End-proximal tubule phosphate concentration increases as GFR falls in humans: measurement by means of a lithium clearance-based methodology.

BACKGROUND: Microscopic nephrocalcinosis secondary to intratubular calcium phosphate (CaP) precipitation is thought to accelerate progression to end-stage renal failure in chronic kidney diseases. In phosphorus (P)-loaded uninephrectomized rats, intratubular CaP crystal formation and progressive tubular damage occurred when end-proximal tubule P concentration (ePTpc) increased above a threshold level. METHODS: We have calculated ePTpc in humans by urine P and creatinine concentration, with the end-proximal tubule fluid volume calculated either as lithium (Li) clearance (ePTpc-Li) or as a fixed 0.7 fraction of glomerular filtration rate (GFR), as published (ePTpc-70). Healthy people undergoing living transplant kidney donation before (DON-pre, n = 70) and after (DON-post, n = 64) nephrectomy and 25 patients with stage 2-5 CKD were investigated while on regular free diet. RESULTS: ePTpc showed a stepwise increase with decreasing functional renal mass (DON-pre 2.51 ± 0.99 and 1.56 ± 0.47 mg/dL for ePTpc-Li and -70 calculation, respectively; DON-post 3.43 ± 1.14 and 2.18 ± 0.44;  CKD 5.68 ± 3.30 and 3.00 ± 1.30, P < .001 for all); ePTpc was inversely correlated with Ccr and directly with PTH, fractional P excretion and excretion (UpV) corrected for GFR (P < .001 for all), but not with Pp. ePTpc-Li and ePTpc-70 were significantly correlated (r = 0.62, P < .001), but ePTpc-70 was lower than the corresponding ePTpc-Li. Levels of ePTpc increased above a suggested dangerous threshold when daily UpV/GFR was higher than about 10 mg/mLCcr. CONCLUSIONS: ePTpc progressively increases in humans as functional renal mass falls independently from plasma P levels. Main determinants of ePTpc rise are GFR fall, degree of phosphaturia per unit GFR and P intake corrected for GFR. It may become a novel, potentially useful, indicator to guide management of CKD patients.

Clinical and genetic characteristics of Dent's disease type 1 in Europe.

BACKGROUND: Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis-nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. METHODS: A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. RESULTS: A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. CONCLUSIONS: Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.

Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey.

BACKGROUND: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). METHODS: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1°follow-up (FU) year; secondary endpoint: response at 1°line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. RESULTS: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. CONCLUSIONS: sGIN-AKI-patients with no complete recovery at 1°line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

Dialysis urea removal metrics may not translate into proportional removal efficiency of non-urea solutes. We show that the Kt factor (plasma volume totally cleared of any solutes) differentiates removal efficiency of non-urea solutes in different technologies, and can easily be calculated by instant blood-dialysate collections. We performed mass balances of urea, creatinine, phosphorus and beta2-microglobulin by whole dialysate collection in 4 low-flux and 3 high-flux hemodialysis, 2 high-volume post-hemodiafiltration and 7 short-daily dialysis with the NxStage-One system. Instant dialysate/blood determinations were also performed at different times, and Kt was calculated as the product of the D/P ratio by volume of delivered dialysate plus UF. There were significant differences in single session and weekly Kt (whole dialysate and instant calculations) between methodologies, most notably for creatinine, phosphorus and beta2-microglobulin. Urea Kt messured in balance studies was almost equal to that derived from the usual plasma kinetic model-based Daugirdas' equation (eKt/V) and independent V calculation, indicating full correspondence. Non-urea solute Kt as a fraction of urea Kt (i.e. fractional removal relative to urea) showed significant differences between technologies, indicating non-proportional removal of non-urea solutes and urea. Instant Kt was higher than that in full balances, accounting for concentration disequilibrium between arterial and systemic blood, but measured and calculated quantitative solute removal were equal, as were qualitative Kt comparisons between technologies. Thus, we show that urea metrics may not reliably express removal efficiency of non-urea solutes, as indicated by Kt. Kt can easily be measured without whole dialysate collection, allowing to expand the metrics of dialytic efficiency to almost any non-urea solute removed by dialysis.

Single Session and Weekly Beta 2-Microglobulin Removal with Different Dialytic Procedures: Comparison between High-Flux Standard Bicarbonate Hemodialysis, Post-Dilution Hemodiafiltration, Short Frequent Hemodialysis with NxStage Technology and Automated Peritoneal Dialysis.

