and smokers were higher. At univariate analysis, RI was significantly associated with age, presence of diabetes, CVD, serum phosphorus, eGFR, Urea and haemoglobin. Multi-adjusted stepwise regression analysis showed that lower eGFR levels (p<0.001), diabetes (p = 0.042), CVD (p = 0.009), smoking habit (p = 0.021) and higher serum phosphorus levels (p = 0.001) were associated with higher continuous RI. Serum phosphorus showed Area Under the Curves (AUC) values of 0.714 and 0.664 for discriminating RI cut-offs of 0.70 and 0.65. CONCLUSIONS: This analysis suggests that RI is higher in CKD patients with CVD, diabetes, smoking habit and higher serum phosphorus, regardless of eGFR. Further studies are needed to verify whether higher RI indicates more complex pathway of intrarenal damage, besides and beyond kidney function.

Identifying Fabry patients in dialysis population: prevalence of GLA mutations by renal clinic screening, 1995-2019.

BACKGROUND: Fabry disease (FD) is a rare X-linked genetic disorder of glycosphingolipid catabolism caused by mutations in the GLA gene. Its heterogeneous presentation, the paucity of specific early markers, and the absence of a genotype-phenotype correlation are associated with a delayed or missed diagnosis. The true prevalence of FD remains so far unknown. METHODS: A systematic search of FD screening studies in dialysis patients published from January 1995 until January 2019 was performed to reanalyze the prevalence of GLA mutations in this population after assigning their correct phenotype. RESULTS: Twenty five screening studies involving 39,621 dialysis patients were included. Of them, 116 [91 males (0.23%) and 25 females (0.06%)] were positive to the GLA sequencing analysis. 56 (48.2%) had benign variant, 52 (44.8%) a pathogenic GLA mutation (39 classic and 13 late onset mutations) and 8 (6.9%) a mutation of uncertain significance. The overall prevalence of GLA variants was 0.24% [CI 95%, 0.17-0.32] while the overall prevalence recalculated on basis of only pathogenetic mutations was 0.14% [CI 95%, 0.08-0.20]. This difference was significant (P = 0.048). CONCLUSIONS: Although the real prevalence of classic FD is low, the screening in the high-risk renal population remains of primary interest as an early diagnosis is fundamental for a timely specific therapy; moreover, the identification of index cases could allow patients' relatives to be investigated and promptly treated.

Unraveling Cardiovascular Risk in Renal Patients: A New Take on Old Tale.

Chronic kidney disease (CKD), defined by an estimated glomerular filtration rate <60 ml/min/1.73 m2 and/or an increase in urine protein excretion (i.e., albuminuria), is an important public health problem. Prevalence and incidence of CKD have risen by 87 and 89%, worldwide, over the last three decades. The onset of either albuminuria and eGFR reduction has found to predict higher cardiovascular (CV) risk, being this association strong, independent from traditional CV risk factors and reproducible across different setting of patients. Indeed, this relationship is present not only in high risk cohorts of CKD patients under regular nephrology care and in those with hypertension or type 2 diabetes, but also in general, otherwise healthy population. As underlying mechanisms of damage, it has hypothesized and partially proved that eGFR reduction and albuminuria can directly promote endothelial dysfunction, accelerate atherosclerosis and the deleterious effects of hypertension. Moreover, the predictive accuracy of risk prediction models was consistently improved when eGFR and albuminuria have been added to the traditional CV risk factors (i.e., Framingham risk score). These important findings led to consider CKD as an equivalent CV risk. Although it is hard to accept this definition in absence of additional reports from scientific Literature, a great effort has been done to reduce the CV risk in CKD patients. A large number of clinical trials have tested the effect of drugs on CV risk reduction. The targets used in these trials were different, including blood pressure, lipids, albuminuria, inflammation, and glucose. All these trials have determined an overall better control of CV risk, performed by clinicians. However, a non-negligible residual risk is still present and has been attributed to: (1) missed response to study treatment in a consistent portion of patients, (2) role of many CV risk factors in CKD patients not yet completely investigated. These combined observations provide a strong argument that kidney measures should be regularly included in individual prediction models for improving CV risk stratification. Further studies are needed to identify high risk patients and novel therapeutic targets to improve CV protection in CKD patients.

[Infected hepatic cyst in ADPKD patient in peritoneal dialysis].

