Henryk Karkoszka

Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation.

Although chronological donor age is the most potent predictor of long‐term outcome after renal transplantation, it does not incorporate individual differences of the aging‐process itself. We therefore hypothesized that an estimate of biological organ age as derived from markers of cellular senescence in zero hour biopsies would be of higher predictive value. Telomere length and mRNA expression levels of the cell cycle inhibitors CDKN2A (p16INK4a) and CDKN1A (p21WAF1) were assessed in pre‐implantation biopsies of 54 patients and the association of these and various other clinical parameters with serum creatinine after 1 year was determined. In a linear regression analysis, CDKN2A turned out to be the best single predictor followed by donor age and telomere length. A multiple linear regression analysis revealed that the combination of CDKN2A values and donor age yielded even higher predictive values for serum creatinine 1 year after transplantation. We conclude that the molecular aging marker CDKN2A in combination with chronological donor age predict renal allograft function after 1 year significantly better than chronological donor age alone.

Effect of tissue fixatives on telomere length determination by quantitative PCR

Telomere length is a well established marker of cellular senescence and thus biological age. Quantitative PCR allows the determination even from very low amounts of tissue by using telomere specific and single copy gene primers. Comparing a directly processed tissue sample to a 4% formaldehyde fixed one showed a significantly reduced efficiency of PCR reactions (mainly in single copy gene experiments) in a storage time-dependent manner resulting in an artificial increase in reported relative telomere length. This effect was not seen when the tissue was stored in RNA later solution. In summary, telomere length determination from formaldehyde fixed material by quantitative PCR is not a reliable method. Unfortunately therefore, many easily accessible tissue samples from pathology laboratories are unsuitable for this technique.

Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy

Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.

‐174G/C interleukin‐6 gene polymorphism and the risk of transplanted kidney failure or graft loss during a 5‐year follow‐up period

The influence of cytokine gene polymorphisms on transplanted kidney outcome is not well understood. The aim of this one-centre study was to analyse the association between tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10, interferon-γ (IFN-γ) and transforming growth factor-β1 (TGF-β1) genotypes and the incidence of delayed graft function (DGF), acute rejection (AR) and 5-year kidney graft loss. Genotyping was performed in 199 subsequent kidney graft recipients from deceased donors without induction therapy based on polymerase chain reaction method using sequence-specific primers for TNF-α (-308A/G), IL-10 (-1082A/G, -819T/C and -592A/C), IL-6 (-174G/C), IFN-γ (+874T/A) and TGF-β1 (in codons 10T/C and 25G/C). Genotypes were grouped according to the strength of cytokine expression. During a 5-year follow-up period, 14 patients died with functioning graft and 33 developed graft failure. The analysed polymorphisms were not associated with the incidence of DGF. The frequency of early episodes of AR was significantly associated only with TGF-β1 genotype. There was an association between -174G/C IL-6 gene polymorphism and the death-censored kidney graft survival. The risk of graft loss during 5-year follow-up period was greater by 57% for GG or GC (higher IL-6 production) than for CC carriers. None of the other analysed polymorphisms significantly influenced both patients and kidney graft survival, also in the analysis of the subgroup with human leucocyte antigen-DR mismatch. -174G/C IL-6 genotype of the kidney graft recipient could modulate the rate of graft excretory function deterioration and the risk of graft loss by influencing their constitutional expression.

Association Between Gene Polymorphisms of the Components of the Renin-Angiotensin-Aldosteron System, Graft Function, and the Prevalence of Hypertension, Anemia, and Erythrocytosis After Kidney Transplantation

INTRODUCTION Genetic predisposition, including polymorphisms of the renin-angiotensin system (RAS) genes, are among the potential factors that may affect the occurrence of hypertension, anemia, or erythrocytosis as well as transplanted kidney function. However, the association of the RAS genes polymorphism and the kidney transplant outcomes is controversial. The aim of this study was to analyze the association between polymorphic variants of the angiotensin-converting enzyme (insertion/deletion [I/D]), angiotensinogen (M235T), and angiotensin II receptor type 1 (A1166C) genes, and the early and long-term kidney graft outcomes, as well as the prevalence of hypertension, anemia and erythrocytosis after kidney transplantation. PATIENTS AND METHODS We included 331 consecutive kidney transplant patients performed between 1998 and 2003. Of the total, 87.9% of patients completed a 5-year follow-up. Subjects were genotyped for the I/D, M235T, and A1166C polymorphisms. RESULTS None of the examined polymorphism affected early or long-term graft function or was associated with hypertension before or after kidney transplantation. There was no significant difference in genotype distribution between patients with and without posttransplant erythrocytosis. However, posttransplant anemia (PTA) seemed to be significantly more common among kidney recipients with TT and MT than MM angiotensinogen genotypes (35.7% vs 20.7%; P=.03). The T allele was associated with the risk of development of PTA (odds ratio, 2.12; 95% confidence interval, 1.12-3.99; P=.02). CONCLUSION Our results do not support the hypothesis that polymorphism of the genes coding RAS components may by an independent risk factor for the development of interstitial fibrosis/tubular atrophy, posttransplant hypertension, or PTE. Further studies are necessary to investigate the association between angiotensinogen M235T genotypes and PTA.

