Publications by authors named "Volker Kliem"

26 Publications

  • Page 1 of 1

No association of genetic variants in TLR4, TNF-α, IL10, IFN-γ, and IL37 in cytomegalovirus-positive renal allograft recipients with active CMV infection-Subanalysis of the prospective randomised VIPP study.

PLoS One 2021 16;16(4):e0246118. Epub 2021 Apr 16.

Department of Nephrology, University Clinic Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.

Background: Cytomegalovirus (CMV) infection is amongst the most important factors complicating solid organ transplantation. In a large prospective randomized clinical trial, valganciclovir prophylaxis reduced the occurrence of CMV infection and disease compared with preemptive therapy in CMV-positive renal allograft recipients (VIPP study; NCT00372229). Here, we present a subanalysis of the VIPP study, investigating single nucleotide polymorphisms (SNPs) in immune-response-related genes and their association with active CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia.

Methods: Based on literature research ten SNPs were analyzed for TLR4, three for IFN-γ, six for IL10, nine for IL37, and two for TNF-α. An asymptotic independence test (Cochran-Armitage trend test) was used to examine associations between SNPs and the occurrence of CMV infection or other negative outcomes. Statistical significance was defined as p<0.05 and Bonferroni correction for multiple testing was performed.

Results: SNPs were analyzed on 116 blood samples. No associations were found between the analyzed SNPs and the occurrence of CMV infection, rejection and leukopenia in all patients. For IL37 rs2723186, an association with CMV disease (p = 0.0499), for IL10 rs1800872, with graft loss or death (p = 0.0207) and for IL10 rs3024496, with infections (p = 0.0258) was observed in all patients, however did not hold true after correction for multiple testing.

Conclusion: The study did not reveal significant associations between the analyzed SNPs and the occurrence of negative outcomes in CMV-positive renal transplant recipients after correction for multiple testing. The results of this association analysis may be of use in guiding future research efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246118PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051780PMC
April 2021

Repeated kidney re-transplantation-the Eurotransplant experience: a retrospective multicenter outcome analysis.

Transpl Int 2020 06 30;33(6):617-631. Epub 2020 Jan 30.

Department of Nephrology, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tri.13569DOI Listing
June 2020

Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials.

BMC Nephrol 2018 09 19;19(1):237. Epub 2018 Sep 19.

Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes.

Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497).

Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes).

Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes.

Trial Registration: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 ).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-018-1031-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146542PMC
September 2018

Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy.

Am J Transplant 2018 12 3;18(12):2965-2976. Epub 2018 Jun 3.

Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.

HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m , P < .001) or low CNI (difference 7.6 mL/min/1.73 m , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m  and 10.1 mL/min/1.73 m , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.14897DOI Listing
December 2018

Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: Long-term Results After 7 Years of a Randomized Clinical Trial.

Transplantation 2018 05;102(5):876-882

Department of Internal Medicine and Nephrology, Nephrology Center of Lower Saxony, Klinikum Hann. Muenden, Hann, Muenden, Germany.

Background: The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients.

Methods: Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 × 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 × 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over ≥14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D-]/R+).

Results: The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared with preemptive group experienced a CMV infection or disease up to month 84 (11.5%; 95% confidence interval [95% CI], 6.8-17.8%] vs 39.7%; 95% CI, 31.9-48.0%; P < 0.0001 and 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.002). Incidences of graft loss (7.4% vs 8.6%), death (9.5% vs 11.3%), rejection (29.1% vs 28.5%), and renal function (estimated glomerular filtration rate [mean ± SD]: 58.2 ± 26.3 vs 59.9 ± 25.7 mL/min per 1.73 m) were not significantly different between prophylaxis and preemptive treatment. Tolerability was comparable between groups.

Conclusions: Prophylaxis was more effective than the preemptive approach, applying a low-intense surveillance protocol in preventing CMV infection and disease in intermediate-risk patients. Both strategies were similarly effective in preventing graft loss and death under the conditions of this long-term trial with a threshold of 400 copies/mL for initiation of anti-CMV treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002024DOI Listing
May 2018

Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial.

Nephrol Dial Transplant 2017 Jun;32(6):1060-1070

Department of Nephrology, University of Heidelberg, Heidelberg, Germany.

Background.: Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain.

Methods.: In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514).

Results.: The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively.

Conclusions.: Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfx075DOI Listing
June 2017

Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial.

