Publications by authors named "Markus J Kemper"

115 Publications

Bone and Mineral Metabolism in Children with Nephropathic Cystinosis Compared with other CKD Entities.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Context: Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD); however, systematic analyses are lacking.

Objective: To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across all stages of CKD.

Design: Cross-sectional multicenter study.

Setting: Hospital clinics.

Patients: Forty-nine children with NC, 80 CKD controls of the same age and CKD stage.

Main Outcome Measures: Fibroblast growth factor 23 (FGF23), soluble Klotho, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, osteoprotegerin (OPG), biochemical parameters related to mineral metabolism, and skeletal comorbidity.

Results: Despite Fanconi syndrome medication, NC patients showed an 11-fold increased risk of short stature, bone deformities, and/or requirement for skeletal surgery compared with CKD controls. This was associated with a higher frequency of risk factors such as hypophosphatemia, hypocalcemia, low parathyroid hormone (PTH), metabolic acidosis, and a specific CKD stage-dependent pattern of bone marker alterations. Pretransplant NC patients in mild to moderate CKD showed a delayed increase or lacked an increase in FGF23 and sclerostin, and increased BAP, TRAP5b, and OPG concentrations compared with CKD controls. Post-transplant, BAP and OPG returned to normal, TRAP5b further increased, whereas FGF23 and PTH were less elevated compared with CKD controls and associated with higher serum phosphate.

Conclusions: Patients with NC show more severe skeletal comorbidity associated with distinct CKD stage-dependent alterations of bone metabolism than CKD controls, suggesting impaired mineralization and increased bone resorption, which is only partially normalized after renal transplantation.
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http://dx.doi.org/10.1210/clinem/dgaa267DOI Listing
August 2020

Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes.

Kidney Int 2020 02 31;97(2):393-401. Epub 2019 Oct 31.

Department of Paediatric Nephrology, Great Ormond Street Hospital for Children National Health Service Trust, London, UK. Electronic address:

Rituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m), medium (750mg/m) and high (1125-1500mg/m), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes.
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http://dx.doi.org/10.1016/j.kint.2019.09.033DOI Listing
February 2020

Levamisole in Children with Idiopathic Nephrotic Syndrome: Clinical Efficacy and Pathophysiological Aspects.

J Clin Med 2019 Jun 16;8(6). Epub 2019 Jun 16.

Department of Pediatrics, University Hamburg-Eppendorf, 20246 Hamburg, Germany.

Steroid sensitive nephrotic syndrome is one of the most common pediatric glomerular diseases. Unfortunately, it follows a relapsing and remitting course in the majority of cases, with 50% of all cases relapsing once or even more often. Most children with idiopathic nephrotic syndrome respond initially to steroid therapy, nevertheless repeated courses for patients with relapses induce significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, levamisole, or rituximab. To reduce the relapse rate, several drugs have been used. Among these, levamisole has been considered the least toxic and least expensive therapy. Several randomized controlled trials (RCT) showed that levamisole is effective in reducing the relapse risk in steroid sensitive forms of nephrotic syndrome with a low frequency of side effects. Levamisole is a synthetic imidazothiazole derivative with immune-modulatory properties. In this article, we review recent data from randomized trials and observational studies to assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome.
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http://dx.doi.org/10.3390/jcm8060860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617114PMC
June 2019

Oxalate retinopathy is irreversible despite early combined liver-kidney transplantation in primary hyperoxaluria type 1.

Am J Transplant 2019 12 27;19(12):3328-3334. Epub 2019 Jun 27.

University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

In primary hyperoxaluria type 1 (PH1), systemic oxalate deposition (oxalosis) in end-stage renal disease (ESRD) is associated with high morbidity and mortality, particularly in children with infantile oxalosis (IO). Combined liver and kidney transplantation (CLKT) is the only curative treatment option in these patients. After CLKT, systemic oxalosis decreases continuously, although only insufficient data are available regarding oxalate retinopathy (ROx), leading to severe visual impairment. We analyzed long-term follow-up data of ROx in 13 patients undergoing CLKT for PH1 at our center between 1998 and 2018. Age at transplantation was 1.3-14.2 years, including nine patients with IO. We performed visual acuity testing, slit lamp investigation, funduscopy, fundus photography, and spectral-domain optical coherence tomography (SD-OCT) imaging. Severe (grade 2-4) ROx was present in all nine children with IO but not in the four patients developing ESRD in adolescence. A significant negative correlation was found between age at onset of ESRD and grade of ROx (r = -0.66; P < .001). Notably, follow-up assessment after CLKT demonstrated no regression of ROx after a median of 5.3 years (range 0.6-14). The data show that despite early CLKT in IO, ROx is irreversible and the concomitant visual deterioration occurs prior to transplantation.
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http://dx.doi.org/10.1111/ajt.15484DOI Listing
December 2019

Greater Susceptibility for Metabolic Syndrome in Pediatric Solid Organ and Stem Cell Transplant Recipients.

