Molecular diagnosis of antibody-mediated rejection: Evaluating biopsy-based transcript diagnostics in the presence of donor-specific antibodies but without microvascular inflammation, a single-center descriptive analysis.

Biopsy-based transcript diagnostics may identify molecular antibody-mediated rejection (AMR) when microvascular inflammation (MVI) is absent. In this single-center cohort, biopsy-based transcript diagnostics were validated in 326 kidney allograft biopsies. A total of 71 histological AMR and 35 T cell-mediated rejection (TCMR) cases were identified as molecular AMR and TCMR in 55% and 63%, respectively. Among 121 cases without MVI (glomerulitis + peritubular capillaritis = 0), 45 (37%) donor-specific antibody (DSA)-positive and 76 (63%) DSA-negative cases were analyzed. Twenty-one out of the 121 (17%) cases showed borderline changes, or TCMR, while BK nephropathy was excluded. None of the 45 DSA-positive patients showed molecular AMR. Among 76 DSA-negative patients, 2 had mixed molecular AMR/TCMR. All-AMR phenotype scores (sum of R4-R6) exhibited median values of 0.13 and 0.12 for DSA-positive and DSA-negative patients, respectively (P = .84). A total of 13% (6/45) DSA-positive and 11% (8/76) DSA-negative patients showed an all-AMR phenotype score > 0.30 (P = .77). Patients with a higher all-AMR phenotype score showed 33% more histologic TCMR (P = .005). The median all-AMR phenotype scores of glomerular basement membrane double contours = 0 and glomerular basement membrane double contours > 0 biopsies were 0.12 and 0.10, respectively (P = .35). Biopsy-based transcript diagnostics did not identify molecular AMR in cases without MVI. Follow-up biopsies and outcome data should evaluate the clinical relevance of subthreshold molecular alterations.

Limitations of biopsy-based transcript diagnostics to detect T cell-mediated allograft rejection.

BACKGROUND AND HYPOTHESIS: Isolated Tubulitis, Borderline Changes, and Isolated Arteritis suspicious for histologic T cell-mediated rejection (hTCMR) remain findings of uncertain significance. Although the Molecular Microscope Diagnostics System (MMDx) has not been trained on those lesions, it was suggested that MMDx might reclassify a subgroup to molecular TCMR (mTCMR). METHODS: In this single-center cohort of 326 consecutive, unselected kidney allograft biopsies assessed by histology and MMDx, we analyzed 249 cases with Isolated Tubulitis (i0, t1-3, v0; n=101), Borderline Changes (according to Banff 2022, v0; n=9), Isolated Arteritis (no borderline, v1; n=37), No Inflammation (i0, t0, v0; n=67) and a Positive Control Cohort (hTCMR, n=27; Mixed histologic Rejection, n=8; both according to Banff 2022; total n=35). The first three groups were summarized as TCMR-Suspicion (n=147). Subcategorization included the presence and absence of microvascular inflammation (MVI; g+ptc≥2). Molecular rejection rates and differentiation were investigated. RESULTS: Molecular rejection rates were 37/147 cases (25.2%; 32 with MVI) in TCMR-Suspicion, 6/67 (9%; 4 with MVI) in No Inflammation and 30/35 (85.7%; 19 with MVI) in the Positive Control Cohort. Molecular antibody-mediated rejection (mAMR) was present in 39/73 (53.4%) of cases. The presence of donor-specific antibodies (DSA) at the time of the biopsy was high (127/249, 51%). Only 3 mAMR/TCMR and no pure mTCMR cases were detected in TCMR-Suspicion and No Inflammation, compared to 12 mAMR/TCMR and 10 mTCMR cases in the Positive Control Cohort (p<0.001). Even though the TCMR-specific molecular (Classifier) score differentiated between TCMR-Suspicion and No Inflammation (p=0.005), rejection phenotype scores (R2 and R3) did not (p=0.157 and 0.121). CONCLUSIONS: MMDx did not identify pure mTCMR among Isolated Tubulitis, Borderline Changes, or Isolated Arteritis, likely due to low sensitivity for TCMR-lesions. However, it identified mAMR or mAMR/TCMR, especially in cases with MVI. Subthreshold findings remain to be further studied.

