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.

Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

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.

Vascular endothelial growth factor D is a biomarker of fluid overload in haemodialysis patients.

BACKGROUND: Improved understanding and assessment of the complex physiology of volume regulation in haemodialysis (HD) patients are required to improve patient care and reduce mortality associated with fluid overload (FO). METHODS: We searched for FO-related biomarkers among 184 peptides associated with cardiovascular disease in a cohort of 30 HD patients. First, we assessed the direct impact of HD on the peptides of interest by comparing plasma concentrations before and after treatment. Then, we compared cardiovascular peptide profiles between patients with and without FO as defined by bioimpedance analysis (BIA). The plasma concentration of selected candidate biomarkers for FO was determined by enzyme-linked immunosorbent assay (ELISA) and correlated with previously described FO-related clinical and laboratory parameters. For validation, results were confirmed in an independent cohort of 144 HD patients. RESULTS: We found seven peptides positively [NT-proBNP, B-type natriuretic peptide (BNP), vascular endothelial growth factor D (VEGFD), tumour necrosis factor-related apoptosis-inducing ligand receptor 2, growth differentiation factor 15, tumour necrosis factor ligand superfamily member 13B, chitinase-3-like protein 1] and five negatively (leptin, renin, epidermal growth factor receptor, interleukin-1 receptor antagonist, myeloblastin) correlated to FO. In addition to natriuretic peptides, VEGFD emerged as third peptide highly correlated with BIA (ρ = 0.619, P < 0.0001). In line with this, VEGFD concentration verified by ELISA correlated with BIA, BNP and soluble CD146 but not with vascular endothelial growth factor C (VEGFC). Notably, levels of VEGFD were unrelated to cardiac systolic function (P = 0.63), contrary to BNP (P = 0.0003). Finally, we observed that 1-year all-cause mortality was higher in patients with high BNP (P = 0.0002), FO (defined by BIA, P = 0.04) and high VEGFD (P = 0.02), but not with high VEGFC (P = 0.48). CONCLUSION: VEGFD is a novel FO-related biomarker with unique diagnostic and prognostic properties.

Use of letermovir-valganciclovir combination as a step-down treatment after foscarnet for ganciclovir-resistant CMV infection in kidney transplant recipients.

BACKGROUND: Letermovir (LTV) might be an alternative treatment to nephrotoxic foscarnet (FOS) in Ganciclovir (GCV) resistant cytomegalovirus (CMV) infection. However, its efficacy in controlling active CMV viremia is unclear, as it is only approved for CMV prophylaxis in hematopoietic stem-cell transplantation. METHODS: This case series describes 14 kidney transplant recipients (KTR) with moderate-level GCV resistant CMV infection, treated by different step-down strategies after initial FOS therapy: (1) Observation without antiviral follow-up or switch to valganciclovir (VGCV) (pre-LTV era), and (2) Switch to LTV±VGCV (LTV era). RESULTS: One patient died under FOS. Thirteen patients were followed under step-down regimens. All but two patients had ongoing CMV viremia when stopping FOS. In pre-LTV era, 5/9 (56%) experienced a CMV breakthrough > 10 000 IU/ml calling for another course of FOS, as compared to 1/4 (25%) in the LTV era. Addition of VGCV to LTV at low-level viral breakthrough, addressing a possible developing resistance against LTV, prevented viral surge in two patients. In the pre-LTV era, CMV-related death or graft loss occurred in three of nine (33%), compared to no death or graft loss in the LTV era. CONCLUSION: A step-down strategy combining LTV+VGCV, might allow to safely stop FOS at ongoing low-level viremia.

Age-associated decrease in de novo donor-specific antibodies in renal transplant recipients reflects changing humoral immunity.

