Impact of Pre-existing Comorbidities on Long-term Outcomes in Kidney Transplant Recipients.

BACKGROUND: Outcomes of patients with end-stage renal disease are mainly affected by their comorbidities. Detailed data evaluating the impact of pre-transplant comorbidities on long-term outcome after kidney transplantation are largely missing. METHODS: In a long-term retrospective analysis, we investigated 839 deceased donor kidney transplant recipients (KTRs) who received transplants between 1999 and 2014. The prevalence and impact of the most relevant comorbidities were studied in detail. RESULTS: At the time of transplantation, 25% of KTRs had coronary artery disease (CAD), 16% had diabetes mellitus (DM), 11% had peripheral arterial disease (PAD), 8% had chronic heart failure (CHF), and 7% had cerebrovascular disease (CVD). KTRs with pre-existing CAD, DM, PAD, and CHF showed a significantly inferior patient survival. Multivariate analysis adjusting for all relevant factors and comorbidities confirmed CAD as most hazardous independent risk factor for premature death (hazard ratio [HR] 1.70; P = .002). A multivariate analysis revealed CHF and PAD as independent risk factors for death censored graft loss (HR 2.20; P = .003 and HR 1.80; P = .013). Diabetes was independently and significantly associated with T-cell- (HR 1.46; P = .020) and antibody-mediated rejections (HR 2.27; P = .030). CONCLUSIONS: Detailed quantification of the impact of pre-transplant comorbidities may facilitate the evaluation of transplant candidates, guide post-transplant follow-up, and may help to further refine prediction algorithms and allocation systems.

Late Steroid Withdrawal Following AB0-Incompatible Renal Transplantation.

BACKGROUND: Current evidence on steroid withdrawal following AB0-incompatible (AB0i) renal transplantation is low. We compared clinical outcomes of patients who agreed to late steroid withdrawal and patients who remained on steroid treatment. METHODS: Steroid withdrawal was carried out in 11 patients at ≥12 months after transplantation (group W). For comparison, we analyzed 19 patients who remained on triple immunosuppression including steroids (group M). Minimum follow-up was 24 months following transplantation and 12 months after steroid withdrawal. RESULTS: Baseline characteristics, including observation times, were not different between groups W and M. Graft survival was 100% in group W compared with 84% (16/19) in group M (P = .15). In group M, 1 patient experienced graft failure because of suspected antibody-mediated rejection (ABMR) following temporary cessation of mycophenolate treatment after a diagnosis of cryptococcal pneumonia. Two patients died with functioning graft because of sepsis. In group W, we observed 1 episode of ABMR following steroid withdrawal. At the end of follow-up, estimated glomerular filtration rates (eGFR) were 54 (19-91) versus 60 (15-85) mL/min/1.73 m2 in group W versus M, respectively (P = .67). CONCLUSIONS: Late steroid withdrawal following AB0i transplantation is feasible at a moderate risk of rejection. We recommend close monitoring of renal function and HLA antibodies during and after steroid withdrawal. On the other hand, the occurrence of severe infections causing death and graft loss in patients on triple maintenance immunosuppression including steroids should remind us to consider the overall immunosuppressive burden.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

Long-Term Outcomes of Kidney Transplant Recipients With Primary Idiopathic Focal Segmental Glomerulosclerosis.

BACKGROUND: Few data exist on recurrence rates, treatment response, and long-term outcomes in kidney transplant recipients (KTR) with primary focal segmental glomerulosclerosis (FSGS). METHODS: This retrospective, observational study included 1218 consecutive KTR during 2002 to 2016. All patients with primary idiopathic FSGS were identified through application of strict diagnostic criteria. Outcomes were followed over an average of 70.4 months. RESULTS: We identified 48 KTR (3.9%) with primary FSGS. Seven-year death-censored graft survival rate was 81% (primary FSGS) versus 85% (control) (P = .297). Eighteen KTR had FSGS recurrence (predicted incidence, 50% after 7 years). Seven-year death-censored graft survival rate in KTR with FSGS recurrence was significantly worse than in FSGS KTR without recurrence (63% versus 96%, P = .010). In the case of FSGS recurrence, a multi-modal treatment approach was applied, including plasma exchange (PE) (100% of patients), intravenous cyclosporine (50%), rituximab (61%), and the "Multiple Target Treatment" (39%). The median number of PE sessions was 27. Proteinuria decreased significantly and persistently during the course of treatment. Complete remission of FSGS was observed in 7 patients (39%); another 7 patients (39%) had partial remission (PE dependence was observed in 4 patients [22%]). Four patients (22%) with FSGS recurrence had early graft loss (<6 months after transplant) despite all treatment efforts. CONCLUSIONS: In KTR with primary FSGS, a high proportion of recurrence occurred, and recurrence was associated with significantly worse death-censored graft survival rates. However, a multi-modal treatment approach led to improvement of proteinuria and full or partial remission in most patients. Importantly, overall death-censored graft survival rate in KTR with primary FSGS was comparable with that in the control group.

