Giorgia Comai

Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment

BACKGROUND Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterized by paraesthesia, dysaesthesia and the irresistible urge to move the legs especially at night. Its prevalence is much higher among dialysis patients at 12 to 62% compared to 3 to 9% in the general population. Here, we investigated the association between RLS and cardiovascular events risk and laboratory parameters in end-stage kidney disease (ESKD) patients on dialysis. METHODS One hundred ESKD patients undergoing haemodialysis were enrolled in an 18-month prospective observational study. The main outcomes were the associations of RLS with new cardiovascular events and cardiovascular mortality. RESULTS RLS affected 31% of the study population. It was associated with female gender, gradual reduction in residual diuresis, lower albumin (P = 0.039) and inflammation, but not the dialysis parameters Kt/V and URR. During observation, 47% of patients experienced new cardiovascular events (64.5% with and 39.1% without RLS; P = 0.019). New cardiovascular events increased with severity of RLS [intermittent (I-RLS) vs continuous (C-RLS)]. Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (P = 0.04). In patients with I-RLS, mortality was 23.8% compared to 55.6% in patients with C-RLS (P = 0.014). Multivariate analysis confirmed the relationship between RLS and mortality. CONCLUSIONS This study confirmed the high prevalence of RLS among dialysis patients and the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality.

5-Methyltetrahydrofolate Administration Is Associated with Prolonged Survival and Reduced Inflammation in ESRD Patients

BACKGROUND Hemodialysis (HD) patients have a greatly increased risk of cardiovascular morbidity and mortality. For this reason, attempts are often made to normalize hyperhomocysteinemia. This randomized prospective study sought to determine which risk factors are predictors of mortality and whether high doses of folates or 5-methyltetrahydrofolate (5-MTHF) could improve hyperhomocysteinemia and survival in HD patients. METHODS 341 patients were divided into two groups: group A was treated with 50 mg i.v. 5-MTHF, and group B was treated with 5 mg/day oral folic acid. Both groups received i.v. vitamin B(6) and B(12). By dividing patients into C-reactive protein (CRP) quartiles, group A had the highest survival for CRP <12 mg/l, whereas no survival difference was found for group B. CRP was the only predictive risk factor for death (RR 1.17, range 1.04-1.30, p = 0.02). Dialysis age, hyperhomocysteinemia, methylenetetrahydrofolate reductase polymorphism, albumin, lipoprotein (a) and folate did not influence mortality risk. Survival in group A was higher than that in group B, namely 36.2 +/- 20.9 vs. 26.1 +/- 22.2 months (p = 0.003). RESULTS Our results suggest that CRP, but not hyperhomocysteinemia, is the main risk factor for mortality in HD patients receiving vitamin supplements. Intravenous 5-MTHF seems to improve survival in HD patients independent from homocysteine lowering.

Automatic Adaptive System Dialysis for Hemodialysis-Associated Hypotension and Intolerance: A Noncontrolled Multicenter Trial

BACKGROUND Hemodialysis is complicated by a high incidence of intradialytic hypotension and disequilibrium symptoms caused by hypovolemia and a decrease in extracellular osmolarity. Automatic adaptive system dialysis (AASD) is a proprietary dialysis system that provides automated elaboration of dialysate and ultrafiltration profiles based on the prescribed decrease in body weight and sodium content. STUDY DESIGN A noncontrolled (single arm), multicenter, prospective, clinical trial. SETTING & PARTICIPANTS 55 patients with intradialytic hypotension or disequilibrium syndrome in 15 dialysis units were studied over a 1-month interval using standard treatment (642 sessions) followed by 6 months using AASD (2,376 sessions). INTERVENTION AASD (bicarbonate dialysis with dialysate sodium concentration and ultrafiltration rate profiles determined by the automated procedure). OUTCOMES Primary and major secondary outcomes were the frequency of intradialytic hypotension and symptoms (hypotensive events, headache, nausea, vomiting, and cramps), respectively. RESULTS More stable intradialytic systolic and diastolic blood pressures with lower heart rate were found using AASD compared with standard treatment. Sessions complicated by hypotension decreased from 58.7% ± 7.3% to 0.9% ± 0.6% (P < 0.001). The incidence of other disequilibrium syndrome symptoms was lower in patients receiving AASD. There were no differences in end-session body weight, interdialytic weight gain, or presession natremia between the standard and AASD treatment periods. LIMITATIONS A noncontrolled (single arm) study, no crossover from AASD to standard treatment. CONCLUSIONS This study shows the long-term clinical efficacy of AASD for intradialytic hypotension and disequilibrium symptoms in a large number of patients and dialysis sessions.