J Clin Oncol 2017 Feb 19;35(5):536-543. Epub 2016 Dec 19.

Ralf U. Trappe and Heiner Zimmermann, DIAKO Evangelisches Diakonie-Krankenhaus Bremen, Bremen; University Medical Centre Schleswig-Holstein, Kiel; Ralf U. Trappe, Petra Reinke, Ioannis Anagnostopoulos, and Hanno Riess, Charité-Universitätsmedizin Berlin, Berlin; Martin H. Dreyling and Marion Subklewe, University of Munich, Munich; Ulrich Dührsen and Andreas Hüttmann, University of Duisburg-Essen, Essen; Volker Kliem, Nephrological Centre Lower Saxony, Hann. Münden; Ingeborg A. Hauser, J.W. Goethe University Hospital, Frankfurt, Germany; Daan Dierickx, Gregor Verhoef, Thomas Tousseyn, and Olivier Gheysens, Catholic University Leuven, Leuven; Eric Van Den Neste, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Franck Morschhauser, Hôpital Claude Huriez, Lille; Gilles Salles, Hospices Civils de Lyon and Université de Lyon, Pierre-Bénite; Veronique Leblond and Sylvain Choquet, Université Pierre et Marie Curie, Paris, France; Peter Mollee, University of Queensland, Brisbane, Queensland, Australia; Jan M. Zaucha, Medical University of Gdansk, Gdansk; Polish Lymphoma Research Group, Warsaw, Poland; and Corrado Tarella, European Institute of Oncology, Milan, Italy.

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20 PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.69.3564DOI Listing
February 2017

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

Nephrol Dial Transplant 2016 09 4;31(9):1515-22. Epub 2016 Feb 4.

Department of Vascular Surgery, Universitätsklinikum Düsseldorf, D-40225 Düsseldorf, Germany.

Background: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial.

Methods: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups.

Results: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome.

Conclusions: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfv446DOI Listing
September 2016

[Cytomegalovirus after renal transplantation - diagnosis, prevention and treatment].

Dtsch Med Wochenschr 2015 Apr 16;140(8):612-5. Epub 2015 Apr 16.

Klinik für Nephrologie, Universitätsklinikum Essen, Universität Duisburg-Essen.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-100777DOI Listing
April 2015

Long-term kidney allograft survival in patients with transplant glomerulitis.

Transplantation 2015 Feb;99(2):331-9

1 Department of Nephrology, Nephrology Center of Lower Saxony, Hann. Muenden, Germany. 2 Department of Nephrology, 1st St. Petersburg Pavlov State Medical University, St. Petersburg, Russian Federation. 3 Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. 4 Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.

Background: Renal transplant glomerulitis (G) is associated with acute antibody-mediated rejection (ABMR) in the presence of donor-specific antibodies. However, the long-term prognosis of isolated G (isG) in the absence of donor-specific antibodies or G in combination with T cell-mediated rejection (TCMR) remains unexplored.

Methods: Seventy recipients with G were included in this retrospective study and subdivided into 3 groups: isG, G with TCMR (G+TCMR), and G with acute ABMR. The control groups were: patients with TCMR Banff type I or II without G (TCMR) and patients without rejection (NR). Kaplan-Meier death-censored survival plots and Cox regression were used to analyze graft survival. The combined graft survival endpoint was defined as a return to dialysis or estimated glomerular filtration rate less than 15 mL/min/1.73 m. The median follow-up was 37 (14; 77) months from biopsy.

Results: Graft survival was significantly lower in patients with G than in the NR and TCMR groups. No significant differences were observed among the isG, G+TCMR, and ABMR groups. Graft survival was lower in the G+TCMR group than in the TCMR group. Glomerulitis was independently associated with the risk of adverse graft outcome in a multivariate Cox regression model adjusted for other confounders (hazard ratio, 4.52 [95% confidence interval, 2.37-8.68] vs controls; P<0.001).

Conclusions: Glomerulitis is strongly associated with increased risk of graft failure. Graft survival in patients with isG that do not meet the Banff criteria for acute/active ABMR and in patients with G accompanying TCMR is comparable to the ABMR group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000000606DOI Listing
February 2015

Anemia control in kidney transplant recipients using once-monthly continuous erythropoietin receptor activator: a prospective, observational study.

J Transplant 2014 4;2014:179705. Epub 2014 May 4.

Nephrology Center of Lower Saxony and Transplant Center, Vogelsang 105, 34346 Hann. Münden, Germany.