Therapeutic Drug Monitoring of Mycophenolic Acid Identifies Kidney Transplant Recipients Responsive to Two SARS-CoV-2 mRNA Vaccine Doses.

Immune-responsiveness to SARS-CoV-2 mRNA vaccination is reduced in kidney transplant recipients (KTRs). Previous reports point to a role of mycophenolic acid (MPA). Our observational cohort study included all KTRs at University Hospital Zurich receiving two SARS-CoV-2 mRNA vaccine doses more than 6 months post-transplantation, who were assessed by measuring anti-spike immunoglobulin G (IgG). We applied principles of therapeutic drug monitoring (TDM) to correlate MPA exposure and lymphocyte counts with SARS-CoV-2 IgG. MPA trough levels differ largely among KTRs with a median of 3.1 mg/L (range 0.7-9.5 mg/L). 34 of 84 KTRs (40%) developed positive SARS-CoV-2 IgG after two vaccine doses. KTRs who developed positive SARS-CoV-2 IgG showed significantly higher eGFR (p < 0.001), lower MPA trough levels (p < 0.001) and higher CD19+ lymphocytes (p < 0.001). MPA trough levels <2.5 mg/l and CD19+ lymphocytes >40/µl identify KTRs with seroconversion. Upon logistic regression, MPA trough levels <2.5 mg/L were associated with a 7-fold (CI 95%: 1.589-29.934) and ciclosporin use with a 6-fold (CI 95%: 1.148-30.853) increase in the odds of seroconversion. Our study indicates that immune-responsiveness to SARS-CoV-2 mRNA vaccines correlates with MPA exposure measured by MPA trough level but argues against a class effect of MPA. TDM-guided MPA dosing may be a strategy to increase seroconversion rate.

Association between PIRCHE-II scores and de novo allosensitization after reduction of immunosuppression during SARS-CoV-2 infection in kidney transplant recipients.

BACKGROUND: Before the availability of mRNA vaccines, many transplant centers chose to significantly reduce maintenance immunosuppression in kidney transplant recipients (KTRs) with SARS-CoV-2 infection. The extent to which this increases the risk of allosensitization is unclear. METHODS: In this observational cohort study, we analyzed 47 KTRs from March 2020 to February 2021 who underwent substantial reduction of maintenance immunosuppression during SARS-CoV-2 infection. KTRs were followed at 6 and 18 months concerning the development of de novo donor-specific anti-HLA (human leukocyte antigen) antibodies (DSA). The HLA-derived epitope mismatches were calculated using the predicted indirectly recognizable HLA-epitopes (PIRCHE-II) algorithm. RESULTS: In total, 14 of 47 KTRs (30%) developed de novo HLA antibodies after the reduction of maintenance immunosuppression. KTRs with higher total PIRCHE-II scores and higher PIRCHE-II scores for the HLA-DR locus were more likely to develop de novo HLA antibodies (p = .023, p = .009). Furthermore, 4 of the 47 KTRs (9%) developed de novo DSA after reduction of maintenance immunosuppression, which were exclusively directed against HLA-class II antigens and also showed higher PIRCHE-II scores for HLA-class II. The cumulative mean fluorescence intensity of 40 KTRs with preexisting anti-HLA antibodies and 13 KTRs with preexisting DSA at the time of SARS-CoV-2 infection remained stable after the reduction of maintenance immunosuppression (p = .141; p = .529). CONCLUSIONS: Our data show that the HLA-derived epitope mismatch load between donor and recipient influences the risk of de novo DSA development when immunosuppression is temporarily reduced. Our data further suggest that reduction in immunosuppression should be made more cautiously in KTRs with high PIRCHE-II scores for HLA-class II antigens.

