Martin Zeier

Assessment of renal allograft fibrosis by transient elastography

Transient elastography (TE, Fibroscan) has been established as a noninvasive assessment tool of liver fibrosis. We evaluated potentials and limitations of TE for identifying renal allograft fibrosis. The technical possibility of kidney examination by TE was assessed in two 10‐week‐old German landrace pigs and kidney stiffness (KS) was evaluated in 164 renal transplant patients. KS could be determined in all animals at the pole and pars media (29 ± 10 kPa vs. 31 ± 17 kPa). In human renal allografts KS was successfully performed in 94.5% of the test series with reliable results in 72% of the measurements. Mean KS at the pole or pars media were comparable (35.0 ± 19.9 kPa vs. 33.2 ± 18.6 kPa). Significantly higher KS was detected in renal allografts with histologically confirmed advanced fibrosis. Body‐mass‐index, skin‐allograft distance, and peri or intrarenal fluid accumulation were important confounders of successful KS measurements (BMI: r = −0.31; P < 0.001; distance: r = −0.50; P < 0.001). Notably, KS did not correlate with renal function. TE represents a noninvasive approach in selected transplant recipients to identify allografts with severe fibrosis. The heterogeneous kidney morphology and several other confounding factors negatively affect measurability of KS by TE. Further technical modifications are required to improve applicability of TE for kidney assessment.

Simultaneous pancreas–kidney transplantation in type 1 diabetes

The outcome of simultaneous pancreas–kidney (SPK) transplantation in type 1 diabetes has dramatically improved in recent years because of optimized surgical techniques and new immunosuppressive drug regimens. Normoglycemia is followed by stabilization or even regression of diabetic lesions, i.e., of heart and kidneys. However, these effects are only visible after more than five yr of normoglycemia (achieved by a functioning allograft). This is also a likely explanation for the conflicting results of studies that investigated patient or kidney graft survival in SPK transplantation compared to kidney transplantation alone. Most studies had too short follow‐up periods, i.e., less than five yr, to compare effectively different transplant strategies in patients with type 1 diabetes and therefore failed to discover a survival benefit in favor of simultaneously transplanted patients. Recent data now indicate that, with a longer follow‐up, there is an increasing survival benefit for simultaneously transplanted patients compared to patients who received a single kidney transplant. This is paralleled by the comparison of simultaneously transplanted patients to patients who received a single kidney transplant from a living donor. A survival benefit for the combined procedure was here visible after  10 yr of follow‐up. We give a short overview on SPK transplantation, with a focus on the effects of this procedure on diabetic complications as well as patient and kidney graft survival.

Calcineurin inhibitors and NFAT-regulated gene expression.

Calcineurin inhibitors (CNIs) have a narrow therapeutic window; therefore, regular monitoring of the drug is necessary to balance sufficient efficacy with minimal toxicity. Until now, monitoring of immunosuppressive drugs is performed by pharmacokinetic assessments, mainly by trough concentrations (C0) of the drug. All these methods rely on pharmacokinetic data, which does not reflect the biological effects of CNI on the immune system. Several approaches have been undertaken to measure the biologic effects of CNI-based immunosuppression. Recently, a new quantitative analysis of gene expression has been employed to calculate the inhibition of the transcription of NFAT-regulated genes in peripheral blood. Methodological aspects and clinical data on the potential benefit of this specific CNI monitoring assay are discussed.

Immunomonitoring of nuclear factor of activated T cells–regulated gene expression: The first clinical trial in liver allograft recipients