BACKGROUND: NxStage System One cycler (NSO) is a widespread system for home daily dialysis. Few data are available on the impact of this "low dialysate volumes system" on the removal rate of poorly diffusible, time-dependent solutes like ß2-microglobulin (ß2M). METHODS: Single-session and weekly balances of ß2M were performed and compared in 12 patients on daily NSO, 13 patients on standard high-flux bicarbonate dialysis (BHD), 5 patients on standard post-dilution on line hemodiafiltration (HDF), and 13 patients on automated peritoneal dialysis (APD). RESULTS: Intradialytic fall of plasma water ß2M levels (corrected for rebound) was 65.2 ± 2.6% in HDF, 49.8 ± 9.1% in BHD, and 32.3 ± 6.4% in NSO (p < 0.001 between all groups). Single treatment dialysate removal was much less in APD (19.4 ± 20.4 mg, p < 0.001) than in any extracorporeal technologies, and was less in NSO (126.2 ± 35.6 mg, p < 0.001) than in BHD (204.9 ± 53.4 mg) and HDF (181.9 ± 37.6 mg), with no differences between the latter 2; however weekly removal was higher in NSO (757.3 ± 213.7 mg, p < 0.04) than in BHD (614.8 ± 160.3 mg) and HDF (545.8 ± 112.8 mg). Extrapolated ß2M adsorption to the membrane was negligible in BHD, 14.7 ± 9.5% of total removal in HDF and 18.3 ± 18.5% in NSO. Integration of single session data into a weekly efficiency indicator (K × t) showed total volume of plasma cleared in NSO (33.4 ± 7.7 L/week) to be higher than in BHD (26.9 ± 7.2 L/week, p < 0.01) and not different than in HDF (36.2 ± 4.7 L/week); it was negligible (3.2 ± 1.0) in APD. CONCLUSIONS: Weekly ß2M removal efficiency proved equal and highest in HDF and NSO (at a 6/week prescription), slightly lesser in BHD and lowest in APD.

Treatment and long-term outcome in primary distal renal tubular acidosis.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. METHODS: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. RESULTS: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. CONCLUSION: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

Home hemodialysis treatment and outcomes: retrospective analysis of the Knowledge to Improve Home Dialysis Network in Europe (KIHDNEy) cohort.

BACKGROUND: Utilization of home hemodialysis (HHD) is low in Europe. The Knowledge to Improve Home Dialysis Network in Europe (KIHDNEy) is a multi-center study of HHD patients who have used a transportable hemodialysis machine that employs a low volume of lactate-buffered, ultrapure dialysate per session. In this retrospective cohort analysis, we describe patient factors, HHD prescription factors, and biochemistry and medication use during the first 6 months of HHD and rates of clinical outcomes thereafter. METHODS: Using a standardized digital form, we recorded data from 7 centers in 4 Western European countries. We retained patients who completed ≥6 months of HHD. We summarized patient and HHD prescription factors with descriptive statistics and used mixed modeling to assess trends in biochemistry and medication use. We also estimated long-term rates of kidney transplant and death. RESULTS: We identified 129 HHD patients; 104 (81%) were followed for ≥6 months. Mean age was 49 years and 66% were male. Over 70% of patients were prescribed 6 sessions per week, and the mean treatment duration was 15.0 h per week. Median HHD training duration was 2.5 weeks. Mean standard Kt/Vurea was nearly 2.7 at months 3 and 6. Pre-dialysis biochemistry was generally stable. Between baseline and month 6, mean serum bicarbonate increased from 23.1 to 24.1 mmol/L (P = 0.01), mean serum albumin increased from 36.8 to 37.8 g/L (P = 0.03), mean serum C-reactive protein increased from 7.3 to 12.4 mg/L (P = 0.05), and mean serum potassium decreased from 4.80 to 4.59 mmol/L (P = 0.01). Regarding medication use, the mean number of antihypertensive medications fell from 1.46 agents per day at HHD initiation to 1.01 agents per day at 6 months (P < 0.001), but phosphate binder use and erythropoiesis-stimulating agent dose were stable. Long-term rates of kidney transplant and death were 15.3 and 5.4 events per 100 patient-years, respectively. CONCLUSIONS: Intensive HHD with low-flow dialysate delivers adequate urea clearance and good biochemical outcomes in Western European patients. Intensive HHD coincided with a large decrease in antihypertensive medication use. With relatively rapid training, HHD should be considered in more patients.

Renal transplants from older deceased donors: Is pre-implantation biopsy useful? A monocentric observational clinical study.

