Association between PNPLA3rs738409 polymorphism decreased kidney function in postmenopausal type 2 diabetic women with or without non-alcoholic fatty liver disease.

AIM: Evidence is emerging that PNPLA3 rs738409 polymorphism (the major genetic variant associated with susceptibility to non-alcoholic fatty liver disease [NAFLD]) is associated with chronic kidney disease (CKD) in non-diabetic individuals. Currently, little is known about this association in type 2 diabetic (T2DM) patients with and without NAFLD. METHODS: We studied 101 Caucasian post-menopausal women with T2DM, consecutively attending our diabetes outpatient service during a 3-month period. Glomerular filtration rate (eGFRCKD-EPI) was estimated using the CKD-Epidemiology Collaboration (CKD-EPI) equation, whilst albuminuria was measured with an immunonephelometric assay on morning spot urine samples. NAFLD was detected either by fatty liver index (FLI ≥ 60, n = 101) or by ultrasonography (n = 77). Genotyping was performed by TaqMan-Based RT-PCR system. RESULTS: Eight patients had G/G, 41 G/C and 52 C/C PNPLA3 rs738409 genotypes, and 21 (20.8%) patients had CKD (eGFRCKD-EPI < 60 mL/min/1.73 m2 or abnormal albuminuria). Compared to those with G/C or C/C genotypes, patients with G/G genotype had significantly lower eGFRCKD-EPI (63.7 ± 11 vs. 77.4 ± 17 vs. 81.9 ± 15 mL/min/1.73 m2, P = 0.014) and higher prevalence of CKD (50% vs. 24.4% vs. 13.5%, P = 0.04). After adjustment for age, duration of diabetes, haemoglobin A1c, HOMA-estimated insulin resistance, systolic blood pressure, hypertension treatment and FLI ≥ 60, rs738409 G/G genotype was independently associated with both lower eGFRCKD-EPI (ß coefficient: -15.5, 95% CI -26.0 to -5.0, P = 0.004) and higher risk of CKD (adjusted-odds ratio 8.05, 95% CI 1.26-41.4, P = 0.03). Similar results were found when we adjusted for hepatic steatosis on ultrasography (instead of FLI ≥ 60). CONCLUSION: Regardless of the presence of NAFLD and common cardio-renal risk factors, in post-menopausal women with T2DM, the G/G genotype of rs738409 in the PNPLA3 gene was strongly associated with lower eGFRCKD-EPI and higher prevalence of CKD.

Impact of 3 Major Maintenance Immunosuppressive Protocols on Long-term Clinical Outcomes: Result of a Large Multicenter Italian Cohort Study Including 5635 Renal Transplant Recipients.

BACKGROUND: Although optimization of immunosuppressive schemes in renal transplantation have minimized acute posttransplant complications, long-term outcomes are still not optimal and most of the chronic graft damage is drug-related. Therefore, to define the best long-term maintenance immunosuppressive regimen is of major importance in renal transplantation. To assess this objective, we undertook a large, multicenter cohort study in Italy. METHODS: We retrospectively analyzed data of 5635 patients (enrolled from 1983 to 2012) and we assessed the impact of 3 major immunosuppressive regimens (calcineurin inhibitors+antimetabolites+corticosteroids [CNI+ANT+CS] vs CNI+mammalian target-of-rapamycin (mTOR) inhibitors+CS [CNI+mTOR-I+CS] vs CNI+CS) on long-term clinical outcomes by employing several statistical algorithms. RESULTS: The overall difference in the incidence of outcome over time was not statistically different within the first 5 years of follow-up (P = .13); however, it became significant at 10 years and 20 years (P < .01), with the CNI+CS group showing the lowest cumulative incidence of outcome. Compared with the CNI+ANT+CS group, the CNI+mTOR-I+CS group patients had a significantly higher risk of outcome (hazard ratio [HR], 1.30; P = .024); the difference remained significant and even increased in magnitude after adjustment for potential confounders (HR, 1.38; P = .006). Similarly, patients in the CNI+CS group had a significantly higher risk of the outcome (HR, 1.64; P < .001). CONCLUSION: Our data confirm that CNI+ANT+CS is the "gold standard" therapy in renal transplantation, but, whenever required, the introduction of mTOR-Is instead of ANT may not dramatically modify major clinical outcomes. The use of mTOR-I could be a valuable pharmacologic tool to minimize CNI complications and insure adequate immunosuppression.

Living kidney donation from people at risk of nephrolithiasis, with a focus on the genetic forms.

Deciding whether to accept a donor with nephrolithiasis is a multifaceted task because of the challenge of finding enough suitable donors while at the same time ensuring the safety of both donors and recipients. Until not long ago, donors with a history of renal stones or with stones emerging during screening on imaging were not considered ideal, but recent guidelines have adopted less stringent criteria for potential donors at risk of stones. This review goes through the problems that need to be approached to arrive at a wise clinical decision, balancing the safety of donors and recipients with the need to expand the organ pool. The risk of declining renal function and worsening stone formation is examined. Documents (consensus statements, guidelines, etc.) on this issue released by the most important medical societies and organizations are discussed and compared. Specific problems of living kidney donation associated with certain systemic (chronic hypercalcemia due to CYP24A1 gene mutations, primary hyperoxaluria, APRT deficiency) and renal (medullary sponge kidney, cystinuria, distal renal tubular acidosis, Dent's disease, Bartter syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis) Mendelian disorders that cause nephrolithiasis are also addressed.

Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients.

INTRODUCTION: Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. METHODS: 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn-Tolosa-Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). RESULTS: Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. CONCLUSIONS: Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.

Safety and Efficacy of Citrate Anticoagulation for Continuous Renal Replacement Therapy for Acute Kidney Injury After Liver Transplantation: A Single-Center Experience.

BACKGROUND: Acute kidney injury (AKI) after liver transplantation (LT) is a frequent and serious complication. The incidence of AKI requiring continuous renal replacement therapy (CRRT) ranges from 10% to 30%. Kidney Disease: Improving Global Outcomes guidelines indicate the use of citrate as a locoregional anticoagulant drug for CRRT regardless of the patient's hemorrhagic risk. Despite this indication, however, the use of citrate is still under debate in patients with liver failure and/or LT owing to the potential risk of plasmatic citrate accumulation due to reduced liver clearance. The aim of this study was to evaluate the safety and efficacy of citrate as a locoregional anticoagulation drug in CRRT for AKI after LT. METHODS: A retrospective analysis was performed in patients with AKI after liver transplantation who were treated with CRRT using citrate as local anticoagulant. Five patients were enrolled from January to December 2015. RESULTS: No patients showed complications related to citrate (metabolic acidosis, hyperlactatemia, hypercalcemia, or hypernatremia). All treatments with heparin were stopped owing to circuit clotting. Treatments with citrate was interrupted where it was no longer needed or when other examinations had to be made. None were stopped because of circuit coagulation. CONCLUSIONS: At our center, 5 patients have been successfully treated with the use of CRRT with citrate for AKI during the post-LT course. Our results, though on a small series of patients, provide evidence that CRRT with citrate can be a safe and promising treatment for AKI after LT.

Sclerostin and Dickkopf-1 in post-menopausal renal allograft recipients.

BACKGROUND: Age, pre-existing renal osteodistrophy, impaired renal function, and chronic use of immunosuppressive drugs are the main factors involved in the onset and development of bone metabolism disturbances and skeletal alterations occurring after renal transplantation. However, at the state of the art, no reports have analyzed the additional post-menopausal physiological mechanisms associated with the onset and development of bone complications in renal transplant recipients. METHODS: We measured by means of molecular strategies (enzyme-linked immunoassay, chemiluminescence) the serum levels of Sclerostin and Dickkopf-1 (DKK1), two major antagonists of the Wnt/ß-catenin pathway, and several bone resorption/formation biomarkers (N-terminal procollagen type 1, bone-specific alkaline phosphatase, and serum C-terminal telopeptides of type I collagen) in 19 post-menopausal kidney transplant patients and 12 post-menopausal chronic kidney disease patients (CKD group) matched for age and renal function. RESULTS: Our results showed that the levels of both Wnt antagonists were similar in the two study groups (P=.15 and .96, respectively). Additionally, no correlation was found between Sclerostin and DKK1 serum levels in all patients included in the study (R2=0.03, P=.2). After statistical analysis, we found no differences in the bone resorption/formation biomarkers between renal transplant and CKD patients. Multivariate analysis showed that Sclerostin levels were significantly positively correlated with serum phosphorus levels (P=.008) and inversely correlated with renal function (P=.026). Surprisingly, no significant correlation was found between all the analyzed demographic and clinical parameters and DKK1. CONCLUSIONS: Our study demonstrated for the first time that renal transplantation per se and immunosuppressive treatments do not represent additional factors contributing to bone metabolic/biochemical alterations in post-menopausal women. However, our results emphasized that a better preservation of the graft function could significantly slow down the progression of bone metabolic deregulations and prevent clinical bone complications.

Glycosaminoglycans, proteoglycans and sulodexide and the endothelium: biological roles and pharmacological effects.

The glycocalyx is a jelly layer covering the endothelium constituted by glycosaminoglycans (GAGs), proteoglycans and adsorbed plasma proteins. This structure take part in several physiological and pathological vascular events. The glycocalyx acts as mechanosensor to shear stress and participates to regulation of vascular tone, permeability, coagulation and complement activation. Moreover it regulates the interaction and activation of blood cells with endothelial cells. The presence of a thick, normal glycocalyx is required for physiological vascular functions, whereas these functions are impaired by its damage by noxious agents. Indeed, glycocalyx alterations are involved in the pathogenesis of atherosclerosis, ischemia-reperfusion and diabetic vascular complications. GAGs such as sulodexide are promising agents to control endothelial dysfunction. They act at multiple levels: they promote glycocalyx reconstitution, control glycocalyx degrading enzymes, exert anti-inflammatory effects and have anti-apoptotic and anti-senescence effects on endothelial cells. Clinical studies support the evidence that glycosaminoglycans are useful to restore a normal endothelial function.

