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In this viewpoint, we summarize the relevance of thromboinflammation in COVID-19 and discuss potential mechanisms of endothelial injury as a key point for the development of lung and distant organ dysfunction, with a focus on direct viral infection and cytokine-mediated injury. Entanglement between inflammation and coagulation and resistance to heparin provide a rationale to consider other therapeutic approaches in order to preserve endothelial function and limit microthrombosis, especially in severe forms. These strategies include nebulized heparin, N-acetylcysteine, plasma exchange and/or fresh frozen plasma, plasma derivatives to increase the level of endogenous anticoagulants (tissue factor pathway inhibitor, activated protein C, thrombomodulin, antithrombin), dipyridamole, complement blockers, different types of stem cells, and extracellular vesicles. An integrated therapy including these drugs has the potential to improve outcomes in COVID-19.

Background and Aims Very few information about COVID-19 in kidney transplant recipients (KTRs) are known and the available evidence are based on limited case series. In KTRs, Acute Kidney Injury (AKI) of different causes is known to be associated with a decreased graft survival: direct viral infection and local inflammation may potentially lead to a premature loss of graft function and to an increased risk of death in COVID-19 patients. To evaluate prevalence, stage, causes of AKI and mortality in KTRs with a positive pharyngeal swab for SARS-CoV-2 in our transplant center located in a 500-bed University Hospital. Method In March-June 2020, we evaluated in 25 COVID-19 KTRs demographic and transplant characteristics, comorbidities, immunosuppressive therapies (IT). Patients were screened for type of symptoms, management of IT, complications and outcome. AKI was graded according to 2012 KDIGO guidelines and causes were investigated basing on both clinical and laboratory variables. AKI prevalence in KTRs was compared to that observed in the whole hospitalized COVID-19 patients. Results During the first wave of pandemic, a total of 945 patients were admitted to our hospital with a reported AKI prevalence of 37%. AKI classified using 2012 KDIGO guidelines associated with an increased mortality risk in the whole population. In this setting, we observed that 25 KTRs followed-up in our University Hospital had a positive molecular diagnosis for COVID-19: median age was 58 years and 80% were males. Considering the most frequent comorbidities, 100% of KTRs had hypertension and 7/25 (29%) had diabetes. Clinical symptoms at enrollment were fever (95%), cough (47%), dyspnea (30%). Regarding IT, 100% of patients were taking CNI, 64% antimetabolite agents and 76% steroids. Of note, 19/25 patients (76%) were hospitalized and 6/19 (31.5%) were admitted to Intensive Care Unit (ICU). Mean length of hospital stay was 23 days. At admission, all KTRs stopped MMF and increased steroid doses, concomitantly decreasing CNI levels. AKI occurred in 60% of KTRs (12/25), AKI KDIGO grading as follow: stage 1 4/12 (33.3%), stage 2 3/12 (25%), stage 3 5/12 (41.7%); development favored by low eGFR/increased serum creatinine (mean serum creatinine 2.06 mg/dl): 4/25 (16%) required hemodialysis and the most frequent cause of AKI was sepsis or septic shock. Overall mortality in KTRs was 37,5% (9/25): of note, 88% (8/9) of patients with a worse outcome had developed AKI. Conclusion AKI prevalence was significantly higher in KTRs than in non-transplanted COVID-19 patients. AKI development was associated with an increased risk of mortality: of note, mortality rate in KTRs was significantly higher than that observed in the non-transplanted patients. COVID-19 lead to a difficult management of IT, in particular for elevated tacrolimus levels due to associated antiviral and antibiotic therapies. COVID-19-associated AKI in KTRs may lead to an increased risk of rejection and premature loss of graft function with the need of skilled nephrological follow-up.