In a multicenter, prospective, observational study of 279 kidney transplant recipients with anemia, the efficacy and safety of once-monthly continuous erythropoietin receptor activator (C.E.R.A.) were assessed to a maximum of 15 months. The main efficacy variable was the proportion of patients achieving a hemoglobin level of 11-12 g/dL at each of visits between months 7 and 9. At study entry, 224 patients (80.3%) were receiving erythropoiesis stimulating agent (ESA) therapy including darbepoetin alfa (98), epoetin beta (61), and C.E.R.A. (45). The mean (SD) time between C.E.R.A. applications was 34.0 (11.9) days. Among 193 patients for whom efficacy data were available, mean (SD) hemoglobin was 11.1 (0.99) g/dL at study entry, 11.5 (1.1) g/dL at month 7, 11.6 (1.3) g/dL at month 9, and 11.4 (1.1) g/dL at month 15. During months 7-9, 20.7% of patients had all hemoglobin values within the range 11-12 g/dL and 64.8% were within 10-13 g/dL. Seven patients (2.5%) discontinued C.E.R.A. due to adverse events or serious adverse events. In this observational trial under real-life conditions, once-monthly C.E.R.A. therapy achieved stable hemoglobin levels in stable kidney transplant recipients with good tolerability, and with no requirement for any dose change in 43% of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2014/179705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026977PMC
June 2014

Mycophenolate mofetil maintenance therapy in renal transplant patients: long-term results of the TranCept STAY study.

Clin Transplant 2012 Nov-Dec;26(6):919-26. Epub 2012 Sep 19.

Department of Nephrology, Clinic rechts der Isar, Technical University Munich, Munich, Germany.

Background: This prospective observational study documented long-term renal function in transplant recipients receiving mycophenolate mofetil (MMF).

Methods: Kidney allograft recipients>6 months post-transplantation, with a glomerular filtration rate (GFR)>20 mL/min, receiving MMF from time of transplantation were enrolled and followed for four yr. Subgroups were identified based on time between transplantation and enrollment: Y<1 (6 months-1 yr); Y1-2 (>1-2 yr); Y2-5 (>2-5 yr) and Y>5 (>5 yr).

Results: A total of 2040 patients were analyzed; 780, 410, 541 and 309 in subgroups Y<1, Y1-2, Y2-5 and Y>5. For all patients combined GFR decreased during the observational period by approximately 1 mL/min/yr (median GFR (mL/min) was 50.8, 50.5, 48.7, and 47.6 at one, two, three, and four yr). Survival estimates for decline in renal function (>20% GFR decline at one time point) were 78%, 66%, 57%, and 51% at one, two, three and four yr, with no significant differences between subgroups (p>0.05). In adult patients, higher doses of MMF (≥1 g/d) were associated with better GFR outcomes (median GFR (mL/min) 48.1 vs. 39.9 at four yr post-enrollment; p=0.0037). When comparing the effects of MMF combined with calcineurin inhibitors (CNIs), GFR was increased with lower doses of tacrolimus or cyclosporin. There were no major tolerability or acute rejection problems and graft survival was similar in all subgroups (graft survival estimates for all patients combined were 99%, 95%, 92%, and 90% at one, two, three, and four yr).

Conclusions: Long-term MMF immunosuppression preserves renal function and higher MMF doses combined with lower CNI doses may provide better patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ctr.12008DOI Listing
May 2013

Unilateral nephrectomy causes an abrupt increase in inflammatory mediators and a simultaneous decrease in plasma ADMA: a study in living kidney donors.

Am J Physiol Renal Physiol 2011 Nov 10;301(5):F1042-6. Epub 2011 Aug 10.