AIM: To compare survival of kidney transplants from deceased extended criteria donors (ECD) according to: (1) donor graft histological score; and (2) allocation of high score grafts either to single (SKT) or dual (DKT) transplant. METHODS: Renal biopsy was performed as part of either a newly adopted DKT protocol, or of surveillance protocol in the past. A total 185 ECD graft recipients were categorized according to pre-implantation graft biopsy into 3 groups: SKT with graft score 1 to 4 [SKT(1-4), n = 102]; SKT with donor graft score 5 to 8 [SKT(> 4), n = 30]; DKT with donor graft score 5 to 7 (DKT, n = 53). Graft and patient survival were analyzed by Kaplan-Meier curves and compared by log-rank test. Mean number of functioning graft years by transplant reference, and mean number of dialysis-free life years by donor reference in recipients were also calculated at 1, 3 and 6 years from transplantation. RESULTS: There were no statistically significant differences in graft and patient survival between SKT(1-4) and SKT(> 4), and between SKT(> 4) and DKT. Recipient renal function (plasma creatinine and creatinine clearance) at 1 years did not differ in SKT(1-4) and SKT(> 4) (plasma creatinine 1.71 ± 0.69 and 1.69 ± 0.63 mg/dL; creatinine clearance 49.6 + 18.5 and 52.6 + 18.8 mL/min, respectively); DKT showed statistically lower plasma creatinine (1.46 ± 0.57, P < 0.04) but not different creatinine clearance (55.4 + 20.4). Due to older donor age in the DKT group, comparisons were repeated in transplants from donors older than 70 years, and equal graft and patient survival in SKT and DKT were confirmed. Total mean number of functioning graft years by transplant reference at 1, 3 and 6 post-transplant years were equal between the groups, but mean number of dialysis-free life years by donor reference were significantly higher in SKT (mean difference compared to DKT at 6 years: 292 [IQR 260-318] years/100 donors in SKT(1-4) and 292.5 [(IQR 247.8-331.6) in SKT(> 4)]. CONCLUSION: In transplants from clinically suitable ECD donors, graft survival was similar irrespective of pre-implantation biopsy score and of allocation to SKT or DKT. These results suggest use of caution in the use of histology as the only decision criteria for ECD organ allocation.

Long-term Effect of Islet Transplantation on Glycemic Variability.

Islet transplantation has been reported to restore normoglycemia and the overall metabolic control in type 1 diabetes mellitus (DM). In the most experienced centers, islet transplantation clinical outcome is similar to that of the whole pancreas transplantation. Long-term islet transplantation function remains a very interesting matter worth discussing. A progressive islet function decrease was reported, probably due to islet exhaustion. In 5 islet-transplanted patients with at least 3-yr follow-up and still insulin independent, their glycemic control was characterized by a blinded retrospective continuous glucose monitoring system (CGMS). Islet transplantation restored glycemic control and glucose variability. Data were compared with patients in the waiting list. All the parameters of glycemic variability tested had improved significantly in patients who had islet transplantation compared with those patients who were on the waiting list. In conclusion, islet transplantation is able to maintain a proper glucose control and normalize glycemic variability in selected patients. A blinded retrospective CGMS is a useful method to characterize glucose homeostasis deeply in vivo in islet-transplanted patients.

Renal Transplants from Older Deceased Donors: Use of Preimplantation Biopsy and Differential Allocation to Dual or Single Kidney Transplant according to Histological Score Has No Advantages over Allocation to Single Kidney Transplant by Simple Clinical Indication.

BACKGROUND: Grafts from elderly donors (ECD) are increasingly allocated to single (SKT) or dual (DKT) kidney transplantation according to biopsy score. Indications and benefits of either procedure lack universal agreement. METHODS: A total of 302 ECD-transplants in period from Jan 1, 2000, to Dec 31, 2015, were allocated to SKT (SKTpre) on clinical grounds alone (before Dec 2010, pre-DKT era, n = 170) or according to a clinical-histological protocol (after Dec 2010, DKT era, n = 132) to DKT (n = 48), SKT biopsy-based protocol ("high-risk", SKThr, n = 51), or SKT clinically based protocol ("low-risk", SKTlr, n = 33). Graft and patient survival were compared between the two periods and between different transplant categories. RESULTS: Graft and overall survival in recipients from ECD in pre-DKT and DKT era did not differ (5-year graft survival 87.7% and 84.2%, resp.); equal survival in the 2 ECD periods was shown in both donor age ranges of 60-69 and >70-years, and in low-risk or high-risk ECD categories. Within the DKT protocol SKThr showed worst graft and overall survival in the 60-69 donor age range; DKT did not result in significantly better outcome than SKT from ECD in either era. One-year posttransplant creatinine clearance in recipients did not differ between any ECD transplant category. At 3 and 5 years after transplantation there were significantly higher total dialysis-free recipient life years from an equal donor number in the pre-DKT era than in the DKT protocol. CONCLUSIONS: Use of a biopsy-based protocol to allocate grafts from aged donors to SKT or DKT did not result in better short term graft survival than a clinically based protocol with allocation only to SKT and reduced overall recipient dialysis-free life years in time.

