Nele Kanzelmeyer

Developmental changes in the L-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age.

BACKGROUND The L-arginine/nitric oxide (NO) pathway has multiple physiological functions including vasodilation, inhibition of platelet aggregation and neurotransmission. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of all known NO synthase isoforms, has adverse effects on renal and cardiovascular function in adults. It is unknown whether ADMA might also exert similar effects in younger individuals including infants. Also, reference data for important members of the L-arginine/NO family, notably ADMA and the NO metabolites, nitrite and nitrate, in infancy are lacking. METHODS In the present study, we investigated the status of the L-arginine/NO pathway in 34 healthy volunteers aged 2 days to 24 years by measuring the concentration of ADMA, nitrite, nitrate and L-arginine in plasma and urine using gas chromatography-mass spectrometry and gas chromatography-tandem mass spectrometry methods. RESULTS We found that ADMA levels in plasma decreased with age (Pearson correlation coefficient r=-0.619, p<0.001). In contrast, urinary excretion of nitrate (r=0.471, p=0.036) and nitrite increased with age (r=0.484, p=0.037). CONCLUSIONS Our study suggests that in infants ADMA biosynthesis accompanied by an inhibition of NO synthesis is higher than in adults and diminishes considerably with age.

Protocol biopsy‐driven interventions after pediatric renal transplantation

Kanzelmeyer NK, Ahlenstiel T, Drube J, Froede K, Kreuzer M, Broecker V, Ehrich JHH, Melk A, Pape L. Protocol biopsy‐driven interventions after pediatric renal transplantation.
Pediatr Transplantation 2010: 14:1012–1018

Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS)

BACKGROUND Steroid-resistant nephrotic syndromes (NS) with focal and segmental glomerulosclerosis (FSGS) can be differentiated into sporadic and syndromic forms. In sporadic NS, a circulating FSGS-factor is discussed in the pathogenesis and is thought to inhibit the synthesis of nitric oxide (NO) from L-arginine by blocking the NO synthase (NOS). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all types of NOS. In a previous study we did not find an elevation of ADMA in a syndromic form of FSGS, the Schimke-immuno-osseous dysplasia. Here we report for the first time data on the L-arginine/NO pathway in sporadic FSGS of childhood. METHODS Nine children (5 to 18 years of age) suffering from sporadic FSGS and age-matched healthy controls were investigated. ADMA in plasma and urine as well as L-arginine in plasma were determined by gas chromatography-tandem mass spectrometry. The NO metabolites nitrate and nitrite were measured in plasma and urine by gas chromatography-mass spectrometry (GC-MS). The ADMA metabolite dimethylamine (DMA) was measured in urine by GC-MS. RESULTS We found elevated plasma levels of ADMA in children suffering from sporadic FSGS compared to healthy controls (851 nmol/L versus 684 nmol/L, P = 0.008). An inverse correlation between ADMA and glomerular filtration rate (GFR) was found in sporadic FSGS (Pearsons correlation coefficient -0.784, P = 0.012). CONCLUSION Our study suggests that ADMA synthesis is elevated in sporadic FSGS. This finding argues for the involvement of ADMA in the pathogenesis of this disease in childhood.

Belatacept after kidney transplantation in adolescents: a retrospective study.

Regardless of recipient age at kidney transplantation (KTx), patients are at greatest risk for graft loss in adolescence, partly due to nonadherence to an oral immunosuppressive regimen. Belatacept, a non‐nephrotoxic, first‐in‐class immunosuppressant that inhibits costimulation of T cells requires intravenous application only every 4 weeks, potentially leading to better adherence. However, it is only approved for use in adults. We report here the findings of the first study of belatacept in adolescents, comprising all patients in our department switched to belatacept post‐KTx. Six patients (median age 15.5 years) were switched after a median of 7.5 months (range 23 days to 12 years), treatment range 3–28 months (cumulative 83 months): Three patients switched early (<3 months after KTx) had increased estimated glomerular filtration rate (GFR); one patient switched 12 years post‐KTx has stable GFR; two patients were switched following rapid decline of and with markedly impaired GFR, changing slope in one patient. One patient had one acute rejection. In addition of two patients who received belatacept for other conditions, the only relevant adverse event was neutropenia (after a cumulative 109 months). Belatacept as primary immunosuppression is an option in Epstein–Barr virus‐seropositive nonadherent adolescents if administered sufficiently early before deterioration of graft function.

Correlations with six-month protocol biopsy findings in pediatric transplant recipients on low- and regular-dose CNI regimens

Protocol biopsies (PB) are seldom performed after pediatric kidney transplantation (KTx), and factors influencing PB results have not previously been investigated. We performed PB in 79 children six months after KTx and evaluated the results using Banff 2007 criteria. Complications such as bleeding or infections were not detected. The influence of different variables on PB results was evaluated by covariance analysis. Children treated with a low‐dose calcineurin inhibitor (CNI) together with an mTOR inhibitor exhibited decreased subclinical rejection (0% vs. 19%, p = 0.001) and decreased interstitial fibrosis and tubular atrophy (IF/TA) (15% vs. 42%, p = 0.013) compared with patients treated with a conventional regimen consisting of normal‐dose CNI and mycophenolate mofetil. Children with IF/TA had a lower GFR four wk after Tx (83 ± 22 vs. 62 ± 20 mL/min/1.73 m2, p = 0.001). Cold ischemia time, living‐related donors, pre‐emptive KTx, and donor age did not influence PB results. Treatment with low‐dose CNI and mTOR inhibitor and high GFR directly after Tx are the main factors associated with less inflammation and fibrosis in PB and might therefore lead to better long‐term graft function.

Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke‐immuno‐osseous dysplasia

Abstract:  SIOD is a multisystem disorder caused by a mutant chromatin remodelling protein. The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid‐resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF. Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft. However, with respect to the underlying immune disorder and the increased susceptibility to life threatening infections, the question of the optimal immunosuppressive therapy after renal transplantation remains unresolved. Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease. We present several cases of children with SIOD (four of five had SMARCAL1 mutations) and monotherapy maintenance immunosuppression after renal transplantation and compare them with 13 patients from the SIOD registry. We have found that post‐renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections. Due to the underlying immunodeficiency in SIOD, limited immunosuppression may be possible without increasing the risk of acute or chronic rejection.

Consequences of the change in Eurotransplant allocation system on kidney allocation in children.

Eurotransplant (ET) applies an algorithm using medical and logistical criteria and is mainly based on HLA match and waiting time for organ allocation (1). In kidney transplantation (KTX), children are favored in most allocation systems because of the negative influence of dialysis on growth and development. In the former ET system, including a fixed threshold age of 16 yr and different numbers of pediatric bonus points matched to three age cohorts (33, 66 or 99 points), leading to a waiting time of 1–2 yr as compared to seven yr in adults. In opposite to allocation systems as UNOS (2), no donor–recipient age match was performed. In the UNOS-Share-35 program, a different age range of kidneys from donors <35 yr to recipients <35 yr has been chosen. The ET allocation systemwas changed in December 2010 (3): all children under 16 yr, who are listed, receive 100 extra points and a doubling of the HLA match points. Children >16 yr with growth potential—proven by an X-ray of the left hand—are granted pediatric bonus. Organs from donors <16 yr are now preferably allocated to pediatric recipients. A higher priority for pediatric organs is given to zeroHLAmismatch recipients.

Graft outcomes following diagnosis of post-transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study

Data related to graft outcomes following post‐transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow‐up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED‐PTLD‐2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet‐PHL C1. In four patients, donor‐specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody‐mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range‐based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B‐cell‐depleting therapy of PTLD with rituximab.

Schimke-immunoossäre Dysplasie

ZusammenfassungHintergrund:Die Schimke-immunoossäre Dysplasie (SIOD) ist eine seltene autosomal-rezessiv vererbte Multisystemerkrankung, der Mutationen im SMARCAL-1-Gen (“SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1”) zugrunde liegen.Klinik:Zu den klinischen Hauptsymptomen zählen ein Kleinwuchs bei spondyloepiphysärer Dysplasie, eine Immunopathie sowie eine fortschreitende Glomerulopathie. Bei der schwer verlaufenden SIOD erweisen sich zerebrovaskuläre Symptome auf der Basis einer frühen generalisierten Arteriopathie oft als lebenslimitierend. Nur wenige Patienten erreichten bislang das Erwachsenenalter.Fallbeispiele:Exemplarisch wird über die Krankheitsverläufe bei vier adulten SIOD-Patienten berichtet.Schlussfolgerung:Patienten mit klinisch schwer verlaufender SIOD können heutzutage das Erwachsenenalter erreichen. Das Krankheitsbild der SIOD sollte dem Internisten/Hausarzt daher bekannt sein.AbstractBackground:Schimke immunoosseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1).Clinical Features:Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vasoocclusive processes. Only a few patients reached adulthood.Case Reports:The clinical course of four adult SIOD patients is presented.Conclusion:Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.

[Schimke immuno-osseous dysplasia. A pediatric disease reaches adulthood].

ZusammenfassungHintergrund:Die Schimke-immunoossäre Dysplasie (SIOD) ist eine seltene autosomal-rezessiv vererbte Multisystemerkrankung, der Mutationen im SMARCAL-1-Gen (“SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1”) zugrunde liegen.Klinik:Zu den klinischen Hauptsymptomen zählen ein Kleinwuchs bei spondyloepiphysärer Dysplasie, eine Immunopathie sowie eine fortschreitende Glomerulopathie. Bei der schwer verlaufenden SIOD erweisen sich zerebrovaskuläre Symptome auf der Basis einer frühen generalisierten Arteriopathie oft als lebenslimitierend. Nur wenige Patienten erreichten bislang das Erwachsenenalter.Fallbeispiele:Exemplarisch wird über die Krankheitsverläufe bei vier adulten SIOD-Patienten berichtet.Schlussfolgerung:Patienten mit klinisch schwer verlaufender SIOD können heutzutage das Erwachsenenalter erreichen. Das Krankheitsbild der SIOD sollte dem Internisten/Hausarzt daher bekannt sein.AbstractBackground:Schimke immunoosseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1).Clinical Features:Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vasoocclusive processes. Only a few patients reached adulthood.Case Reports:The clinical course of four adult SIOD patients is presented.Conclusion:Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.