Impact of different urinary tract infection phenotypes within the first year post-transplant on renal allograft outcomes.

In this study, we investigated the clinical impact of different urinary tract infection (UTI) phenotypes occurring within the first year after renal transplantation. The population included 2368 transplantations having 2363 UTI events. Patients were categorized into four groups based on their compiled UTI events observed within the first year after transplantation: (i) no colonization or UTI (n = 1404; 59%), (ii) colonization only (n = 353; 15%), (iii) occasional UTI with 1-2 episodes (n = 456; 19%), and (iv) recurrent UTI with ≥3 episodes (n = 155; 7%). One-year mortality and graft loss rate were not different among the four groups, but patients with recurrent UTI had a 7-10 ml/min lower eGFR at year one (44 ml/min vs. 54, 53, and 51 ml/min; p < .001). UTI phenotypes had no impact on long-term patient survival (p = .33). However, patients with recurrent UTI demonstrated a 10% lower long-term death-censored allograft survival (p < .001). Furthermore, recurrent UTI was a strong and independent risk factor for reduced death-censored allograft survival in a multivariable analysis (HR 4.41, 95% CI 2.53-7.68, p < .001). We conclude that colonization and occasional UTI have no impact on pertinent outcomes, but recurrent UTI are associated with lower one-year eGFR and lower long-term death-censored allograft survival. Better strategies to prevent and treat recurrent UTI are needed.

Long-term outcomes of transplant kidneys donated after circulatory death.

BACKGROUND: Donation after circulatory death (DCD) represents up to 40% of used kidney grafts. While studies have shown similar outcomes compared with donation after brain death (DBD) in the short term and mid-term, no data on long-term outcomes exist. METHODS: We retrospectively analysed patients transplanted at our institution between January 1985 and March 2000. All DCD recipients were matched one-to-one with patients transplanted with DBD grafts during this period according to sex, age and year of transplantation and followed up until December 2020. During this period, 1133 kidney transplantations were performed, of which 122 were with a DCD graft. RESULTS: The median graft survival after 35 years of follow-up was 23 years [277 months {95% confidence interval (CI) 182-372}] in DBD recipients and 24.5 years [289 months (95% CI 245-333)] in DCD recipients (P = 0.65; hazard ratio 0.91). Delayed graft function occurred in 47 patients in the DCD group compared with 23 in the DBD group (P < 0.001), albeit without a significant long-term outcome difference in graft or patient survival. We could not show any difference in graft function in terms of creatinine levels (133 versus 119 µmol/L), proteinuria (370 versus 240 mg/24 h) and glomerular filtration rate slope (-0.6 versus -0.3 mL/min/year) between the two groups for graft survival >20 years. CONCLUSIONS: This is the first study to show similar graft survival and function in DCD kidneys compared with DBD kidneys after 35 years of follow-up. DCD grafts are a valuable resource and can be utilized in the same way as DBD grafts.

Entering the Third Decade After Kidney Transplantation: Excellent Graft Function Refers to Superior Graft but Not Patient Survival.

Kidney transplant recipients (KTRs) with ultralong-term survival represent a growing, yet insufficiently studied patient cohort. In this single-center retrospective study, we analyzed 248 ultralong-term survivors (≥20 years). KTRs were classified into those with superior graft function (defined as eGFR ≥45 ml/min + proteinuria ≤300 mg/day + eGFR-slope ≤ 2 ml/min/1.73 m2/year) and inferior graft function regarding the risk of CKD progression. 20 years post-transplant, median eGFR was 54 ml/min (11-114), proteinuria 200 mg/24 h (0-7,620), eGFR decline 0.45 ml/min/1.73 m2/year (11.7 6.5) and DSA had been detected in 19.7% of KTRs. We identified 96 KTRs (38.7%) with superior (group 1) and 152 KTRs (61.3%) with inferior graft function (group 2). Donation after cardiac death, female sex, glomerulonephritis as primary disease, and early TCMR were independently associated with inferior graft function. Graft survival was significantly better in group 1 compared to group 2 (LogRank, p < 0.001). Besides group affiliation (HR 20.515, p = 0.003), multivariable analysis identified DSA development (HR 3.081, p = 0.023) and donor age (HR 1.032, p = 0.024) as independent factors. Interestingly, there was no significant difference in patient survival (LogRank, p = 0.350). In ultralong-term survivors, excellent graft function refers to superior graft survival but does not extend ultimate patient survival. DSA-formation should be taken seriously even in the ultralong-term.