The Donor Action Project: a valuable tool to measure quality and efficacy of the donation process in Emilia-Romagna.

INTRODUCTION: The international project Donor Action (DA) started in Emilia-Romagna (ER) in July 1998, involving 24 main regional intensive care units (ICUs) of which 6 have neurosurgery units. Using a data-analysis computer system, we sought to measure the efficiency and quality of the donation process. METHODS: Our study analyzed all data collected by the DA system from July 1998 to December 2008. In particular, we evaluated the following markers: patients with brain damage (BD)/total ICU deaths (Index I); brain death assessments/potential donors (PD, patients in the ICU for more than 6 hours; Index II); refusals/consent requests (Index III); effective donors/total encephalic deaths (PROC 1); and brain death assessments/total encephalic deaths (PROC 2). After collection, data were analyzed by the Regional Transplant Reference Center (CRT)-ER and sent to the National Transplant Centre (CNT) using Q-pido software for comparison with other Italian regions. RESULTS: During the study period, despite a significant decrease in Index I, we observed a considerable increase in Index II, and, consequently, in donation efficacy. Additionally, we reported a slight increase in Index III. Finally, both PROC 1 and PROC 2 increased through the years, suggesting an improved efficacy of the donation/transplantation system. CONCLUSIONS: Based on our experience, the DA project to increase the level of attention of ICU medical staff about organ donation and to increase interactions between transplantation coordinators and CRT-ER seemed to ameliorate both procurement and transplantation activities.

Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients.

Although notable progress has been made in the therapeutic management of patients with chronic kidney disease in both conservative and renal replacement treatments (dialysis and transplantation), the occurrence of medication-related problems (lack of efficacy, adverse drug reactions) still represents a key clinical issue. Recent evidence suggests that adverse drug reactions are major causes of death and hospital admission in Europe and the United States. The reasons for these conditions are represented by environmental/non-genetic and genetic factors responsible for the great inter-patient variability in drugs metabolism, disposition and therapeutic targets. Over the years several genetic settings have been linked, using pharmacogenetic approaches, to the effects and toxicity of many agents used in clinical nephrology. However, these strategies, analysing single gene or candidate pathways, do not represent the gold standard, being the overall pharmacological effects of medications and not typically monogenic traits. Therefore, to identify multi-genetic influence on drug response, researchers and clinicians from different fields of medicine and pharmacology have started to perform pharmacogenomic studies employing innovative whole genomic high-throughput technologies. However, to date, only few pharmacogenomics reports have been published in nephrology underlying the need to enhance the number of projects and to increase the research budget for this important research field. In the future we would expect that, applying the knowledge about an individual's inherited response to drugs, nephrologists will be able to prescribe medications based on each person's genetic make-up, to monitor carefully the efficacy/toxicity of a given drug and to modify the dosage or number of medications to obtain predefined clinical outcomes.

[Selection and follow-up of living donor kidney transplant recipients]. / Selezione e follow-up del ricevente di trapianto di rene da donatore vivente.

The objectives of pre-transplant assessment are: a) to ensure that transplantation is technically possible; b) to ensure that the recipient's chances of survival are not compromised by transplantation; c) to ensure that graft survival is not limited by premature death; d) to ensure that pre-existing conditions are not exacerbated by transplantation; e) to identify measures to be taken to minimize perioperative and postoperative complications; f) to inform patients of the likely risks and benefits of transplantation. During the long-term follow-up of living donor kidney transplant recipients, clinicians have to pay attention to the possible recurrence of the primary renal disease, to the identification and, if possible, prevention of noncompliance, and, finally, to immunological monitoring.

Searching for IgA nephropathy candidate genes: genetic studies combined with high throughput innovative investigations.

Idiopathic IgA Nephropathy (IgAN) is the most common biopsy-proven glomerulonephritis worldwide. All races with the exception of Blacks and Indians are involved. Families with two or more relatives affected by IgAN may be observed in 15-20% of pedigrees of IgAN patients. Genome wide linkage study has been considered the most promising approach to identify IgAN susceptibility genes. Therefore, some European investigators constituted the European IgAN Consortium which was initially funded by the European Union. Data from linkage analysis studies, family association studies and case-control association studies are reported. To date, the Consortium has identified two loci (located on chromosomes 4q26-31 and 17q12-22), in addition to the previous study which described the first IgAN locus on chromosome 6q22-23. The functional mapping of genes involved in the disease proceeds from the identification of susceptibility loci identified by linkage analysis (step 1) to the isolation of candidate genes within gene disease-susceptibility loci, after obtaining information by microarray analysis carried out on peripheral leukocytes and renal tissue samples (step 2). Then, the process will proceed from the design of RNA interferenceagents against selected genes (step 3) to the application of systematically tested effect of RNA agents on functional cellular assay (step 4). The above combined high-throughput technologies will give information on the pathogenic mechanisms of IgAN. In addition, these data may indicate potential targets for screening, prevention and early diagnosis of the disease and more appropriate and effective treatment.