BACKGROUND:The correct valganciclovir dose for cytomegalovirus (CMV) prophylaxis depends on renal function estimated by the Cockcroft-Gault (CG) estimated creatinine clearance (CG-CrCl) formula. Patients with delayed or rapidly changing graft function after transplantation (tx) will need dose adjustments.METHODS:We performed a retrospective investigation of valganciclovir dosing in renal transplant patients receiving CMV prophylaxis between August 2003 and August 2011, and analysed valganciclovir dosing, CG-CrCl, CMV viraemia (CMV-PCR <750 copies/mL), leucopenia (<3500/µL) and neutropenia (<1500/µL) in the first year post-transplant. On Days 30 and 60 post-transplant, dosing pattern in relation to estimated creatinine clearance was analysed regarding CMV viraemia, leucopenia and neutropenia.RESULTS:Six hundred and thirty-five patients received valganciclovir prophylaxis that lasted 129 ± 68 days with a mean dose of 248 ± 152 mg/day of whom 112/635 (17.7%) developed CMV viraemia, 166/635 (26.1%) leucopenia and 48/635 (7.6%) neutropenia. CMV resistance within 1 year post-transplant was detected in three patients. Only 137/609 (22.6%) patients received the recommended dose, while n = 426 (70.3%) were underdosed and n = 43 (7.1%) were overdosed at Day 30 post-tx. Risk factors for CMV viraemia were donor positive D (+)/receptor negative R (-) status and short prophylaxis duration, but not low valganciclovir dose. Risk factors for developing leucopenia were D+/R- status and low renal function. No significant differences in dosing frequency were observed in patients developing neutropenia or not (P = 0.584).CONCLUSION:Most patients do not receive the recommended valganciclovir dose. Despite obvious underdosing in a large proportion of patients, effective prophylaxis was maintained and it was not associated as a risk factor for CMV viraemia or leucopenia.

Background Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti-thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. Methods Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. Results Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 ± 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-β1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-β1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). Conclusions The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions.

Herzinsuffizienz (HI) ist die häufigste kardiovaskuläre Diagnose bei Patienten mit chronischer Niereninsuffizienz (CNI) im Endstadium. Ein gemeinsames Begleitsymptom dieser doppelt belasteten und äußerst vulnerablen Patientengruppe ist die Anämie. Aufgrund neuerer Studiendaten mit Eisencarboxymaltose wird intravenöses (i. v.) Eisen auch als Therapieoption bei HI intensiv diskutiert. Damit stellt sich die Frage, ob eine Gabe von i. v. Eisen bei CNI-Patienten mit HI zu erwägen wäre, auch wenn diese unter dem Blickwinkel der reinen Anämiekontrolle eigentlich nicht behandlungsbedürftig sind. Im Hinblick auf die aktuelle Studienevidenz ist es vorerst zu früh, i. v. Eisen bei CNI-Patienten auch zur Therapie einer HI einzusetzen. Aktuell sollte i. v. Eisen auch bei CNI-Patienten mit HI zur Anämietherapie appliziert und die Empfehlungen hinsichtlich der maximalen Serum-Ferritin-Spiegel beachtet werden. Aufgrund der heterogenen Empfehlungen zur Obergrenze ist jedoch eine individuelle Nutzen-Risiko-Analyse für jeden Patienten notwendig.

BACKGROUND:Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. METHODS:Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. RESULTS:The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. CONCLUSION:The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.

BACKGROUND:Primary focal segmental glomerulosclerosis (FSGS) often causes nephrotic proteinuria and frequently results in end-stage renal disease and recurrence after kidney transplantation. Recent studies describe soluble urokinase-type plasminogen activator receptor (suPAR) as a circulating factor implicated in FSGS. METHODS:This single-center study included 12 adult patients with histologically proven primary FSGS (n = 2) or recurrent FSGS after transplantation (n = 10). The effect of plasma exchange (PE) on clinical outcome, suPAR levels, and in vitro podocyte β3-integrin activation was investigated over a median of 11 (6-18) sessions of PE. RESULTS:The course of treatment was monitored in a total of 70 sessions of PE, which partly eliminated suPAR, with a mean reduction of 37 ± 12% of serum concentration per session. However, a substantial rebound was observed between sessions, with suPAR levels reaching 99 ± 22% of the pretreatment levels after a median of 4 days. Podocyte β3-integrin activation dropped significantly after PE but rebounded within 4 days concomitant with a rising suPAR level. In 11 of 12 patients, multimodal treatment (including extensive PE) reduced proteinuria significantly (from 5.3 [2.0-7.8] to 1.0 [0.4-1.6] g/d), indicating clinical efficacy of the therapy. One patient suffered allograft loss due to FSGS recurrence. A persisting response was independent of a lasting reduction in the level of total suPAR because there was no sustained significant change in suPAR levels before and after the course of intensified treatment (3814 ± 908 to 3595 ± 521 pg/mL; P = 0.496). CONCLUSIONS:We conclude that multimodal therapy including extensive PE was associated with stabilization of recurrent FSGS and a temporary lowering of plasma suPAR as well as podocyte β3-integrin activation. Whether a sustained lowering of total suPAR results in further improved outcomes requires additional study.

