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Kidney transplantation represents the gold standard treatment option for patients with end-stage renal disease. Improvements in surgical technique and pharmacologic treatment have continuously prolonged allograft survival in recent years. However, urological complications are frequently observed, leading to both postoperative morbidity and putative deterioration of allograft function. While open redo surgery in these patients is often accompanied by elevated surgical risk, endoscopic management of urological complications is an alternative, minimal-invasive option. In the present article, we reviewed the literature on relevant urological postoperative complications after kidney transplantation and describe preventive approaches during the pre-transplantation assessment and their management using minimal-invasive approaches.

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.

Summary Background In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). Methods In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6–8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602. Findings Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74–1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group. Interpretation In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients. Funding Gambro, Janssen, and Binding Site.

Background In patients with obesity and end-stage kidney disease, implantation of the peritoneal dialysis (PD) catheter may be complicated by increased abdominal circumference or skin folds. Relocation of the implantation site to the upper abdomen could solve this problem. However, this would require an extended catheter. Methods We developed an extended PD catheter based on a swan neck Missouri PD catheter with the help of two adaptors and a straight intraperitoneal extension segment. The extended catheter was assembled intraoperatively, and its length was adjusted individually to ensure correct positioning. After the operation, PD was commenced and handled as usual. Results In the period from 2011 to 2021, we implanted 31 extended PD catheters in 29 patients (38% men) with end-stage renal failure and obesity. Median age was 53 (range 28–77) years and body mass index was 35.5 (range 26.4–46.9) kg/m2. The postoperative course was unremarkable except for seroma formation in one patient and dialysate leakage in another. Continuous ambulatory peritoneal dialysis (CAPD) was initiated in 20 and APD in 9 patients. The achieved median Kt/V was 2.10 (range 1.50–3.10). During the follow-up period lasting up to 51 months, there was one case of intraperitoneal catheter disconnection due to an avoidable handling error. The peritonitis rate was 1:40 months. The 1- and 2-year catheter survival was 92% and 67%, respectively, and paralleled patient survival. Conclusions When using a PD catheter with an intraperitoneal extension, PD catheter implantation can be relocated to the upper abdomen in patients with obesity, thus providing optimal position and easy surgical access.

Hemolytic uremic syndrome; Kidney failure; Ravulizumab Síndrome hemolítico urémico; Insuficiencia renal; Ravulizumab Síndrome hemolític urèmic; Insuficiència renal; Ravulizumab Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare, complex, multisystem disease of dysregulated complement activity, characterized by progressive thrombotic microangiopathy (TMA), acute kidney injury, and multiorgan dysfunction, which often progresses to chronic kidney disease. Results from the prospective clinical trial of ravulizumab (NCT02949128) reveal rapid resolution of TMA in patients with aHUS, with sustained efficacy and safety in a 26-week initial evaluation period. Methods The aim of this analysis was to characterize the long-term efficacy and the safety profile of ravulizumab in adults with aHUS who had completed the initial evaluation period of the trial. Complete TMA response, hematologic and kidney functions, and safety were evaluated for all patients available for follow-up in the extension period (median follow-up: 76.7 weeks; range: 0.6–118.3). This trial included a total of 58 patients, 49 of whom entered the extension period. Results A total of 4 additional patients achieved complete TMA response during the follow-up period. Normalization of platelet count, serum lactate dehydrogenase (LDH), and hemoglobin observed in the 26-week initial evaluation period was sustained until the last available follow-up, as were the improvements in the estimated glomerular filtration rate (eGFR) and patient quality of life. All efficacy endpoints were correlated with the sustained inhibition of complement C5. Most adverse events (AEs) occurred early during the initial evaluation period and decreased substantially during the extension period. No patient developed a meningococcal infection or died during the extension period. Conclusion This analysis reveals that ravulizumab administered every 8 weeks is efficacious with an acceptable safety profile for the long-term treatment of adults with aHUS and provides additional clinical benefit beyond 6 months of treatment.

Post-transplantation diabetes mellitus (PTDM) is a relevant complication following liver transplantation with profound impact on morbidity and mortality. To date, little is known about the evolution and dynamics of glucose metabolism and the impact of prediabetes in long-term follow-up. To address this issue, all consecutive adult liver transplant recipients (n = 429) from a European university hospital transplant center between 2007 and 2017 were analyzed retrospectively. In patients without pre-existing diabetes (n = 327), we conducted a longitudinal characterization of glucose metabolism. Median follow-up was 37 [9-64, IQR] months. Median prevalence of prediabetes was 39 [37-39]% and of PTDM 21 [17-22]%. Throughout follow-up, intra-individual glucose regulation of patients was highly variable, continuously fluctuating between different states of glucose metabolism (normal glucose tolerance, prediabetes, PTDM). Whereas overall survival and long-term kidney function of patients with PTDM were significantly lower than that of patients with normal glucose metabolism, prediabetes was not associated with adverse outcome. This study provides new insight into the dynamics and impact of glucose metabolism after liver transplantation. Unlike PTDM, prediabetes is not associated with adverse outcome, providing a window of opportunity for targeted intervention. The results underline the need for constant screening and intervention in posttransplant care of liver allograft recipients.

Background and Aims Ravulizumab is a long-acting C5 inhibitor, derived from eculizumab, that is dosed every 8 weeks. Ravulizumab was approved in the United States for patients with atypical haemolytic uraemic syndrome (aHUS) and it is currently under evaluation in the EU based on the phase 3 trial (NCT02949128) efficacy and safety results at 26 weeks in patients with aHUS. Here, we report longer term efficacy and safety of ravulizumab obtained from the trial during the ongoing extension period. Method This phase 3 trial was a single arm, global, open label study in adults (≥18 years of age) with aHUS naïve to complement-inhibitor therapy. Ravulizumab was administered by intravenous infusion (IV) every 8 weeks during the maintenance phase. Patients fulfilling laboratory criteria for active TMA, ADAMTS13>5%, and negative STEC-HUS testing were eligible. Patients that completed the 26-week initial evaluation period could enter the extension period. The primary endpoint was complete TMA response (normalisation of platelet count and lactate dehydrogenase [LDH], and ≥ 25% improvement in serum creatinine from baseline, measured at 2 separate assessments obtained at least 28 days apart). Secondary endpoints included changes from baseline in haematological parameters, kidney function, and FACIT-fatigue scores. Treatment emergent adverse events were also evaluated. Here, interim cumulative data on primary and secondary endpoints through at least 52 weeks are reported. Results Forty-seven of 56 enrolled patients completed the initial evaluation period and received at least one dose of ravulizumab in the extension period. All patients achieved complete inhibition of terminal complement as demonstrated by sustained suppression of free-C5 ( Although three new SAEs were reported during the extension period, there were no further fatal adverse events. As in the primary analysis period, no meningococcal infections occurred through the last patient follow-up. Conclusion In the extension period of the phase 3 trial, ravulizumab continued to have a good benefit: risk profile. At last follow-up, the cumulative efficacy of ravulizumab to treat complement mediated TMA in patients with aHUS improved to 61% from 54% in the initial evaluation period. Most AEs occurred in the first 26 weeks, and there were no meningococcal infections identified in the study. These results suggest that with ravulizumab further improvement in efficacy is possible with longer treatment with no compromise in safety and improved convenience of 8-week dosing intervals.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naive adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