Dept. of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOS). Reducing inducible NOS activity in acute inflammation seems to be desirable. In vitro data show that ADMA increases in response to inflammatory mediators, yet the effect of acute inflammation in vivo is scarcely studied. The aim of the study was to evaluate ADMA plasma levels before, during, and after the acute (nonbacterial) inflammatory-like state. Plasma ADMA, l-arginine, C-reactive protein, and IL-6 were determined in 24 healthy subjects undergoing living related kidney donation before as well as 1, 6, 12, 24, 72, and 168 h thereafter. Six hours after nephrectomy, ADMA levels decreased compared with baseline (0.488 ± 0.075 vs. 0.560 ± 0.060 μmol/l, P < 0.05). This difference became even more marked 24 h after the operation (0.478 ± 0.083 μmol/l, P < 0.01 vs. baseline), when the proinflammatory cytokine IL-6 peaked. Seven days after unilateral nephrectomy, ADMA levels were elevated above baseline (0.63 ± 0.05 μmol/l, P < 0.001 vs. baseline). l-Arginine levels decreased already 1 h after nephrectomy (97.5 ± 22.5 μmol/l, P < 0.01 vs. baseline) and paralleled the change in ADMA thereafter. At the end of the observation period when inflammation markers were regressing, l-arginine levels were significantly elevated above baseline (160.6 ± 25.1 μmol/l, P < 0.001 vs. baseline). In summary, this is the first study showing that both ADMA and l-arginine decrease temporarily after unilateral nephrectomy coinciding with the increase in inflammatory mediators. The l-arginine/ADMA ratio, a surrogate for NO production capacity, was only altered for <24 h.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00640.2010DOI Listing
November 2011

SDMA is an early marker of change in GFR after living-related kidney donation.

Nephrol Dial Transplant 2011 Jan 9;26(1):324-8. Epub 2010 Jul 9.

Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School Hannover, Germany.

Background: Early detection of changes in the glomerular filtration rate (GFR) is crucial in detecting acute kidney injury. There is burgeoning evidence from preclinical and clinical studies that symmetrical dimethylarginine (SDMA) correlates well with different parameters of renal function. In some studies, SDMA even outperformed creatinine as a marker of GFR. It is however unknown how fast SDMA is increasing after reduction in GFR. The aim of our study was therefore to determine the temporal change of SDMA in comparison with cystatin C after a defined reduction in GFR.

Methods: Blood samples from 24 healthy living-related kidney donors (19 F/5 M), mean age 55.2 ± 8.3 years, were collected prior to donation of the kidney as well as 1, 6, 12, 24, 72 and 168 h after unilateral nephrectomy. SDMA levels were measured using a liquid chromatography-mass spectrometry-based method.

Results: Within 6 h after unilateral nephrectomy, i.e. reduction of GFR by 50%, SDMA rose from 0.571 ± 0.120 to 0.659 ± 0.135 µmol/L (P < 0.001). Baseline cystatin C levels increased from 0.87 ± 0.16 to 1.07 ± 0.15 mg/L (P < 0.001). Also, serum creatinine rose significantly within 6 h after removal of one kidney from 65.4 ± 8.4 to 88.8 ± 10.2 µmol/L (P < 0.001).

Discussion: SDMA might be a valuable and early marker of change in GFR in the clinical and experimental setting. Future studies will have to clarify whether sensitivity, specificity and temporal resolution of SDMA make it an attractive candidate for the assessment of renal function in both the experimental and clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfq395DOI Listing
January 2011

Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease.

Mol Cell Proteomics 2010 Nov 8;9(11):2424-37. Epub 2010 Jul 8.

Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/mcp.M110.001917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984241PMC
November 2010

Circulating levels of osteopontin are closely related to glomerular filtration rate and cardiovascular risk markers in patients with chronic kidney disease.

Eur J Clin Invest 2010 Apr;40(4):294-300

Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: The pleiotropic cytokine osteopontin (OPN) is thought to be involved in the pathogenesis of atherosclerosis. However, the relationship between OPN and renal function, a cardiovascular risk factor itself, is not known. Therefore, we assessed the relationship between OPN plasma levels and renal function in patients at different stages of chronic kidney disease (CKD).

Methods: We studied 49 non-diabetic and non-smoking patients with primary kidney disease at different CKD stages (K/DOQI 1-5). True glomerular filtration rate (GFR) in patients was assessed using the inulin-clearance technique. To examine the role of an abrupt change in GFR on circulating OPN, 15 living related kidney donors were studied before and after unilateral nephrectomy. Twenty matched non-smoking healthy subjects served as controls.

Results: OPN plasma levels in patients with CKD stage 1 (i.e. GFR above 90 mL min(-1) 1.73 m(-2)) were comparable with controls. OPN levels increase in a linear fashion with declining GFR (r = -0.9, P < 0.0001), so that the increase in OPN mirrors the severity of renal impairment. After unilateral nephrectomy, circulating OPN increased significantly in parallel to the decrease in GFR. We found a direct association between OPN and other markers of renal function (serum-creatinine, homocysteine and symmetric dimethylarginine,) as well as with cardiovascular risk factors such as asymmetric dimethylarginine (r = 0.36, P = 0.0213).

