Fabian Halleck

The need for minimization strategies: current problems of immunosuppression.

New immunosuppressants and the better use of immunosuppressant combination therapy have led to significant improvements in renal allograft outcomes over the last decades. Yet, despite dramatic reduction in rejection rates and improvement in 1‐year graft survival, long‐term graft attrition rates remained rather constant. Current immunosuppressant combinations are frequently leading to overimmunosuppression and are increasing cardiovascular risk. Importantly, calcineurin inhibitors are nephrotoxic, contribute to cardiovascular risk and chronic allograft dysfunction. Furthermore, immunosuppressant‐associated toxicities aggravate immune‐mediated nephron injury and side effects lead to nonadherence, an identified important reason for late acute and chronic antibody‐mediated rejections. The frequent development of a chronic humoral response indicates rather insufficient immunosuppression of current combinations than simple under‐immunosuppression. While there is no evidence that increasing immunosuppressive doses will improve outcomes or reduce de novo HLA‐antibody formation, there is clear evidence that adequate minimization strategies will reduce side effect burden. Because of low rejection risk, but frequent side effects, drug minimization is particularly relevant for the many maintenance patients. In summary, new therapeutic strategies need to be developed from adequately powered clinical trials for reduction of the many side effects of immunosuppressants. Such evidence‐based and time‐dependent immunosuppressive minimization strategies are needed to achieve better long‐term outcomes in the future.

An evaluation of sirolimus in renal transplantation

Introduction: Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. Areas covered: The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. Expert opinion: Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.

Volume matters: CT‐based renal cortex volume measurement in the evaluation of living kidney donors

Currently, no international standard for the pre‐transplant evaluation of living donor renal function exists. Following a standardized questionnaire on current practice in all Eurotransplant (ET) centers, we compared a new CT‐based technique to measure renal cortex volume with our standard of DTPA‐clearance combined with MAG3‐scintigraphy (DTPA × MAG3) and with creatinine‐based methods in 167 consecutive living kidney donors. Most ET centers use creatinine‐clearance (64%) to measure total renal function and radioistopic methods (82%) to assess split renal function. Before transplantation, CT‐measured total cortex volume (r = 0.67; P < 0.001) and estimated GFR using the Cockcroft‐Gault formula [eGFR(CG)] (r = 0.55; P < 0.001) showed the strongest correlation with DTPA‐clearance. In contrast, the correlation between DTPA‐clearance and creatinine clearance was weak (r = 0.21; P = 0.02). A strong correlation was observed between CT‐measured split cortex volume and MAG3‐measured split renal function (r = 0.93; P < 0.001). A strong correlation was also found between pre‐transplant split renal function assessed by eGFR(CG) together with cortex volume measurement and post‐transplant eGFR(CG) of both, the donor (r = 0.83; P < 0.001) and the recipient (r = 0.75; P < 0.001). In conclusion CT‐based assessment of renal cortex volume bears the potential to substitute existing methods to assess pre‐transplant living donor split renal function.

The preferences and perspectives of nephrologists on patients' access to kidney transplantation: a systematic review.

We aimed to describe nephrologists’ attitudes to patients’ access to kidney transplantation. Studies that assessed nephrologists’ perspectives toward patient referral, screening, and eligibility for kidney transplantation were synthesized. Twenty-four studies (n≥4695) were included. Patients with comorbidities, were nonadherent, of older age, ethnic minorities, or low socioeconomic status were less likely to be recommended. Six themes underpinned nephrologists’ perspectives: prioritizing individual benefit and safety, maximizing efficiency, patient accountability, justifying gains, protecting unit outcomes, and reluctance to raise patients’ expectations. Evidence-based guidelines may support systematic and equitable decision-making. Interventions for high-risk or disadvantaged patient populations could reduce disparities in access to transplantation.

Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor-Mediated Podocyte β3-integrin Activation.