Background. Scientific interest in cardiorenal syndrome (CRS) affecting the native kidneys is increasing. In contrast, no relevant literature exists on CRS after kidney transplantation. Methods. Prompted by the clinical course of a renal allograft recipient, who lost his graft because of CRS, we systematically investigated the frequency, the clinical appearance, the underlying cardiac pathophysiology, and the renal pathology of patients with graft loss caused by CRS between 2006 and 2011 at our center. Results. We identified seven cases of graft loss caused by CRS, six cases of CRS type II, and one case of CRS type I. The proportion of death-censored graft losses caused by CRS was 4.6% (7/152 patients). Median graft survival after diagnosis was 6 (1-62) months. Clinically, all patients suffered from repeated episodes of decreasing renal function together with severe volume overload necessitating multiple hospitalizations (range, 23-308 days) and ultrafiltration treatments (range, 4-45). Cardiac investigation revealed a combination of left heart failure, right heart failure and moderate-to-severe tricuspid regurgitation in 5/6 CRS type II patients. Renal allograft pathology showed the same pattern of tubular injury in all biopsy specimens: microvesicular tubular epithelial cytoplasmatic vacuolization and luminal dilatation with flattening of the epithelium. Conclusion. We propose that the diagnosis of CRS after renal transplantation should be based on the following triad: (i) otherwise unexplained decrease of renal function together with severe volume overload; (ii) functionally relevant heart disease, predominantly left heart failure in combination with right heart failure, and tricuspid regurgitation; and (iii) a typical histopathologic pattern of tubular injury.

AIMS:Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug-drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration-time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy. METHODS:In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC0-12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1-2 g day(-1) ) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined. RESULTS:MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml(-1) mg(-1) [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml(-1) mg(-1) (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml(-1) mg(-1) (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml(-1) mg(-1) (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min-max: 0.5-10.0)] than EC-MPS intake alone [3 h (1.5-12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5-5.0)] ± pantoprazole [1.0 h (0.5-6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found. CONCLUSION:Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired.