Conclusion: There is a close inverse association between GFR and circulating OPN in patients with CKD. Furthermore, OPN plasma levels correlate with established cardiovascular risk markers in patients with CKD. Assessment of renal function is important for the interpretation of OPN levels in patients with atherosclerotic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2362.2010.02271.xDOI Listing
April 2010

Circulating angiopoietin-2 levels increase with progress of chronic kidney disease.

Nephrol Dial Transplant 2010 Aug 22;25(8):2571-6. Epub 2010 Feb 22.

Division of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.

Background: Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels of Ang-2 and renal function throughout all stages of chronic kidney disease (CKD). In addition, we aimed to detect a potential link between the nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) and the Ang-2 levels.

Methods: Glomerular filtration rate (GFR) was assessed by the inulin clearance technique ((i)GFR) and compared to serum Ang-2 (immunoluminometric assay) and ADMA levels (liquid chromatography-electrospray tandem mass spectrometry) in 44 untreated non-smokers at the different stages of CKD 1-4. Ang-2 was also measured in 19 patients on dialysis (CKD stage 5). In addition, the Ang-2 and (c)GFR (cystatin C) measurements were taken in 15 healthy individuals before and 72 h after kidney donation.

Results: The median Ang-2 levels steadily increased across the following groups: healthy controls: 0.77 (0.32-1.08) ng/mL; CKD 1: 0.83 (0.67-1.09) ng/mL; CKD 2: 0.93 (0.74-1.15) ng/mL; CKD 3: 1.13 (0.87-1.49) ng/mL; CKD 4: 1.75 (1.23-2.61) ng/mL; and CKD 5: 4.87 (3.22-7.59) ng/mL, respectively (non-parametric ANOVA P < 0.0001). Ang-2 was associated with the degree of CKD as evidenced by an inverse correlation with the (i)GFR (r = -0.509, P < 0.0001) and positive correlations with homocysteine (r = 0.365, P = 0.015) and phosphate (r = 0.53, P < 0.0001). Additionally, Ang-2 correlated with the ADMA levels (r = 0.35, P = 0.01). We detected a close inverse correlation between the mean changes in GFR and circulating Ang-2 at 72 h after kidney donation (r = -0.54, P = 0.03).

Conclusions: Circulating Ang-2, a putative marker and potential mediator of accelerated atherosclerosis, is inversely related to GFR and increases with advanced CKD. The correlation between Ang-2 and ADMA points towards the hypothesis that the ADMA-driven NO deficiency might trigger Ang-2 release and account for the Ang-2 increase in CKD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfq060DOI Listing
August 2010

Majocchi's granuloma after kidney transplantation.

Exp Clin Transplant 2006 Dec;4(2):518-20

Department of Internal Medicine and Nephrology, Nephrologisches Zentrum Niedersachsen, Hann. Muenden, Germany.

Mycosis may follow an atypical course in an individual undergoing immunosuppressive therapy. We describe a patient with a fungal infection that was manifested as a bilateral inguinal granuloma. Owing to suspected inguinal lymphadenopathy characterized by distinct subcutaneous swellings in the groin, a 39-year-old man who had undergone kidney transplantation 14 years earlier was admitted to the Nephrologisches Zentrum in Hann. Muenden, Germany. The results of a clinical examination revealed bilateral, soft, partly fluctuant, indolent swellings in the groin as well as onychomycosis of the right great toe. An ultrasonographic scan showed bilateral hypoechogenic lesions (
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2006

Follow-up after renal transplantation with organs from donors after cardiac death.

Transpl Int 2006 Sep;19(9):715-9

Renal Unit, Westmead Hospital, Westmead, NSW, Australia.