Background and Aims In 2020, SARS-CoV-2 pandemic had a devastating impact on individuals and on national health systems worldwide. Although being primarily a lung disease, COVID-19-associated systemic inflammation and activation of coagulation/complement cascades lead to multiple organ dysfunction including Acute Kidney Injury (AKI). Our aim is to evaluate AKI prevalence and mortality in hospitalized patients during COVID-19 pandemic in a 500-bed University Hospital. Method Observational study on 945 COVID-19 patients (March-May 2020). Data collection from Board Hospital Discharge and serum creatinine (Lab database). AKI stratification in accordance to KDIGO criteria and evaluation of outcome in the different subgroups. The same methodology was adopted to assess AKI prevalence and outcome in 2018-2019. Results 351/945 (37.14%) of all hospital admissions for COVID-19 showed AKI further sub-classified as follows: 173 (18.3%) stage 1, 112 (11.9%) stage 2 and 66 (6.9%) stage 3: the control NO AKI group was 594/945 (62.86%). COVID-associated AKI prevalence was higher than that observed in 2018 (total AKI 17.9%, stage 1 10.7%, stage 2 4.5%, stage 3 2.7%) and 2019 (total AKI 17.2%, stage 1 10.1%, stage 2 4.5%, stage 3 2.6%). During COVID-19 pandemic, in-hospital mortality was 27% for NO AKI group, 28% for total AKI group, further subdivided 24% for stage 1, 45% for stage 2 and 42% for stage 3 group, respectively. Mortality was different from that observed during 2018 (NO AKI 3.77%, total AKI 15.2%, stage 1 9.69%, stage 2 17.24%, stage 3 18.9%) and 2019 (NO AKI 3.56%, total AKI 18.35%, stage 1 10.6%, stage 2 20.1%, stage 3 24.3%). In COVID-19 patients, mean age of NO AKI group was 64.6 ys vs. 71.7 ys of total AKI group divided in 71.6 ys for stage 1, 74.3 ys for stage 2 and 67.9 ys for stage 3, respectively. Mean eGFR at admission was 74.2 ml/min for NO AKI group, 61.3 ml/min for total AKI group divided in 64.3 ml/min for stage 1, 57.8 ml/min for stage 2 and 52.5 ml/min for stage 3. Mean serum creatinine at admission was 1.17 mg/dl in NO AKI group, 1.43 mg/dl for total AKI group divided in1.22 mg/dl for stage 1, 1.4 mg/dl for stage 2 and 2.25 mg/dl for stage 3. Among evaluated comorbidities, only diabetes (p=0,048) and cognitive impairment (p=0,001) were associated with a significant increased risk for AKI development. ICU admission rate was 5% for NO AKI group and 18% for total AKI group divided in 14% for stage 1, 22% for stage 2 and 44% for stage 3. Mean length of hospital stay for NO AKI group was 7.22 days vs 15.08 days for total AKI group divided in 13.67 for stage 1, 15.83 for stage 2 and 21.82 for stage 3. Of note, all different therapies administered to COVID-19 patients did not correlate with AKI incidence. Mean eGFR at discharge was 76 ml/min for NO AKI group vs 66 ml/min for total AKI group divided in 68.7 ml/min for stage 1, 59.3 ml/min for stage 2 and 59.3 ml/min for stage 3. Mean serum creatinine at discharge was 1.14 mg/dl for NO AKI group vs 1.45 mg/dl for total AKI group divided in 1.28 mg/dl for stage 1, 1.58 mg/dl for stage 2 and 2.05 mg/dl for stage 3. Conclusion COVID-19 pandemic is associated with an increased AKI prevalence in hospitalized patients (2-fold increase in all KDIGO stages). AKI associated with an increased risk of mortality: of note, AKI stage2-3 had a strong impact on mortality in comparison to NO AKI group (OR 2.59 and 2.11, respectively). The presence of eGFR >60 ml/min and serum creatinine < 1.2 mg/dl at admission were associated with a lower risk of AKI development: reduced eGFR levels were observed at discharge particularly in AKI stage 2-3. The length of hospital stay and risk of ICU admission depended on AKI incidence and severity. COVID-19 lead to an increased burden for Nephrologists due to increased AKI prevalence: a nephrological follow-up is needed to avoid progression from AKI to chronic kidney disease (CKD).

Background A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. Methods We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. Results At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. Conclusions This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. Clinical trial registry name and registration number Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

Background The risk of life-threatening complications, such as visceral disseminated varicella zoster virus (VZV) infection, is greater in immunosuppressed individuals, such as systemic lupus erythematosus (SLE) patients. Case presentation Here, a case is reported of a Caucasian woman diagnosed with lupus nephritis and anti-phospholipid syndrome, who was subjected to mycophenolate mofetil and high-dose steroid remission-induction therapy. Two months later she developed abdominal pain followed by a fatal rapid multi-organ failure. As no typical skin rashes were evident, death was initially attributed to catastrophic anti-phospholipid syndrome. However, autopsy and virological examinations on archival material revealed a disseminated VZV infection. Conclusions Overall, this case highlights the importance of having a high clinical suspicion of fatal VZV infections in heavily immunosuppressed SLE patients even when typical signs and symptoms are lacking.

New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

Background and Aims EVs (Extracellular vesicles) are circulating microparticles able to mediate cell-to cell communication by carrying proteins, DNA, RNA or antibodies on their surface. EV are emerging as pivotal in renal Antibody-mediated rejection (AMR), one of the major causes of transplant failure associated to a massive complement activation. AMR is characterized by endothelial to mesenchymal transition (EndMT) and the occurrence of tubular accelerated senescence process, known as graft “Inflammaging”. However, the potential role of EVs in accelerating the renal aging and graft fibrosis after AMR is not well understood. Method Plasma EVs were isolated from 10 Acute AMR (AAMR), 10 Chronic AMR (CAMR) patients, 5 stable graft transplanted patients and 5 healthy volunteers. EVs were isolated by ultracentrifugation at 100.000 g for 1h at 4°C, quantified by Nanoparticle Tracking Analysis (Nanosight, NTA EV/ml) and characterized by FACS (Attune Nxt). RPTEC and endothelial cell culture were incubated with EVs (5e+4 EVs/cells target for 24h. MTT test was performed to assess cell viability. Cellular senescence was investigated by qPCR for p21, p53, Klotho and CYP1B1 and SA-β-gal staining were performed. To assess EndMT analysis for CD31, VE-cadherin, Vimentin, Collagen I was performed by FACS. mRNA level of C3 and CFH were also measured by qPCR and C4d deposits were evaluated in endothelial cell colture by IF. Renal biopsies were then analyzed for inflammaging (p16INK4a) and EndMT markers (CD31/αSMA) by IHC and IF. Results The Nanosight analysis showed significant differences in the amount of-EVs count per ml of plasma in AMR patients compared to healthy subjects. EVs appeared to be significantly augmented in acute AMR, in a higher manner than chronic AMR (NTA, p=0.0154). By cytofluorimetric analysis, the endothelial markers CD31 and VE- cadherin appeared to be significantly increased compared of healthy control, indicating a predominant endothelial EV origin (p Conclusion These results suggest a putative role for circulating AMR derived-EVs in inducing the tubular inflammaging by local complement activation and early fibrosis by EndMT. The EVs cargo characterization that is ongoing might highlight novel targets for therapeutic intervention.

Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) are a group of autosomal dominant hereditary nephropathies which share a rather aspecific pathological picture of interstitial fibrosis...

Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium.We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to CKD-epidemiology collaboration), hypertension, maternal age, parity, ethnicity.Maternofetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. Kidney transplantation patients with estimated glomerular filtration rate greater than 90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ("progressive CKD") are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 vs 1: relative risk 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient.The maternofetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney disease.

Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) are a group of autosomal dominant hereditary nephropathies which share a rather aspecific pathological picture of interstitial fibrosis and tubular atrophy (IFTA) and a slowly progressing tubulointerstitial clinical profile: end-stage renal disease (ESRD) generally occurs between 30 and 50 years. Four types of ADTKD have been described so far, each showing some peculiarities: hepatocyte nuclear factor-1 β (HNF1β) ADTKD, in which ADTKD can be associated with renal cysts and a wide spectrum of congenital abnormalities of kidney and urinary tract (CAKUT) and extra-renal manifestations (diabetes, liver enzyme alterations, genital malformations), uromodulin (UMOD) ADTKD, characterised by early onset of hyperuricemia and gout, mucin-1 (MUC-1) ADTKD, a recently discovered form which appears to be an isolated tubulointerstitial nephropathy, and renin (REN) ADTKD, which appears in childhood and is characterised by anemia and mild signs of hyporeninism. A better awareness is needed in order to perform genetic analysis whenever clinical setting is compatible with this nephropathy. A timely diagnosis can have an important impact on both the patient and his family members in terms of therapy and prognosis, also at the prospect of renal transplant.

BACKGROUND Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies. RESULTS We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate

Renal tubular acidosis (RTA) refers to a group of disorders of multiple etiology characterised by a hyperchloremic, normal anion-gap metabolic acidosis caused by different defects affecting several mechanisms of urinary acidification: an impaired secretion of protons by collecting duct in distal hypokalemic RTA (type 1), impaired resorption of bicarbonate in proximal RTA (type 2), a mixed proximal and distal defect in RTA type 3 and an impaired ammoniagenesis due to an absolute or functional hypoaldosteronism in distal hyperkalemic RTA (type 4). Etiology is heterogeneous and ranges from primitive genetic forms to secondary RTA within a multi-system disorder such as autoimmune disease, paraproteinemia and calcium-phosphate disorders. Drug-induced RTA has been increasingly reported over the last decade due to widespread use of some molecules (e.g. antiviral and oncologic agents, inhibitors of renin-angiotensin system). The diagnosis of RTA is based on assessment of serum and urine anion-gap, whereas differe...

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host-response to infections. Osteopontin (OPN) is an extracellular matrix protein involved in the inflammatory response. Our aim was to evaluate the diagnostic and prognostic performance in sepsis of a single OPN determination in the Emergency Department (ED). We conducted a single-centre prospective observational study in an Italian ED where we enrolled 102 consecutive patients presenting with suspected infection and qSOFA &ge, 2. OPN plasma concentration was found to be an independent predictor of sepsis (OR = 1.020, 95% CI 1.002&ndash, 1.039, P = 0.031) and the diagnostic receiver operating characteristic (ROC) curve resulted in an area under the curve (AUC) of 0.878. OPN levels were positively correlated to plasma creatinine (r = 0.401 with p = 0.0001), but this relation was not explained by the development of acute kidney injury (AKI), since no difference was found in OPN concentration between AKI and non-AKI patients. The analysis of 30-days mortality showed no significant difference in OPN levels between alive and dead patients (p = 0.482). In conclusion, a single determination of OPN concentration helped to identify patients with sepsis in the ED, but it was not able to predict poor prognosis in our cohort of patients.

Aim: To perform a systematic review and meta-analysis of studies evaluating the influence of recipient angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism on kidney function in renal transplant recipients. Materials & methods: A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to December 2014. The methodological quality of identified studies was assessed using the MINORS criteria. Results: A total of 15 studies evaluating the role of recipient ACE I/D were included in the meta-analysis. In overall analyzes and subsequent subgroup and sensitivity analyzes, no evidence emerged of an effect of ACE I/D on serum creatinine levels, creatinine clearance or glomerular filtration rate. Conclusion: Although further investigation is still needed to determine the role of donor ACE genotype, recipient ACE I/D does not play a significant role on kidney function in renal transplant patients.

Rituximab (RTX), a B-lymphocytes depleting monoclonal antibody, deeply changed the therapeutic landscape of secondary glomerulonephritis in the past decade.RTX has proved to be as effective as cyclophosphamide in inducing remission in ANCA-associated vasculitis and better than azathioprine as maintenance therapy in three different RCT. Treatment's duration and modality, however, remain debated.RTX has been widely used in resistant or relapsing proliferative lupus nephritis (LN), with positive results reported by retrospective studies; however, when employed as an “add-on” induction therapy in a RCT, it did not show a definite additive effect to standard therapy with mycophenolate mofetil and steroid in moderate forms of LN. In prospect, it remains a promising tool both as second-line therapy for resistant forms and as a “steroid-sparing” agent to strengthen induction and to allow reduced or minimal maintenance therapy.RTX is effective in the treatment of HCV-related cryoglobulinemic vasculitis, including ...