Background Primary focal segmental glomerulosclerosis (FSGS) often causes nephrotic proteinuria and frequently results in end-stage renal disease and recurrence after kidney transplantation. Recent studies describe soluble urokinase-type plasminogen activator receptor (suPAR) as a circulating factor implicated in FSGS. Methods This single-center study included 12 adult patients with histologically proven primary FSGS (n = 2) or recurrent FSGS after transplantation (n = 10). The effect of plasma exchange (PE) on clinical outcome, suPAR levels, and in vitro podocyte &bgr;3-integrin activation was investigated over a median of 11 (6-18) sessions of PE. Results The course of treatment was monitored in a total of 70 sessions of PE, which partly eliminated suPAR, with a mean reduction of 37 ± 12% of serum concentration per session. However, a substantial rebound was observed between sessions, with suPAR levels reaching 99 ± 22% of the pretreatment levels after a median of 4 days. Podocyte &bgr;3-integrin activation dropped significantly after PE but rebounded within 4 days concomitant with a rising suPAR level. In 11 of 12 patients, multimodal treatment (including extensive PE) reduced proteinuria significantly (from 5.3 [2.0-7.8] to 1.0 [0.4-1.6] g/d), indicating clinical efficacy of the therapy. One patient suffered allograft loss due to FSGS recurrence. A persisting response was independent of a lasting reduction in the level of total suPAR because there was no sustained significant change in suPAR levels before and after the course of intensified treatment (3814 ± 908 to 3595 ± 521 pg/mL; P = 0.496). Conclusions We conclude that multimodal therapy including extensive PE was associated with stabilization of recurrent FSGS and a temporary lowering of plasma suPAR as well as podocyte &bgr;3-integrin activation. Whether a sustained lowering of total suPAR results in further improved outcomes requires additional study.

Pretransplant virtual PRA and long-term outcomes of kidney transplant recipients

Virtual panel‐reactive antibodies (vPRA) have been implemented to gauge sensitization worldwide. It is unclear how it associates with long‐term outcomes, and its correlation with peak (pPRA) or actual (aPRA) has not been studied. We retrospectively reviewed data from 18‐ to 65‐year‐old kidney‐only transplant patients during 1.1.1996–31.7.2011 in our center. PRAs were calculated based on solid‐phase techniques. Of the 726 qualified cases, regardless of the PRA type, sensitized patients (PRA > 5%) had more females and previous transplant. Highly sensitized (HS, PRA > 50%) had longer waiting time, lower transplant rate, less living donor, more delayed graft function, and acute rejection. The conformity between vPRA and pPRA in HS was 75%, 57% between pPRA and aPRA. Forty‐three percent (61/142) patients whose pPRA was >5% had no detectable aPRA and maintained similar outcomes as sensitized patients. Multivariate analysis showed consistently lower death‐censored graft survival in HS defined by vPRA [HR 2.086 (95% CI 1.078–4.037), P < 0.05] and pPRA [HR 2.139 (95% CI 1.024–4.487), P < 0.05]. Both vPRA and pPRA provided reliable way estimating sensitization and predicting long‐term graft survival, while aPRA might underestimate true sensitization. vPRA might be the most objective parameter to gauge sensitization.

Donor–Recipient Matching Based on Predicted Indirectly Recognizable HLA Epitopes Independently Predicts the Incidence of De Novo Donor-Specific HLA Antibodies Following Renal Transplantation

De novo donor‐specific HLA antibodies (dnDSA) are recognized as a risk factor for premature allograft failure. Determinants of DSA specificity are generated via the indirect allorecognition pathway. Here, we present supportive data for the relevance of predicted indirectly recognizable HLA epitopes (PIRCHE) to predict dnDSA following kidney transplantation. A total of 2787 consecutive kidney transplants performed between 1995 and 2015 without preformed DSA have been analyzed. De novo DSA were detected by single antigen bead assay. HLA epitope mismatches were determined by the HLAMatchmaker and PIRCHE approach and correlated in uni‐ and multivariate analyses with 10‐year allograft survival and incidence of dnDSA. The PIRCHE‐II score moderately predicted allograft survival. However, the predictive value of elevated PIRCHE‐II scores >9 for the incidence of dnDSA was statistically significant (p < 0.001). In a multivariate Cox regression analysis adjusted for antigen mismatch and HLAMatchmaker epitopes, the PIRCHE‐II score could be identified as an independent risk factor for dnDSA. The PIRCHE‐II score independently from the antigen mismatch and HLAMatchmaker epitopes could be revealed as being a strong predictor for dnDSA. PIRCHE may help to identify acceptable mismatches with decreased risk of dnDSA and thus improve long‐term renal allograft survival.