Renal and hepatic cysts infections are among the most important infectious complications of ADPKD and often require hospitalization. Liver cysts are even more complex than renal cysts and their diagnosis and treatment are quite controversial. We report the case of a 58-year-old patient with ADPKD undergoing peritoneal dialysis treatment. He presented fever and severe asthenia and was diagnosed with a hepatic cyst infection. Given the presence of the peritoneal catheter, and in order to facilitate the targeted treatment of the infection, we administered antibiotics (ceftazidime and teicoplanin) in the bags used for peritoneal dialysis exchanges for 4 weeks, obtaining the complete disappearance of symptoms and laboratory and ultrasound alterations. Intraperitoneal antibiotics administration in the treatment of infected hepatic cysts represents an effective and safe therapeutic alternative, never described in literature so far.

Exercise training in kidney transplant recipients: a systematic review.

BACKGROUND AND AIMS: Evidences on the benefits of physical exercise in kidney transplant patients (KTx) are not conclusive and concerns on safety remain. We here gather and interpret current evidence on the benefits/harms of exercise training intervention in KTx. METHODS: Systematic review of exercise training programs in KTx. RESULTS: A total of 24 studies including 654 KTx patients on intervention and 536 controls were evaluated. The median age was 46 years; the transplant vintage was 2 days to 10 years. The intervention was an aerobic or resistance exercise program or a combination of both; interventions consisted of 20-60 min' sessions, 2-3 times per week repetitions and 5.5 months' median duration. Most studies improved cardiorespiratory fitness (expressed as VO2peak) as well as maximum heart rate, which was associated with a significant increase in muscle performances and strength. No significant changes in body weight or composition were observed, but a trend towards weight reduction in overweight or obese patients on stable KTx was noted. The arterial blood pressure reduced a little after exercise when it was high at start. Exercise intervention had no clinically relevant impact on anaemia, glycaemia or lipidaemia. In contrast, exercise training improved several aspects of quality of life. No data on long-term hard outcomes or on high-risk subpopulations such comorbid or elderly patients were available. CONCLUSIONS: In adult kidney transplant patients, a structured physical exercise program improved the aerobic capacity and ameliorated muscle performance and quality of life. No harms were observed in the short-term, but long-term RCTs are required. Overall, in mid-age kidney transplant patients without major comorbidities, an aerobic or resistance supervised exercise lasting 3-6 months could be suggested within the comprehensive treatment of kidney transplant.

Generalizability of SPRINT-CKD cohort to CKD patients referred to renal clinics.

BACKGROUND: The Systolic Blood Pressure Intervention Trial-CKD substudy (SPRINT-CKD) has suggested a lower blood pressure (BP) target in CKD patients. However, it is questionable whether the SPRINT-CKD results may be generalized to CKD patients under nephrology care. METHODS: To compare SPRINT-CKD cohort versus referred CKD patients in terms of patients' risk profile and outcomes, we pooled four prospective cohorts of consecutive CKD patients referred to 40 Italian renal clinics. We implemented the same inclusion/exclusion criteria adopted in SPRINT and same endpoints: (1) a composite of fatal and non-fatal cardiovascular (CV) events (2) all-cause mortality and (3) ESRD (composite of chronic dialysis, transplantation or 50% eGFR decline). Findings were compared with those attained in the control arm of SPRINT-CKD trial that mirrored standard BP management in clinical practice. RESULTS: Out of 2847 patients referred to renal clinics, only 20.1% (n = 571) were identified as eligible for SPRINT-CKD. Age (72 ± 9 years), gender (42.2% female) and systolic BP (142 ± 10 mmHg) did not differ from the SPRINT-CKD while referred patients had a worse risk profile at baseline: larger prevalence of prior CV disease (25.7% versus 19.5%), higher Framingham risk score (31.9 ± 14.6% versus 27.2 ± 24.7%) and lower GFR (38 ± 11 versus 48 ± 10 mL/min/1.73 m2). During 4.0 years of follow-up, 86 CV events (50 fatal), 78 all-cause death and 59 ESRD occurred with annual incidence rates higher than those observed in the SPRINT-CKD control group (CV events 4.18 vs 3.19; all-cause death 3.64 vs 2.21; ESRD 2.80 vs 0.41%/year). CONCLUSIONS: The SPRINT-CKD cohort is poorly representative of the CKD population under nephrology care, thus suggesting that conclusions may not apply to patients referred to nephrologist.

Incremental dialysis in ESRD: systematic review and meta-analysis.