Phosphate and Calcium Control in Short Frequent Hemodialysis with the NxStage System One Cycler: Mass Balance Studies and Comparison with Standard Thrice-Weekly Bicarbonate Dialysis.

BACKGROUND: Short frequent dialysis with NxStage System One cycler (NSO) has become increasingly popular as home hemodialysis prescription. Short dialysis sessions with NSO might not allow adequate phosphate (P) removal. METHODS: Single-session and weekly balances of P and calcium (Ca) were compared in 14 patients treated with NSO (6 sessions/week) and in 14 patients on standard bicarbonate dialysis (BHD). RESULTS: NSO and BHD showed similar plasma P fall, with end-dialysis plasma P slightly lower in BHD (2.2 ± 0.5 vs. 2.7 ± 0.8 mg/dL, p < 0.02). Single-session P removal was lower in NSO, but weekly removal was higher (3,488 ± 1,181 mg vs. 2,634 ± 878, p < 0.003). Plasma Ca increase was lower in NSO, with similar PTH fall. Ca balance varied according to start plasma Ca, dialysate to blood Ca gradient and net ultrafiltration. CONCLUSIONS: short, frequent home hemodialysis with NSO, on a 6/week-based prescription, allows higher weekly P removal than BHD. With the dialysate Ca concentration in use (6 mg/dL), total plasma Ca and iCa concentration increase is lower in NSO.

[Home Daily Hemodialysis with NxStage System One: monocentric italian casistic results]. / Dialisi domiciliare quotidiana con Nxstage System One: analisi dei risultati in una casistica monocentrica italiana.

NxStage System One is a new dialytic technology based on easy setup, simplicity of use and reduced dimensions, which is increasingly in use worldwide for home hemodialysis treatments. The system utilizes a low amount of dialysate, usually 15-30 liters according to anthropometric patients' values. The dialysate is supplied at very low flux, generally about 1/3 of blood flow, in order to obtain an elevated saturation of dialysate for solutes. In these conditions the clearance of urea will be almost equal to dialysate flow rate. In order to achieve an obptimal weekly clearance evaluated by Std Kt/V the dialysis sessions are repeated six times a week. In this way a good control of blood voleme can be reached. In this paper we report our experience of treatment with NxStage System One in 12 patients from May 2011 to Dicember 2016.

[Dialysis and cookers: a project for the empowerment of patients in managing their own chronic renal failure].

The phosphate and potassium control is indispensable to dominate the secondary hyperparathyroidism and reduce cardiovascular mortality in dialysis patients. Most of them receive only theoretical nutritional information. We therefore organized a cooking workshop for dialysis patients, with a multidisciplinary team consisting of nurses, nephrologists, a dietitian and a professional chef, to directly teach the patients and their families how to realize a low phosphorus and potassium menu, assessing the proper use of phosphate binders, and blood tests at baseline and at three and six months. Twenty-four patients, out of 133, attended the workshop with a family member, filling out a questionnaire on eating habits, knowledge about phosphorus and potassium, and about binders. Theoretical and practical information about phosphorus and potassium metabolism, about binders, and cooking techniques were given during the evening, we then prepared a meal, eaten all together. The questionnaire was repeated at the end of the evening, and all the participants reported an improvement of the considered variables. Phosphorus and potassium plasma levels and the number of binders did not change after three and six months. Coping with the dietary changes related to the start of the dialytic therapy in an informal atmosphere, with a family member, is highly appreciated, clinically useful, logistically and economically sustainable. A customized and long-lasting counselling is probably required to modify plasma levels of phosphorus and potassium and binder's consumption. The poor dietary knowledge detected in our patients and the satisfaction about the course both confirm the training needs in this area.

[Immunosuppression in kidney transplantation: a way between efficacy and toxicity].