Background: Polyomavirus-associated nephropathy (PVAN) remains a relevant complication following kidney transplantation with allograft loss rates of up to 50%. Reduction in overall immunosuppression is a cornerstone of therapy, whereas no specific antiviral regimen has shown conclusive benefit to date. The present case series demonstrates the efficacy of a dual therapeutic approach with low-dose cidofovir and conversion to mTOR-based immunosuppression in PVAN. Methods: Patients with biopsy-proven PVAN having received low-dose cidofovir (0.25mg/kg) according to the Tübingen Cidofovir Protocol and been converted to mTOR-based immunosuppression were analyzed retrospectively. Results: Twenty-three patients with a median follow-up of 2.24 [IQR 1.55-5.01] years were included in the analysis. Median time to PVAN diagnosis was 268 [IQR 153-869] days after transplantation. Polyomavirus clearance from plasma was achieved in 78% of patients after a median of 118 [IQR 76-293] days. Of the 23 patients, nine patients (39%) lost their allograft function during follow-up, but only three of these (13%) due to PVAN. Fourteen patients (61%) stabilized or improved allograft function. The cidofovir protocol allowed for specific antiviral therapy without adverse nephrotoxicity, even in patients with low allograft function. Conclusions: Low-dose cidofovir and conversion to mTOR-based immunosuppression allow for effective virus clearance and preservation of allograft function in a high proportion of patients with PVAN and progressive allograft dysfunction and may prolong allograft survival in these patients.

Transplantation proceedings 52(10), 3103-3111 (2020). doi:10.1016/j.transproceed.2020.02.159, Published by Elsevier Science, Amsterdam [u.a.]

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Background Ravulizumab, a humanized anti-complement C5 monoclonal antibody designed by targeted modification of eculizumab to achieve an extended half-life, is approved to treat aHUS in the USA (2019), EU and Japan (2020). Data at 26 weeks (wk) and 1 year (yr) from the phase 3 studies of ravulizumab in adults and children with aHUS have been published. Here we report 2-yr data from these trials. Methods Efficacy and safety data from ravulizumab clinical trials in adults naïve to complement inhibitor treatment (NCT02949128), and in children either naïve to (naïve) or switched from (switch) eculizumab (NCT03131219), were assessed at 2 yr and presented alongside data from the initial 26-wk evaluation periods; patients were dosed every 8 wk (adult), or every 4 or 8 wk (children), according to body weight. Descriptive statistical analyses were conducted on these data. No statistical comparisons between data at 26 wk and 2 yr, or between trials, were conducted. Results Efficacy data in adults and treatment-naïve children are presented in the Table. Complete thrombotic microangiopathy (TMA) response (platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine from baseline, met concurrently at 2 separate assessments, at least 4 wk apart) was achieved in more patients at 2 yr vs 26 wk in both studies (adult: 34 [61%) vs 30 [54%]; naïve: 18 [90%] vs 15 [75%]). All complete TMA response components were either numerically improved or maintained at 2 yr vs 26 wk. Kidney function continued to improve, with the median change in estimated glomerular filtration rate from baseline numerically increasing at 2 yr vs 26 wk in both adults (35 vs 29 mL/min/1.73m 2) and naïve children (82.5 vs 80 mL/min/1.73m 2). Most patients receiving dialysis at baseline were able to discontinue dialysis at 26 wk; this was sustained in adults (67% vs 67%) while all naïve children receiving dialysis at baseline had discontinued by 2 yr (83% vs 100%). No patients who discontinued dialysis by 26 wk subsequently restarted. Chronic kidney disease (CKD) stage improved in most patients through 26 wk in both studies (adult, 68%; naïve, 88%); improvements were sustained at 2 yr (adult, 71%; naïve, 94%). No naïve children experienced a worsening of CKD stage at 2 yr. Improvements from baseline in quality of life were seen at both 26 wk and 2 yr, as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (adults: 20 vs 12; naïve: 10 vs 8), EQ-5D-3L visual analog scale (adults: 32 vs 33) and EQ-5D-3L time trade-off (adults: 0.32 vs 0.31). Most adverse events (AEs) and serious AEs (SAEs) occurring in these studies were reported during the initial 26-wk evaluation period, with a general reduction in the number of patients with any new S/AE events being reported at 2 yr. The most common AEs reported through 2 yr, which had not met the 15% reporting threshold through 26 wk, were (n, %): adults - constipation (9, 16%), fatigue (9, 16%) and nasopharyngitis (9, 16%); naïve children - abdominal pain (6, 25%), contusion (5, 21%), cough (5, 21%), nausea (4, 17%), myalgia (4, 17%), rash (4, 17%) and rhinorrhea (4, 17%); switch children - upper respiratory tract infections (URTI; 4, 40%), oropharyngeal pain (3, 30%), pharyngitis (3, 30%), cough (2, 20%), gastroenteritis (2, 20%), nasopharyngitis (2, 20%), otitis media (2, 20%), viral URTI (2, 20%) and dehydration (2, 20%). No patients discontinued either study due to treatment-emergent AEs after 26 wk. No meningococcal infections were recorded in either study at any timepoints. One adult patient, who had previously met complete TMA response criteria while receiving therapy, discontinued treatment by choice and subsequently experienced recurrent disease, as evidenced by an increase in serum creatinine (SCr). This patient then restarted therapy, leading to improvements in SCr levels. Conclusions In both treatment-naïve adults and children, ravulizumab was associated with numerically sustained or increased improvements in hematologic outcomes and kidney function at 2 yr vs 26 wk. Fewer S/AEs were reported during the extension period of these studies vs the initial 26-wk evaluation periods. Importantly, no meningococcal infections were reported in either study at any timepoint. The data suggest that long-term treatment with ravulizumab is well tolerated and may be associated with continuing improvements in TMA parameters and renal function in adults and children with aHUS. Figure 1 Figure 1. Disclosures Dixon: Apellis Pharmaceuticals: Consultancy; Horizon Pharmaceuticals: Consultancy; Alexion Pharmaceuticals: Consultancy. Kavanagh: Gyroscope Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Apellis: Honoraria, Speakers Bureau; Idorsia: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Kang: Alexion Pharmaceuticals: Honoraria, Research Funding; Handok: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Research Funding. Wang: Alexion, AstraZeneca Rare Disease Inc.: Current Employment. Garlo: Alexion: Current Employment; AstraZeneca: Current Employment. Greenbaum: Alexion Pharmaceuticals: Honoraria, Research Funding. Ogawa: Alexion Pharmaceuticals: Current Employment. Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Alexion: Consultancy, Research Funding; Takeda: Consultancy. Miyakawa: Sanofi: Consultancy; Zenyaku Kogyo: Consultancy; Sanofi: Research Funding; argenx: Consultancy, Research Funding.