Transplantation 2019 11;103(11):2423-2433

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hanover, Germany.

Background: Cardiovascular comorbidity is of increasing importance after transplantation. Metabolic syndrome (MS) contributes to the risk for cardiovascular sequelae. Our aim was to assess the risk for MS in pediatric solid organ and stem cell transplant recipients by comparing them with matched untransplanted peers in a multicenter study.

Methods: We prospectively assessed MS in 295 pediatric transplant recipients and compared them with 1475 age- and sex-matched controls.

Results: Posttransplant metabolic syndrome (PTMS) was most frequent in lung (43%) and kidney (39%), followed by liver (16%) and stem cell (13%) recipients, compared with nontransplanted peers (4%; P < 0.01). The risk of displaying PTMS was almost 22-fold higher after lung (95% confidence interval, CI, 8.2-57.4), 16-fold higher after kidney (95% CI, 9.1-28.9), 5-fold higher after liver (95% CI, 2.1-10.1), and 4-fold higher after stem cell (95% CI, 1.4-9.5) transplantation. The contribution of individual components leading to MS differed depending on transplant type. In the combined analysis of all transplant groups, older age, less physical activity, calcineurin or mammalian target of rapamycin inhibitor-based immunosuppression, and hypovitaminosis D were associated with PTMS.

Conclusions: By investigating a large group of patients, our study not only shows a high prevalence of PTMS but also identifies kidney and lung transplant patients as being at a particularly high risk. Moreover, knowledge on the factors associated with PTMS allows for individualized treatment approaches as well as potential preventive measures.
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http://dx.doi.org/10.1097/TP.0000000000002675DOI Listing
November 2019

Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study).

BMJ Open 2018 10 10;8(10):e024882. Epub 2018 Oct 10.

Department of Pediatrics, University Children's Hospital Köln, University Hospital Köln, Köln, Germany.

Introduction: Idiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only.

Methods And Design: The study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment.

Ethics And Dissemination: Ethics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal.

Trial Registration Number: DRKS0006547; EudraCT2014-001991-76; Pre-result.

Date Of Registration: 30 October 2014; 24 February 2017.
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http://dx.doi.org/10.1136/bmjopen-2018-024882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252704PMC
October 2018

Eculizumab in STEC-HUS: need for a proper randomized controlled trial.

Pediatr Nephrol 2018 08 17;33(8):1277-1281. Epub 2018 May 17.

Department of Pediatrics, AK Hamburg Nord, Asklepios Medical School, Hamburg, Germany.

Hemolytic uremic syndrome caused by Shiga toxin-producing E. coli (STEC-HUS) is often associated with a severe morbidity including neurological involvement and a mortality of 1-5%. Although STEC-HUS is often self-limited, improvement of treatment strategies is needed for cases with complications and, among others, plasma exchange/plasmapheresis and use of antibiotics have been advocated. With the availability of the complement blocker eculizumab, now a standard treatment of atypical HUS, several series have addressed its use in STEC-HUS, with variable response; randomized controlled trials are lacking.In this issue of Pediatric Nephrology, Pecheron et al. present a cohort of 33 pediatric patients with severe HUS treated with eculizumab. Neurological involvement was observed in 85% of the patients and 94% required dialysis. Most patients (55%) did not benefit from eculizumab and renal dysfunction as well as neurological sequelae did not resolve. In a subgroup of patients, however, rapid neurological improvement was described. In the post-hoc-defined group of patients with favorable outcome, there was a trend towards more sustained complement inhibition, although this finding was not significant compared to patients with an unfavorable outcome.Because multiple interventions were used and the study did not include any control group, future controlled studies are urgently needed to resolve the debate as to whether eculizumab can be an effective treatment for both prevention and treatment of complications in STEC-HUS.
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http://dx.doi.org/10.1007/s00467-018-3972-9DOI Listing
August 2018

Treatment of Genetic Forms of Nephrotic Syndrome.

Front Pediatr 2018 26;6:72. Epub 2018 Mar 26.

Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Idiopathic steroid-resistant nephrotic syndrome (SRNS) is most frequently characterized by focal segmental glomerulosclerosis (FSGS) but also other histological lesions, such as diffuse mesangial sclerosis. In the past two decades, a multitude of genetic causes of SRNS have been discovered raising the question of effective treatment in this cohort. Although no controlled studies are available, this review will discuss treatment options including pharmacologic interventions aiming at the attenuation of proteinuria in genetic causes of SRNS, such as inhibitors of the renin-angiotensin-aldosterone system and indomethacin. Also, the potential impact of other interventions to improve podocyte stability will be addressed. In this respect, the treatment with cyclosporine A (CsA) is of interest, since a podocyte stabilizing effect has been demonstrated in various experimental models. Although clinical response to CsA in children with genetic forms of SRNS is inferior to sporadic SRNS, some recent studies show that partial and even complete response can be achieved even in individual patients inherited forms of nephrotic syndrome. Ideally, improved pharmacologic and molecular approaches to induce partial or even complete remission will be available in the future, thus slowing or even preventing the progression toward end-stage renal disease.
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http://dx.doi.org/10.3389/fped.2018.00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879576PMC
March 2018

Levamisole in relapsing steroid-sensitive nephrotic syndrome: where do we stand?

Kidney Int 2018 02;93(2):310-313

Children's Hospital Lucerne, Lucerne, Switzerland.

Many patients with steroid-sensitive nephrotic syndrome develop a relapsing course; therefore, alternative treatment may be necessary to avoid steroid toxicity. In this issue, a multicenter controlled study in relapsing steroid-sensitive nephrotic syndrome shows the effectiveness of levamisole. Time to first relapse was significantly increased compared with placebo. In addition, possible differential treatment effects were suggested for subgroups: patients with frequent relapses might have a superior response to those with steroid dependency.
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http://dx.doi.org/10.1016/j.kint.2017.09.024DOI Listing
February 2018

Vaccination titres pre- and post-transplant in paediatric renal transplant recipients and the impact of immunosuppressive therapy.

Pediatr Nephrol 2018 05 10;33(5):897-910. Epub 2018 Jan 10.

Department of Paediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication.

Methods: In the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national study and analysed vaccination titres pre- and post-transplant in 155 patients with serial titre measurements in comparison with published data in healthy children.

Results: The percentage of patients with positive vaccination titres before renal transplantation (RTx) was low, especially for diphtheria (38.5%, control 75%) and pertussis (21.3%, control 96.3%). As few as 58.1% of patients had a hepatitis B antibody (HBsAb) titre >100 IU/L before RTx. 38.1% of patients showed a vaccination titre loss post-transplant. Patients with an HBsAb titre between 10 and 100 IU/L before RTx experienced a significantly (p < 0.05) more frequent hepatitis B vaccination titre loss post-transplant than patients with an HBsAb titre >100 IU/L. The revaccination rate post-transplant was low and revaccination failed to induce positive titres in a considerable number of patients (27.3 to 83.3%). Treatment with rituximab was associated with a significantly increased risk of a vaccination titre loss post-transplant (odds ratio 4.26, p = 0.033).

Conclusions: These data show a low percentage of patients with positive vaccination titres pre-transplant, a low revaccination rate post-transplant with limited antibody response, and a high rate of vaccination titre losses.
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http://dx.doi.org/10.1007/s00467-017-3868-0DOI Listing
May 2018

Causes of renal oligohydramnios: impact on prenatal counseling and postnatal outcome.

Pediatr Nephrol 2018 04 11;33(4):541-545. Epub 2017 Nov 11.

Department of Pediatrics, AK Hamburg Nord, Asklepios Medical School, Hamburg, Germany.

The presence of renal oligohydramnios (ROH) in a fetus has been associated in the past with a poor prognosis for survival, although recent studies have shown that survival has improved considerably due to the advances in neonatology and pediatric nephrology. In an article recently published in Pediatric Nephrology, evaluation of a large series by Mehler and colleagues confirms the improved prognosis, showing a survival rate of 32 of 38 (84%). In addition, only 12 of 35 (34%) neonates required renal replacement therapy. In five of these 12 children the dialysis could be terminated after the neonatal period. This study has important implications on the decision-making process and counseling of families. While 37% of families of the study opted for termination of pregnancies, palliative care was chosen by 8% of the families, representing an important option when a decision cannot be made rapidly by affected families. A multidisciplinary approach is not only necessary in the active treatment of neonates with a history of ROH but also in antenatal counseling. In this regard future efforts should establish consensus on an ethical framework for the decision-making process in ROH.
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http://dx.doi.org/10.1007/s00467-017-3833-yDOI Listing
April 2018

Immunohistochemical and serological characterization of membranous nephropathy in children and adolescents.

Pediatr Nephrol 2018 03 15;33(3):463-472. Epub 2017 Oct 15.

III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Background: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, but is less frequent in children. Antibodies against four antigens leading to MN have been described in children: phospholipase A receptor 1 (PLAR1), thrombospondin type-1 domain-containing 7A (THSD7A), neutral endopeptidase (NEP), and cationic bovine serum albumin (BSA).