Histopathological Examination may be Useful for Assessment of Fibrosis and Lipomatosis of Pancreas Allograft Prior to Solid Organ Transplantation

BACKGROUND The results of pancreas transplantation depend in a large degree on appropriate pancreas allograft donor selection. Several risk factors of early surgical complications or pancreas allograft loss following transplantation have been identified, but the final decision on pancreas harvesting for transplantation belongs to the surgeon. In the present study we aimed to assess whether histopathological examination may be utilized for detection of fibrosis and lipomatosis in tissue from a potential pancreas allograft. Additionally, we aimed to test whether presence of pancreatic fibrosis and lipomatosis may be explained solely by donor age and/or body mass index (BMI). MATERIAL AND METHODS Pancreata retrieved from 50 deceased organ donors referred to our institution and not transplanted between 2010 and 2013 were used for the present study. Tissue samples were excised from pancreata, fixed in formalin, and embedded in paraffin. Presence and intensity of pancreatic fibrosis and lipomatosis were assessed semi-quantitatively. RESULTS Fibrosis was found in the majority of study samples (72%), but it was usually mild or moderate. Lipomatosis was present in 34% of the study cases. Presence of fibrosis was more frequent in older donors, but was still not rare in donors under 40 years old. Presence of lipomatosis did not seem to be significantly related to donor age. Neither pancreatic fibrosis nor lipomatosis was related to donor BMI. CONCLUSIONS There is no clear relationship between histological parenchymal changes in potential pancreas allograft and donor age and BMI. Histopathological assessment of pancreatic fibrosis and/or lipomatosis can potentially facilitate decision making on pancreas allograft acceptance for solid organ transplantation.

Erratum to: Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort

Rosanna Coppo & Danilo Lofaro & Roberta R. Camilla & Shubha Bellur & Daniel Cattran & H. Terence Cook & Ian S. D. Roberts & Licia Peruzzi & Alessandro Amore & Francesco Emma & Laura Fuiano & Ulla Berg & Rezan Topaloglu & Yelda Bilginer & Loreto Gesualdo & Rosaria Polci & Malgorzata Mizerska-Wasiak & Yasar Caliskan & Sigrid Lundberg & Giovanni Cancarini & Colin Geddes & Jack Wetzels & Andrzej Wiecek & Magdalena Durlik & Stefano Cusinato & Cristiana Rollino & Milena Maggio & Manuel Praga & Hilde K. Smerud & Vladimir Tesar & Dita Maixnerova & Jonathan Barratt & Teresa Papalia & Renzo Bonofiglio & Gianna Mazzucco & Costantinos Giannakakis & Magnus Soderberg & Diclehan Orhan & Anna Maria Di Palma & JadwigaMaldyk &YaseminOzluk &Birgitta Sudelin &Regina Tardanico &DavidKipgen & Eric Steenbergen & Henryk Karkoszka & Agnieszka Perkowska-Ptasinska & Franco Ferrario & Eduardo Gutierrez & Eva Honsova

A case of acute rejection shortly after initiation of lamivudine therapy in a simultaneous pancreas and kidney recipient with viral hepatitis type B

Abstract: We describe a patient with hepatitis B antigenemia, who received a simultaneous pancreas and kidney transplant, developed reactivation of hepatitis B virus infection with aminotransferase elevation, and unexpectedly suffered an acute rejection episode within a few weeks after initiation of lamivudine therapy. At the time of rejection diagnosis, the cyclosporin A (CyA) trough level was 2 times lower than before the start of lamivudine therapy. Only an improvement in liver CyA metabolism in the course of lamivudine therapy can explain such an essential decline. Thus, it is important to emphasize how crucial it is to frequently monitor the CyA level in the early period of lamivudine therapy in transplanted patients with hepatitis to ensure adequate immunosuppression and to avoid acute rejection episodes.