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.

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.

[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.

Posttranslational protein translocation across the membrane of the endoplasmic reticulum.

Posttranslational protein translocation across the membrane of the endoplasmic reticulum is mediated by the Sec complex. This complex includes a transmembrane channel formed by multiple copies of the Sec61 protein. Translocation of a polypeptide begins when the signal sequence binds at a specific site within the channel. Binding results in the insertion of the substrate into the channel, possibly as a loop with a small segment exposed to the lumen. While bound, the signal sequence is in contact with both protein components of the channel and the lipid of the membrane. Subsequent movement of the polypeptide through the channel occurs when BiP molecules interact transiently with a luminal domain of the Sec complex, hydrolyze ATP, and bind to the substrate. Bound BiP promotes translocation by preventing the substrate from diffusing backwards through the channel, and thus acts as a molecular ratchet.

Interaction of BiP with the J-domain of the Sec63p component of the endoplasmic reticulum protein translocation complex.

Proteins of the Hsp70 family of ATPases interact with a conserved domain of their J-protein partners, the J-domain, to function in numerous cellular processes. We have studied the interaction of BiP, an Hsp70 family member in the lumen of the endoplasmic reticulum, with the J-domain of Sec63p, a component of the Sec complex involved in post-translational protein translocation across the endoplasmic reticulum membrane. In a real-time solid phase binding assay, BiP binds to the immobilized Sec complex or to a fusion protein of the J-domain and glutathione S-transferase in a reaction that requires ATP hydrolysis. In the final complex, BiP is bound in the ADP form with its peptide binding pocket occupied. An intact peptide binding pocket is required for this interaction. Our experiments suggest that the activation of BiP by the J-domain involves a transient contact between these components, and that in the absence of physiological substrates, J-activated BiP binds even to the J-proteins themselves.

J proteins catalytically activate Hsp70 molecules to trap a wide range of peptide sequences.

Proteins of the Hsp70 family of ATPases, such as BiP, function together with J proteins to bind polypeptides in numerous cellular processes. Using a solid phase binding assay, we demonstrate that a conserved segment of the J proteins, the J domain, catalytically activates BiP molecules to bind peptides in its immediate vicinity. The J domain interacts with the ATP form of BiP and stimulates hydrolysis resulting in the rapid trapping of peptides, which are then only slowly released upon nucleotide exchange. Activation by the J domain allows BiP to trap peptides or proteins that it would not bind on its own. These results explain why BiP and probably all other Hsp70s can interact with a wide range of substrates and suggest that the J partner primarily determines the substrate specificity of Hsp70s.