Purpose The evaluation process of potential living kidney donors focusses on renal anatomy and split renal function. This study aimed to evaluate a magnetic resonance imaging (MRI)-based approach for simultaneous evaluation of both and its impact on clinical decision making. Method Over a 3-year period, 65 potential living kidney donors were consecutively enrolled. The MRI protocol was extended by MR-nephrography to measure split renal function. Standard DTPA-scintigraphy was used for functional comparison. Results Split renal function showed no systematic bias between the two methods (mean difference 0.3%, p = 0.08). Both methods would have yielded the same clinical decision for donor nephrectomy in 75% of the patients. In 25 % of the patients, one method indicated a relevant side difference while the other did not, and a different clinical decision could have been made based on split renal function alone. Conclusions MRI proved eligible for comprehensive living kidney donor evaluation and non-inferior to scintigraphy for determining split renal function. In clinical decision making, these two methods would have resulted in the same side for donor nephrectomy in a large proportion of potential donors. Whether MRN will be implemented in clinical practice depends on transplant centre infrastructure and policy.

The authors regret that 2 investigators were not included in the 311 Study Group. Members of the 311 Study Group are listed in the Appendix. The authors would like to apologize for any inconvenience caused.

Background: Adequate removal of sodium (Na) and phosphorus (P) is of paramount importance for patients with dialysis-dependent kidney disease can easily quantified in peritoneal dialysis (PD) patients. Some studies suggest that automated PD (APD) results in lower Na and P removal. Methods: In this study we retrospectively analysed our data on Na and P removal in PD patients after implementation of a routine monitoring in 2011. Patients were stratified in those treated with continuous ambulatory PD (CAPD, n=24), automated PD (APD, n=23) and APD with one bag change (CAPD+APD, n=10). Until 2015 we collected time-varying data on Na and P removal from each patient (median 5 [interquartile range 4-8] values). Results: Peritoneal Na and P removal (mmol per 24h ± standard deviation) was 102 ± 48 and 8 ± 2 in the CAPD, 90 ± 46 and 9 ± 3 in the APD and 126 ± 39 and 13 ± 2 in the CAPD+APD group (ANOVA P=0.141 and Conclusions: Overall Na and P removal were similar with different PD modalities. Individualized adjustments of PD prescription including icodextrin use or higher glucose concentration can improve Na removal while P removal is mainly determined by the dialysate volume.

Background and objectives Hypervolemia is a common feature of patients with CKD and associated with hypertension. Recent work has shown stimulation of sodium retention by urinary plasmin during nephrotic syndrome. However, it is unclear whether plasminuria plays a role in patients with stable CKD and non-nephrotic proteinuria. Design, setting, participants, & measurements In this cross-sectional study, we analyzed the fluid status of 171 patients with CKD consecutively presenting to our outpatient clinic from 2012 to 2013 using bioimpedance spectroscopy (Body Composition Monitor [BCM]; Fresenius Medical Care, Germany) and its associations to the urinary excretion of plasminogen and plasmin from a spot urine sample. Two–electrode voltage clamp measurements were performed in Xenopus laevis oocytes expressing human epithelial sodium channel to investigate whether plasmin in concentrations found in urine can activate the channel. Results Overhydration >5% and overhydration >10% of the extracellular volume were found in 29% and 17% of the patients, respectively, and overhydration was associated with edema, hypertension, higher stages of CKD, and proteinuria. Proteinuria was the strongest independent predictor for overhydration (+0.58 L/1.73 m 2 per 10-fold increase; P r =0.87) and overhydration ( r =0.47). Using a chromogenic substrate, active plasmin was found in 44% of patients and correlated with proteinuria and overhydration. Estimated urinary plasmin concentrations were in a range sufficient to activate epithelial sodium channel currents in vitro . In multivariable analysis, urinary excretion of plasmin(ogen) was associated with overhydration similar to proteinuria. Conclusions Hypervolemia in patients with CKD is strongly associated with proteinuria, even in the non-nephrotic range. Protein-rich urine contains high amounts of plasminogen and active plasmin, rendering plasminuria as a possible link between proteinuria and hypervolemia.

Uterus transplantation (UTx) can provide a route to motherhood for women with Mayer&ndash, Rokitansky&ndash, K&uuml, ster&ndash, Hauser syndrome (MRKHS), a congenital disorder characterized by uterovaginal aplasia, but with functional ovaries. Based on our four successful living-donor transplantations and two resulting births, this analysis presents parameters relevant to standardizing recipient/donor selection, UTx surgery, and postoperative treatment, and their implementation in routine settings. We descriptively analyzed prospectively collected observational data from our four uterus recipients, all with MRKHS, their living donors, and the two newborns born to two recipients, including 1-year postnatal follow-ups. Analysis included only living-donor/recipient pairs with completed donor/recipient surgery. Two recipients, both requiring ovarian restimulation under immunosuppression after missed pregnancy loss in one case and no pregnancy in the other, each delivered a healthy boy by cesarean section. We conclude that parameters crucial to successful transplantation, pregnancy, and childbirth include careful selection of donor/recipient pairs, donor organ quality, meticulous surgical technique, a multidisciplinary team approach, and comprehensive follow-up. Surgery duration and blood vessel selection await further optimization, as do the choice and duration of immunosuppression, which are crucial to timing the first embryo transfer. Data need to be collected in an international registry due to the low prevalence of MRKHS.

Objective To report our experience with the screening and selection of potential recipients and living donors of our uterus transplantation (UTx) program. Design Part of an observational program. Setting University hospital. Patient(s) Patients with absolute uterine factor infertility (AUFI). Intervention(s) Screening by e-mail and telephone, selection during surgical consultation, and preoperative investigations according to a multistep procedure for living donation. Main Outcome Measure(s) Age, cause of AUFI, exclusion reasons, and preoperative workup. Result(s) A total of 212 potential recipients expressed interest in participation. Among the 46 potential recipients and 49 directed donors were 4 potential recipients, each with 2 directed donors. Mean (range) age of potential recipients was 29.6 (19–41) years. Of the potential recipients, 39 (84.8%) had congenital AUFI and 7 (17.3%) had acquired AUFI. Ultimately, 15 potential recipients with 16 directed donors were selected for participation, with 1 potential recipient having 2 directed donors. Mean age of included potential recipients was 28.9 (22–35) years, and mean donor age was 51.3 (37–62) years. Fourteen potential recipients (93.3%) had congenital AUFI, and one potential recipient (6.7%) had undergone hysterectomy for obstetric complications. Conclusion(s) The number of potential candidates for UTx is not inconsiderable, with congenital AUFI being the leading cause of AUFI in our cohort. However, our findings highlight that large numbers of AUFI patients need to be screened, considering our exclusion rates were >50%, owing to ABO incompatibility, unavailability of a directed donor, and self-withdrawal. Moreover, meticulous preoperative screening, including in-depth psychological assessment, is mandatory to maximize living donor safety and UTx success.