Methods: Twelve children with MN were included in this study. Sera of all patients were analyzed for antibodies against PLAR1, THSD7A, NEP, and BSA. All sera were also analyzed using Western blot with human glomerular extracts (HGE) under non reducing conditions. In 5 cases renal biopsies were analyzed for PLAR1, THSD7A, NEP, BSA, and all IgG subclasses.

Results: Six patients were PLAR1-antibody-positive, whereas THSD7A, NEP, and BSA antibodies were not found in any of our 12 patients. All sera were analyzed by Western blot using human glomerular extracts; however, no further potential antigens were found. Five kidney biopsies from 2 PLAR1-antibody-positive and 3 PLAR1-antibody-negative patients were available for additional analyses, confirming the diagnosis of PLAR1-associated MN in 2 cases, whereas none of the biopsies revealed enhanced staining for THSD7A, NEP or BSA. IgG2 and IgG4 stainings were positive in both patients with PLAR1-associated MN and negative in the other biopsies. During follow-up (median 24 months), 4 children with PLAR1-associated MN went into remission, preceded by decline of PLAR1 antibodies. Five of the 6 PLAR1-antibody-negative children went into remission.

Conclusions: In children with MN, PLAR1-associated MN appears to be common, whereas MN associated with THSD7A, NEP or BSA was not encountered. PLAR1 antibody levels are closely associated with disease activity, whereas PLAR1-antibody-negative patients often have a good prognosis. However, the pathophysiology of MN in a considerable number of children remains unclear.
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http://dx.doi.org/10.1007/s00467-017-3817-yDOI Listing
March 2018

Incomplete vaccination coverage in European children with end-stage kidney disease prior to renal transplantation.

Pediatr Nephrol 2018 02 5;33(2):341-350. Epub 2017 Oct 5.

Department of Paediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Because infections constitute a major cause of morbidity and mortality in paediatric renal allograft recipients, avoidance of preventable systemic infections by vaccination before transplantation is of utmost importance. However, data on the completeness of vaccinations and factors associated with incomplete vaccination coverage are scarce.

Methods: Within the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national, retrospective study investigating the vaccination coverage before transplantation of 254 European children with end-stage renal disease (mean age 10.0 ± 5.6 years).

Results: Only 22 out of 254 patients (8.7%) presented complete vaccination coverage. In particular, the respective vaccination coverage against human papillomavirus (27.3%), pneumococci (42.0%), and meningococci (47.9%) was low. Patients with complete pneumococcal vaccination coverage had numerically less lower respiratory tract infections during the first 3 years post-transplant than children without vaccination or with an incomplete status (16.4% vs 27.7%, p = 0.081). Vaccine-preventable diseases post-transplant were 4.0 times more frequently in unvaccinated than in vaccinated patients. Factors associated with an incomplete vaccination coverage were non-Caucasian ethnicity (OR 9.21, p = 0.004), chronic dialysis treatment before transplantation (OR 6.18, p = 0.001), and older age at transplantation (OR 1.33, p < 0.001).

Conclusions: The vaccination coverage in paediatric kidney transplant candidates is incomplete. Paediatric nephrologists, together with primary-care staff and patients' families, should therefore make every effort to improve vaccination rates before kidney transplantation.
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http://dx.doi.org/10.1007/s00467-017-3776-3DOI Listing
February 2018

Early Effects of Renal Replacement Therapy on Cardiovascular Comorbidity in Children With End-Stage Kidney Disease: Findings From the 4C-T Study.

Transplantation 2018 03;102(3):484-492

Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.

Background: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis.

Methods: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis).

Results: RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ß = -0.67; P < 0.001) and intima media thickness (ß = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ß = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ß = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ß = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ß = 1.47; P = 0.01).

Conclusions: In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001948DOI Listing
March 2018

Difficult-to-treat idiopathic nephrotic syndrome: established drugs, open questions and future options.

Pediatr Nephrol 2018 10 6;33(10):1641-1649. Epub 2017 Sep 6.

Christliches Kinderhospital Osnabrück, Johannisfreiheit 1, 49074, Osnabrück, Germany.