Background The renal assist device (RAD) is a blood purification system containing viable renal tubular epithelial cells (TECs) that has been proposed for the treatment of acute kidney injury (AKI) and multiple organ failure. Perfluorocarbons (PFCs) are oxygen carriers used for organ preservation in transplantation. The aim of this study was to investigate the effect of PFCs on hypoxia- and sepsis-induced TEC injury and on renal CD133+ progenitor differentiation in a microenvironment similar to the RAD. Methods TECs were seeded in a polysulphone hollow fibre under hypoxia or cultured with plasma from 10 patients with sepsis-associated AKI in the presence or absence of PFCs and were tested for cytotoxicity (XTT assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay, caspases, enzyme-linked immunosorbent assay, Fas/Fas Ligand pathway activation), mitochondrial activity, cell polarity [transepithelial electrical resistance (TEER)] and adenosine triphosphate production. The effect of PFCs on proliferation and differentiation of human CD133+ progenitors was also studied. Results In the presence of PFCs, TECs seeded into the polysulphone hollow fibre showed increased viability and expression of insulin-like growth factor 1, hepatocyte growth factor and macrophage-stimulating protein. Plasma from septic patients induced TEC apoptosis, disruption of oxidative metabolism, alteration of cell polarity and albumin uptake, down-regulation of the tight junction protein ZO-1 and the endocytic receptor megalin on the TEC surface. These detrimental effects were significantly reduced by PFCs. Moreover, PFCs induced CD133+ renal progenitor cell proliferation and differentiation towards an epithelial/tubular-like phenotype. Conclusions PFCs improved the viability and metabolic function of TECs seeded within a polysulphone hollow fibre and subjected to plasma from septic AKI patients. Additionally, PFCs promoted differentiation towards a tubular/epithelial phenotype of CD133+ renal progenitor cells.

Despite the growing interest in daily hemodialysis (DHD), logistic and economic factors limit its dissemination. Not the least of these factors is the lack of uniform criteria for measuring efficiency. From November 1998 to November 2000, 19 patients were on DHD in our unit. The dialysis prescription was bicarbonate buffer; 6 sessions per week; 2 - 3 hours; blood flow 250 - 350 mL/min; individual K, HCO3 , and Na levels; membrane 1.6 - 2 m2 (polysulfone, polycarbonate). The prescription represented the minimum dialysis requirement; patients were free to add up to 30 minutes per session, further increase or any decreases needed confirmation by the caregivers. The aim of the study was to assess Kt/Vurea variability in this clinical setting, and to identify the minimum number of dialysis sessions required to obtain a reliable estimate of weekly Kt/Vurea [relative error (RE) < 10%]. We studied 169 dialysis sessions in 13 clinically stable patients on DHD for ≥ 3 months, with ≥ 3 Kt/Vurea measurements within 2 weeks (median: 10; range: 3 - 32 sessions), tested in the same laboratory. To assess variability, we employed the simplest formula (the Lowrie Kt/Vurea ), the widely used Daugirdas II formula, and the derived single-pool equivalent renal clearance (EKRc ), according to Casino. The variability of Kt/Vurea per session was high (Lowrie: RE = 2.5% - 22.1%; Daugirdas II and EKRc : RE = 3.6% - 24%). Averaging several dialysis sessions leads to a more reliable estimate of weekly efficiency (6 sessions: RE = 0; 3 sessions, Lowrie formula: Kt/Vurea RE = 1.1% - 9.7%; Daugirdas II and EKRc : RE = 1.6% - 10.6%). In patients with wide time variations, variability may be lower if weekly efficiency is determined on the basis of "average hourly Kt/Vurea ," which is calculated by dividing Kt/Vurea by the number of hours in the studied sessions, and then multiplying by the hours of dialysis performed in the whole week (Lowrie formula, Kt/Vurea : RE = 4.8% - 16.6% for 1 session, 2.1% - 7.3% for 3 sessions). Once again, the RE decreases sharply when data from 3 sessions are considered. Therefore, for flexible DHD, we suggest averaging the data from ≥ 3 sessions for weekly Kt/Vurea assessment.

Daily hemodialysis (DHD) is a promising option; however, logistic obstacles and clinical perplexities limit its dissemination. Understanding the mechanisms of, and the time until, the onset of improved well-being may help to quantify clinical advantages and to define the minimum length of a "trial" of daily dialysis. By following 30 patients treated in 4 centers, this study aimed to determine how long a period of time is needed until a patient experiences subjective improvement. From November 1998 to November 2000, 30 patients tried at least 2 weeks of short daily dialysis in four Northern Italian centers of Piemonte and Valle d'Aosta. The DHD (2 - 3 hours; blood flow 270 - 350 mL/min; individual HCO3 , Na, K) was performed at home or in a center. Motivations to try DHD, fears and concerns regarding DHD, and changes in perceived well-being were assessed by semi-structured interview. The main clinical indications for a trial of DHD were poor tolerance of conventional treatment, cardiovascular disease, and hypertension or hypotension; only 6 patients had no comorbidity at start. The patients' main reasons for choosing DHD were related to job problems and the search for a better treatment. Most of the patients continued DHD because of improved well-being; logistic reasons accounted for the drop-outs (5 patients). The main fears were related to logistic aspects, vascular access problems, and excessive involvement of the partner on home dialysis. Improved well-being was reported by 28 of 30 patients; 2 patients reported no difference. Subjective improvement was perceived within 2 weeks in 22 of 30 patients, and within 1 month in 28 of 30 patients. An offer of a 2 - 4 week trial of DHD may help patients and caregivers to determine whether subjective and objective benefits outweigh logistic problems and whether a permanent transfer to DHD is worthwhile.