Background. Although haemodialysis (HD) leads to alterations of systemic haemodynamics that can be monitored using dilution methods, there is a lack of data on the diagnostic and prognostic significance of haemodynamic monitoring during routine HD. Methods. In this multicentre study, we measured cardiac index (CI), access flow (AF) and central blood volume index (CBVI) during a single HD session in stable HD patients (n ¼ 215) using the Transonic HD03 monitor (Transonic, Ithaca, NY, USA). Systemic CI (SCI) was defined as CI corrected for AF. In a subset of patients (n ¼ 82), total end-diastolic volume index (TEDVI) and total ejection fraction (TEF) were derived from dilution curves. Data were correlated with clinical parameters, cardiac biomarkers and bioimpedance measurements (body composition monitor; Fresenius Medical Care, Homburg, Germany). Mortality was assessed prospectively after a median follow-up of 2.6 years. Results. Median CI, CBVI and AF were 2.8 L/min/m2 (interquartile range 2.4–3.4), 15 mL/kg (14.5–15.7) and 980 mL/min (740–1415), respectively, at the beginning of HD. At the end of HD, CI, CBVI and AF significantly fell by 10% (22 to 3, P < 0.0001), 9% (23 to 3, P < 0.0001) and 4% (13 to 5, P ¼ 0.0004), respectively. Peripheral resistance (PR) increased slightly (P ¼ 0.01) and blood pressure fell by 6/3 mmHg to 128/63 mmHg (P < 0.0001). Independent predictors of DCI were age and ultrafiltration rate, whereas AF, overhydration and PR were protective. TEF was strongly associated with mortality [area under the dilution curve 0.77, P < 0.0001], followed by TEDVI (0.72, P ¼ 0.0002) and SCI (0.60, P ¼ 0.02). Conclusions. HD leads to a reduction of CI due to ultrafiltration. Haemodynamic monitoring identifies a significant number of HD patients with cardiac impairment that are at risk for increased mortality.

Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of proinflammatory and upregulation of regenerative factors in cocultured EC and PO, indicating a protective influence of RFSC. However, fetuin-A inverted these benign effects of RSFC from an anti- to a proinflammatory status. RSF was quantified by magnetic resonance imaging and liver fat content by 1H-MR spectroscopy in 449 individuals at risk for type 2 diabetes. Impaired renal function was determined via urinary albumin/creatinine-ratio (uACR). RSF did not correlate with uACR in subjects without NAFLD (n = 212, p = 0.94), but correlated positively in subjects with NAFLD (n = 105, p = 0.0005). Estimated glomerular filtration rate (eGRF) was inversely correlated with RSF, suggesting lower eGFR for subjects with higher RSF (r = 0.24, p

Background. Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disorder for which eculizumab is the only approved treatment. Life-long treatment is indicated; however, eculizumab discontinuation has been reported. Methods. Unpublished authors' cases and published cases of eculizumab discontinuation are reviewed. We also report eculizumab discontinuation data from five clinical trials, plus long-term extensions and the global aHUS Registry. Results. Of six unpublished authors' cases, four patients had a subsequent thrombotic microangiopathy (TMA) manifestation within 12 months of discontinuation. Case reports of 52 patients discontinuing eculizumab were identified; 16 (31%) had a subsequent TMA manifestation. In eculizumab clinical trials, 61/130 patients discontinued treatment between 2008 and 2015. Median follow-up post-discontinuation was 24 weeks and during this time 12 patients experienced 15 severe TMA complications and 9 of the 12 patients restarted eculizumab. TMA complications occurred irrespective of identified genetic mutation, high risk polymorphism or auto-antibody. In the global aHUS Registry, 76/296 patients (26%) discontinued, 12 (16%) of whom restarted. Conclusions. The currently available evidence suggests TMA manifestations following discontinuation are unpredictable in both severity and timing. For evidence-based decision making, better risk stratification and valid monitoring strategies are required. Until these exist, the risk versus benefit of eculizumab discontinuation, either in specific clinical situations or at selected time points, should include consideration of the risk of further TMA manifestations.

Background Renal function is known to affect glucose metabolism. The aim of this study was to assess glucose metabolism in end-stage renal disease (ESRD) patients and in matched controls with normal renal function and to delineate its underlying pathophysiology. Methods ESRD patients without diabetes mellitus on the active kidney transplant waiting list of a large European university hospital were metabolically phenotyped by an oral glucose tolerance test (OGTT) and by calculating insulin sensitivity and secretion indices. Matched controls with normal renal function were derived from the TUEF (Tuebingen Family) study cohort, which includes healthy non-diabetic individuals with an increased risk of developing type 2 diabetes. Matches were made for (i) gender, age and body mass index (BMI) (cohort 1) and for (ii) gender, age, BMI, fasting plasma glucose (FPG) and 2-h glucose in OGTT (cohort 2). Results A total of 107 patients (90 on haemodialysis and 17 on peritoneal dialysis) and two cohorts, each comprising 107 matched controls, were investigated. ESRD patients had significantly lower FPG. Additional matching for OGTT glucose concentrations revealed significantly lower insulin sensitivity in ESRD patients than in controls. This finding was abrogated after adjustment for triglyceride levels. Insulin secretion, however, was significantly higher in ESRD patients. Insulin kinetics during OGTT as well as C-peptide levels demonstrate higher insulin secretion to be a compensation for lower insulin sensitivity and not to result from impaired insulin clearance. Conclusion Our study is the first to provide metabolic phenotyping in patients with ESRD and to compare them with matched controls with normal renal function. Glucose metabolism differs substantially between cohorts, with insulin resistance and a compensatory increase in insulin secretion in ESRD patients.

Expanded hemodialysis (HDx) therapy is a novel treatment concept in hemodialysis patients, using innovative membrane technology with a high retention onset for improved solute clearance in the upper middle molecular range. HDx therapy thereby resolves a key limitation of current hemodialysis techniques and targets an important pathophysiologic link to many of the sequelae of end-stage renal disease. The present chapter reviews the current evidence and discusses considerations for prescription and delivery of HDx therapy upon implementation in clinical practice.

To evaluate improvement in gastrointestinal (GI) symptoms and health-related quality of life (HRQoL) in liver transplant recipients switched from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS).A multicenter, open-label, single-arm study was undertaken in maintenance liver transplant recipients who reported GI complications with MMF therapy. The patients were switched to equimolar doses of EC-MPS at baseline. The primary end point was the change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6 to 8 weeks of treatment with EC-MPS. Other key assessments for GI symptoms and HRQoL included the GSRS subscores, the Gastrointestinal Quality of Life Index (GIQLI), the Psychological General Well-Being Index, and the Overall Treatment Effect (OTE). Paired t-test was used to assess the difference in the mean score changes over time.A total of 34 patients were enrolled and switched to equimolar doses of EC-MPS. After 6 to 8 weeks of EC-MPS treatment, mean GSRS total score improved significantly from 2.88 ± 0.66 to 2.10 ± 0.78. Mean improvement in GSRS total score (-0.77 score points; P = .001) exceeded the minimal clinically important difference. Significant improvements were observed in all GSRS subscales (P.05), GIQLI total scores (P = .001), and GIQLI subscales "GI symptoms" (P.001) and "physical function" (0.013). Patients who continued EC-MPS reported sustained benefits compared with patients who switched back to MMF after 6 to 8 weeks of treatment with EC-MPS. On the OTE scale, improvement in symptoms was reported in 76.5% and 61.8% of the patients as perceived by the physicians and the patients. Improvement in HRQoL was reported by 41.2% of the patients. No deaths, biopsy proven acute rejections, or graft losses were reported during the study.Conversion from MMF to EC-MPS was associated with a significant improvement in GI symptoms and HRQoL in liver transplant recipients.