The idiopathic nephrotic syndrome in childhood can be classified according to the International Study of Kidney Disease in Children (ISKDC) based on the response to steroids. Typically, steroid-sensitive nephrotic syndrome (SSNS) is characterised by minimal changes in disease (MCD) histology, whereas in steroid-resistant nephrotic syndrome (SRNS) focal segmental glomerulosclerosis (FSGS) is the most prevalent lesion. Patients with SSNS may develop frequent relapses and/or steroid dependency, which can be difficult to treat. New studies confirm the value of calcineurin inhibitors (CNIs) and mycophenolic acid in preventing relapses of SSNS. Rituximab also plays an important role, but many questions regarding initial dosing, repetitions of courses, and long-term side effects remain unclear. SRNS, especially when unresponsive to treatment, can lead to chronic kidney disease. In particular, treatment with CNIs has improved the prognosis and recent data indicate that treatment can even be discontinued in many patients with full remission. In CNI-unresponsive SRNS, rituximab is less effective than in SSNS and the role of other biologicals (such as ofatumumab, abatacept, and others) remains unclear. A significant proportion of children with FSGS have genetic causes and most patients do not respond to immunosuppression, although individual patients with partial and even complete response have been documented. Future studies should evaluate treatments leading to long-term remission without maintenance immunosuppression in SSNS; in both genetic and immune-mediated SRNS, novel options to decrease the number of treatment-unresponsive patients seem mandatory, as they are at a high risk of developing end-stage renal disease.
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http://dx.doi.org/10.1007/s00467-017-3780-7DOI Listing
October 2018

Factors associated with cardiovascular target organ damage in children after renal transplantation.

Pediatr Nephrol 2017 Nov 13;32(11):2143-2154. Epub 2017 Aug 13.

Department of Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Background: Cardiovascular disease is the second-most common cause of death in pediatric renal transplant recipients. The aim of this study was to evaluate subclinical cardiovascular target organ damage defined as the presence of arterio- and atherosclerotic lesions and cardiac remodeling and to analyze contributing risk factors in a large cohort of children after renal transplantation (RT).

Methods: A total of 109 children aged 13.1 ± 3.3 years who had undergone RT at one of three German transplant centers were enrolled in this study. Patients had been transplanted a mean of 5.5 (±4.0) years prior to being enrolled in the study. Anthropometric data, laboratory values and office- and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated. Cardiovascular target organ damage was determined through non-invasive measurements of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) and left ventricular mass (LVM).

Results: Elevated PWV or IMT values were detected in 22 and 58% of patients, respectively. Left ventricular hypertrophy was found in as many as 43% of patients. The prevalence of uncontrolled or untreated hypertension was 41%, of which 16% of cases were only detected by ABPM measurements. In the multivariable analysis, higher diastolic blood pressure, everolimus intake and lower estimated glomerular filtration rate were independently associated with high PWV. Higher systolic blood pressure and body mass index were associated with elevated LVM.

Conclusions: Our results showed an alarming burden of cardiovascular subclinical organ damage in children after RT. Hypertension, obesity, immunosuppressive regimen and renal function emerged as independent risk factors of organ damage. Whereas the latter is not modifiable, the results of our study strongly indicate that the management of children after RT should focus on the control of blood pressure and weight.
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http://dx.doi.org/10.1007/s00467-017-3771-8DOI Listing
November 2017

Glutaric Aciduria Type 1 and Acute Renal Failure: Case Report and Suggested Pathomechanisms.

JIMD Rep 2018 12;39:25-30. Epub 2017 Jul 12.

University Children's Hospital, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Building O45, 20246, Hamburg, Germany.

Glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. During catabolic crises, GA1 patients are prone to the development of striatal necrosis and a subsequent irreversible movement disorder during a time window of vulnerability in early infancy. Thus, GA1 had been considered a pure "cerebral organic aciduria" in the past. Single case reports have indicated the occurrence of acute renal dysfunction in children affected by GA1. In addition, growing evidence arises that GA1 patients may develop chronic renal failure during adulthood independent of the previous occurrence of encephalopathic crises. The underlying mechanisms are yet unknown. Here we report on a 3-year-old GA1 patient who died following the development of acute renal failure most likely due to haemolytic uraemic syndrome associated with a pneumococcal infection. We hypothesise that known GA1 pathomechanisms, namely the endothelial dysfunction mediated by 3OHGA, as well as the transporter mechanisms for the urinary excretion of GA and 3OHGA, are involved in the development of glomerular and tubular dysfunction, respectively, and may contribute to a pre-disposition of GA1 patients to renal disease. We recommend careful differential monitoring of glomerular and tubular renal function in GA1 patients.
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http://dx.doi.org/10.1007/8904_2017_44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953902PMC
July 2017

Dyslipidemia after pediatric renal transplantation-The impact of immunosuppressive regimens.

Pediatr Transplant 2017 May 28;21(3). Epub 2017 Mar 28.

Division of Pediatric Nephrology, University Children's and Adolescent's Hospital, Cologne, Germany.

Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry. Data were obtained before and during the first year after RTx to analyze possible non-modifiable and modifiable risk factors. The prevalence of dyslipidemia was 95% before engraftment and 88% at 1 year post-transplant. Low estimated glomerular filtration rate at 1 year post-transplant was associated with elevated serum triglyceride levels. The use of TAC and of MPA was associated with significantly lower concentrations of all lipid parameters compared to regimens containing CsA and mTORi. Immunosuppressive regimens consisting of CsA, MPA, and steroids as well as of CsA, mTORi, and steroids were associated with a three- and 25-fold (P<.001) increased risk of having more than one pathologic lipid parameter as compared to the use of TAC, MPA, and steroids. Thus, amelioration of the cardiovascular risk profile after pediatric RTx may be attained by adaption of the immunosuppressive regimen according to the individual risk profile.
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http://dx.doi.org/10.1111/petr.12914DOI Listing
May 2017

Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4.

Clin Infect Dis 2017 Jun;64(12):1637-1643

University Children's Hospital, University Medical Center Hamburg-Eppendorf.

Background.: In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking.

Methods.: Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak.

Results.: Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes.

Conclusions.: The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.
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http://dx.doi.org/10.1093/cid/cix218DOI Listing
June 2017

Case report - atypical hemolytic uremic syndrome triggered by influenza B.

BMC Nephrol 2017 Mar 20;18(1):96. Epub 2017 Mar 20.

University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany.

Background: Influenza A infections have been described to cause secondary hemolytic uremic syndrome and to trigger atypical hemolytic uremic syndrome (aHUS) in individuals with an underlying genetic complement dysregulation. To date, influenza B has not been reported to trigger aHUS.

Case Presentation: A 6-month-old boy presented with hemolytic uremic syndrome triggered by influenza B infection. Initially the child recovered spontaneously. When he relapsed Eculizumab treatment was initiated, resulting in complete and sustained remission. A pathogenic mutation in membrane cofactor protein (MCP) was detected.

Conclusion: Influenza B is a trigger for aHUS and might be underreported as such. Influenza vaccination may protect patients at risk.
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http://dx.doi.org/10.1186/s12882-017-0512-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358041PMC
March 2017

Health-related quality of life after combined liver and kidney transplantation in children.

Pediatr Transplant 2017 Jun 15;21(4). Epub 2017 Feb 15.

Pediatric Gastroenterology and Hepatology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

While reduced HRQOL following isolated organ transplantation has been previously reported, there are no data in the context of children following CLKT. Twenty-three children who underwent CLKT at our institution were included in the study. The indication for CLKT was PH1 in 13 patients and ARPKD in 10 patients. Quantification of HRQOL was facilitated through the use of the PedsQL 4.0 Generic Core Scale. The results of the study were compared to healthy children and published data of children who had undergone LTx or KTx. The CLKT samples' child self-report showed good HRQOL. No statistically significant difference was found between the patients with PH1 and patients with ARPKD (P=.4). Compared to healthy children, a significant difference in the total scale score, the physical health score, and the school functioning was reported. HRQOL did not differ significantly when compared to patients following isolated LTx or KTx. To improve HRQOL after CLKT, a focus on patients' physical health, educational performances, and overall quality of life is crucial. Thus, coordinated medical care across disciplines and psychological and social support is essential to achieve this goal.
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http://dx.doi.org/10.1111/petr.12902DOI Listing
June 2017

Truncating Wilms Tumor Suppressor Gene 1 Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report.

Nephron 2017 5;135(1):72-76. Epub 2016 Oct 5.

Institute of Human Genetics, Technical University Munich, Munich, Germany.

About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372C>T (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868G>A (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.
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http://dx.doi.org/10.1159/000450709DOI Listing
March 2017

Clinical and Laboratory Consequences of Platelet Transfusion in Shiga Toxin-Mediated Hemolytic Uremic Syndrome.

Transfus Med Rev 2017 01 21;31(1):51-55. Epub 2016 Jun 21.

Department of Nephrology and Hypertension, Hanover Medical School, Hanover, Germany.

Recent studies suggest that platelet transfusions are harmful in patients with thrombotic thrombocytopenic purpura, an entity of thrombotic microangiopathies. As the typical or Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome (STEC-HUS) is also classified as thrombotic microangiopathy, we complement these data with an analysis of 250 patients from the German O104:H4 STEC-HUS outbreak. The effect of platelet transfusion in 44 patients who received platelet transfusions vs 206 control patients was investigated. Criteria for both groups were severe thrombocytopenia less than 50/nL, severe hemolysis with administration of packed red blood cells, and a complicated clinical course with admission to intensive care units. Readouts were clinical complications and changes in routine clinical chemistry and whole blood count. Chemistry values at admission and demographic parameters were comparable. Platelet transfusions were administered in 44 cases a median of 7 (interquartile range, 6-9) days after diarrhea onset. After platelet transfusion, we observed a transient and slight increase in inflammation parameters. No significant difference in major complications such as seizures, or requirement for ventilation or renal replacement therapy could be observed. Thrombotic events such as thrombosis or embolism were comparably rare in both groups (2.3% in platelet transfused vs 4.4% in controls, P=not significant). The mortality was not significantly different (0% vs 2.6%, P=not significant) in our study cohort, but overall in the outbreak, 6 of 711 STEC-HUS patients in Germany died of a procedural-related bleeding complications. In conclusion, platelet transfusions seem comparably safe in adult STEC-HUS patients, considering both the possible necessity for invasive procedures and potential risk for severe bleeding.
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http://dx.doi.org/10.1016/j.tmrv.2016.06.004DOI Listing
January 2017

Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.