Long‐term calcineurin inhibitor (CNI) treatment can cause serious side effects in liver allograft recipients. An optimal risk‐to‐benefit ratio for CNI blood levels has not been established. Pharmacodynamic drug monitoring through the measurement of the CNI biological activity, that is, the expression of nuclear factor of activated T cells (NFAT)–regulated genes, seems to be a promising approach. The residual gene expression (RGE) of NFAT‐regulated genes 2 and 1.5 hours after cyclosporine A (CsA) and tacrolimus (FK‐506) intake was measured in 100 liver allograft recipients with 1 or more years of follow‐up post‐transplantation. The mean RGE in all patients was 62% ± 33%. A significant negative correlation between the CsA (P < 0.0001, r = −0.8026) and FK‐506 peak levels (P < 0.0001, r = −0.6982) and the RGE of all NFAT‐regulated genes was observed. Clinical reliability was proven too. In conclusion, the data presented in this pilot study reveal the applicability of the pharmacodynamic monitoring of CNI efficacy in liver allograft recipients. To confirm the advantage of individualized pharmacodynamic drug monitoring over pharmacokinetic drug monitoring with respect to clinical outcomes, controlled, prospective studies are needed. Liver Transpl, 2011.

Color Doppler Ultrasonography in the Diagnostic Evaluation of Renal Allografts

Color Doppler ultrasonography of large allograft vessels and renal parenchyma is established firmly in the diagnosis of renal allograft perfusion. While conventional color Doppler ultrasonography has proven itself to be an indispensable, rapid, highly valid and practicable method, e.g. in the diagnosis of allograft artery stenosis or allograft vein thrombosis, the diagnostic usefulness of this method with regard to allograft perfusion is considerably limited. With contrast-enhanced sonography, a simple and readily implementable method that enables the early diagnosis of chronic allograft nephropathy is now available. The timely diagnosis of vascular damage prior to a rise in S-creatinine offers the possibility of early therapeutic intervention and thus at least the potential for the improvement of allograft survival.

Guías Europeas sobre manejo y evaluación de receptores y donantes renales

The purpose of this Clinical Practice Guideline is to provide guidance on evaluation of the kidney donor and transplant recipient as well as on the management of the recipient in the perioperative period. It is designed to provide information and aid decision-making. It is not intended to define a standard of care, and should neither be construed as one nor should it be interpreted as prescribing an exclusive course of management. The original version of this guideline was published in Nephrology, Dialysis and Transplantation and this current version is a reduced article aiming to disseminate the guideline into Spanish-speaking countries and transplant communities.

Plasmapheresis adjusts inflammatory responses in potential kidney transplant recipients.

Background Plasmapheresis (PP) has been used in the treatment of various immunologic disorders, and its efficacy has mainly been attributed to the removal of humoral factors and autoantibodies. Besides these effects, PP may induce modifications of the cellular immunologic status, contributing to the restoration of impaired immunologic function. The effect of PP on lymphocyte subpopulations, plasma neopterin, and cytokines in renal transplant recipients was investigated in this study. Methods We compared pre-PP and post-PP lymphocyte subpopulations and plasma neopterin in 37, and cytokine plasma levels in 30, potential renal transplant recipients. Plasma neopterin and cytokines were measured by enzyme-linked immunosorbent assay kits, lymphocyte subsets were determined using four-color fluorescence flow cytometry. Results Lymphocyte subpopulation counts and ratios including CD45+:&mgr;L (P=0.005), CD3+:&mgr;L (P=0.02), CD4+DR+:&mgr;L (P=0.002), CD8+:&mgr;L (P=0.01), and CD8+DR+:&mgr;L (P=0.005) T cells; CD4+DR+:CD4+ (P=0.009) and CD8+DR+:CD8+ (P=0.0004) ratios; DR+ cells:&mgr;L (P=0.003); CD19+ B lymphocytes:&mgr;L (P=0.001); and plasma levels of neopterin (P<;0.0001), soluble interleukin-1 receptor antagonist (P<;0.0001), IL-8 (P=0.0001), and tumor necrosis factor-&agr; (P=0.008) were significantly decreased after PP as compared with before PP. The results indicate a decrease of activated DR+, CD4+, and CD8+ T lymphocytes and B lymphocytes, and a decrease of monocyte and macrophage activation as a result of PP. Conclusion Based on these results, we conclude that PP not only removes antibodies from the plasma but, in addition, modulates T-lymphocyte activation and the inflammatory response by decreasing plasma proinflammatory cytokines.

The impact of type 2 diabetes on the outcome of localized renal cell carcinoma.