The German Sirolimus Study Group has established a database among 10 transplant centers throughout Germany to study the outcomes in 726 renal transplant patients being converted to a sirolimus-containing therapy between 2000 and 2008 with a total of more than 1500 recorded patient years on therapy. In this study, we present a detailed description of the cohort, of characteristic changes over the observation period, proteinuria and graft survival, and new-onset proteinuria after conversion. Over the study period, age, graft function at the time of conversion, and the proportion of patients switched to sirolimus because of malignancy increased, whereas the proportion of patients with significant proteinuria at conversion decreased. Already modest proteinuria (151-268 mg/L) at conversion and new-onset proteinuria (>500 mg/L) after conversion were associated with inferior graft survival. Even mild proteinuria (>71 mg/L) at conversion was associated with new-onset proteinuria (>500 mg/L) post-conversion. Serum creatinine and urinary protein excretion at conversion together with age at transplantation had a significant impact on patient and graft survival. This large data set confirms and extends previous observations that proteinuria is an important indicator for graft outcome after conversion to sirolimus. We conclude that patients without any proteinuria have the greatest benefit from conversion to sirolimus.

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.

EINLEITUNG: Die Nierenlebendspende stellt ein etabliertes Verfahren dar, um die Zeit auf der Warteliste zur Nierentransplantation bei anhaltendem Organmangel zu verkurzen. Trotz weltweiter Etablierung laparoskopischer Verfahren zur Spendernephrektomie, werden in Deutschland mehr als 80 % der Nephrektomien im Rahmen der Lebendspende auf konventionelle Art durchgefuhrt. Ziel dieser Analyse war die retrospektive Auswertung der perioperativen Daten und die Neuerhebung von Langzeitnachsorge-Daten der Spender und Empfanger nach konventioneller Spendernephrektomie. METHODIK: Von Februar 2004 bis Juli 2008 wurden an der Abteilung fur Transplantationschirurgie der Universitat Tubingen insgesamt 51 konventionelle Nierenlebendspenden bei Erwachsenen durchgefuhrt. Ausgewertet wurden 45 Spenden. Postoperative Komplikationen wurden zur besseren Vergleichbarkeit nach der Kocak-Klassifikation eingeteilt. ERGEBNISSE: Das 5-Jahres-Transplantatuberleben betrug 100 %. Intraoperativ traten keine Komplikationen auf. Postoperativ fanden sich bei 10 Spendern (22,2 %) Komplikationen ersten Grades nach der Kocak-Klassifikation. In der Langzeitnachsorge traten bei keinem Spender schwerwiegenden Komplikationen auf. Zwei Spender (4,4 %) entwickelten eine behandlungsbedurftige arterielle Hypertonie. Eine Proteinurie trat bei keinem der Spender auf. Vergleicht man den stationaren Aufenthalt unter Einbezug der Operationstechnik (transabdominell rechts vs. lumbal linksseitig), zeigt sich, dass die transabdominelle Entnahme in einer signifikant fruheren Entlassung resultierte, als die linksseitige lumbale Nephroureterektomie (7,8 ± 2,4 vs. 9,2 ± 1,8 Tage, p < 0,05). SCHLUSSFOLGERUNG: Die konventionelle Spendernephrektomie stellt ein sicheres Verfahren bei der Nierenlebendspende mit exzellentem Transplantatuberleben dar. Die Komplikationsraten bei der konventionellen Spendernephrektomie in unserem Zentrum sind mit den aktuellen Ergebnissen zur laparoskopischen Spendernephrektomie vergleichbar. Daher hat die konventionelle Entnahmetechnik nach wie vor einen hohen Stellenwert.

To test the feasibility of a single MR-based examination allowing for the comprehensive assessment of renal anatomy, function, and vascular status in candidates for kidney transplantation.Twelve healthy potential kidney donors (mean age: 47 +/- 14 [standard deviation] years, 3 men and 9 women) participated in the study, which was approved by the local ethics committee. MR-nephrography was performed using a navigator-gated T1-weighted saturation-recovery sequence (TrueFISP: TR/TE = 621.31 milliseconds/1.27 milliseconds, Flip angle = 70 degrees, TI = 300 milliseconds, BW = 977 Hz/Px, or TurboFLASH: TR/TE = 528 milliseconds/1.15 milliseconds, Flip angle = 8 degrees, TI = 300 milliseconds, BW = 600 Hz/Px). Images were acquired up to 60 minutes after the injection of 4 mL of gadobutrol. The glomerular filtration rate (GFR) was evaluated from the renal clearance of gadobutrol within the extra cellular fluid volume by exponential fitting of time-signal curves measured over the liver. MR-angiography was performed using a T1-weighted 3D-Flash sequence. The overall measuring time was 70 to 80 minutes. For each subject, GFR data were compared with the results of renal scintigraphy with Tc-labeled DTPA from the same day.Kidney anatomy and vascular status were successfully assessed in all subjects. The results of MR-angiography were in excellent accordance with the surgical findings. MR-nephrography presented a good agreement to the scintigraphy (mean GFR from MR-nephrography = 117 +/- 24 mL/min per 1.73 m; mean GFR from scintigraphy = 116 +/- 26 mL/min per 1.73 m). The Bland-Altman-plot showed a mean difference in measurements pairs of -1 +/- 12 mL/min per 1.73 m. The absolute paired difference ranged between 0 and 22 mL/min per 1.73 m.The study showed the feasibility of the comprehensive assessment of renal anatomy, function, and vascular morphology, using 1 single MR examination. The proposed protocol may find immediate clinical application in the preoperative assessment of potential kidney donors.