Intravenous immunoglobulins do not prove beneficial to reduce alloimmunity among kidney transplant recipients with BKV-associated nephropathy.

Reduced immunosuppression during BKV-DNAemia has been associated with T-cell mediated rejection (TCMR), de novo donor-specific antibodies (DSA) and antibody-mediated rejection (ABMR). Intravenous immunoglobulins (IVIG) may reduce alloimmunity. We studied 860 kidney transplant recipients (KTRs) for the development of BKV-DNAuria and BKV-DNAemia (low-level <10 000 IE/ml, high-level >10 000 IE/ml). 52/131 KTRs with high-level BKV-DNAemia received IVIG. The HLA-related immunological risk was stratified by the Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) algorithm. BKV-DNAuria only was observed in 86 KTRs (10.0%), low-level BKV-DNAemia in 180 KTRs (20.9%) and high-level BKV-DNAemia in 131 KTRs (15.2%). KTRs with low-level BKV-DNAemia showed significantly less TCMR compared to KTRs with high-level BKV-DNAemia (5.2% vs. 25.5%; P < 0.001) and no BKV-replication (13.2%; P = 0.014), lowest rates of de novo DSA (21.3%), ABMR (9.2%) and flattest glomerular filtration rate (GFR) slope (-0.8 ml/min). KTRs with low-level BKV-DNAemia showed significantly higher median (interquartile range) total PIRCHE if they developed TCMR [100.22 (72.6) vs. 69.52 (49.97); P = 0.020] or ABMR [128.86 (52.99) vs. 69.52 (49.96); P = 0.005]. Administration of IVIG did not shorten duration of BKV-DNAemia (P = 0.798) or reduce TCMR, de novo DSA and ABMR (P > 0.05). KTRs with low-level BKV-DNAemia showed best protection against alloimmunity, with a high number of PIRCHE co-determining the remaining risk. The administration of IVIG, however, was not beneficial in reducing alloimmunity.

Pre-transplant donor-specific HLA antibodies and risk for poor first-year renal transplant outcomes: results from the Swiss Transplant Cohort Study.

The aim of this study was to analyze first year renal outcomes in a nationwide prospective multicenter cohort comprising 2215 renal transplants, with a special emphasis on the presence of pre-transplant donor-specific HLA antibodies (DSA). All transplants had a complete virtual crossmatch and DSA were detected in 19% (411/2215). The investigated composite endpoint was a poor first-year outcome defined as (i) allograft failure or (ii) death or (iii) poor allograft function (eGFR ≤25 ml/min/1.73 m2 ) at one year. Two hundred and twenty-one (221/2215; 10%) transplants showed a poor first-year outcome. Rejection (24/70; 34%) was the most common reason for graft failure. First-year patient's death was rare (48/2215; 2%). There were no statistically significant differences between DSA-positive and DSA-negative transplants regarding composite and each individual endpoint, as well as reasons for graft failure and death. DSA-positive transplants experienced more frequently rejection episodes, mainly antibody-mediated rejection (both P < 0.0001). The combination of DSA and any first year rejection was associated with the overall poorest death-censored allograft survival (P < 0.0001). In conclusion, presence of pre-transplant DSA per se does not affect first year outcomes. However, DSA-positive transplants experiencing first year rejection are a high-risk population for poor allograft survival and may benefit from intense clinical surveillance.

