Oliver Staeck

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.

Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation

BACKGROUND Systemic citrate accumulation is a complication of regional citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT). Our objective was to determine the incidence of clinical signs consistent with citrate accumulation in a large and representative cohort of intensive care unit patients undergoing RCA-CRRT. METHODS Patients treated with RCA-CRRT during 2008-2010 were retrospectively analyzed. Decreased systemic ionized calcium (iCa), increased demand for calcium substitution, elevated total calcium to iCa ratio, and metabolic acidosis were evaluated as indicators for citrate accumulation. RESULTS In the 3-year period, 1070 patients were treated with RCA-continuous venovenous hemodialysis. Metabolic signs of citrate accumulation occurred in 32 patients (2.99%, 64.5 ± 14.0 years, 65.6% male, Acute Physiology and Chronic Health Evaluation score 34.2 ± 9.7): systemic iCa decreased to 1.01 ± 0.10 mmol/L with a simultaneous increase of the calcium substitution rate to 129% ± 26%, and the mean total calcium to iCa ratio increased to 2.51 ± 0.54. All 32 patients had therapy-resistant shock with severe lactic acidosis (pH 7.20 ± 0.11, lactate 136 ± 61 mg/dL), indicating severe intracellular hypoxia. None of the patients survived. CONCLUSIONS The incidence of disarrangements consistent with citrate accumulation in patients undergoing RCA-continuous venovenous hemodialysis was low, taking place exclusively in patients with severe lactic acidosis due to multiorgan failure. This suggests that the appearance of citrate accumulation is secondary to a severe failure of cellular respiration.

PET/CT visualises inflammatory activity of pulmonary artery aneurysms in Behçet disease.

We report a 32-year-old male patient who presented with thromboses of the sigmoid sinus, the femoral vein and haemoptysis. With clinical suspicion for vasculitis and to rule out malignant disease, the patient underwent FDG-PET/CT. Contrast-enhanced CT was optimised for visualisation of the pulmonary arteries. The scan [posterior view of a 3D CT (a) and PET/CT (b) reconstruction] revealed bilateral pulmonary artery aneurysms with increased FDG accumulation (white arrows), a finding considered to represent inflammatory activity. This criterion led to the diagnosis of Behçet disease with Hughes-Stovin syndrome [1]. It must be discussed whether FDG-PET/CT could aid treatment decision-making in Behçet disease with pulmonary artery aneurysms [2, 3] by permitting the evaluation of inflammatory activity.

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.

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.

Need for optimized immunosuppression in elderly kidney transplant recipients

UNLABELLED The proportion of elderly kidney transplant candidates is increasing worldwide due to higher number of patients with end-stage renal disease in aging societies. ALLOCATION Accordingly, organ allocation policies in this population were adjusted in several countries. The European Senior Program is the most prominent example, where elderly patients (≥65years) receive elderly (≥65years) donor organs with acceptable results. IMMUNOSENESCENCE Because of age-dependent changes in the immune response and higher susceptibility to immunosuppressant side effects, outcomes in elderly patients are different compared to younger kidney transplant recipients. However, elderly patients do reject, especially poorly matched elderly donor organs. This warrants tailored immunosuppressive regimes with regard to the age-related changes of the immune system. SIDE EFFECTS Rejection therapies may have detrimental side effects in the seniors and are frequently leading to over-immunosuppression (malignancy and infections) in long-term therapy. It is hypothesized that after initial graft adaptation elderly patients may benefit from less immunosuppression in order to lower cancer risk and reduce infection rates and cardiovascular comorbidities. LACK OF DATA Current evidence on recommended standard immunosuppressive therapy was mainly derived from trials, where elderly patients were excluded or only a minority. In order to improve immunosuppressive therapy in elderly transplant recipients, current immunosuppressive regimes have to be re-investigated in this growing population. Up to date, only a few well-designed prospective studies were performed in elderly populations and demonstrate the need for effective immunosuppression in the first months after transplantation. CONCLUSION It is evident that novel treatment strategies and adequately powered prospective clinical trials are needed to establish time-adapted immunosuppressive regimens according to the needs of this vulnerable group of kidney transplant recipients.

Advances in pharmacotherapy to treat kidney transplant rejection.

Introduction: Current immunosuppressive combination therapy provides excellent prevention of T-cell-mediated rejection following renal transplantation; however, antibody-mediated rejection remains of high concern and accounts for a large number of long-term allograft losses. The recent development of protocol biopsies resulted in the definition of subclinical rejection (SCR), showing histologic evidence for rejection but unremarkable clinical course. Areas covered: This review describes the current knowledge and evidence of pharmacotherapy to treat kidney allograft rejections and covers SCR treatment options. Each substance is analyzed with regard to its classical indication and further discussed for the treatment of other forms of rejection. Expert opinion: Despite a lack of randomized trials, early acute T-cell-mediated rejection can be treated effectively in most cases without graft loss. The necessity to treat SCR is currently unclear. Due to a lack of effective therapies, new treatment approaches for antibody-mediated rejection are an urgent medical need to improve long-term outcomes. Future research should aim to better define pathophysiology and histology, stratify risk, and develop rational treatment strategies from randomized controlled trials, in order to establish the value of novel therapies in the arsenal of rejection pharmacotherapy. However, the effective prevention of rejection with minimal side effects still remains the goal in immunosuppression.

Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects

Antithymocyte globulins (ATGs) are part of the immunosuppression arsenal currently used by clinicians to prevent or treat acute rejection in solid organ transplantation. ATG is a mixture of non-specific anti-lymphocyte immunoglobulins targeting not only T cell subsets but also several other immune and non-immune cells, rendering its precise immunoglobulin composition difficult to appreciate or to compare from one preparation to another. Furthermore, several mechanisms of action have been described. Taken together, this probably explains the efficacy and the side effects associated with this drug. Recent data suggest a long-term negative impact on allograft and patient outcomes, pointing out the need to better characterize the potential toxicity and the benefit-risk balance associated to this immunosuppressive therapy within large clinical trials.