Hepatorenal syndrome: Update on diagnosis and treatment

Acute kidney injury (AKI) is a common complication in patients with end-stage liver disease and advanced cirrhosis regardless of the underlying cause. Hepatorenal syndrome (HRS), a functional form of kidney failure, is one of the many possible causes of AKI. HRS is potentially reversible but involves highly complex pathogenetic mechanisms and equally complex clinical and therapeutic management. Once HRS has developed, it has a very poor prognosis. This review focuses on the diagnostic approach to HRS and discusses the therapeutic protocols currently adopted in clinical practice.

Role of the hemodialysis vascular access type in inflammation status and monocyte activation

Purpose The aim of this study was to ascertain the role of different vascular access types in inflammatory status, monocyte activation, and senescence in hemodialysis patients. Methods We recruited 126 hemodialysis patients, including 51 with arterovenous fistula (AVF), 32 with arterovenous graft (AVG), and 43 with tunneled cuffed catheters (TCC). In dialysis patients enrolled in the study and in a control group of 40 healthy subjects, we measured the serum levels of albumin, CRP, IL-6, and TNF-α, the expression of CD14, CD44, and CD32 on monocyte surface, and the percentage of monocytes exhibiting a senescent phenotype (CD14+CD32+). Results The patients with AVG compared to those with AVF had: a) higher levels of CRP and TNF-α; b) increased expression of CD14 and CD32 on monocyte surface, with no difference in CD44 expression; c) no difference in the percentage of CD14+CD32+ monocytes. In the comparison of TCC vs. AVF group, we observed significantly higher values of: a) circulating inflammatory markers (CRP, IL-6, TNF-α); b) monocyte surface expression of cellular activation markers (CD14, CD44 and CD32); c) relative count of CD14+CD32+ monocytes. When comparing TCC vs. AVG group, we found: a) no difference in serum levels of CRP, IL-6, and TNF-α; b) no difference in the expression of CD14, CD44, and CD32 on monocyte surface; c) no difference in the percentage of CD14+CD32+ monocytes. Conclusions These results suggest that the use of AVG and TCC for dialysis vascular access is associated with serological and cellular indexes of inflammatory reaction, also resulting in a higher degree of monocyte activation and senescence.

Risk for Contrast Nephropathy in Patients Undergoing Coronarography

Among the causes of in-hospital acute renal failure, contrast-induced nephropathy ranks third in prevalence. Although it represents a condition of renal impairment with spontaneous recovery, contrast nephropathy should always be considered, because it prolongs hospitalization and it may become a severe complication requiring dialysis. The purposes of this study are: (i) to determine if the application of the most effective contrast-induced nephropathy prevention strategies in the Cardiology Intensive Care Unit can prove to be successful in reducing nephropathy risk; and (ii) to identify which of the involved risk factors persist after the preventive treatment. We examined the patients who had a coronarography at the Bentivoglio hospital from April 2007 to April 2008 who required at least 3 days of permanence in hospital due to the presence of potential risk factors; 136 out of 784 patients were included. Among the selected patients, 21 (15.44%) developed a renal impairment compatible with contrast-induced nephropathy. The risk factors that seemed to display the best correlation with risk of contrast nephropathy were advanced age and an ventricular failure (ejection fraction <40%); however, the critical condition did not appear to be due to a single risk factor, but it resulted from the association of more contextual risk factors. Particularly, the concomitant presence of ventricular failure, anemia, diabetes, previous myocardial infarction and advanced age (>70 years) determined a threefold increased risk of contrast nephropathy. Our data suggest that the development of contrast nephropathy following coronarography is associated with worse renal function during hospitalization and at discharge.

Influence of the immunogenetic KIR and HLA systems on long-term renal transplant outcome

BACKGROUND Numerous studies have established the importance of innate immunity, particularly natural killer (NK) cells, in transplantation tolerance. NK cells express killer cell immunoglobulin-like receptors (KIRs) on their surface. By recognizing and binding major histocompatibility complex class I antigens, KIRs prevent autologous cell killing and promote lysis of non-self antigen-presenting cells. This study investigated the role of 16 KIR genes and donor-recipient KIR/HLA combinations on 5-year outcomes in a population of deceased donor kidney transplant recipients. MATERIAL/METHODS We genotyped 126 renal transplant patients and their donors for HLA A, B, C, DR, and KIR genes. Patients underwent standardized transplantation and immunosuppressive protocols and were followed-up for 5 years. Graft function was evaluated by serum creatinine level and glomerular filtration rate calculated using the 4-variable modification of diet in renal disease (MDRD) equation. RESULTS The presence of KIR2DS3 in the recipients was associated with better graft function indexes over time (p<0.05), but this effect was not confirmed by multivariate analysis. Conversely, the presence KIR2DS3 in the recipients combined with the presence of its HLA ligand in the donor had a detrimental effect on the trends of serum creatinine levels and eGFR trends, also confirmed by multivariate analysis. Kidney transplant recipients negative for the KIR2DL1 gene displayed higher creatinine levels after 5 years. Lastly, transplantation of HLA-A3/A11-negative donor kidneys into KIR3DL2-positive patients exerted a protective effect in terms of 5-years outcome (p<0.05). CONCLUSIONS The present study demonstrates an important role of the KIR immunogenetic system in the long-term immune response to kidney transplantation.