Renal transplantation is the best treatment for patients with end-stage renal disease. Over the last decades, the introduction of new immunosuppressive agents resulted into the reduction of the incidence of acute rejection and early graft loss. Despite this progress, there has been little improvement in the average life of the transplant. The main reasons of late failure are patient's death due to several complications (e.g. cancer, infectious or metabolic), and progressive deterioration of renal function caused by immunological and non-immunological factors. The immunosuppressive therapy can be distinguished into two components: the induction therapy and the maintenance therapy. The former has the aim to implement intense and immediate immunosuppression. This therapy is mostly useful in transplant with high immunological risk, although it is correlated with an increased risk of cytopenias and viral infections. The latter offers the rationale to prevent organ rejection and minimize drug toxicity. This is generally constituted by the association of two or three drugs with different mechanism of action. The most common application of this scheme includes a calcineurin inhibitor in combination with an antimetabolite and a minimum dose of steroids. Immunosuppressive therapy is also associated to an increased risk of infections and cancer development. For instance, each class of drugs is related to a different profile of toxicity. The choice of treatment protocol should take into account the clinical characteristics of the donor and recipient. Furthermore, this treatment may change anytime when clinical conditions result into complications.

Acquired Complement Regulatory Gene Mutations and Hematopoietic Stem Cell Transplant-Related Thrombotic Microangiopathy.

Hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA) is a severe complication whose pathophysiology is unknown. We describe 6 patients in which the disease was associated with complement regulatory gene abnormalities received from their respective donors. It is suggested that mutated and transplanted monocyte-derived cells are responsible for production of abnormal proteins, complement dysregulation, and, ultimately, for the disease. This observation might have important drawbacks as far as HSCT-TMA pathophysiology and treatment are concerned.

The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.

Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.

Islet Transplantation in Pediatric Patients: Current Indications and Future Perspectives.

The first islet transplantation in diabetes mellitus was performed more than 20 years ago. Since then, clinical results have progressively improved. Nowadays, islet transplantation can be considered a real therapeutic option after pancreatectomy for painful chronic pancreatitis (autotransplantation) and in selected adult patients affected by type 1 diabetes mellitus (allotransplantation). Better results are mainly due to the advances in the standardization of islet isolation and purification procedures as well as in the pharmacological treatment of recipients. Anti-inflammatory treatments facilitate islet engraftment and prevent metabolic exhaustion and functional ß-cell apoptosis; new strategies better control islet graft rejection. As a consequence, islet transplantation activities are no longer confined to few centers only, rather thousands of transplants are now performed all over the world. Many attempts are actually undertaken to find solutions to current problems of islets transplantation, from toxicity of immunosuppressive therapy to the limited engraftment, function and duration. There is general hope that these procedures will offer a safe and feasible therapeutic option for an increasing number of patients suffering from diabetes mellitus, including pediatric patients.

Risk factors associated with efficacy outcomes in kidney transplantation: analysis of a contemporary cohort of patients from the A2309 trial.

A multivariate analysis of risk factors for a composite endpoint of treated biopsy proven acute rejection (BPAR), graft loss, death, or loss to follow-up was undertaken in a cohort of 833 de novo kidney transplants from an international trial (A2309). Patients were randomized to everolimus (trough concentration 3-8 ng/mL or 6-12 ng/mL) with reduced cyclosporine or to mycophenolic acid (MPA) with standard cyclosporine. Cox proportional hazard modeling, incorporating a range of recipient, donor, and transplant variables, showed that treatment group (i.e., randomization to either everolimus 3-8 ng/mL or 6-12 ng/mL vs. MPA) showed no significant association with risk of the composite efficacy endpoint at either month 12 or month 24 (significance level 0.05). At month 12, Cox proportional hazard modeling showed that black race (hazard ratio (HR) 1.68; 95% confidence interval (CI) 1.08, 2.60; p=0.021), increasing donor age in years (HR 1.01; 95% CI 1.00, 1.03; p=0.022), and delayed graft function (DGF; yes vs. no, HR 2.75; 95% CI 1.82, 4.16; p< 0.001) predicted higher risk of the composite endpoint; female gender (female vs. male HR 0.67; 95% CI 0.48, 0.93; p=0.017), and < 3 HLA mismatches (HR 0.70; 95% CI 0.50, 0.99; p=0.049) were associated with reduced risk. At month 24, increasing recipient age in years (HR 0.99; 95% CI 0.98, 0.99; p=0.028), black recipient race (HR 1.62; 95% CI 1.09, 2.42; p=0.018), increasing donor age in years (HR 1.01; 95% CI 1.00, 1.02; p=0.008) and delayed graft function (DGF) (HR 2.60; 95% CI 1.78, 3.82; p<0.001) were predictive of risk. These findings show that, independently from type of immunosuppression, organ quality (expressed by DGF), donor age and recipient age, race and gender appear to be the main determinants of efficacy within 2 years after kidney transplantation.