BACKGROUND AND OBJECTIVE In patients with chronic glomerular nephropathy associated arterial hypertension and proteinuria are considered to be cardinal risk factors in the progressive deterioration of renal function. Treatment regimens which reduce proteinuria and hypertension improve prognosis. The effect of the new beta-receptor blockers compared to common ACE-Inhibitors is of special interest. PATIENTS AND METHODS The studied cohort consisted of 11 patients with CGN, hypertension and proteinuria > 400 mg/24 h. Four drugs were given for 4 weeks, doubly blinded and randomized according to a "Latin-square design": Celiprolol (beta-1-antagonist, beta-2-agonist, 200 mg/d), Atenolol (selective beta-1-antagonist, 50 mg/d), Ramipril (ACE-inhibitor, 2.5 mg/d) and placebo. There was a two-week wash-out phase between each of the four treatment phases. At the end of each treatment phase glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and para-amino-hippuric acid (PAH) clearance. Proteinuria was determined in the course of a three-day collection period at the end of each treatment phase. During this period blood pressures were measured with a continuous 24-hour blood pressure monitor. RESULTS Mean arterial blood pressure (MAP) was significantly reduced, compared with placebo, by all three antihypertensives (108 +/- 9 mm Hg with placebo, 98 +/- 12 mg Hg with atenolol, 101 +/- 11 mm Hg with celiprolol and 98 +/- 8 mm Hg with ramipril; P < 0.01). Celiprolol produced a significant rise In ERPF (322 +/- 109 ml/min with placebo, 391 +/- 110 ml/min with celiprolol: P < 0.05). GFR was slightly, but not significantly, reduced by celiprolol and atenolol. Filtration fraction remained unchanged with atenolol and celiprolol, while it was slightly, but not significantly, reduced with ramipril. Compared with the placebo, all three drugs significantly reduced proteinuria (P < 0.05): 1.8 +/- 1.3 g/24 h with placebo, 1.2 +/- 1.2 g/24 h with atenolol, 1.2 +/- 1.1 g/24 h with celiprolol and 1.4 +/- 1.4 g/24 h with ramipril. CONCLUSION These data indicate that, in addition to ACE inhibitors, the new generation of beta-receptor blockers in particular, because of their vasodilator action, favourably influence proteinuria and renal blood flow in patients with CGN and arterial hypertension.

The present experiments were designed to assess the renal functional response to alterations in nitric oxide formation in animals with different forms of nephropathy. To address this issue, the effects of Nomega-nitro-L-arginine methyl ester (L-NAME) or L-arginine were assessed in animal models exhibiting arterial hypertension due to chronic nitric oxide inhibition (L-NAME, 50 mg/l in drinking water for 12 weeks) or diabetes mellitus (streptozotocin, 60 mg/kg IP). Vehicle-treated, age-matched animals served as controls. Following 12 weeks of pretreatment, mean arterial pressure (MAP), renal hemodynamics, urinary albumin, and electrolyte excretion were determined in standard clearance experiments prior to and following infusion of L-NAME (50 microg/kg/min), l-arginine (5 mg/kg/min), or saline vehicle. In control animals, L-NAME resulted in an increase in MAP and renal vascular resistance and a decline in glomerular filtration rate and renal plasma flow, as expected. L-arginine had no effect on renal hemodynamics. In nitric oxide-depleted hypertensive animals, L-NAME had no additional effect on MAP or renal hemodynamics. Infusion of L-arginine reduced elevated MAP but did not reverse changes in renal hemodynamics. Diabetic rats demonstrated glomerular hyperfiltration and proteinuria. No significant changes in MAP or renal hemodynamics were observed following infusion of L-NAME or L-arginine, respectively. However, L-NAME increased urinary albumin excretion in the absence of hemodynamic changes. The effects of nitric oxide on vascular tone were shown to be dependent on the vascular bed and the underlying disease. Variations in local nitric oxide formation and susceptibility may account for the differential response of the systemic and renal vasculature and contribute to the degree of renal functional impairment observed in different systemic diseases.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 postrandomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 postrandomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] −1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m2 (95% CI −0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m2 (95% CI −1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years. The beneficial effect on renal function achieved by early CNI withdrawal and treatment with everolimus after liver transplantation is still evident after three years.

Several studies have recently suggested a principal role of adenosine in the pathogenesis of radiocontrast media-induced nephropathy. In the present experiments, we therefore investigated the renal protective effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a potent and selective adenosine A1 receptor antagonist, on radiocontrast media-induced nephropathy in the model of the N-ϖ-nitro- l -arginine methyl ester ( l -NAME) hypertensive, chronic nitric oxide (NO)-depleted rat. Chronic NO depletion was induced by pretreatment with l -NAME, 50 mg/ml, added to drinking water for 8 weeks. Clearance experiments were performed in anesthetized rats and glomerular filtration rate was assessed prior to and following the application of high osmolar radiocontrast media (sodium diatrizoate, 3 ml/kg, i.v.) or an equivalent volume of isoosmolar mannitol to examine the role of hyperosmolarity in radiocontrast media-induced nephropathy. Subgroups received KW-3902 (0.1 mg/kg, i.v.), 20 min prior to radiocontrast media administration. Age-matched, untreated rats served as controls. Radiocontrast media application induced a significant decline in glomerular filtration rate in l -NAME hypertensive animals, whereas no effects were observed in control rats. KW-3902 fully prevented the drop in glomerular filtration rate in response to radiocontrast media in l -NAME hypertensive rats. No renal hemodynamic alterations were observed in mannitol-infused animals. The present experiments demonstrate that the decrease in glomerular filtration rate following radiocontrast media occurred independently of the osmotic load, and that KW-3902 effectively prevented the radiocontrast media-induced deterioration in renal function. KW-3902 may be especially beneficial in patients at high risk for developing acute renal failure following radiocontrast media application or in patients in which extracellular fluid volume expansion is limited by clinical conditions such as congestive heart failure.

The prevalence of obesity is increasing worldwide and contributes to many health problems, including kidney disease. Unexpectedly, 10-30% of obese individuals are apparently not at increased risk of metabolic diseases, e.g. type 2 diabetes, cardiovascular disease and risk of renal disease. Their phenotype is labeled 'metabolically healthy obesity'. In the search for mechanisms explaining this unexpected condition, a favourable type of body fat distribution with low insulin resistance and with low subclinical inflammation has been identified. Furthermore, signalling pathways have been found that distinguish between metabolically benign and malignant obesity. In addition, the important roles of fatty acids, adipokines and hepatokines were identified. These factors regulate insulin resistance and subclinical inflammation. Onset and evolution of chronic kidney disease (CKD) are affected by obesity. CKD also increases the risk of insulin resistance and subclinical inflammation, two pathways that play an important role in the pathogenesis of renal malfunction. This brief review summarizes novel insights, specifically how distinct body fat compartments (including perivascular and even renal sinus fat) may have an impact on progression of CKD.

Background/Aim: Rhabdomyolysis is associated with the release of myoglobin into the circulation, promoting acute kidney injury (AKI). In severe rhabdomyolysis, dialysis-dependent AKI doubles mortality. Standard blood purification techniques have limited efficacy in removing myoglobin. We describe high cut-off (HCO) renal replacement therapy (RRT) as a novel approach for extracorporeal elimination of myoglobin in rhabdomyolysis-associated AKI. Methods: With an in vivo molecular cut-off at 45 kDa, HCO filters are effective in removing myoglobin (17.8 kDa). Clearances across standard and HCO filters using continuous or intermittent RRT are reviewed in a case series of 11 patients with severe rhabdomyolysis and dialysis-dependent AKI. Results: Median myoglobin clearance across standard high-flux filters was 3.3 (interquartile range 2.3–3.9) ml/min for sustained low-efficiency daily dialysis (SLEDD) batch hemodialysis (HD) and 3.7 (2.9–6.7) ml/min for conventional HD. Respective clearances using HCO filters (membrane surface area: 1.1 m2) were 21.7 (20.3–26.1) ml/min (SLEDD) and 44.2 (41.3–47.0) ml/min (HD). Corrected for filter size, up to 20-fold higher clearances were obtained using HCO filters, resulting in profound and sustained reduction of plasma myoglobin concentration. Conclusions: As a novel approach, HCO RRT allows for rapid and effective removal of myoglobin from the circulation. In light of the pathogenic role in AKI, reducing exposure of the kidney to myoglobin may improve renal recovery and patient outcome. Our data pave the way for prospective trials, addressing this issue.