Immunologic Long-term Outcomes of Living-Related Kidney Transplantations Depending on the Donor-Recipient Relationship.

BACKGROUND: The aim of this study is to analyze the long-term immunologic outcomes of living-related kidney transplantations depending on the donor-recipient relationship. METHODS: This retrospective single-center study included adult kidney transplant recipients (KTR) transplanted between 2000 and 2014. Among 1117 KTRs, 178 patients (15.9%) received living-related donations. Those patients were further categorized according to the donor-recipient relationship: 65 transplantations between siblings, 39 father-to-child (F-t-C) and 74 mother-to-child (M-t-C) donations. Allograft biopsies were performed for clinically suspected rejections. Data analysis included patient and graft survival, biopsy proven rejections (T-cell mediated [TCMR] or antibody mediated) and development of de novo donor-specific antibody. Outcome data were assessed over a period of a maximum 14 years. RESULTS: There was no significant difference between the groups (F-t-C, M-t-C, and siblings) with regard to HLA-mismatches, prior kidney transplantations, time on dialysis, and cold ischemia time. Among KTRs with related donors, the type of relationship had no significant influence on graft survival. F-t-C and M-t-C pairs showed comparable incidences of TCMR at 7 years post-transplantation, both significantly exceeding the rate in sibling-to-sibling pairs (26.2% and 26.8% vs 10%, respectively; P = .043). A multivariate Cox regression analysis adjusted for recipient age, donor age, and HLA (A, B, DR)-mismatches identified both M-t-C- and F-t-C-donations as important independent risk factors for TCMR (hazard ratio: 8.13; P < .001 and hazard ratio: 8.09; P = .001, respectively). There was no significant difference between the groups concerning the incidence of antibody-mediated rejection and de novo donor-specific antibody. CONCLUSION: Our results indicate that parent-to-child kidney donation is an independent risk factor for TCMR.

Incidence of Infectious Disease and Malignancies After Rituximab Therapy in Kidney Transplant Recipients: Results From a Cohort in Germany.

BACKGROUND: Rituximab is frequently used in solid organ transplantation off-label, especially in patients with renal allografts. Few data are available on the safety aspects of solid organ transplant recipients receiving rituximab. There is a knowledge gap on long-term follow-up data, in particular on infectious complications. PATIENTS AND METHODS: A retrospective observational registry study (German Registry on Autoimmune Diseases) comprising a total of 681 patients was conducted. The data of 63 adult kidney transplant recipients who received rituximab between 2006 and 2013 were used in this analysis. RESULTS: Median follow-up was 42 (1-109) months. At least 1 severe infection occurred in 57% of patients. The median time between the first rituximab infusion and the first infection was 4 (1-48) months. Of the overall 88 infections, 74 were severe bacterial infections, 5 were severe viral infections, 3 were severe fungal infections, 2 were combined severe bacterial and fungal infections, and 4 were combined severe viral, fungal and bacterial infections. Seven patients died during the observational period, 2 of them due to infectious complications. In the observational period, 1 case of squamous cell carcinoma but no other malignancies were observed. CONCLUSION: Consistent with previous data, a high incidence of infections was observed after rituximab treatment in kidney transplant recipients. Most infections occurred within 6 months after rituximab initiation. With more than 3 years of follow-up, we were able to document a low incidence of secondary malignancies after rituximab with only 1 case in our cohort.

Prolonged Low-Dose Prophylaxis With Valganciclovir in Cytomegalovirus-Negative Recipients of Kidney Transplants From Cytomegalovirus-Positive Donors Allows Seroconversion and Prevents Cytomegalovirus Disease.

BACKGROUND: Cytomegalovirus-negative recipients of kidneys from cytomegalovirus (CMV)-positive donors (D+/R-) are at high risk to develop severe clinical manifestations of CMV disease. Long-term data about incidence and timing of CMV seroconversion, CMV disease, and the influence of prolonged valganciclovir prophylaxis on the clinical course of CMV infection are missing. METHODS: We conducted a retrospective long-term study of 89 consecutive CMV D+/R- kidney transplant recipients transplanted between 2003 and 2012. All recipients received valganciclovir prophylaxis after transplantation (median 187 [126-261] days) with a median dose of 213 (181-338) mg/d. Long-term outcome was assessed over a maximum of 10 years post-transplant. RESULTS: During follow-up (median 62 months) 60 of 89 (67%) patients had CMV seroconversion, and 29 of 89 (33%) developed symptomatic CMV disease. In addition, in 38 of the 60 (63%), seroconversion occurred during prophylaxis (median 154 days post-transplant), and in 22 patients, after the end of prophylaxis (median 320 days after transplantation). Baseline characteristics of the 2 groups did not differ significantly. Seroconversion during prophylaxis vs seroconversion after the end of prophylaxis was associated with significantly lower incidence of CMV disease (34% vs 73%, P = .007), less severe CMV disease (16% vs 64%, P < .001), and fewer organ manifestations (26% vs 64%, P = .006). The risk of CMV disease was limited to the first 475 days after transplantation. Valganciclovir resistance occurred in just 1 case (1%). CONCLUSIONS: Prolonged prophylaxis with low-dose valganciclovir allowed CMV seroconversion during prophylaxis in a high proportion of D+/R- patients. Seroconversion occurred after a median of 154 days and was associated with significantly lower incidence of CMV disease, less severe CMV disease, and fewer CMV complications.