TCF7L2 rs7903146 CT polymorphism is associated with diabetes in the general population but its independent impact on cardiovascular disease is debated. On this basis, we investigated its association with major adverse cardiac events (MACE) in a single-center cohort of non-diabetic kidney transplant recipients (KTRs).Patients with pretransplant diabetes were excluded and patients who developed post-transplant diabetes were censored at time of diagnosis.rs7903146 CT polymorphism appeared to modulate the risk of MACE: 5-year prevalence was 0.8% in CC patients, 7.2% in CT patients and 9.7% in TT patients (P.001). TCF7L2 rs7903146 was an independent predictor of MACE in a multivariate Cox regression model (for each T allele, HR: 2.99, 95%CI: 1.62-5.52, P.001), together with history of cardiac ischemic events (HR: 8.69, 95%CI: 3.57-21.16, P.001), DGF (HR: 2.42, 95%CI: 0.98-5.95, P=.056) and HLA-mismatches (for each mismatch: HR: 1.55, 95%CI: 1.00-2.43, P=.053). Introduction of rs7903146 CT polymorphism into a model based on these clinical variables significantly increased predictive power for MACE (P=.003).TCF7L2 rs7903146 T allele may be strongly and independently associated with MACE in non-diabetic KTRs. These findings suggest the possibility of employing this SNP to more accurately stratify cardiological risk in KTRs.

Type IV renal tubular acidosis (RTA IV) is a form of hyperchloremic RTA caused by an absolute or functional hypoaldosteronism that determines a distal acidification defect by inhibiting ammoniagene...

L'acidosi tubulare tipo IV (RTA di tipo IV) è una forma di acidosi metabolica ipercloremica causata da un ipoaldosteronismo assoluto o funzionale, che determina un deficit dell'acidificazione distale attraverso un'inibizione dell'ammoniogenesi e dell'escrezione di H+ a livello del dotto collettore. L'eziologia è spesso multifattoriale e include disordini che determinano una riduzione dei livelli di aldosterone o della sensibilità del dotto collettore alle azioni dell'ormone. I farmaci che inibiscono il sistema renina-angiotensina (RAS) a qualunque livello aumentano il rischio di sviluppare una RTA di tipo IV, soprattutto quando sono impiegati in associazione in pazienti anziani affetti da diabete mellito, scompenso cardiaco e insufficienza renale cronica oppure portatori di trapianto renale. La diagnosi si basa sul riscontro di un'iperkaliemia sproporzionata alla funzione renale associata a un'acidosi metabolica con anion gap sierico normale e anion gap urinario positivo; il pH urinario può essere inferiore a 5.5. Vari elementi laboratoristici consentono la diagnosi differenziale con l'acidosi tubulare distale di tipo 1. L'impatto clinico della RTA di tipo IV sta diventando sempre più rilevante a causa della diffusione di farmaci bloccanti il RAS in pazienti anziani già affetti da condizioni a rischio per questa complicanza, contribuendo a una rivalutazione critica delle indicazioni ad alcune terapie di associazione. Lo sviluppo di iperkaliemia pone in questi contesti un dilemma terapeutico, in quanto proprio i pazienti a maggior rischio per RTA di tipo IV sono quelli che possono trarre il massimo vantaggio cardiovascolare dal blocco farmacologico del RAS. È, quindi, essenziale trovare un punto di equilibrio nel rapporto rischio/beneficio nel singolo paziente, prevenendo la RTA di tipo IV con opportune misure.

Background Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. The aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician. Methods We retrospectively assessed all patients who had received a diagnosis of a rare genetic disorder after KTx. Results In our center, more than 30% (278/911) of kidney transplant (KTx) recipients were diagnosed with a causal nephropathy: Prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8-dihydroxyadeninuria (2,8-DHA) disease (n = 2), HNF-1B-associated nephropathy (n = 2), UMOD-related nephropathy (n = 5), Fabry disease (n = 1), INF2 focal segmental glomerulosclerosis (n = 1), and Senior-Loken syndrome (n = 1). 2,8-DHA nephropathy relapsed in both patients causing an acute renal failure and jeopardizing the graft. Conclusions Kidney transplant recipients without a diagnosis of causal nephropathy appear to be a selected population in which rare genetic diseases might be more common than expected. As even a belated diagnosis after KTx can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in KTx recipients without a known causal nephropathy.

The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/β1, p = 0.039; LPM7/β5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin–proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.

Background HNF1B gene mutations might be an underdiagnosed cause of nephropathy in adult patients mainly because of their pleomorphic clinical presentations. As most studies are based on paediatric populations, it is difficult to assess the likelihood of finding HNF1B mutations in adult patients and consequently define clinical settings in which genetic analysis is indicated. The aim of this study was the search for mutations in the HNF1B gene in a cohort of unrelated adult patients with nephropathy of unknown aetiology. Methods Patients were tested for the HNF1B gene if they had chronic kidney disease of unknown origin and renal structure abnormalities (RSA) or a positive family history of nephropathy. The HNF1B coding sequence and intron–exon boundaries were analysed by direct sequencing. The search for gene deletions was performed by Multiple Ligation Probe Analysis (MLPA). Results Heterozygous mutations were identified in 6 out of 67 screened patients (9.0%) and included two whole gene deletions, one nonsense (p.Gln136Stop), two missense (p.Gly76Cys and p.Ala314Thr) mutations and a frameshift microdeletion (c.384_390 delCATGCAG), the latter two (c.384_390 del and p.Ala314Thr) not ever being reported to date. Mean age of the mutated patients at screening was 48.5 years with a M/F ratio of 2/4. The clinical manifestations of affected patients were extremely pleomorphic, including several urological and extra-renal manifestations. Conclusions Mutations of HNF1B could explain chronic kidney disease in up to 9% of adult patients with a nephropathy of unknown aetiology and RSA: therefore an HNF1B mutation analysis should be considered in this group of patients.

