Antigen-Specific versus Non-Antigen-Specific Immunoadsorption in ABO-Incompatible Renal Transplantation

Introduction: ABO-incompatible (ABOi) renal transplantation (RTx) from living donors is an established procedure to expand the donor pool for patients with end stage renal disease. Immunoadsorption (IA) is a standard procedure for the removal of preformed antibodies against the allograft. In this study, antigen-specific and non-antigen-specific IA in ABOi RTx were compared. Patients and Methods: 10 patients underwent antigen-specific IA (Glycosorb group) and 13 patients non-antigen-specific IA (Immunosorba group). The effects of both procedures regarding antibody reduction, number of treatments, complications, costs, as well as the allograft function and patient survival were compared between both groups. Results: Although the IgG levels were reduced equally by both procedures (p=0.82), the reduction of the IgM level was more effective in the Glycosorb group (p=0.0172). Patients in both groups required a median number of 6 IA before ABOi RTx. Allograft function at one year after AB0i RTx was similar in both groups (estimated glomerular filtration rate: 66 vs. 64 ml/min/1.73m² respectively), with a death-censored graft survival of 90.0% and 92.3% respectively. Complication rates did not differ between procedures. Due to the reuse of non-antigen-specific Immunosorba columns, costs were considerably lower in this group; however, the use of the Immunosorba-based IA was less time-efficient. Conclusion: Considering upcoming alternatives as simultaneous performance of dialysis and IA or a possible reuse of Glycosorb columns, this might become less relevant in the future

The Tacrolimus Metabolism Rate Influences Renal Function after Kidney Transplantation

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient’s risk management strategies.</p

The Effect of Proton Pump Inhibitor Use on Renal Function in Kidney Transplanted Patients

Recently, proton pump inhibitor (PPI) intake has been linked to acute kidney injury and chronic kidney disease. The objective of this study was to assess the effect of PPIs on renal function and rejection rate in kidney transplant patients. We performed a single center, retrospective analysis of 455 patients who received a kidney transplant between May 2010 and July 2015. Median follow-up time was 3.3 years. PPI prescription was assessed in half-year intervals. Primary outcome parameters were the estimated glomerular filtration rate (eGFR), change in the eGFR, and >30% and >50% eGFR decline for different time periods (up to four years post-transplantation). Our secondary outcome parameter was occurrence of biopsy proven acute rejection (BPAR) in the first two years after transplantation. Except for >30% eGFR decline from half a year to two years post-transplantation (p = 0.044) and change in the eGFR, >30% and >50% eGFR decline showed no association with PPI intake in our patient cohort (p > 0.05). Similarly, by analyzing 158 rejection episodes, BPAR showed no correspondence with mean daily PPI intake. We conclude that prolonged PPI intake has no relevant adverse effect on kidney transplant function or rejection rates. Polypharmacy, however, remains a problem in renal transplant recipients and it is thus advisable to question the necessity of PPI prescriptions when clear indications are missing

Validation of the Kidney Donor Profile Index (KDPI) to assess a deceased donor’s kidneys’ outcome in a European cohort

The Kidney Donor Profile Index (KDPI) was introduced in the United States in 2014 to guide the decision making of clinicians with respect to accepting or declining a donated kidney. To evaluate whether the KDPI can be applied to a European cohort, we retrospectively assessed 580 adult patients who underwent renal transplantation (brain-dead donors) between January 2007 and December 2014 at our center and compared their KDPIs with their short- and long-term outcomes. This led to the observation of two associations: one between the KDPI and the estimated glomerular filtration rate at one year (1-y-eGFR) and the other between the KDPI and the death-censored allograft survival rate (both p < 0.001). Following this, the individual input factors of the KDPI were analyzed to assess their potential to evaluate the quality of a donor organ. We found that a donor’s age alone is significantly predictive in terms of 1-y-eGFR and death-censored allograft survival (both p < 0.001). Therefore, a donor’s age may serve as a simple reference for future graft function. Furthermore, we found that an organ with a low KDPI or from a young donor has an improved graft survival rate whereas kidneys with a high KDPI or from an older donor yield an inferior performance, but they are still acceptable. Therefore, we would not encourage defining a distinct KDPI cut-off in the decision-making process of accepting or declining a kidney graft

Clinical features of BK-polyomavirus and cytomegalovirus co-infection after kidney transplantation