[Tranexamic acid for bleeding prophylaxis in orthopedic surgery and trauma-standard or customized therapy?] / Tranexamsäure zur Blutungsprophylaxe bei Trauma und orthopädischen Eingriffen ­ Standard oder individualisierte Anwendung?

The use of tranexamic acid (TXA) is established in the treatment of bleeding, especially of bleeding due to hyperfibrinolysis. In recent years the prophylactic use of TXA in trauma and orthopedic surgery has increased leading to open questions regarding potentially associated risks and a possible classification as off label use. The available literature provides a sound basis for the recommendation that TXA can be used in these indications provided that an individual risk assessment is done in patients with increased risks for thromboembolic complications. Although the prophylactic use of TXA in orthopedic surgery and trauma is not explicitly listed in the product characteristics, it should not be regarded as an off label use.

Preformed donor-reactive T cells that persist after ABO desensitization predict severe T cell-mediated rejection after living donor kidney transplantation - a retrospective study.

Preformed donor-reactive T cells are relatively resistant to standard immunosuppression and account for an increased incidence of T cell-mediated rejection (TCMR) and inferior kidney allograft outcomes. We analyzed 150 living donor kidney transplant recipients (KTRs) of a first kidney allograft. Ninety-eight ABO-compatible (ABOc) and 52 ABO-incompatible (ABOi) KTRs were included. Samples were collected at 6 time points, before rituximab, before immunoadsorption and pretransplantation, at +1, +2, and +3 months posttransplantation, and donor-reactive T cells were measured by interferon-γ ELISPOT assay. Twenty of 98 ABOc (20%) and 12 of 52 ABOi KTRs (23%) showed positive pretransplant ELISPOT. Eight of 20 ABOc-KTRs (40%) with positive pretransplant ELISPOT showed TCMR, whereas 17 of 78 ABOc-KTRs (22%) with negative pretransplant ELISPOT did (P = 0.148). Seven of 12 ABOi KTRs (57%) with positive pretransplant ELISPOT showed TCMR, whereas only 3 of 40 ABOi KTRs (8%) with negative pretransplant ELISPOT did (P < 0.001). Interestingly, 6 of 7 ABOi KTRs with positive pretransplant ELISPOT that persists after ABO desensitization developed TCMR. Among 118 KTRs with negative pretransplant ELISPOT, 10 of 72 ABOc-KTRs (14%), but 0 of 46 ABOi KTRs, developed positive posttransplant ELISPOT (P = 0.006). Preformed donor-reactive T cells that persist despite ABO desensitization identify KTRs at highest risk of TCMR. Less de-novo donor-reactive T cells after ABO desensitization may account for less TCMR. Both, the use of rituximab and early initiation of calcineurin inhibitor-based maintenance immunosuppression may contribute to these findings.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Ex vivo expanded natural regulatory T cells from patients with end-stage renal disease or kidney transplantation are useful for autologous cell therapy.

Novel concepts employing autologous, ex vivo expanded natural regulatory T cells (nTreg) for adoptive transfer has potential to prevent organ rejection after kidney transplantation. However, the impact of dialysis and maintenance immunosuppression on the nTreg phenotype and peripheral survival is not well understood, but essential when assessing patient eligibility. The current study investigates regulatory T-cells in dialysis and kidney transplanted patients and the feasibility of generating a clinically useful nTreg product from these patients. Heparinized blood from 200 individuals including healthy controls, dialysis patients with end stage renal disease and patients 1, 5, 10, 15, 20 years after kidney transplantation were analyzed. Differentiation and maturation of nTregs were studied by flow cytometry in order to compare dialysis patients and kidney transplanted patients under maintenance immunosuppression to healthy controls. CD127 expressing CD4+CD25highFoxP3+ nTregs were detectable at increased frequencies in dialysis patients with no negative impact on the nTreg end product quality and therapeutic usefulness of the ex vivo expanded nTregs. Further, despite that immunosuppression mildly altered nTreg maturation, neither dialysis nor pharmacological immunosuppression or previous acute rejection episodes impeded nTreg survival in vivo. Accordingly, the generation of autologous, highly pure nTreg products is feasible and qualifies patients awaiting or having received allogenic kidney transplantation for adoptive nTreg therapy. Thus, our novel treatment approach may enable us to reduce the incidence of organ rejection and reduce the need of long-term immunosuppression.

Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study.

Background: Kidney transplant recipients (KTRs) are at increased risk of avascular necrosis (AVN) due to bone disorder, steroid use and common comorbidities. However, knowledge on risk factors and outcomes of AVN among KTRs in the modern era of immunosuppression remains scarce. Methods: We analysed 765 KTRs between 2001 and 2013 for AVN. Cases of symptomatic AVN were diagnosed by hip X-ray, radioisotope bone scan or magnetic resonance imaging. We evaluated risk factors and clinical characteristics of AVN. Results: KTRs showed a constant incidence rate of AVN of 4.1% at 10 years after transplantation. The use of cyclosporine compared with tacrolimus was identified as an independent risk factor, with a rate of 8.0% compared with 2.7% at 10 years (P < 0.01). In addition, male gender was independently associated with AVN (P = 0.047). Eighty-three per cent of AVN cases were of the femoral head and treated operatively. None of the operated KTRs experienced complications in the long term. Thirty-three per cent of KTRs had bilateral AVN. Ninety-two per cent of KTRs showed AVN at the allograft side. Conclusions: The decreasing incidence of AVN may be attributed to the replacement of cyclosporine by tacrolimus over the last decade. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney impacting AVN at the allograft side.

Transplantectomy is associated with presensitization with donor-reactive T cells and graft failure after kidney retransplantation: a cohort study.

Background: The number of kidney transplant recipients (KTRs) being waitlisted for a subsequent transplantation has disproportionately increased to almost 25%. Evidence for the optimal management of the failed allograft, however, remains inconsistent. Methods: We studied 111 KTRs who underwent their second kidney transplantation from 1998 to 2015. In 51/111 KTRs (46%) the failed allograft was removed and in 60/111 (54%) the failed allograft was retained. KTRs with primary non-function and allograft loss <12 months of the first failed allograft were excluded from analysis. Samples were collected before transplantation and at 1 month posttransplantation and donor-reactive T cells were measured using an interferon-γ enzyme-linked immunosorbent spot assay. Results: KTRs with the previous allograft removed showed significantly higher rates of acute cellular rejection compared with KTRs with the previous allograft retained [27/51 KTRs (53%) versus 18/60 KTRs (30%); P = 0.019]. KTRs with the previous allograft removed showed significantly inferior death-censored allograft survival compared with KTRs with the previous allograft retained (P = 0.022). Here, KTRs with the previous allograft removed showed significantly higher donor-reactive T cells pretransplantation compared with KTRs with the previous allograft retained (P = 0.012). Interestingly, no differences were observed for the presence of panel reactive antibodies and for the development of de novo donor-specific antibodies. Conclusions: Our data suggest higher cellular presensitization among KTRs with the previous allograft removed, which is associated with higher rates of acute cellular rejection and inferior allograft survival. Immunological mechanisms that may account for these differences may include prolonged maintenance immunosuppression to save urine output in KTRs with the first kidney allograft retained and cellular presensitization after withdrawal of maintenance immunosuppression, which lead to allograft rejection and ultimately to allograft nephrectomy.

Factors and outcomes in association with sepsis differ between simultaneous pancreas/kidney and single kidney transplant recipients.