BACKGROUND: Older age at organ transplantation is associated with increased risk of infection and malignancy but reduced risk of cellular rejection. De novo donor-specific anti-HLA antibodies (dnDSA), are key biomarkers associated with reduced long-term allograft survival, yet there is a lack of data focusing on age-associated changes. METHODS: Development of dnDSA was restrospectively analyzed in all subjects who received a kidney transplant at the University Hospital Zurich between 01/2006 and 02/2015. Follow up continued until 03/2016. The incidence of dnDSA in different age categories was compared with special focus on the extremes of age: children < 10 years (n = 19) and adults ≥60 years of age (n = 110). RESULTS: Incidence of dnDSA gradually decreased with age, with older recipients having a significantly lower risk (HR 0.21, p = 0.0224) compared to pediatric recipients. Cumulative incidence of dnDSA at 2, 5 and 10 years was 6.2, 9.1 and 36% in the older recipients versus 5.3, 29.5 and 47.1% in pediatric recipients. Median time to development of dnDSA was similar (older 720 days, min 356, max 3646 days; children 1086 days, min 42, max 2474 days). Annual incidence was highest within the first two years after transplantation in the older recipients and peaked in years two to four in pediatric recipients. DnDSA were predominantly class II. More dnDSA were observed with cyclosporine as compared to tacrolimus. CONCLUSION: Older kidney transplant recipients have a lower risk of developing dnDSA than pediatric recipients, pointing towards reduced humoral immune reactivity with increasing age. This observation raises the question of adjustment in immunosuppression.

Soluble CD146 and B-type natriuretic peptide dissect overhydration into functional components of prognostic relevance in haemodialysis patients.

Background: Accurate volume status evaluation and differentiation of cardiac and non-cardiac components of overhydration (OH) are fundaments of optimal haemodialysis (HD) management. Methods: This study, by combining bioimpedance measurements, cardiovascular biomarkers and echocardiography, aimed at dissecting OH into its major functional components, and prospectively tested the association between cardiac and non-cardiac components of OH with mortality. In the first part, we validated soluble CD146 (sCD146) as a non-cardiac biomarker of systemic congestion in a cohort of 30 HD patients. In the second part, we performed a prospective 1-year follow-up study in an independent cohort of 144 HD patients. Results: sCD146 incrementally increased after the short and long intervals after HD (+53 ng/mL, P = 0.006 and +91 ng/mL, P < 0.001), correlated with OH as determined by bioimpedance and well-diagnosed OH (area under the receiver operating characteristics curve 0.72, P = 0.005). The prevalence of OH was lower for low-sCD146 and low-BNP patients (B-type natriuretic peptide, 29%) compared with subjects with either one or both biomarkers elevated (65-74%, P < 0.001). Notably, most low-BNP but high-sCD146 subjects were overhydrated. Systolic dysfunction was 2- to 3-fold more prevalent among high-BNP compared with low-BNP patients (44-68% versus 21-23%, chi-square P < 0.001), regardless of sCD146. One-year all-cause mortality was markedly higher in patients with high-BNP (P = 0.001) but not with high-sCD146. In multivariate analysis, systolic dysfunction and BNP, but not OH, were associated with lower survival. Conclusions: The combination of BNP and sCD146 dissects OH into functional components of prognostic value. OH in HD patients is associated with higher mortality only if resulting from cardiac dysfunction.

High accuracy of proximity extension assay technology for the quantification of plasma brain natriuretic peptide.

BACKGROUND: Novel multiplex assays allow the simultaneous identification of a large number of plasma proteins. While these new technologies have been shown to be highly sensitive and accurate for the identification of plasma proteins, the use of this technology to quantify those proteins has not been properly investigated. In this pilot study, we tested the accuracy of the proximity extension assay (PEA) for the quantification of the cardiac biomarker brain natriuretic peptide (BNP) compared to a standard clinically approved method. METHODS: Concentrations of BNP were assessed in 120 plasma samples from 30 patients with PEA and compared to chemiluminescent microparticle immunoassay (CMIA). Venous blood samples were collected from in tubes containing ethylenediaminetetraacetic acid, centrifuged within 6 hours at 3,500 rpm for 15 minutes at 4°C, frozen and stored at -80°C until analyzed. Correlation between the CMIA and PEA techniques was tested using the Spearman's rank correlation coefficient (rho) and the agreement was described with a Bland-Altman plot. RESULTS: Brain natriuretic peptide values obtained by CMIA and PEA were highly correlated (Spearman's rho = 0.865, P < .0001). In two patients, PEA consistently overestimated resp. underestimated BNP values compared to CMIA. After removal of those two patients, a very high correlation between the two techniques was shown (rho = 0.966, P < .0001). A high agreement between the two techniques over the whole range of tested concentrations was shown. CONCLUSION: This pilot study showed for the first time an excellent correlation between a clinically approved method and the PEA-based approach for quantification of circulating plasma BNP.