Nat Genet 2016 Apr 15;48(4):457-65. Epub 2016 Feb 15.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Nucleoporins are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid-resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.
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http://dx.doi.org/10.1038/ng.3512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811732PMC
April 2016

Surgical complications after peritoneal dialysis catheter implantation depend on children's weight.

J Pediatr Surg 2016 Aug 11;51(8):1317-20. Epub 2015 Dec 11.

Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. Electronic address:

Background: Surgical complications are estimated to be as high as 30%-40% during the first 8 weeks after implantation of peritoneal dialysis (PD) catheters.

Methods: 70 PD catheters which were implanted by transplant surgeons in 61 children (median age 3.3years, range 0.01-15.5years, 31 boys and 30 girls) in 2009-2014 were retrospectively reviewed. The incidence of complications and revisions during the first 6months after implantation was analyzed depending on children's weight and diagnosis.

Results: 17 out of 70 catheters needed a surgical revision within 6months after implantation (24.3%). Peritonitis was the most common complication affecting 18.6% of peritoneal dialysis catheters followed by obstruction and dislocation, which it occurred in 9 (12.9%) and 7 (10%) catheters, respectively. Leakage (n=5) only occurred in children with a weight of less than 10kg. The total proportion of complications was higher in children with less than 10kg of weight (P<0.001).

Conclusion: PD is safe in children with acute renal failure and older children with chronic renal failure; however children with a weight of less than 10kg are more likely to develop complications.
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http://dx.doi.org/10.1016/j.jpedsurg.2015.12.005DOI Listing
August 2016

Febrile urinary tract infection after pediatric kidney transplantation: a multicenter, prospective observational study.

Pediatr Nephrol 2016 Jun 11;31(6):1021-8. Epub 2016 Jan 11.

Pediatric Nephrology, University Medical Center Jena, Kochstrasse 2, 07743, Jena, Germany.

Background: Febrile urinary tract infections (fUTIs) are common after kidney transplantation (KTx); however, prospective data in a multicenter pediatric cohort are lacking. We designed a prospective registry to record data on fUTI before and after pediatric KTx.

Methods: Ninety-eight children (58 boys and 40 girls) ≤ 18 years from 14 mid-European centers received a kidney transplant and completed a 2-year follow-up.

Results: Posttransplant, 38.7% of patients had at least one fUTI compared with 21.4% before KTx (p = 0.002). Before KTx, fUTI was more frequent in patients with congenital anomalies of kidneys and urinary tract (CAKUT) vs. patients without (38% vs. 12%; p = 0.005). After KTx, fUTI were equally frequent in both groups (48.7% vs. 32.2%; p = 0.14). First fUTI posttransplant occurred earlier in boys compared with girls: median range 4 vs. 13.5 years (p = 0.002). Graft function worsened (p < 0.001) during fUTI, but no difference was recorded after 2 years. At least one recurrence of fUTI was encountered in 58%.

Conclusion: This prospective study confirms a high incidence of fUTI after pediatric KTx, which is not restricted to patients with CAKUT; fUTIs have a negative impact on graft function during the infectious episode but not on 2-year graft outcome.
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http://dx.doi.org/10.1007/s00467-015-3292-2DOI Listing
June 2016

Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome.

Clin J Am Soc Nephrol 2016 Feb 14;11(2):245-53. Epub 2015 Dec 14.

Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany;

Background And Objectives: Treatment of congenital nephrotic syndrome (CNS) and steroid-resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high-throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease.

Design, Setting, Participants, & Measurements: Cross-sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50-178). Genotyping was performed systematically in all patients.

Results: The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA-induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy.

Conclusions: The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.
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http://dx.doi.org/10.2215/CJN.07370715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741047PMC
February 2016

Transitional Care and Adherence of Adolescents and Young Adults After Kidney Transplantation in Germany and Austria: A Binational Observatory Census Within the TRANSNephro Trial.