BK polyomavirus (BKPyV) and cytomegalovirus (CMV) are the main viral pathogens affecting the graft and recipient outcome after allogenic kidney transplantation. It has recently been found that infection with both viruses has a greater impact on kidney graft function than a single infection. We retrospectively analyzed a cohort of 723 recipients who received kidney transplantation between 2007 and 2015 after living and postmortal donation for differences in risk and outcome parameters regarding BKPyV (DNAemia) and CMV (CMV DNAemia) co-infection compared to sole viremias and to patients without viremia. Of all kidney allograft recipients in our cohort, 8.2% developed co-infection with BKPyV DNAemia and CMV DNAemia, 15.1% showed BKPyV viremia alone and 25.2% sole CMV DNAemia. Acute rejection was closely linked with co-infection (multivariable analysis, p = 0.001). Despite the fact that the estimated glomerular filtration rate of patients with co-infection was noticeably reduced compared to patients with BKV or CMV infection alone, transplant survival and patient survival were not significantly reduced. Co-infection with BKPyV and CMV in kidney transplanted patients is significantly associated with inferior allograft function. Since co-infection is strongly associated with acute rejection, co-infected individuals should be considered a risk collective

Fast Tac Metabolizers at Risk—It is Time for a C/D Ratio Calculation

Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL × 1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality

Conversion to Everolimus was Beneficial and Safe for Fast and Slow Tacrolimus Metabolizers after Renal Transplantation

Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio <1.05 ng/mL/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio <1.05 ng/mL/mg vs. 17 patients with a C/D ratio ≥1.05 ng/mL/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5–21.9) months and slow metabolizers 3.3 (1.8–23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73 m2 (p = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues

Cytomegalovirus Viremia after Living and Deceased Donation in Kidney Transplantation

Despite screening, effective anti-viral drugs and risk-balanced prophylaxis, cytomegalovirus (CMV) remains a major cause of morbidity in transplant patients. The objective of this study was to retrospectively analyze the risk factors associated with CMV viremia after kidney transplantation in a large European cohort with standardized valganciclovir prophylaxis in the present era. A special focus was placed on the comparison of living and postmortal donation. We conducted a longitudinal observational study involving 723 adult patients with a total of 3292 patient-years who were transplanted at our center between 2007 and 2015. Valganciclovir prophylaxis was administered over 100 days for CMV+ donors (D) or recipients (R), over 200 days for D+/R−, and none in D−/R−. A CMV+ donor, rejection episodes, and deceased donor transplantation were identified to be associated with increased incidences of CMV viremia. Although we did not find a reduced overall survival rate for patients with CMV viremia, it was associated with worse graft function. Since we observed a relevant number of CMV infections despite prescribing valganciclovir prophylaxis, a pre-emptive strategy in patients with (suspected) adherence restrictions could be favored. Our data can help transplant physicians educate their patients about their individual CMV risk and choose the most appropriate CMV treatment approach

Case Report: Management of a Multidrug-Resistant CMV-Strain in a Renal Transplant Recipient by High-Dose CMV-Specific Immunoglobulins, Modulation in Immunosuppression, and Induction of CMV-Specific Cellular Immunity

The management of multidrug-resistant strains of cytomegalovirus after solid organ transplantation is challenging. This case report demonstrates the successful treatment of a multidrug-resistant strain of cytomegalovirus that may represent a valuable option for problematic cases. This report illustrates the emergence of a multidrug-resistant cytomegalovirus (CMV) UL54 mutant strain in a renal transplant recipient with severe lymphopenia and thrombocytopenia. We show that the combined treatment with high-dose intravenous cytomegalovirus-specific immunoglobulins (CMV-IVIG) after the switch to a mammalian target of rapamycin (mTOR)-inhibitor and cyclosporine A was a successful treatment alternative to direct antiviral treatment with high-dose ganciclovir and foscarnet. This treatment was associated with a quantitative induction of CMV-specific CD4 and CD8 T cells that showed maturation in phenotype and functionality with decreasing viral load. Our case report illustrates that high-dose CMV-IVIG and conversion of immunosuppressive drugs to mTOR inhibitors and cyclosporine A can be a successful treatment in a situation where the use of direct antiviral drugs was considered insufficient

Male kidney allograft recipients at risk for urinary tract infection?

Background: Urinary tract infection (UTI) is the most common infection after renal transplantation (RTx). Although female sex is a well-known risk factor for the development of UTI after RTx, the role of the donor sex in this context remains unclear. Methods: In this case control study 6,763 RTx cases were screened for UTI when presenting at our transplant outpatient clinics. 102 different RTx patients fulfilled the inclusion criteria and were compared to 102 controls. Data on renal function was prospectively followed for 12 months. Results were compared to a previous RTx cohort from our transplant center. Additionally, we assessed the immunological response of leukocytes from 58 kidney recipients and 16 controls to lipopolysaccharide stimulation. Result: After identification by univariate analysis, multivariate logistic regression analysis indicated female sex, minor height, advanced age and male kidney allograft sex to be associated with the occurrence of UTI after RTx. Female recipients who received male grafts had the best renal function 12 months after presentation. However, leukocyte response of recipients to lipopolysaccharide was impaired irrespective of donor and recipient sex to the same extend. Conclusions: We conclude from our data that male kidney allografts are associated with the occurrence of UTI after RTx but did not influence the response of leukocytes to lipopolysaccharide. Further prospective studies are needed to identify the underlying mechanisms of higher male kidney donor dependent UTI