Kidneys obtained from donors after cardiac death (DCD) are known to have higher rates of primary nonfunction and delayed graft function (DGF) than heart beating cadaveric donor (CAD) kidneys, but little is known about long-term function of DCD grafts that survive to 1 year. To investigate the outcomes of renal transplant recipients whose DCD graft functioned for at least 1 year, this study analyzed data collected from 326 DCD graft recipients and 340 CAD-matched controls enrolled in a prospective, multinational, observational study--Neoral-MOST (Multinational Observational Study in Transplantation) (Novartis, Basel, Switzerland). No differences were found in the demographics or immunosuppression between the two groups. All patients received a Neoral-based immunosuppressive regimen. Donors after cardiac death graft recipients had a higher incidence of DGF (40% vs. 27% CAD; P < 0.001). One year glomerular filtration rate (GFR) and GFR-decline after 1 year were similar in DCD and CAD recipients (GFR 56 ml/min DCD vs. 59 ml/min CAD; GFR-decline -1.3 ml/min DCD vs. -1.4 ml/min CAD; P = not significant). Multifactorial analyses confirmed that GFR at 1 year was significantly influenced by donor age and gender, DGF, and acute rejection; however, DCD status was not an independent risk factor in cyclosporine-treated patients with grafts that had functioned for at least 1 year.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1432-2277.2006.00337.xDOI Listing
September 2006

Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant.

Transplantation 2006 Jan;81(2):202-6

Renal Unit, Careggi University Hospital, Florence, Tuscany, Italy.

Background: Long-term success of renal transplantation depends upon the quality of the donor organ, avoidance of peritransplant and early posttransplant damage (rejection), and optimal maintenance of graft function after the first 6-12 months. Glomerular filtration rate (GFR) at 1 year is a standard way to evaluate short-term success, whereas calculated GFR at 5 years gives a better appreciation of long-term outcomes. The objective of this study was to assess the effect of various demographic and transplant-related parameters on renal function via GFR at 1 year and 5 years post transplantation, using univariate and multivariate data analysis.

Methods: Data on 1-year GFR were available from 10,397 patients, whereas 2,889 patients provided data on both 1-year and 5-year GFR. All patients were enrolled in the Neoral Multinational Observational Study in Transplantation (Neoral-MOST), an ongoing, prospective, observational study of adult renal transplant recipients.

Results: One-year GFR was the most relevant predictor for 5-year GFR. In a multifactorial analysis (ANCOVA) using 1-year GFR as a continuous variable, the effects of several highly relevant parameters from univariate analysis (such as acute rejection and delayed graft function) on 5-year GFR appeared to be fully mediated by their influence on 1-year GFR, whereas immunological risk factors like HLA match or previous transplantation had an ongoing effect on graft function beyond year 1.

Conclusions: The findings of this study corroborate and augment data from previous registry surveys, and confirm the importance of observational studies in investigating the role of peritransplant parameters on long-term graft outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.tp.0000188135.04259.2eDOI Listing
January 2006

Polyomavirus DNA and RNA detection in renal allograft biopsies: results from a European multicenter study.

Transplantation 2005 Sep;80(5):600-4

Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.

Polyomavirus mediated nephropathy is an increasingly recognized complication in renal transplant recipients. In all, 362 renal biopsies collected from 15 European transplant centers were analyzed for presence of Polyomavirus nucleic acid (BK virus [BKV] and JC virus [JCV]). We evaluated 302 biopsies of patients with renal allograft dysfunction, including three with known BKV allograft nephropathy (BKVAN), and 60 native kidney biopsies. BKV DNA was detected in 8 of the 302 (2.6 %) biopsies obtained for transplant dysfunction, but in none of the controls. BKV RNA, indicating active viral replication, was found in all BKV DNA positive biopsies available for mRNA expression studies. Retrospective immunohistochemical staining was positive for SV40 large T antigen in all seven evaluated biopsies. BKV DNA and RNA were detected in biopsy tissues from patients with inconspicuous light microscopy for BKVAN. Further studies will evaluate the potential of intrarenal viral BKV RNA as an early predictor for BKVAN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.tp.0000173385.45918.39DOI Listing
September 2005

BK virus associated nephropathy in native kidneys of a heart allograft recipient.

Am J Transplant 2005 Jun;5(6):1562-8

Nephrologisches Zentrum Niedersachsen, Hann. Münden, Germany.

Polyomavirus-mediated nephropathy is an increasingly recognized complication in renal transplant recipients, but data on the status of viral activity in the native kidneys of non-renal solid organ recipients are limited. Thirteen native kidney biopsies of heart transplant recipients with significant renal impairment were evaluated for the evidence of polyomavirus reactivation by immunohistochemistry and PCR. One case of BK virus-mediated nephropathy in a cardiac transplant recipient exposed to high levels of immunosuppressive drugs was identified. Clinical and histopathological findings of this patient progressing to terminal renal failure are discussed in detail. In conclusion, polyomavirus reactivation in native kidneys of heart transplant recipients can cause significant renal impairment and should be considered in the differential diagnosis in this patient cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1600-6143.2005.00883.xDOI Listing
June 2005

Improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study.