BACKGROUND: Incremental dialysis may preserve residual renal function and improve survival in comparison with full-dose dialysis; however, available evidence is limited. We therefore compared all-cause mortality and residual kidney function (RKF) loss in incremental and full-dose dialysis and time to full-dose dialysis in incremental hemodialysis (IHD) and incremental peritoneal dialysis (IPD). METHODS: We performed a systematic review and meta-analysis of cohort studies of adults with ESRD starting IHD and IPD. We identified in PubMed and Web of Science database all cohort studies evaluating incremental dialysis evaluating three outcomes: all-cause mortality, RKF loss, time to full dialysis. IPD was defined as < 3 daily dwells in Continuous Ambulatory Peritoneal Dialysis and < 5 sessions per week in Automated Peritoneal Dialysis, while IHD was defined as < 3 HD sessions per week. RESULTS: 22 studies (75,292 participants), 15 in HD and 7 in PD, were analyzed. Mean age at dialysis start was 62 and 57 years in IHD and IPD subjects, respectively. When compared to full dose, incremental dialysis (IHD or IPD) had an overall mortality risk of 1.14 [95% CI 0.85-1.52] with high heterogeneity among studies (I2 86%, P < 0.001), and lower mean RKF loss (- 0.58 ml/min/months, 95% CI 0.16-1.01, P = 0.007). Overall, time to full-dose dialysis was 12.1 months (95% CI 9.8-14.3) with no difference between IHD and IPD (P = 0.217). CONCLUSIONS: Incremental dialysis allows longer preservation of RKF thus deferring full-dose dialysis, by about 1 year in HD and PD, with no increase in mortality risk. Large and adequate studies are needed to confirm these findings.

Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer.

Chronic kidney disease is a growing public health problem, as its prevalence and incidence have almost doubled over the last three decades. Chronic kidney disease is defined as the presence of an estimated glomerular filtration rate < 60 ml/min/1.73 m² and/or proteinuria ≥ 0.150 g/24 h. It has been demonstrated that both proteinuria and reduction in estimated glomerular filtration rate can predict the development of fatal and non-fatal cardiovascular events, regardless of traditional cardiovascular risk factors, namely blood pressure, smoking habit, cholesterol, age, gender. This relationship is found in the general population, high-risk cohorts and in patients referred to Nephrologists (tertiary care). The accuracy by which proteinuria or estimated glomerular filtration rate can predict these events, exceeds that obtained by the combination of all the other traditional risk factors. These important findings have led to chronic kidney disease being considered as a cardiovascular risk equivalent. Although this needs further investigation, a great effort has been made to reduce the cardiovascular risk in chronic kidney disease patients. Indeed, many clinical trials have been carried-out testing the effect of antihypertensive, proteinuria-lowering, lipid-lowering and hypoglycemic agents on cardiovascular risk protection. All these trials reduced, but did not eliminate, the overall cardiovascular risk. Future studies should be undertaken to identify high cardiovascular risk patients and novel therapeutic targets for cardiovascular protection in chronic kidney disease patients.

Effect of Increased Convection Volume by Mid-Dilution Hemodiafiltration on the Subclinical Chronic Inflammation in Maintenance Hemodialysis Patients.

Mid-dilution hemodiafiltration (MID) is a dialytic technique that might improve systemic inflammation of patients in chronic hemodialysis (HD) by increasing substitution volumes. To verify this hypothesis, we performed a prospective cross-over study comparing the effect on inflammatory biomarkers of higher convection by MID versus standard convection by post-dilution hemodiafiltration (HDF). Patients under chronic HD were therefore treated by MID and HDF by crossover design. Each treatment period lasted 4 months, with 1 month of wash-out where patients were treated by HD, for a total of 9 months. Primary outcome was the change of serum pre-dialytic C-Reactive Protein (CRP), interleukin 6 (IL-6), IL-1, IL-10, transforming growth factor-ß (TGF-ß), tumor necrosis factor-α, albumin and pre-albumin. Samples were obtained monthly. Ten HD patients were enrolled (age: 64.9 ± 12.6 years; 70% males; dialytic vintage: 10.6 [2.7-16.2] years). Mean convection volume was 40.1 ± 2.5 L/session in MID and 20.1 ± 2.6 L/session in HDF. A significant reduction of ß2-Microglobulin was detected as a result of either treatment. In MID, CRP decreased from 11.3 (3.2-31.0) to 3.1 (1.4-14.4) mg/L (p = 0.007), IL-6 from 12.7 (5.0-29.7) to 8.3 (4.4-14.0) pg/mL (p = 0.003), and TGF-ß from 10.6 (7.4-15.6) to 7.4 (5.9-9.3) ng/mL (p = 0.001). A significant reduction of CRP from 8.5 (3.2-31.0) to 4.6 (3.2-31.0) mg/L was also detected in HDF (p = 0.037), whereas no significant reduction of IL-6 (p = 0.147) and TGF-ß (p = 0.094) was found. Percentage reduction of IL-6 correlated with mean convective volume in HDF (R = 0.666; p = 0.036) and in MID (R = 0.760; p = 0.020). Therefore, MID and HDF are associated with an attenuation of inflammatory pattern that is correlated with a high convective volume.