IntroductionPrimary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease may have different long-term outcomes. After 10 years of follow-up, 35%–50% of the untreated patients with persistent nephrotic syndrome may die or progress to end stage renal disease. The 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend that initial therapy should consist of alternating steroids and an alkylating agent for 6 months. Recent observational studies showed that the anti-CD20 antibody rituximab may be effective in inducing remission. We designed a pilot multicentre randomised trial to inform the design of a larger trial testing the efficacy and safety of treatment with steroids and cyclophosphamide versus rituximab in patients with primary MN and heavy proteinuria (>3.5 g/24 hours).Methods and analysisThis pilot, open-label, two-parallel-arm, randomised clinical trial will enrol 70 patients with primary MN and heavy proteinuria. Patients will be randomised in a 1:1 ratio to either the intervention arm (rituximab) or the active comparator arm (corticosteroid/alkylating-agent therapy). The study will provide estimates of the probability of complete remission of proteinuria and risk of serious side effects at 12 months to inform the design of a larger trial. We will also assess the recruitment potential of each participating centre to address study feasibility.Ethics and disseminationThe trial received ethics approval from the local ethics boards. We will publish pilot data to inform the design of a larger clinical trial.Trial registration numbersNCT03018535; 2011-006115-59.

Background We sought to evaluate the best therapeutic management of postbiopsy arteriovenous fistulas (AVFs) in transplanted kidneys. Methods Between January 2005 and December 2011, we observed 17 cases of postbiopsy AVF in transplanted kidneys (9 asymptomatic; 8 symptomatic). Asymptomatic cases were managed conservatively, while patients with symptomatic AVF underwent endovascular treatment. We used a technique that consisted in a superselective transcatheter embolization of the afferent branch. We evaluated the technical success (postoperative closure of AVF), the immediate clinical efficacy (cessation of symptoms), and clinical efficacy at follow-up (measurement of serum creatinine at 7 days and 6 and 12 months compared with preoperative levels using t -tests). Results Asymptomatic AVFs resolved spontaneously, while the endovascular treatment in symptomatic AVFs showed a complete technical and clinical success with prompt remission of the presented symptoms. We observed a statistically significant reduction in serum creatinine at 7 days and 6 and 12 months postoperatively (mean creatinine—preoperative: 3.23 ± 1.4 mg/dL; 7 days: 2.25 ± 0.8 mg/dL; 6 months: 1.65 ± 0.28 mg/dL; 12 months: 1.4 ± 0.26 mg/dL; in all cases P Conclusions In our experience, asymptomatic AVFs could be managed conservatively with close follow-up while the endovascular treatment for symptomatic AVFs is both safe and effective in the short- and long-term.

Introduction Dual kidney transplantation (DKTx) to reduce the disparity between demand and supply of organs was evaluated in two Italian centers (Bari and Novara). Materials and Methods Between October 2000 and October 2011, we performed 97 DKT (26 ipsilateral/71 bilateral) following routine biopsy of all kidneys obtained from expanded criteria donors by Remuzzi-Karpinsky scores. The reference group was 379 single grafts from donors older than 60 years single kidney transplantation ([SKT] × > 60). Results Good postoperative renal function was observed in 56 DKTx (57.7%); whereas acute tubular necrosis requiring dialysis was observed in 41 (42.3%) patients. After a mean follow-up of 60 months, DKTx graft survivals were 96%, 93%, and 90% and patient survivals, 96%, 91%, and 91% at 1, 3, and 5 years, respectively. Complications in expanded criteria donor kidney transplantations included a high rate of cytomegalovirus (CMV) disease especially dual kidney cases. DKTx represented the only independent risk factor for CMV disease upon multivariate analysis (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.28–4.2; P = .006). We did not observe any significant difference in graft or patient survival between DKTx and SKTx > 60 years. Conclusions We observed good outcomes up to 5 years after transplantation in terms of graft and patient survival despite the use of inferior grafts. Comparing DKTx and SKT > 60, we noted that the mean Karpinski score for SKTx was significantly better than DKTx, although patient and graft survivals were similar. This trend confirms that the use of a biopsy to allocate expanded criteria donor kidneys may be too protective; therefore, the criteria to select DKTx require further refinement.

Objectives To assess prospectively the safety and efficacy of transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms attributable to benign prostatic hyperplasia (BPH) in patients who have undergone renal transplantation (RT). To assess the impact of TURP on renal graft function. Patients and Methods Urological and renal functional outcomes of TURP performed in RT recipients for treatment of lower urinary tract obstruction attributable to BPH were prospectively assessed in a series of 32 consecutive patients with follow-up of ≥48 months. Maximum urinary flow rate (Qmax) at uroflowmetry, International Prostate Symptom Score (IPSS), post-void residual urine volume (PVR), haemoglobin and serum creatinine (sCr) levels were recorded before TURP and 1, 6, 24 and 48 months after the procedure. The trends in these variables after TURP were evaluated. Early and delayed complications were assessed and graded according to the Clavien classification system. Results TURP was performed at a mean of 6 months after RT. No intraoperative complications occurred. Seven postoperative complications were observed (21.9%): two Clavien grade II and five Clavien grade IIIa. Qmax, IPSS and PVR improved significantly after surgery and the improvement was maintained until 48 months. No patient required a repeat TURP during follow-up. SCr levels significantly decreased 1 and 6 months after TURP and did not significantly increase at long-term follow-up. Conclusions TURP for lower urinary tract obstruction attributable to BPH in RT recipients is safe and effective since it improves urinary flow, bladder emptying and related urinary symptoms. TURP allows an early significant improvement of graft function that is maintained at a follow-up of 48 months.