BACKGROUND: As immunosuppressive therapy has improved in simultaneous pancreas/kidney transplant recipients (SPKTRs), infection has become the major limitation of disease-free survival. METHODS: We studied all SPKTRs and deceased-donor kidney transplant recipients (KTRs) between 2003 and 2015. Thirty-six of 134 SPKTRs (26.9%) were diagnosed with sepsis among which 13/36 SPKTRs (36.1%) developed severe sepsis/septic shock. A control group of 98 SPKTRs without sepsis and 61/538 KTRs (11.3%) with sepsis were used for comparison. RESULTS: Among SPKTRs, female sex, low BMI, CMV seronegativity, CMV disease, and acute cellular rejection increased the risk for sepsis (P < .05). Patient and allograft survival was comparable among SPKTRs with and without sepsis (P > .05), but showed inferior kidney allograft function (P < .05). While urosepsis was less common among SPKTRs (45%), pneumonia (33%) and peritonitis (15%) as site of infections were more frequent (P < .05). Here, gram-positive and fungal sepsis were more common among SPKTRs compared to KTRs (P < .05). SPKTRs showed a higher incidence and an earlier onset of sepsis compared to KTRs (P < .001). SPKTRs with severe sepsis/septic shock were more likely to show pneumonia as site of infection with gram-positive/polymicrobial bacteremia (P < .05). Mortality from severe sepsis was 29% among SPKTRs compared to 58% among KTRs (P < .05). CONCLUSION: Differences in incidence, site, causative pathogens, and onset of sepsis between SPKTRs and KTRs may be attributed to more intense immunosuppression, major surgery, and complications of diabetes among SPKTRs. Lower sepsis-related mortality may reflect younger age and more timely diagnosis, but also supports recent findings of less sepsis-related mortality among recipients of solid organ transplantation.

Diabetic kidney transplant recipients: Impaired infection control and increased alloreactivity.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) has been associated with inferior patient and allograft outcomes. However, previous studies did not identify differences in infection control and alloreactivity. METHODS: We studied 449 kidney transplant recipients (KTRs) between 2005 and 2013. Fifty (11.1%) KTRs were diagnosed with PTDM and 60 (13.4%) KTRs with pre-existing diabetes. Samples were collected pretransplantation, at +1, +2, +3 months post-transplantation. CMV specific and alloreactive T cells were quantified by interferon-γ Elispot assay. Lymphocyte subpopulations were quantified by flow cytometry. RESULTS: Upon multivariate analysis, age, obesity, and the use of tacrolimus increased the risk of PTDM (P<.05). KTRs with pre-existing diabetes/PTDM showed higher rates of sepsis (P<.01). Total CD3+ and CD4+ T cell counts were significantly lower in KTRs with PTDM/pre-existing diabetes post-transplantation (P<.05). No differences were observed for CMV-specific T cells between any group (P>.05). KTRs developing PTDM showed increased frequencies of alloreactive T-cells post-transplantation (P<.05). CONCLUSIONS: Our results suggest higher rates of infection in KTRs with pre-existing diabetes/PTDM that may be attributed to impaired overall immunity. Higher frequencies of alloreactive T cells contribute to inferior long-term outcomes. As acute rejection, but not pre-existing diabetes/PTDM, was associated with inferior allograft survival and function, maintaining adequate immunosuppression to prevent rejection seems important.

Sepsis after renal transplantation: Clinical, immunological, and microbiological risk factors.