[Hyperuricaemia and Chronic Kidney Disease].

Hyperuricemia is defined as serum uric acid values greater than 6 mg/dl and could occur either due to hyperproduction or as a result of reduced renal excretion, which exceeds gut compensation. In Italy, prevalence is around 12% of the general population and increases in renal disease up to 60%. Recent experimental studies demonstrated a role of uric acid in the development of arterial hypertension and systemic arteriosclerosis, with an increase in cardiovascular risk. It also appears from observational studies that high uric acid is an independent risk factor associated with de novo onset of chronic kidney disease after adjustment of main confounding variables. Hyperuricemic subjects treated with febuxostat, a selective inhibitor of xantino-oxidase, showed in RCTs a better control of hyperuricaemia in comparison with those receiving allopurinol. Moreover, observational studies indicate that urate lowering treatment could be helpful in reducing cardiovascular events as well as in slowing the progression of chronic kidney disease; randomized controlled studies, designed to assess as primary outcome the nephroprotective effect of urate lowering treatment, are in progress.

High-flow arteriovenous fistula and heart failure: could the indexation of blood flow rate and echocardiography have a role in the identification of patients at higher risk?

BACKGROUND: Although only high-flow arteriovenous fistulas (AVFs) are postulated to cause high-output cardiac failure (HOCF), there are currently no universally accepted criteria defining a high-flow fistula. METHODS: To verify if vascular access blood flow (Qa) ≥ 2000 ml/min provides an accurate definition of high-flow fistula, we selected 29 consecutive patients with Qa ≥ 2000 ml/min at color-duplex ultrasound examination and assessed them for the presence of cardiac failure symptoms; transthoracic echocardiography was also performed. RESULTS: Nineteen patients (65%) had heart failure symptoms and were classified with HOCF. At receiver operating characteristic (ROC) curve analysis, Qa ml/min values did not identify patients with heart failure symptoms but when AVF blood flow was indexed for height2.7, Qa ≥ 603 ml/min/m2.7 detected the occurrence of HOCF with good accuracy (sensitivity 100%, specificity 60%, efficiency 86%, positive predictive value 83%, negative predictive value 100%, area under curve 0.75). At echocardiographic evaluation, patients with Qa ≥ 603 ml/min/m2.7 had a more severe increase of left ventricular mass (63 ± 18 vs. 47 ± 7 g/m2.7, p < 0.003), left ventricular diastolic volume (140 ± 42 vs. 109 ± 14 ml, p < 0.007), left atrial volume (53 ± 23 vs. 39 ± 5 ml/m2, p < 0.015), a higher incidence of diastolic dysfunction (70 vs. 17%, p < 0.019) and higher CO reduction after AVF manual compression (2151 ± 875 vs. 1292 ± 527 ml/min, p < 0.009) than patients with Qa < 603 ml/min/m2.7. CONCLUSIONS: Indexation of AVF blood flow should be considered in defining high-flow fistula because the effect of Qa may differ in individuals of different sizes. A Qa value ≥ 603 ml/min/m2.7 and its association with some echocardiographic alterations could identify patients at higher risk for HOCF.

[Iron deficiency in ND-CKD: from diagnosis to treatment]. / Deficit marziale nella Malattia Renale Cronica non dialitica: dalla diagnosi al trattamento.

In non-dialysis-chronic kidney disease (CKD), iron deficiency is a frequent nutritional disorder due to either the greater tendency to occult gastrointestinal bleeding or to the chronic inflammatory state resulting in a reduced intestinal iron reabsorption through an increased synthesis of hepcidin. These phenomenon are responsible for a negative iron balance that compromises erythropoiesis and contributes to the pathogenesis of anemia in CKD. Several laboratory tests are now available to allow an adequate diagnosis of iron deficiency. Among the new parameters, the percentage of hypochromic red cells (% HYPO) and the reticulocyte hemoglobin content (CHr) are now considered as the most specific markers for diagnosing iron-deficiency erythropoiesis. Unfortunately, their implementation in clinical practice is limited by the scarce availability. In non-dialyzed CKD , subjects intolerant or non-responsive to oral iron therapy, can be effectively treated with novel intravenous iron preparations, such as iron carboxymaltose, that allow a complete and rapid correction of iron deficient anemia. Furthermore, this iron compound is associated with lower rate of adverse effects since the carbohydrate shell (carboxymaltose) is more stable than gluconate and saccarate thus reducing the release of free iron in the bloodstream. Of note, the possibility of administering this drug at high doses and reduced frequency decreases the risk of infusion reactions. Finally, a substantial economic saving mainly dependent on a reduction in indirect costs represents a further advantage in the use of iron carboxymaltose in this population.