Sensitization to human leukocyte antigens remains a major barrier for successful kidney transplantation increasing the risk of antibody-mediated rejection (ABMR) and premature graft loss. Because of organ shortage and poor long-term outcomes on dialysis some transplant centers introduced “desensitization” protocols to overcome human leukocyte antigen incompatibility in case of an available living donor (1). The Johns Hopkins group (2) pioneered these protocols, which generally include plasmapheresis, intravenous immunoglobulins, and T-cell and B-cell depletions before transplantation under tacrolimus-based triple maintenance immunosuppression. The hope was that current modern and strong multimodal immunosuppression would overcome the immunologic barrier leading to acceptable outcomes. The reality is that up to 9.4% of patients (approximately 44 years old) die in the first year after desensitization (2), 25% to 45% of patients present with transplant glomerulopathy at 1 year (1, 3), resulting in suboptimal 5-year patient and graft survival rates. In addition, more than 50% of surviving grafts show transplant glomerulopathy after 5 years (3), suggesting chronic active ABMR and premature graft failure. Moreover, rebound of donor-specific antibodies (DSA) after desensitization with acute ABMR and oliguric renal failure occurs, and even more aggressive measures are necessary to prevent immediate graft loss. This scenario is impressively described in the article by Orandi et al. (4), published in this journal: 24 of 267 patients (9%) developed severe ABMR between 2003 and 2010 after desensitization. Three different treatment modalities were used: rescue splenectomy, eculizumab alone, or the combination of both. The rationale for these interventions can be briefly summarized as following: splenectomy could inhibit DSA production from newly formed plasmablasts migrating into the spleen. The humanized monoclonal antibody eculizumab inhibits complement protein C5 and complement-dependent injury (e.g. formation of membrane-attack-complex) protecting vascular endothelium against antibody-mediated injury. The hope was that rescue therapy with splenectomy (n=14) or eculizumab (n=5) would reverse severe acute ABMR, when given in combination with intensified immunosuppression and extensive plasmapheresis. In reality, neither splenectomy (4/14 graft losses) nor eculizumab (5,760 mg/patient; 4/5 graft losses) alone could halt ABMR. Even more disappointing, only 4 of 19 patients (all in splenectomy group) had a functioning graft without transplant glomerulopathy at 1 year. The authors are applauded for their honest description of their failures, which is of particular importance, because case reports suggested hope for both measures. The hope now is that combination of splenectomy and complement blockade may increase outcome of devastating ABMR. In reality, we have evidence for this hypothesis from only five patients (4). However, these patients differed in their baseline and treatment characteristics from failures, all showed a negative flow crossmatch before transplantation, suggesting that the pretransplant response of the recipient to desensitization is important for reversal of ABMR. Furthermore, they received more plasma exchanges and more eculizumab (13,000 mg/patient). Splenectomy is an invasive method, and high rates of complications may elicit further concerns. The immense costs of eculizumab (approximately 110,000–250,000 Euros) and questions about its optimal use are further issues around this interesting drug. Nevertheless, data are encouraging and providing additional proof for the importance and limitations of complement blockade in ABMR. In summary, the present report highlights the constraints of current desensitization protocols, even if performed in a pioneering centre. The results confirm common wisdom that prevention is better than treatment (5). For desensitization protocols prophylactic complement inhibition seems more promising than rescue therapy (6). Physicians should aim to prevent sensitization already in dialysis populations, and alternatives such as acceptable mismatch programs and kidney exchange programs should be considered first (7). In the future, risk stratification strategies might help to identify those patients, who develop a rebound of DSA and severe ABMR. More research is needed to characterize those DSAs, which are leading to graft loss. Unfortunately, the determination of C1q-binding DSA before transplantation could not predict outcome (8). Given all the concerns, registries with assessment of long-term outcome after desensitization as well as prospective randomized trials are overdue. Until then, centers should take a cautious approach, look for alternatives and send patients to specialized centers. Nephrologists should aim to increase dialysis quality for those patients because long-term intensified dialysis protocols (9) result in 5-year patient survival rates (83%), similar to desensitization protocols (1–3). For each individual, one should carefully weigh the risks of desensitization against the risks of waiting on dialysis for a suitable kidney (10). In light of the risks of the living donor (11), and the risks of the recipient, we should concentrate on those transplants, which provide a reasonable chance of a long-term success avoiding that the recipient is coming back through the revolving door of the transplant center with even higher sensitization.

OBJECTIVES:Whether T-cell-mediated rejection Banff classification type Ib (severe tubulointerstitial rejection) and type IIa (mild vascular rejection) are associated with responses to antirejection therapy and long-term graft survival are unclear. MATERIALS AND METHODS:One hundred ten patients were enrolled who had at least 1 episode of T-cell-mediated rejection and whose highest T-cell-mediated rejection severity was T-cell-mediated rejection type Ib or IIa. RESULTS:T-cell-mediated rejection Ib occurred significantly later than T-cell-mediated rejection IIa (P < .001). The proportion of partial/no response to antirejection therapy was comparable between the 2 groups (P = .83). Up to 8-year posttransplant, death-censored graft survival rate of the T-cell-mediated rejection Ib group was similar to that of the T-cell-mediated rejection IIa group (P = .51). Early T-cell-mediated rejection IIa had a statistically higher death-censored graft survival rate than did late T-cell-mediated rejection IIa (P < .001), while no significant difference in the death-censored graft survival was found between early and late T-cell-mediated rejection Ib (P = .11) or between early T-cell-mediated rejection Ib and early T-cell-mediated rejection IIa (P = .11) or between late T-cell-mediated rejection Ib and late T-cell-mediated rejection IIa (P = .07). Furthermore, the T-cell-mediated rejection IIa with isolated v1 lesion (v1, i0-1, t0-1) showed a similar death-censored graft survival rate compared to T-cell-mediated rejection IIa with intensive tubulointerstitial inflammation (v1, i2-3, t2-3). The timing of rejection, graft number, the number of indicated biopsies and the presence of ci/ct lesions were associated with long-term graft loss. CONCLUSIONS:The designation of T-cell-mediated rejection type Ib and IIa reflects the different type rather than the distinct severity of rejection and has no independent prognostic significance.