BACKGROUND: As immunosuppressive therapy and allograft survival have improved, the increased incidence of sepsis has become a major hurdle of disease-free survival after renal transplantation. METHODS: We identified 112 of 957 kidney transplant recipients (KTRs) with sepsis. In all, 31 KTRs developed severe sepsis or septic shock, and 30 KTRs died from sepsis. KTRs without sepsis were used for comparison. CMV-specific and alloreactive T cells were measured using an interferon-γ Elispot assay. The extent of immunosuppression was quantified by lymphocyte subpopulations. RESULTS: Five-year patient survival was 70.3% with sepsis compared to 88.2% without (P<.001). Five-year estimated glomerular filtration rate was lower in KTRs developing sepsis (P<.001). Upon multivariate analysis, diabetes, lymphocyte-depleting induction, donor age, CMV replication, and acute rejection increased the risk of sepsis (P<.05). Age, diabetes, underweight/obesity, and pneumonia as site of infection were predictive factors of mortality (P<.05). Early-onset sepsis was associated with decreased CD3+ and CD4+ T cells pre-transplantation (P<.05). Impaired CMV-specific cellular immunity pre-transplantation was associated with CMV replication and early-onset sepsis (P<.05). High frequencies of alloreactive T cells were associated with acute rejection, lymphocyte-depleting rejection treatment, and early-onset sepsis (P<.05). CONCLUSION: KTRs developing sepsis show inferior patient survival and allograft function. Identified risk factors and differences in lymphocyte counts, CMV-specific immunity, and alloreactivity may prove useful to identify KTRs at increased risk.

Simultaneous pancreas/kidney transplant recipients are predisposed to tissue-invasive cytomegalovirus disease and concomitant infectious complications.

BACKGROUND: Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with cytomegalovirus (CMV) infection being the most important viral infection with adverse impact on patient and allograft outcomes. METHODS: We studied all primary SPKTRs and deceased-donor kidney transplant recipients (KTRs) between 2008 and 2015 for the development of CMV infection. A total of 21/62 SPKTRs (33.9%) and 90/335 KTRs (26.9%) were diagnosed with CMV infection. A control group of 41 SPKTRs without CMV infection was used for comparison. RESULTS: SPKTRs showed an increased incidence of CMV infection compared with KTRs. SPKTRs were more likely to develop CMV disease, CMV pneumonia, recurrent CMV infection, higher initial and peak CMV loads, and more need for intravenous antiviral therapy compared with KTRs (P<.05). High-risk CMV serostatus (D+R-) and 2 HLA-B/-DR mismatches increased the risk of CMV infection in SPKTRs (P<.05). No differences were observed for patient and allograft outcomes (P>.05). SPKTRs with CMV infection were more likely to show concomitant Epstein-Barr virus (EBV) viremia compared with SPKTRs without CMV infection (P<.05). SPKTRs with CMV infection showed higher incidences of concomitant BK polyomavirus-associated nephropathy, EBV viremia, and sepsis compared with KTRs with CMV infection (P<.05). CONCLUSION: Our results suggest a higher incidence and more severe course of CMV infection in SPKTRs compared with KTRs. The increased incidence of concomitant infectious complications among SPKTRs with CMV infection suggests an overall impaired immunity, and calls for more intense screening.

Estimated nephron number of the remaining donor kidney: impact on living kidney donor outcomes.

BACKGROUND: It has been demonstrated that low birth weight gives rise to a reduction in nephron number with increased risks for hypertension and renal disease. Its impact on renal function in kidney donors, however, has not been addressed. METHODS: To investigate the impact of birth weight, kidney weight, kidney volume and estimated nephron number on kidney function, we collected data from 91 living kidney donors before nephrectomy, at +12, +36 and +60 months after nephrectomy. RESULTS: Birth weight showed a positive correlation with estimated glomerular filtration rate (eGFR) at +12, +36 and +60 months after nephrectomy (P < 0.05). The strongest link was observed in donors >50 years old (R = 0.535, P < 0.001 at +12 months). Estimated nephron number and eGFR showed a strong positive correlation at +12, +36 and +60 months after nephrectomy (R = 0.540; R = 0.459; R = 0.506, P < 0.05). Daily proteinuria at +12 months showed a negative correlation with birth weight (P = 0.009). Donors with new-onset hypertension showed significantly lower birth weights and higher uric acid levels (P < 0.05). Kidney weight and volume did not show any impact on donor outcomes (P > 0.05). CONCLUSIONS: Low nephron number predisposes donors to inferior remaining eGFR, hypertension and proteinuria. The strong correlation in elderly donors may be attributed to reduced renal functional reserve due to the decline of renal function with age.