Comparison of microneedles and adhesive-tape stripping in skin preparation for epicutaneous allergen delivery.

BACKGROUND: Epicutaneous immunotherapy targets the network of dendritic cells in the epidermis. Allergen exposure of the dermal layers should be limited as these contain mast cells and blood vessels, which increases the risk for local and systemic allergic reactions. METHODS: This intraindividually controlled trial included 20 subjects with birch pollen allergy. Three areas of the volar forearms were treated by repeated adhesive-tape stripping, single-prick lancet piercing and microneedle array application. Four 10-fold dilutions of allergen extract were applied to each area and the IgE-mediated immediate-phase reactions and cell-mediated eczema were assessed. RESULTS: Allergen application after tape stripping led to an immediate-phase reaction in 2 subjects (10%) at the highest allergen concentration of 10 HEP/ml. Both prick needle and microneedle pretreatment resulted in immediate-phase reactions in all subjects (100%). The reactivity pattern, however, differed significantly: 95% of the reactions after pricking occurred at concentrations of ≤0.1 HEP/ml, whereas 50% of the reactions after microneedle preparation were noted at ≥1 HEP/ml. In 3 subjects (15%), eczema was observed on the microneedle-treated skin area. No serious adverse events occurred. CONCLUSIONS: Microneedles enhance stratum corneum penetration when compared to tape stripping. However, they do not resolve the problem of mast cell-mediated local reactions, possibly due to diffusion into the dermis. The occurrence of eczema after the microneedle treatment suggests induction of dendritic cell-mediated T cell responses. Therefore, skin preparation with microneedles may be a promising method for epicutaneous allergen immunotherapy.

Functionalized magnetic nanoparticles remove donor-specific antibodies (DSA) from patient blood in a first ex vivo proof of principle study.

The presence of donor-specific antibodies (DSA) such as antibodies directed against donor class I human leucocyte antigen (e.g., HLA-A) is a major barrier to kidney transplant success. As a proof of concept, functionalized magnetic nanoparticles have been designed to eliminate DSA from saline, blood and plasma of healthy donors and sensitized patients. Specific HLA-A1 protein was covalently bound to functionalized cobalt nanoparticles (fNP), human serum albumin (HSA) as control. fNP were added to anti-HLA class I-spiked saline, spiked volunteers' whole blood, and to whole blood and plasma of sensitized patients ex vivo. Anti-HLA-A1 antibody levels were determined with Luminex technology. Antibodies' median fluorescent intensity (MFI) was defined as the primary outcome. Furthermore, the impact of fNP treatment on blood coagulation and cellular uptake was determined. Treatment with fNP reduced MFI by 97 ± 2% and by 94 ± 4% (p < 0.001 and p = 0.001) in spiked saline and whole blood, respectively. In six known sensitized anti-HLA-A1 positive patients, a reduction of 65 ± 26% (p = 0.002) in plasma and 65 ± 33% (p = 0.012) in whole blood was achieved. No impact on coagulation was observed. A minimal number of nanoparticles was detected in peripheral mononuclear blood cells. The study demonstrates-in a first step-the feasibility of anti-HLA antibody removal using fNP. These pilot data might pave the way for a new personalized DSA removal technology in the future.

Risk assessment of Hymenoptera re-sting frequency: implications for decision-making in venom immunotherapy.

BACKGROUND: Venom immunotherapy is highly efficacious in preventing anaphylactic sting reactions. However, there is an ongoing discussion regarding patient selection and whether and how to apply a cost-benefit analysis of venom immunotherapy. In order to help decision-making, we investigated the re-sting frequency of hymenoptera-venom-allergic patients to single out those at high risk. METHODS: In this retrospective study, re-sting data of 96 bee-venom-allergic patients and 95 vespid-venom-allergic patients living mainly in a rural area of Switzerland were analyzed. Hymenoptera venom allergy status was rated according to the classification system of H.L. Mueller [J Asthma Res 1966;3:331-333]. Different risk-groups were defined according to sting exposure and their median sting-free interval was calculated. RESULTS: The risk factors for a wasp or bee re-sting were outdoor occupation, beekeeping and habitation close to a bee-house. Half of all vespid-venom-allergic outdoor workers were re-stung within 3.75 years compared to 7.5 years for indoor workers. Similarly, 50% of the bee-venom-allergic beekeepers or subjects with a bee-house in the vicinity suffered a bee re-sting within 5.25 years compared to 10.75 years for individuals who were not beekeepers. CONCLUSIONS: The high degree of exposure of vespid-venom-allergic outdoor workers and bee-venom-allergic beekeepers and subjects living close to bee-houses underlines the high benefit of venom immunotherapy for these patients even if they suffered a non-life-threatening grade II reaction. Yet, bee-venom-allergic individuals with no proximity to bee-houses and with an indoor occupation face a very low exposure risk, which justifies epinephrine rescue treatment for these patients especially if they have suffered from grade II sting reactions.

Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: A double-blind, placebo-controlled dose escalation study.

BACKGROUND: Epicutaneous allergen administration using a patch may be an alternative to subcutaneous or sublingual immunotherapy. OBJECTIVE: To optimize treatment dose and to demonstrate the efficacy and safety of epicutaneous immunotherapy. METHODS: This monocentric, placebo-controlled, double-blind trial included 132 patients with grass pollen-induced rhinoconjunctivitis. In February 2008, patients were randomly allocated to receive placebo or 3 different doses of allergen. Before and during the pollen season 2008, patients received 6 weekly patches. Efficacy was assessed 4 to 5 months later (n = 110) and during the pollen season of the treatment-free follow-up year in 2009 (n = 93). The primary outcome was patient-reported changes in hay fever symptoms assessed by a visual analog scale. Secondary outcome measures were weekly visual analog scale symptom scores during pollen season, use of rescue medication, changes in conjunctival and skin reactivity, as well as safety. RESULTS: Hay fever symptoms during the pollen season were reduced by more than 30% in 2008 and by 24% in 2009 in the high-dose group as compared with that in the placebo group, and the alleviation of symptoms in the follow-up year was dependent on the treatment dose. Higher allergen doses were associated with drug-related adverse events (AEs), predominantly manifested by pruritus, erythema, wheal, or eczema. Eleven systemic AEs of grades 1 to 2 required treatment and led to study exclusion. The dropout rate due to AEs was 8.3%. No drug-related serious AE was recorded. CONCLUSION: Epicutaneous immunotherapy is safe and efficacious in a dose-dependent manner after 6 patches only.

Growth Differentiation Factor 15 and Risk of Death in Haemodialysis Patients.

Aim: Noninvasive identification of haemodialysis patients at high risk of cardiovascular events and death might improve their outcome. Growth differentiation factor 15 is a prognostic biomarker in multiple disease entities, including cardiovascular disease. The aim of this study was to assess the association between plasma GDF-15 and mortality in a cohort of haemodialysis patients. Methods: Circulating GDF-15 was measured in 30 patients after a regular haemodialysis session, followed by a clinical follow-up for all-cause death. Measurements were performed using the Proseek Multiplex Cardiovascular disease panels (Olink Proteomics AB) and validated using the Elecsys GDF-15 electrochemiluminescence immunoassay on a Cobas E801 analyzer (Roche Diagnostics). Results: During a median of 38 months, 9 patients (30%) died. Seven deaths occurred in the group of patients with a circulating GDF-15 above the median and two in the group with lower GDF-15. Mortality was significantly higher in patients with circulating GDF-15 levels above the median, log-rankP = 0.044. The performance of circulating GDF-15 to predict long-term mortality has an area under the ROC curve of 0.76, P = 0.028. Prevalence of most relevant comorbidities and the Charlson comorbidity index were similar across the two groups. A high agreement with a correlation among both diagnostic methods was observed (Spearman's rho = 0.83, P < 0.001). Conclusion: Plasma GDF-15 displays promising prognostic properties for the prediction of long-term survival beyond clinical parameters in patients on maintenance haemodialysis.

Collaboration between local nephrologists and the transplant centre ensures good outcomes in post-transplant care.