Background. To determine the efficacy of immunoglobulin free light chain (FLC) removal by high cut-off haemodialysis (HCO-HD) as an adjuvant treatment to chemotherapy for patients with acute kidney injury complicating multiple myeloma (MM). Methods. Sixty-seven patients with dialysis-dependent renal failure secondary to MM were treated with HCO-HD and chemotherapy. Results. The population was predominately male (62.7%) with new presentation MM (75%) and did not have a history of chronic kidney disease (84%). The mean serum creatinine at presentation was 662 (SD ¼ 349) lmol/L and of the 56.7% of patients who had a renal biopsy, 86.7% had cast nephropathy as the principal diagnosis. Eighty-five percent of patients were treated with a chemotherapy regime consisting of dexamethasone in combination with a novel agent (bortezomib or thalidomide). The median number of HCOHD sessions was 11 (range 3–45), 97% received an extended dialysis regime. Seventy-six percent of the population had a sustained reduction in serum FLC concentrations by Day 12, of these 71% subsequently became independent of dialysis. In total, 63% of population became independent of dialysis. Factors which predicted independence of dialysis were the degree of FLC reduction at Days 12 (P ¼ 0.002) and 21 (P ¼ 0.005) and the time to initiating HCO-HD (P ¼ 0.006). Conclusion. The combination of extended HCO-HD and chemotherapy resulted in sustained reductions in serum FLC concentrations in the majority of patients and a high rate of independence of dialysis.

Acute kidney injury (AKI) is frequent in multiple myeloma (MM) patients and strongly affects prognosis, with particularly poor outcomes in patients requiring hemodialysis. Introduction of the novel therapeutic agents to MM therapy has improved myeloma response and renal outcome. This case series reviews the efficacy of combined systemic and extracorporeal therapy to further optimize time to light chain (serum-free light chain (sFLC)) reduction and renal recovery in MM patients with dialysis-dependent AKI (n = 19). High cut-off (HCO) hemodialysis for extracorporeal sFLC removal was initiated in parallel to chemotherapy. Combined therapy resulted in early sFLC response after a median of 13 (range 4–48) days and 6 (3–22) HCO hemodialysis sessions. Time to sFLC response was shorter in patients recovering renal function. Median time to dialysis independence was 15 (4–64) days. By intent-to-treat analysis, sustained renal recovery was achieved in 73.7% (77.8% adjusted for death) of patients. In multivariate analysis, duration of AKI prior to initiation of therapy was an independent predictor of renal functional outcome. Combining HCO hemodialysis for extracorporeal sFLC elimination and effective chemotherapy is a novel treatment strategy allowing for early and sustained sFLC reduction and a high proportion of renal recovery in these patients. Timely diagnosis and onset of therapy is essential for improving renal outcome.

The effects of four different antihypertensive drugs (the Ca(2+)-channel blocker felodipine, the beta-blocker metoprolol, the angiotensin converting enzyme inhibitor ramipril, and the alpha-blocking agent doxazosin) on microalbuminuria and renal hemodynamics were evaluated in a double-blind, crossover study in 17 patients (10 women, seven men, aged 39 +/- 14 years) with mild-to-moderate essential arterial hypertension and microalbuminuria. Patients were studied after a 2-week placebo phase preceded by 2 weeks off all medication and after 12 weeks of treatment with each drug. Between each drug treatment, there was another 14-day placebo washout period. At the end of the study, we performed two additional 2-week placebo periods. After each placebo and treatment period, we measured albumin excretion during a 3-day collecting period. Renal hemodynamics were assessed by clearance techniques (inulin and p-aminohippurate clearance) at the end of the first and last placebo periods and after each treatment period. All drugs reduced mean arterial pressure and microalbuminuria to a similar and statistically significant (p < 0.05) extent (mean arterial pressure: placebo phase, 116 +/- 5 mm Hg; felodipine, 101 +/- 4 mm Hg; metoprolol, 101 +/- 5 mm Hg; ramipril, 101 +/- 4 mm Hg; doxazosin, 102 +/- 5 mm Hg; urinary albumin excretion: placebo phase, 46 +/- 50 mg/day; felodipine, 18 +/- 23 mg/day; metoprolol, 14 +/- 12 mg/day; ramipril, 16 +/- 16 mg/day; doxazosin, 14 +/- 14 mg/day). Mean arterial pressure levels and urinary albumin excretion returned to baseline after the last placebo period (110 +/- 6 mm Hg and 40 +/- 46 mg/day, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Evaluation of potential kidney donors requires the assessment of both kidney anatomy and function. In this prospective study, we sought to expand the diagnostic yield of magnetic resonance (MR) by adding functional measurements of glomerular filtration rate (GFR) and split renal function. METHODS: Between 2007 and 2009, all potential kidney donors presenting to our facility underwent a comprehensive single-stop MR study that included an assessment of anatomy, angiography and functional measurements. GFR was measured after a bolus injection of gadobutrol (4 ml, approximately 0.05 mmol/kg) and calculated from the washout of the signal intensity obtained over the liver. Split renal function was calculated from the increase of signal intensity over the renal cortex. Values were compared to renal scintigraphy with (99m)Tc-DTPA from the same day. RESULTS: The MR investigation was successfully performed in 21 participants. The GFR derived from MR (MR-GFR) correlated well (r = 0.84) with the GFR derived from scintigraphy (DTPA-GFR). The mean value of the paired differences was 4 +/- 13 [SD] ml/min/1.73 m(2) and was not significantly different from zero. The ratio between right and left kidney function was similar with both techniques (1.01 +/- 0.17 with MR and 1.06 +/- 0.12 with scintigraphy, P = 0.20). CONCLUSIONS: We demonstrate an MR-based approach to comprehensively evaluate both kidney anatomy and function in a single investigation, thereby facilitating the evaluation of potential kidney donors.