Monoclonal components (MC) formed by chains/fragments of intact/truncated globulin components produced in different lymphoproliferative diseases are responsible for monoclonal immunoglobulin deposition disease (MIDD) and consequent tissue damage by organized (amyloid fibrils) or non-organized (amorphous) deposits. The kidneys are the most commonly affected organs in MIDD, and renal failure represents an important adverse factor for prognosis. The renal outcome and the role of renal pathology in diagnosing MIDD was evaluated in 289 elderly patients with multiple myeloma (MM, n=115) and monoclonal gammopathy (MGUS, n=174). Renal impairment was the only significant risk factor for patient death, while significant risk factors for renal impairment were diabetes (HR 3.65, 95% CI: 2.08-6.41), light chain (LC) proteinuria (HR 2.18; 95% CI: 1.10-4.32) and type of MC (p=0.0019). Renal pathology documented MIDD in 12/30 cases (40%): six cases of AL-amyloidosis, two of LC disease, one of heavy chain disease and three of cast nephropathy, as well as four cases of glomerulonephritis, eight of arteriolosclerosis and six of normal picture. Main conclusions are that diabetes, sharing common glomerular damage with LC disease, is the strongest risk factor for progression of renal disease, and glomerular proteinuria or heavy LC proteinuria should raise a strong suspicion index of MIDD and prompt pathology assessment to reach the correct diagnosis.

Heparins are used in "therapeutic doses" for systemic anticoagulation to treat patients who have confirmed venous thromboembolism, or in "prophylactic doses "for the prevention of venous thromboembolism: they are generally lower doses and are employed once a day. Structure-function relationships are strongly influenced by the chain length of the molecules. In fact, unfractionated heparin (UFH) binds to ATIII lysine site leading to a conformational change of the ATIII arginine reactive centre able to create a covalent binding to the active centre serine of thrombin in a ternary complex formation composed by heparin, ATIII and thrombin. On the other side, low molecular weight heparins (LMWHs) are too short to be able to form this ternary complex, and mainly exert their anticoagulant effect by binding the factor Xa, always via ATIII. Lastly, the short unique pentasaccharidic sequence which is crucial for heparin's activity and has been recently synthesized as Fondaparinux, only acts via the formation of the high affinity ternary complex with ATIII-factor Xa. Due to their structure-function relationships, LMWHs cannot be monitored by conventional coagulation test used for monitoring UFH and need more specific anti-factor Xa activity determinations, but monitoring has been considered unnecessary in the general population due to a predictable dose/effect ratio. However, a disturbing rise of bleeding complications in patients with renal failure treated with LMWH has been published in the last years, that is explained by the accumulation of LMWHs in this setting, due the consequences of structure-metabolisms relationships of the small members of the heparin's family. In this context, physicians are often left to a "best guess" method of empiric dose adjustment, which is at risk of achieving inappropriate targets, with a percentage of values above and below target of 51% and 34%, respectively, depending on LMWHs dosage, body mass index and renal function. Without anti-Xa activity monitoring, the quality of care delivered in the setting of renal failure is poor, as over-prophylaxis can result in potentially dangerous anticoagulation, while under-prophylaxis can result in life-threatening thrombosis.

Treatment of idiopathic membranous nephropathy is based on a 'symptomatic' therapy that includes ACE inhibitors or angiotensin II receptor antagonists, and on an 'aetiological' therapy aimed at modulating underlying immunological mechanisms. The role of the latter is still debated given the usually indolent course of disease; furthermore, traditional immunosuppressants would not have an impact on patient and renal survival according to a systematic review of literature. However, up to 40% of untreated patients eventually develop end-stage renal disease and remission of nephrotic syndrome protects patients from related life-threatening complications and is the strongest positive prognostic factor for long-term kidney function. Therefore, immunosuppressive therapy seems to be rational in high-risk patients with nephrotic syndrome or deteriorating renal function. This article outlines a possible role for each 'aetiological' therapy on the basis of available evidence in order to provide some practical recommendations. The first-line therapy is based on a 6-month regimen of alternating corticosteroids and an alkylating agent ('Ponticelli' regimen), whereas oral ciclosporin and intramuscular corticotrophin (adrenocorticotrophic hormone) are alternatives that provide comparable results in terms of remission of proteinuria, with a different adverse effect profile. New drugs are emerging as potential treatments, such as mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Specific settings, such as chronic renal failure or elderly age, require a careful balance between benefits and toxicity of immunosuppression. The tailor-made use of this repertoire of drugs can provide a tool to achieve remission of proteinuria and modify the natural course of idiopathic membranous nephropathy.