Medicine (Baltimore) 2015 Dec;94(48):e2196

From the Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School (MK, JP, JD, LP); German Society of Transition Medicine, Hannover (MK, MO, SM, LP); Division of Pediatric Nephrology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg (DB, SR); Department of Epidemiology, Social Medicine and Health System Research, Hannover Medical School, Hannover (M-LD); Berliner Transitions Programm (BTP), DRK-Kliniken (German Red Cross hospitals) Berlin Westend (SM); Department of Pediatric Nephrology, Charité, Berlin (JT); University Hospital of Bonn, Bonn (BH); Department of Pediatrics II, Essen University Hospital, Essen (AB); Childrens' Hospital, University of Erlangen, Erlangen (WR); KfH Center of Pediatric Nephrology, Clementine Childrens' Hospital, Frankfurt (MH); Department of General Pediatrics, Adolescent Medicine and Neonatology, Freiburg University Hospital, Freiburg (MP); University Childrens' Hospital Eppendorf, Hamburg (MJK); University Childrens' Hospital, Jena (UJ); Pediatric Nephrology, University Hospital of Cologne, Cologne (CT); University Childrens' Hospital (KD); KfH Center of Pediatric Nephrology, St. Georg Hospital, Leipzig (SH); KfH Center of Pediatric Nephrology, University Hospital of Marburg, Marburg (GK); KfH Center of Pediatric Nephrology, Childrens' Hospital Memmingen, Memmingen (HF); University Childrens' Hospital Münster (BK); KfH Center of Pediatric Nephrology, University Childrens' Hospital München Schwabing (CM); Dr. von Haunersches Kinderspital, Ludwigs Maximilian University, Munich (BL-S); Childrens' Hospital, Olgahospital Klinikum Stuttgart, Stuttgart (BR); University Childrens' Hospital Tübingen, Tübingen (HB); University Childrens' Hospital, Rostock, Germany (HS); University Childrens' Hospital, Vienna, Austria (KH-R); and KfH Center of Nephrology, Hospitals of the Hannover Region, Hannover, Germany (RB).

Transition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure. We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012. Most centers (73%) confirmed agreements on the transition procedure. Patients' age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5-36.7). Median serum creatinine increased from 123 to 132 μmol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine ≥ 20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy.Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 ± 0.1. Increased creatinine levels ≥ 20% just before transfer were less frequently seen in patients with CoV < 0.20 (P = 0.007). The majority of pediatric nephrology centers have internal agreements on transitional care. More than half of the patients had CoV of immunosuppression trough levels consistent with good adherence. Although, 20% of the patients showed increase in serum creatinine close to transfer.
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http://dx.doi.org/10.1097/MD.0000000000002196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674210PMC
December 2015

Rat renal transplant model for mixed acute humoral and cellular rejection: Weak correlation of serum cytokines/chemokines with intragraft changes.

Transpl Immunol 2015 Oct 20;33(2):95-102. Epub 2015 Aug 20.

Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Acute renal allograft rejection remains a major cause of allograft dysfunction; especially for episodes with mixed humoral and cellular character which can be detrimental for graft survival. We established a rat RT model with exclusive and complete MHC-disparity to investigate pathomechanisms of acute rejection and evaluate serum multiplex assays as a diagnostic tool in this context.

Methods: LEW rats receive congeneic LEW.1W allografts (allo), no immunosuppression. Planned duration of the experiment was 4 weeks (n = 13 allo, n = 3 iso). To study kinetics of rejection, additional animals were sacrificed at day 7 (n = 6 allo and n = 3 iso) and day 21 (n = 3 allo). Serum cytokines and chemokine were longitudinally analyzed with multiplex assays in n = 5 allo and n = 5 controls. Allografts were assessed by histopathology, immunohisto-chemistry and PCR.

Results: Animals develop allograft dysfunction acute humoral rejection with additional cellular components. Donor-specific MHC-antibodies are already detectable at day seven (d7) after RT. Leukocytic graft infiltrates are dominated by macrophages and additionally consist of T-cells, B-cells and NK-cells. Increased intragraft expression of interleukin-2, interferon gamma, tumor necrosis factor alpha as well as B-cell activating factor and its receptor are observed. Of the 24 serum cytokines/chemokines, only CCL2 is significantly different (higher)in allo vs. controls at d7 (p = 0.02).

Conclusions: Correlation of serum chemokines/cytokines with features of humoral and cellular rejection, as reproduced in our LEW.1W to LEW rat renal transplant model, is limited. Macrophages, B-cells and their signaling pathways deserve more attention in genesis and possibly also treatment of acute rejection.
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http://dx.doi.org/10.1016/j.trim.2015.08.003DOI Listing
October 2015

Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development.

Am J Hum Genet 2015 Aug 30;97(2):291-301. Epub 2015 Jul 30.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute. Electronic address:

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.
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http://dx.doi.org/10.1016/j.ajhg.2015.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862256PMC
August 2015