Background Renal failure is a frequent complication of multiple myeloma and when severe is associated with a greatly increased morbidity and mortality. The principal cause of severe renal failure is cast nephropathy, a direct consequence of high concentrations of monoclonal free light chains (FLCs) in patients' sera. FLC removal by extended haemodialysis, using a high cut-off dialyser, has recently been described as a novel therapeutic option. Methods The EUropean trial of free LIght chain removal by exTEnded haemodialysis in cast nephropathy (EuLITE) trial is a prospective, randomised, multicentre, open label clinical trial to investigate the clinical benefits of FLC removal haemodialysis in patients with cast nephropathy, dialysis dependent acute renal failure and de novo multiple myeloma. Recruitment commenced in May 2008. In total, 90 patients will be recruited. Participants will be randomised, centrally, upon enrolment, to either trial chemotherapy and FLC removal haemodialysis or trial chemotherapy and standard high flux haemodialysis. Trial chemotherapy consists of bortezomib, doxorubicin and dexamethasone. FLC removal haemodialysis is undertaken with two Gambro HCO 1100 dialysers in series using an intensive treatment schedule. The primary outcome for the study is independence of dialysis at 3 months. Secondary outcomes are: duration of dialysis, reduction in serum FLC concentrations; myeloma response and survival. Hypothesis FLC removal haemodialysis will increase the rate of renal recovery in patients with severe renal failure secondary to cast nephropathy in de novo multiple myeloma. Trial registration ISRCTN45967602

Adenosine and extracellular volume in radiocontrast media-induced nephropathy. Renal hemodynamic changes could play a key role in radiocontrast media-induced nephropathy (RCIN), although the pathophysiological mechanisms are unclear. We investigated the role of adenosine in RCIN caused by sodium diatrizoate (Urografin, 3 ml/kg) in nitro-L-Arg methyl ester (L-NAME)-hypertensive rats in different hydration states [eight weeks of L-NAME (50 mg/liter) in drinking water; high or low sodium intake for the last two weeks]. In clearance experiments under thiobutabarbital anesthesia in these previously mentioned animals, glomerular filtration rate (GFR), renal blood flow (RBF), and mean arterial pressure (MAP) were measured in the presence or absence of the adenosine A1-receptor antagonist 8-cyclopropyl-1,3-dipropylxanthine (DPCPX, 100 μg/kg bolus plus 10 μg/kg/hr). DPCPX or pretreatment did not change control hemodynamics. Contrast medium caused GFR and RBF to fall significantly in volume-depleted rats (from 0.29 ± 0.02 to 0.21 ± 0.02 ml/min/100 g and 5.4 ± 0.3 to 4.0 ± 0.4 ml/min, respectively) without change in MAP. In volume-expanded rats, changes were not significant (0.25 ± 0.01 to 0.24 ± 0.02 ml/min/100 g and 5.6 ± 0.3 to 5.3 ± 0.4 ml/min, respectively). In the volume-depleted rats, changes were prevented by DPCPX (0.27 ± 0.02 to 0.24 ± 0.02 ml/min/100 g and 4.8 ± 0.1 to 5.0 ± 0.1 ml/min, respectively). The acute hemodynamic effects elicited by contrast medium in L-NAME hypertensive rats thus can be prevented by volume expansion. Adenosine, via A1-receptors, contributes to the adverse effects of contrast media.

Background. Adenosine is a vasoactive metabolite of ATP hydrolysis that is involved in the regulation of renal haemodynamics, tubular reabsorption and renin release. Elevated tissue levels are found under conditions of increased metabolic load, ischaemia or renal injury. Urinary adenosine excretion (EADO) may therefore provide a sensitive marker of renal functional impairment in allograft rejection and kidney disease. To provide a basis for evaluation of EADO in clinical settings, we investigated, in an intra-individual, crossover clinical trial the physiological variability and regulation of EADO in response to altered sodium and fluid balance. Methods. Twelve healthy volunteers were randomized to normal (ad libitum), low (

To study the possible mechanism of renoprotective effects of adenosine A1-receptor antagonist against radiocontrast media (RCM)-induced nephropathy, we investigated the effects of adenosine A1receptor antagonist on tubuloglomerular feedback (TGF) activity prior to and following application of RCM in chronic NO-depleted rats. TGF in NO-depleted rats was significantly enhanced compared with that in normal rats. After RCM application, the enhanced TGF was continued. A selective adenosine Ai-receptor antagonist, KW-3902 (8-(noradamantan-3-yl)-l,3-dipropylxanthine), inhibited the enhanced TGF. These results suggest that KW-3902 could inhibit TGF in chronic NO-depleted rats. Renoprotective effects by adenosine antagonists could be partly due to an inhibition of TGF via the blockade of the adenosine A1-receptor.

Acute kidney injury (AKI) either in primary diagnosis or at relapse is one of the frequent complications in multiple myeloma (MM). Myeloma cast nephropathy is induced by mechanical occlusion of the distal tubule by casts consisting of free light chains (FLC) and Tamm Horsfall protein. Impairment of renal function affects prognosis, with particularly poor outcomes in patients requiring hemodialysis with a historically reported median survival of 3-4 months. Introduction of novel therapeutic agents in MM therapy has improved MM response as well as renal outcome mainly due to a short time to initial response and consecutively reduction of the toxic FLC component. Extracorporeal light chain elimination in addition to chemotherapeutic treatment has been discussed controversially so far. We and others introduced the high-cut off (HCO) dialysis which allows effective elimination of FLC in an extended standard dialysis protocol. Recently, we demonstrated the efficacy of combined systemic and extracorporeal therapy regarding time to FLC reduction and renal recovery in a first case series of MM patients with dialysis-dependent AKI (Heyne et al., Ann Haematol 2012). Here, we report long-term renal outcome and overall survival data. 19 MM patients with dialysis dependent AKI were treated between November 2006 and October 2009 with HCO dialysis in parallel to systemic chemotherapy. The applied chemotherapy was chosen by the treating haematologist. All data was calculated by intent-to-treat (ITT) analysis. Progression-free survival (PFS) was analysed from the first day of HCO dialysis to progression or death, whichever occurred first. Overall survival was calculated from the first day of HCO dialysis to death. For statistical analysis GraphPad Prism (GraphPad Software Inc., La Jolla/CA, USA) and R (R Foundation for Statistical Computing, Vienna) biostatistical software was used. The ITT cohort consisted of 19 patients. Median age was 69 (range 50-83) years. 10 patients had newly diagnosed, 9 relapsed or refractory MM. All patients had ISS stage III disease. Median serum FLC concentration at baseline was 8,580 (1 590-66 100) mg/L. Median serum creatinine was 6.8 (4.4-11.6) mg/dL, median eGFR 7.0 (3.3-10.9) mL/min/1.73m². Four (21%) early deaths occurred in the first three months of treatment, 2 patients with newly diagnosed and 2 patients with relapsed disease. Chemotherapy consisted mainly of bortezomib based regimens. As we reported previously, sustained renal recovery was achieved in 73.7% or 14/19 patients with a median time to independence of hemodialysis of 15 (4-64) days. In the long-term follow up analysis with a median follow-up of 62 months, 11/14 dialysis independent patients remained free of dialysis during further disease course. 3 patients again requiring dialysis all showed terminally refractory disease. Median PFS of the IIT population was 7.8 months for primary diagnosed and 4.8 months for relapsed and refractory patients, median OS of the whole population was 9.5 (range 2.8-not reached) months for primary diagnosed patients and 4.8 (range 1.0-19.8) months for the relapsed and refractory group. Combination of systemic treatment and HCO dialysis in patients with myeloma cast nephropathy and dialysis dependent renal failure results in durable renal remissions in the majority of patients. Close monitoring of patients and early treatment intervention can prevent recurrent severe AKI in myeloma relapse. Survival data reflect the critically ill patient population with high tumor burden and high-risk of early death, but also show encouraging long-term myeloma and renal remissions. The benefit of the additional HCO dialysis in addition to conventional chemotherapy is currently investigated in a randomised multicenter trial (EuLITE study). Disclosures: Weisel: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.