Improved Left Ventricular Structure and Function After Successful Kidney Transplantation

Background/Aims: Cardiac changes observed in chronic kidney disease patients are of multifactorial origin including chronic uremia, hemodynamics or inflammation. Restoration of renal function by kidney transplantation (KTX) may reverse cardiac changes. Novel echocardiographic methods such as speckle tracking echocardiography (STE) allow early and sensitive detection of subtle changes of cardiac parameters. We evaluated changes of cardiac structure and function after KTX by advanced echocardiographic modalities. Methods: Thirty-one KTX recipients (female n=11) were evaluated by medical examination, laboratory testing and echocardiography before and after KTX (median follow-up 19 months). Left ventricular (LV) and right ventricular (RV) diameters and function were assessed by echocardiographic standard parameters. Longitudinal 2D strain of the LV (GLPS) and left atrium (LA) was determined by 2D STE. Results: After KTX, median serum creatinine level was 1.3 mg/dl (IQR, 1.2-1.5). Systolic blood pressure decreased significantly after KTX. Echocardiography showed a significant reduction in LV end-diastolic septal and posterior wall thickness and LV mass index after KTX, which was accompanied by an improvement of GLPS. There were no relevant changes in parameters of LA (reservoir, conduit or contractile) function, LV diastolic or RV function after KTX. Conclusion: LV hypertrophy reversed after successful KTX and was accompanied by an improvement in longitudinal LV function as assessed by STE. Diastolic function and STE-derived LA function parameters did not change significantly after KTX.

Clinical Outcome of Patients with De Novo C1q-Binding Donor-Specific HLA Antibodies after Renal Transplantation.

Background De novo donor specific anti-HLA antibodies (dnDSA) may cause graft loss in renal transplant recipients. The capability to bind the complement may help to stratify the risk for inferior outcomes associated with dnDSA. We developed a modified C1q-binding assay and hypothesized that C1q-binding dnDSA could differentiate between indolent and harmful dnDSA causing antibody-mediated rejection (AMR) and graft loss. Methods We retrospectively identified 59 renal transplant recipients who developed dnDSA and had serum available and complete follow-up. All patients were analyzed for C1q-binding dnDSA at the time of dnDSA detection, and 1-year later or at time of AMR. AMR-positive patients were also tested 6 to 12 months before the event if IgG dnDSA was present. Results Thirty-seven of 59 dnDSA+ patients developed AMR during 5.9 ± 3.1 years follow-up. AMR-positive patients had more dnDSA with a significant higher frequency of class I, a higher frequency and a higher mean fluorescence intensity value of C1q+-dnDSA at all time-points. Death-censored AMR-free and allograft survivals were significantly lower in C1q+-dnDSA patients. In multivariate analysis, C1q+-dnDSA was an independent risk factor for AMR. Conclusions C1q-binding dnDSA is associated with inferior outcomes, yet not in all patients. Nevertheless, C1q+-dnDSA was shown to be an independent risk factor of AMR and graft loss and may be a useful tool to stratify the immunological risk for AMR.

‘Suspended in a paradox’—patient attitudes to wait-listing for kidney transplantation: systematic review and thematic synthesis of qualitative studies

Patients on waiting lists for kidney transplantation have higher mortality rates and have specific anxieties about their eligibility, process, and outcomes of wait‐listing. We aimed to describe patient experiences and attitudes to wait‐listing for kidney transplantation. Electronic databases were searched to September 2014. Thematic synthesis was used to analyze the findings. From 22 studies (n = 795 patients), we identified six themes: accepting the only option (chance to regain normality, avoiding guilt, impulsive decision‐making); maintaining hope (determined optimism, appreciating a fortuitous gift, enduring for optimal outcomes, trust in clinical judgment); burden of testing (strenuous commitment, losing the battle, medical mistrust); permeating vulnerability (eligibility enigma, being threatened, angst of timing uncertainty, desperate urgency, living in limbo, spiraling doubt and disappointment, residual ambivalence); deprived of opportunity (unfairly dismissed, unexpected disqualification, self‐resignation and acceptance, jealousy, suspicious of inequity); and moral guilt (awaiting someones death, questioning deservingness). The waiting list offered hope of restored normality. However, the demands of workup, uncertainty about eligibility, and waiting times that exceeded expectations impelled patients to disillusionment, despair, and suspicion of inequity. Managing patient expectations and ensuring transparency of wait‐listing and allocation decisions may allay patient disappointment and skepticism, to improve patient satisfaction and treatment outcomes.