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.

Successful Recovery of Acute Renal Transplant Failure in Recurrent Hepatitis C Virus-Associated Membranoproliferative Glomerulonephritis.

Recurrence of hepatitis C virus (HCV)-associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct-acting antiviral agents (DAAs) allow a highly effective and interferon-free treatment option for chronic HCV-infected patients. Data on the therapeutic safety and efficacy in HCV-infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63-year-old female HCV-positive renal transplant patient with biopsy-proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti-HCV-directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy-associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis-dependent renal transplant failure after treatment of recurrent HCV-associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs.

[Immunosuppression and its use in kidney transplantation]. / Immunsuppression und Ergebnisse in der Nierentransplantation.

BACKGROUND: Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES: The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS: Review of the current topic-related literature and discussion of our own experience. RESULTS: The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS: Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.

New perspectives of immunosuppression.

Efficient rejection prophylaxis and excellent short-term results in organ transplantation can not obscure the fact that long-term outcomes have not improved substantially over the last decade with rather constant graft attrition rates beyond the first year. There remains an unmet medical need for new immunosuppressive regimens to improve long-term graft and patient survival while carrying a low side effect burden. Several trials in renal transplant recipients are in the planning stages. In general there are two major strategies to improve outcomes: (a) the constant evolution of new immunosuppressive regimens with the currently approved immunosuppressants, and/or (b) the use of novel immunosuppressants. In this review, we give an overview of the most recent developments of novel immunosuppressive regimes. We show promising new immunosuppressive drugs and new immunosuppressive strategies serving as potential alternative's for calcineurin inhibitor-based regimens. Such regimens should provide similar efficacy and eventually better tolerability or a different side-effect profile with clinical benefits.

Pre-operative assessment of living renal transplant donors with state-of-the-art imaging modalities: computed tomography angiography versus magnetic resonance angiography in 118 patients.

PURPOSE: To compare current technology multislice computed tomography angiography (CTA) with magnetic resonance angiography (MRA) in the pre-operative evaluation of vascular anatomy of living renal transplant donors. METHODS AND MATERIALS: Two hundred and thirty-six kidneys were included in the CTA and MRA analysis. Renal vasculature was evaluated independently by two readers in each modality with a delay of 4 weeks between reading sessions. Surgical correlation on the operated side was available in all patients. The reference standard was defined by surgical correlation and consensus reading of both modalities. RESULTS: Detection rate of CTA for arteries was 99.1 and 95.0 % for reader 1 and reader 2, respectively. Detection rate of MRA for arteries was 95.0/94.3 %. Most of the undetected arteries were ≤ 1 mm diameter (reader 1: 2 of 3 in CTA and 9 of 16 in MRA; reader 2: 11 of 16 in CTA, and 8 of 18 in MRA). Detection rates for arteries ≥ 2 mm for reader 1/reader 2 were 99.7/98.7 % in CTA and 99.1/97.8 % in MRA, respectively. Detection rates for veins were 99.6/97.4 % in CTA and 97.8/96.9 % in MRA, respectively. Both readers misdiagnosed between 0 and 1 non-present arteries and between 2 and 3 non-present veins in both modalities. CONCLUSIONS: Modern multislice CT and MRI scanners allow highly accurate evaluation of the vascular anatomy, especially for vessels of ≥ 2 mm diameter. CTA may provide slightly better depiction of very small arteries; however, this may be reader-dependent. Additional factors affecting the choice of imaging modality should include local availability, cost, and the desire to avoid ionizing radiation in healthy transplant donors.

Criteria for determining steam sterilization cycles for lubricated and nonlubricated mechanical equipment.

Requirements and procedures for determining steam sterilization cycles for lubricated and nonlubricated, complex, mechanical equipment are established. Factors affecting exposure times are discussed, as are procedures and data needed to determine the penetrability of steam into mechanical equipment, and the effect of lubricating oil in impeding steam penetration to the spore. The total effects of these factors in sterilizing times are presented. Sterilizers with a prevacuum cycle, which can remove air from the equipment efficiently and replace it with saturated steam, are recommended for complex mechanical equipment.

Hospital microbicidal processes.

Due to the multiplicity of hospital operations, numerous specialized procedures are required to control the dissemination of infectious agents. More stringent microbicidal control procedures are required in standard hospital operations to reduce this growing problem. The major processes of microbial control, i.e., sterilization and disinfection, should be more broadly applied to all hospital operations rather than simply to "dirty cases". Sterilization and disinfection processes are discussed and summarized showing their specific applications to infection control, their limitations, and recommended control measures that should be undertaken to give greater assurance of efficacy.