Background Although renal biopsy is largely employed, even in old patients with systemic diseases, few clinical studies have addressed its risk management. We aimed to obtain a comprehensive assessment of safety/utility ratio of percutaneous renal biopsy. Patients and methods Retrospective review of all the 1387 patients who consecutively underwent renal biopsy in a single centre over three decades (1973–2002) was made, with calculation of complications, multivariate logistical analyses to evaluate risk factors of complications, and rate of alteration of clinical hypotheses by pathological diagnosis. Results There were no deaths and five major complications, (0·36%). One nephrectomy (0·07%), two surgical revisions (0·1%) and two arterial-venous fistulae (0·1%). There were also 337 minor bleeding complications (24·2%) (16·4% gross haematuria and 7·8% clinically relevant haematomas needing at least prolonged bed rest). Multivariate analyses demonstrated that the risk for complications was significantly increased by systemic autoimmune diseases with odds ratio (OR) 2·06, 95% confidence interval (CI) = 1·40–3·01, end-stage kidney/acute-tubular necrosis (OR 2·96, 95% CI = 1·19–7·30), and prolonged bleeding time test (BTT) (OR 1·87, 95% CI = 1·17–2·83). Among the 1288 cases in which a clinical hypothesis before renal biopsy was recorded, renal pathology changed previous diagnoses in 423/1,288 (32·8%) of cases. Conclusions Risk assessment demonstrates that renal biopsy is a useful procedure with a low incidence of serious complications. Platelet function is the only modifiable factor significantly related to bleeding complications, suggesting the need for a more standardized alternative to the BTT. Platelet function should be evaluated to select low-risk patients for renal biopsy as ‘a day case procedure’, in order to build adequate risk management strategies.

Components of the renin-angiotensin system and endothelial nitric oxide synthase may co-operate in spiral artery remodelling during placentation, and thus reduce the uteroplacental resistance typical of normal pregnancy. Since lack of such remodelling and abnormal placentation are specific features of pre-eclampsia, it has been suggested that abnormal function of both components of the renin-angiotensin system and endothelial nitric oxide synthase may be involved in its pathogenesis. However, previous studies of the association between pre-eclampsia and polymorphisms of single genes encoding renin-angiotensin system components and endothelial nitric oxide synthase have yielded conflicting results. The aim of this study was to assess if interactions among different polymorphisms of the renin-angiotensin system and nitric oxide synthase are involved in the pathogenesis of pre-eclampsia.Some 359 pregnant women were enrolled: 103 normotensive, 50 with chronic hypertension, 86 with gestational hypertension, and 120 with pre-eclampsia. DNA analysis was performed to evaluate angiotensin-converting enzyme I/D, angiotensin-II receptor 1 1166A/C, angiotensinogen M235T and endothelial constitutive nitric oxide synthase 4b/a polymorphisms. Odds ratios (OR) with 95% confidence interval (CI) and chi2 tests were calculated.The frequency of single gene polymorphisms was similar in each group. The frequency of pairs including the DD genotype of the angiotensin-converting enzyme I/D polymorphism plus other homozygous genotypes was significantly higher in pre-eclamptic patients than in controls (OR=3.04, 95% CI=1.16-7.93).Synergism of angiotensin-converting enzyme I/D and other polymorphisms of renin-angiotensin system components and nitric oxide synthase may be a risk factor for pre-eclampsia.

Medullary cystic kidney disease type 1 (MCKD1; OMIM #174000) is a familial progressive tubule-interstitial nephropathy belonging to the recently defined group of autosomal dominant tubulointerstitial kidney diseases (ADTKD). A specific type of cytosine insertion in the extracellular variable number tandem repeat (VNTR) domain of the MUC1 gene causing the disease was tested in a group of 21 families with ADTKD. We identified this type of MUC1 mutation in two families, whose affected members are described in detail in this case report. Affected (ADTKD-MUC1) members developed end-stage renal disease (ESRD) with a higher incidence (p = 0.033) and at a younger age (p = 0.013) than probands with ADTKD but without this type of mutation. All patients with MUC1-associated kidney disease shared a rather unspecific tubule-interstitial laboratory pattern without medullary cysts, leading to ESRD between the age of 33 and 47 years. We were not able to identify any single common extra-renal feature among affected patients, even if they had various comorbidities, which are described in detail. We identified this type of MUC1 mutation in 9.5 % of families from an ADTKD Italian cohort; larger studies are needed to better define the criteria for genetic testing for this type of mutation.

Several genetic polymorphisms modulate the risk of posttransplant diabetes mellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined.Genetic analysis was performed in 464 kidney transplantation recipients to evaluate whether transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism is associated with the risk of PTDM and a meta-analysis of similar studies including our results was performed (total kidney transplantation recipients, n = 3105). A predictive model of PTDM was built on the basis of this polymorphism and clinical parameters.In our cohort, 163 patients possessed the CC genotype of rs7903146 (35.1%), 237 were CT (51.1%), and 64 were TT (13.8%): their 2 years PTDM incidence was, respectively, 7.8%, 11.9%, and 22.7%. At multivariate analysis, age (per year; hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.005-1.054; P = 0.017), body mass index (25.0-29.9 vs25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; ≥30 vs25.0; HR, 5.70; 95% CI, 2.77-11.74; P0.0001), TCF7L2 rs7903146 (per each T allele; HR, 1.81; 95% CI, 1.26-2.59; P = 0.001) and previous transplants (HR, 2.80; 95% CI, 1.39-5.64; P = 0.004) emerged as independent predictive factors for PTDM.Meta-analysis of present and 5 previous studies showed higher risk of PTDM in carriers of rs7903146 TT genotype (odds ratio, 1.95; 95% CI, 1.39-2.74; P0.0001) and absence of heterogeneity among studies (I = 0%).Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM.In renal transplant patients, TCF7L2 rs7903146 is strongly and independently associated with PTDM and might hold the potential to identify patients at risk for this complication.