AbstractPurpose To evaluate the influence of type 2 diabetes on cancer-specific outcome in patients undergoing surgery for localized renal cell carcinoma (RCC). MethodsA total of 1,140 patients with localized RCC undergoing radical or partial nephrectomy were enrolled into this retrospective case–control study. Primary outcome was the cancer-specific survival comparing patients with and without type 2 diabetes at the time of surgery. Secondary outcomes were recurrence-free survival and metastases-free survival comparing the same groups. Additionally, the influence of accompanying factors on cancer-specific survival and overall survival of patients was evaluated in a multivariate analysis. Among 1,140 patients included in the analyses, 202 had diabetes at the time of surgery and 938 patients without diabetes served as control.ResultsThe univariate comparisons between patients with and without diabetes regarding recurrence-free, metastases-free, and cancer-specific survival revealed no significant differences. Multivariate results demonstrate that age, BMI, and diabetes had no significant effect on cancer-specific hazard among participants. After adjustment of the factors in terms of overall survival, however, increased age, increased BMI, and type 2 diabetes at the time of surgery were independent risk factors for the occurrence of the event death.ConclusionsType 2 diabetes and obesity at the time of surgery have no significant impact on cancer-specific and recurrence-free survival in patients with localized renal cancer.

AEB071 – a promising immunosuppressive agent

Abstract: In the past decades, allograft survival improved because of the development of new and more specific immunosuppressive agents. The introduction of calcineurin inhibitors was a landmark and acute rejection in organ transplantation decreased remarkably. Calcineurin inhibitor such as ciclosporin A inhibits T‐cell activation by interfering with the cytosolic protein cyclophilin (immunophilin). This complex of ciclosporin and cyclophilin inhibits calcineurin, which is responsible for activating the transcription of interleukin‐2. More recent research revealed a second pathway for T‐cell activation, which is mediated by a specific protein kinase C., e.g., protein kinase C θ. AEB071 represents a selective protein kinase C inhibitor with promising potential for immunosuppression in organ transplantation. In pre‐clinical studies, AEB071 prolonged allograft survival in kidney and heart transplant models. In human clinical studies, AEB071 reduced severity of psoriasis symptoms and has shown to be safe up to 750 mg single dose treatment. Important adverse events were gastrointestinal disorders and headaches. AEB071 inhibits early T‐cell activation via a calcineurin inhibitor independent pathway and is currently investigated as a therapeutic agent to prevent allograft rejection after renal transplantation.

Evaluation of hepatocyte growth factor as a sensitive marker for early detection of acute renal allograft rejection.

Background. It has been shown that hepatocyte growth factor (HGF), besides its well-established hepatotrophic effect in liver regeneration, is involved in the regeneration of the kidney after injury. In the present study we investigated whether HGF can serve as a marker for detection of acute rejection in the early posttransplantation period. Methods. HGF levels were determined in pre- and posttransplant sera (up to day 21) of 26 recipients with biopsy-proven acute rejection, 30 recipients with acute tubular necrosis (ATN), and 32 recipients without posttransplant complications. Results. Although no association was found between pretransplant HGF and death-censored functional graft survival, receiver operating characteristic (ROC) curves demonstrated that HGF measured during the entire posttransplant study period, and especially on days 3 to 5, was a good marker for differentiating recipients who subsequently developed acute rejection from recipients with an uncomplicated course (P<0.0001, specificity 87%, sensitivity 84%). HGF measured from day 3 until day 21 posttransplantation, and especially on days 7 to 9, was also a sensitive marker for differentiating recipients with ATN from recipients with an uncomplicated course (P<0.0001). If considered in combination with sCD30, the diagnostic value of HGF was further improved. While 73% of samples from patients with impending rejection were positive for both HGF and sCD30, 94% of samples from nonrejecting patients were double-negative and none of the samples from this group fell into the double-positive category (P<0.0001). Conclusions. Our data suggest that HGF measured during the early posttransplant period might be a useful parameter for early detection of acute renal allograft rejection.