Cardiovascular disease in kidney transplant recipients: the prognostic value of inflammatory cytokine genotypes.

Background. Cardiovascular disease (CVD) represents the main cause of morbidity and mortality after renal transplantation. In view of the modern paradigm of atherosclerosis as an inflammatory disease, this study investigated the impact of inflammatory cytokine polymorphisms on posttransplant CVD. Methods. The association between cytokine polymorphisms and CVD was assessed in a case-control study to identify the differences in genotype distributions between kidney allografts with or without posttransplant CVD. To validate our results in two independent groups, we divided a cohort of 798 renal transplant recipients according to geographic area: an evaluation cohort of 478 patients from Emilia-Romagna and a validation cohort of 320 patients from the rest of Italy. Tumor necrosis factor (TNF)-&agr;, transforming growth factor-&bgr;1, interleukin (IL)-10, IL-6, interferon-&ggr;, and IL-8 polymorphisms were analyzed, and thereafter, the cytokine production genotype was assigned. Results. In the evaluation cohort, the patients in the CVD and no-CVD groups differed significantly in TNF-&agr; and IL-10 genotype frequencies. Using multivariate analyses to test the association with CVD, the TNF-&agr; high-producer genotype was associated with a significantly increased cardiovascular risk (odds ratio [OR]=4.41, 95% confidence interval (CI)=2.53–7.67). Conversely, the IL-10 high-producer genotype resulted protective against CVD (OR=0.07, 95% CI=0.02–0.29). These findings were confirmed in the validation cohort where the carriers of the TNF-&agr; high-producer genotype proved to be at 2.45-fold increased cardiovascular risk (OR=2.45, 95% CI=1.29–4.63), whereas the IL-10 high-producer genotype was associated with a 0.08-fold reduced risk (OR=0.08, 95% CI=0.02–0.36). Conclusions. This work suggests a prognostic value of TNF-&agr; and IL-10 genotypes, which might represent cardiovascular risk markers in renal transplant.

Reduction of Oxidative Damage Reflects a Better Kidney Transplantation Outcome

Background/Aims: DNA fragmentation is one of the typical features of apoptosis, frequently induced by oxidative stress. Increased oxidative stress is known to be related to several pathological processes. In this study, we assessed oxidative damage in the early follow-up period after kidney transplantation measuring DNA oxidation and fragmentation of mononuclear cells and the circulating levels of inflammatory cytokines. Methods: Blood samples from 30 kidney transplant recipients were collected before transplantation and after 2 days, 1 month and 6 months. Oxidative DNA fragmentation was measured by Comet Assay, whereas DNA oxidation was evaluated measuring 8-OHdG leukocyte levels. Serum IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ and TNF-α were assayed using a multiplex ELISA analysis. Results: At 6 months after transplantation, a significant reduction in DNA fragmentation and IL-6 plasma levels was observed; DNA oxidation was higher in patients with a worse outcome, with delayed graft function and low nutritional status. We also found a correlation of IL-6 and IL-10 levels with DNA fragmentation and of IL-10 levels with DNA oxidation. Conclusion: Low levels of oxidation and apoptosis at 6 months after transplantation correlate with a better recovery of renal function in kidney allografts. The measurement of cytokine levels confirmed a reduction of inflammatory parameters within 6 months of follow-up.

Combined liver–dual kidney transplant: Role in expanded donors

Kidney injury is a common clinical feature among liver transplantation (LT) candidates that heavily affects prognosis and complicates the surgical decision‐making process. Up to 20% of patients undergoing LT demonstrate some degree of renal impairment, and 2% will benefit from a combined liver‐kidney transplantation (LKT). We present a case‐control study of all patients who underwent LKT and combined liver–dual kidney transplantation (LDKT) from November 2013 to March 2016. For the selection of LDKT candidates, a histological‐based algorithm was applied: when evaluating extended criteria donors (ECDs), with any Remuzzi score between 4 and 7, we would consider performing a LDKT instead of a simple LKT. Study groups were similar for recipient variables. In the LDKT group, donor age, donor risk index, and donor body mass index were found to be significantly higher. Biopsies obtained from all pairs of kidney grafts in the LDKT group demonstrated the following Remuzzi scores: 4+4, 4+4, 7+1, 4+5. Despite longer operative times for the LDKT procedure, no differences were observed regarding the main investigated outcome parameters. Overall survival was 100% (LDKT) and 91% (LKT, P > 0.99). This is a preliminary experience which might indicate that LDKT is a safe, feasible, and resource‐effective technique. The evaluation of a larger cohort, as well as the experience from other centers, would be needed to clearly identify its role in the ECD era. Liver Transplantation 23:28–34 2017 AASLD