Transplantation 2003 Jul;76(1):115-9

Abt. Nephrologie, Zentrum Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Germany.

Background: Diabetes mellitus is the leading cause of renal failure worldwide. The question of which treatment modality-hemodialysis versus renal transplantation-is associated with the lowest risk of cardiovascular morbidity and mortality in the diabetic end-stage renal disease (ESRD) population has not yet been investigated in a controlled trial.

Methods: We therefore conducted a case-control study of patients with ESRD caused by type 1 diabetes mellitus. The case patients were diabetics who received a renal graft between 1978 and 1997, whereas the controls were registered for renal transplantation but stayed on maintenance hemodialysis without ever undergoing transplantation. The groups were matched for age, sex, duration of diabetes, length of hemodialysis (up to the registration), and date of registration for renal transplantation.

Results: Kaplan-Meier life table analysis, based on 46 case patients and 46 controls, demonstrated a highly significant (P=0.0001) poorer survival in the control group compared with the case group. Logistic regression showed that hemodialysis was a significant risk factor for death (P=0.0002) and cardiovascular morbidity (P=0.0023). Patients with cardiovascular complications such as coronary artery and peripheral vascular events were significantly more frequent in the control group. Additionally tested risk factors for cardiovascular complications (serum cholesterol, arterial blood pressure, number of antihypertensive drugs, serum calcium, serum phosphate, and glucose control [hemoglobin A(1c)]) showed no significant correlation to survival or morbidity in either group by logistic regression.

Conclusions: Renal transplantation is associated with a significantly improved survival compared with hemodialysis in patients with ESRD caused by type 1 diabetes mellitus. This seems to be a result of a reduced incidence of cardiovascular complications after renal transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.TP.0000070225.38757.81DOI Listing
July 2003

Prevalence and management of anemia in renal transplant recipients: a European survey.

Am J Transplant 2003 Jul;3(7):835-45

Department of Nephrology, University Hospital Gasthuisberg, Leuven, Belgium.

The TRansplant European Survey on Anemia Management (TRESAM) documented the prevalence and management of anemia in kidney transplant recipients. Data from 72 transplant centers in 16 countries were screened, involving 4263 patients who had received transplants 6 months, 1, 3 or 5 years earlier. The mean age of transplant recipients was 45.5 years at transplantation. The most common etiology was chronic glomerulonephritis. The most common comorbidities were coronary artery disease, hepatitis B/C, and type 2 diabetes. The mean hemoglobin levels before transplantation were significantly higher in the more recently transplanted recipients. At enrollment, 38.6% of patients were found to be anemic. Of the 8.5% of patients who were considered severely anemic, only 17.8% were treated with epoetin. There was a strong association between hemoglobin and graft function; of the 904 patients with serum creatinine > 2 mg/dL, 60.1% were anemic, vs. 29.0% of those with serum creatinine
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1034/j.1600-6143.2003.00133.xDOI Listing
July 2003

Relevance of hepatitis B core gene deletions in patients after kidney transplantation.

Gastroenterology 2003 Jun;124(7):1809-20

Department of Gastroenterology, Hepatology and Oncology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.

Background & Aims: Hepatitis B virus (HBV) infection is a major cause of death in the long-term follow-up after organ transplantation and immunosuppressive therapy. The selection pressure on the HBV genome in these patients is reduced. The aim was to analyze and characterize variations in the HBV core gene after organ transplantation and their impact for prognosis.

Methods: In patients with chronic HBV infection after organ transplantation (liver, n = 60; heart, n = 50; kidney, n = 30) the HBV core gene was amplified by polymerase chain reaction (PCR). Core gene deletions were cloned into replication competent and expression vectors. The impact of these mutations on HBV replication and capsid formation was analyzed and correlated with disease progression.

Results: Central core gene deletions only were detected in patients after kidney transplantation. Two types of core gene deletions--small and large--were found. Large core gene deletions showed no capsid formation and HBV replication, which resulted in nuclear core expression. The occurrence of large core gene deletions was associated with a severe course of liver disease.

Conclusions: Core gene deletions occur specifically after kidney transplantation. Only large core gene deletions resulted in impaired capsid formation and nuclear localization of the core protein. The presence of large core gene deletions was associated with progressive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0016-5085(03)00396-2DOI Listing
June 2003