Background Immunosuppression after kidney transplantation has been associated with weight gain. The aim was to evaluate if sirolimus (SRL) had a different effect on weight gain than calcineurin inhibitor (CNI). Methods Data on body weight in different patient populations were analyzed at several time points: (a) SRL (CNI-free) versus cyclosporine A (CsA) treatment de novo, (b) CsA+SRL versus CsA (SRL-free) treatment de novo, (c) SRL+tacrolimus elimination at 3 months versus SRL+mycophenolate mofetil versus tacrolimus+mycophenolate mofetil de novo, and (d) conversion from CNI to SRL versus CNI in maintenance patients. Results Patients were analyzed from de novo transplantation trials (n=1863) and from the conversion study (n=742). At baseline, weight in the SRL-containing and SRL-free treatment arms was not different, but weight gain was significantly less pronounced in SRL in de novo treatment (group 1: 2.8±4.6 vs. 6.2±6.6 kg every 2 years, P=0.020; group 2: 6.1±9.5 vs. 9.6±9.1 kg every 2 years, P<0.001; and group 3: 3.7±7.0 vs. 3.5±6.2 vs. 5.9±9.0 kg every 1 year, P=0.042). In the conversion study, patients lost weight in the SRL arm and gained weight in the CNI arm (−1.0±6.0 vs. +1.0±5.1 kg every 2 years; P<0.001). Conclusion SRL treatment is associated with less weight gain de novo as well as in late conversion.

Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxia-inducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI.

OBJECTIVE:Obesity in transplant recipients is a frequent phenomenon but data from body composition analyses in long-term survivors are limited. Body composition and energy metabolism were studied in patients after liver (LTX) and kidney (KTX) transplantation and patients with liver cirrhosis (LCI) or on chronic hemodialysis (HD) and compared to healthy controls. METHODS:In 42 patients 50.0 mo (median; range 17.1-100.6) after LTX and 30 patients 93.0 mo (31.2-180.1) after KTX as wells as in LCI (n = 39) or HD (n = 10) patients mid-arm muscle and fat area, body cell mass, and phase angle (bioimpedance analysis), and resting energy expenditure (indirect calorimetry, REE(CALO)) were measured. RESULTS:Obesity was more prevalent in LTX (17%) than LCI (3%) and in KTX (27%) than in HD (10%). In LTX and KTX, phase angle was higher than in end-stage disease (LTX 5.6° [4.1-7.2] versus LCI 4.4° [2.9-7.3], P < 0.001; KTX 5.9° [4.4-8.7] versus HD 4.3° [2.9-6.8]) but was lower in all patient groups than in controls (7.1°; 4.6-8.9; P < 0.001). In LCI and HD REE(CALO) was higher than predicted, while in LTX and KTX REE(CALO) was not different from predicted REE. CONCLUSIONS:Despite excellent graft function, many long-term LTX or KTX survivors exhibit a phenotype of sarcopenic obesity with increased fat but low muscle mass. This abnormal body composition is observed despite normalization of the hypermetabolism found in chronic disease and cannot be explained by overeating. The role of appropriate nutrition and physiotherapy after transplantation merits further investigation.

Introduction: Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. Areas covered: The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. Expert opinion: Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.

Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis.

BACKGROUND:In the course of the influenza A H1N1 pandemic, transplanted patients were recommended to receive vaccination. In the present study, we evaluated the immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix®) in renal allograft recipients. METHODS:Sixty patients and 22 healthy controls participated in a prospective observational study and received a single dose of Pandemrix®. H1N1 antibody titres as well as anti-HLA antibodies were determined before and after vaccination. In 19 patients, a booster vaccination was performed and the outcome of all vaccinated renal allograft recipients (n = 107) in our clinic was reviewed. RESULTS:Two out of sixty patients had an elevated influenza A H1N1 titre before vaccination. Of the remaining 58 patients, only 20/58 (34.5%) developed a protective immune response in contrast to 20/22 (91%) of the control group. After booster vaccination, a protective titre was present in 8/19 (42%) of patients. Of the 107 patients, 6 (5.6%) developed new donor-specific HLA antibodies after vaccination. CONCLUSIONS:These data suggest that Pandemrix® does not provide a protective immune response in the majority of kidney transplant recipients. Therefore, for new vaccines, efficacy as well as safety profiles should be evaluated in this subgroup of patients.