Background: Despite substantial improvements in short-term kidney allograft survival, median long-term survival remains at a standstill. It is unclear whether and to what extent a transplant centre's post-transplant care influences long-term outcomes. Methods: We retrospectively analysed 501 single kidney transplant recipients (KTRs) who underwent transplantation between 2009 and 2018 and did not develop rejection or de novo donor-specific antibodies (dnDSA) within the first post-transplant year. After that, KTRs were either followed exclusively every 3 months by the transplant centre (n = 197) or every 3 months by local nephrologists (n = 304) with only yearly follow-up by the transplant centre. We analysed kidney allograft outcomes regarding estimated glomerular filtration rate (eGFR) decline, proteinuria, development of dnDSA and rejection. Results: No differences between the two groups were observed in the baseline characteristics and the characteristics at the end of the first post-transplant year (P > .05). KTRs followed by local nephrologists were comparable to KTRs followed by the transplant centre concerning patient survival (P = .541), kidney allograft survival (P = .385), eGFR decline (P = .488), progression of proteinuria (P > .05), the development of dnDSA (P = .335) and T-cell-mediated rejection (P = .480). KTRs followed by the transplant centre were more likely to undergo indication biopsies in case of allograft dysfunction and dnDSA (P < .001). Antibody-mediated rejection was diagnosed earlier and more frequently (P = .059), recurrent glomerulonephritis was diagnosed earlier and more frequently (P = .026) and immunosuppression was modified earlier and more frequently in response to histological findings (P = .038). Conclusions: Our findings suggest that close collaboration between local nephrologists and the transplant centre ensures good allograft outcomes independent of the caregiver. Greater biopsy activity in the transplant centre allows for earlier diagnosis of allograft dysfunction as the basis for novel treatment options.

The Molecular Diagnosis Might Be Clinically Useful in Discrepant Kidney Allograft Biopsy Findings: An Analysis of Clinical Outcomes.

BACKGROUND: The Molecular Microscope Diagnostic System (MMDx) may overcome histology shortcomings. Previous studies have simply examined discrepant findings but have not attempted to determine clinical endpoints. To measure performance, clinical outcomes are strongly required. METHODS: This single-center cohort study described discrepancies between MMDx and histology from 51 kidney transplant recipients (KTRs) and analyzed 72 indication biopsies, including 21 follow-up biopsies. Clinical performance was assessed by a combined endpoint of graft failure, rejection on follow-up biopsy, de novo donor-specific antibody, and improvement of kidney allograft function upon antirejection treatment. RESULTS: MMDx agreed in 33 (65%) and differed in 18 (35%) of 51 KTRs. Most discrepancies occurred in biopsies called no rejection by MMDx and rejection by histology (15/24, 63%). In contrast, in biopsies called rejection by MMDx, 3 were classified as no rejection by histology (3/27, 11%). Discrepant findings between MMDx and histology occurred following delayed graft function and MMDx from biopsies with a low percentage of cortex. Among 15 biopsies classified as no rejection by MMDx but rejection by histology, the clinical course suggested no rejection in 9 cases. Six KTRs reached the endpoint, showing predominant t ≥ 2 lesions. CONCLUSIONS: The most often occurring discrepancy is rejection by histology but no rejection by MMDx. As more KTRs do not meet the combined endpoint for rejection, MMDx might be clinically useful in these discrepant cases. Although strong histological findings have priority in indicating the treatment, clinical implementation of MMDx could strengthen treatment strategies.

Criterion Validity and Test-Retest Reliability of a Modified Version of the International Physical Activity Questionnaire-Short Form (IPAQ-SF) in Kidney Transplant Recipients.

Introduction: Accelerometry, the clinically valued standard of physical activity monitoring, has limited acceptance in transplantation rehabilitation; therefore, the International Physical Activity Questionnaire (IPAQ) self-report instrument is widely used. However, while the IPAQ's repeatability is good, its criterion validity is unsatisfactory. We hypothesized that adding a concise oral introduction would help overcome this shortfall. Materials and Methods: This is a secondary analysis of a RCT in a sample of kidney transplant recipients that underwent observational follow-up. We assessed criterion validity of our modified version of the four-item IPAQ-Short Form (mIPAQ-SF) via Pearson, and test-retest reliability via intraclass correlation coefficients. The main difference in the new version is an oral pre-measurement introduction to the questionnaire's concepts. We compared our results with those of published studies. Results: Post-kidney-transplantation data of 92 patients were analyzed. Across the four IPAQ-SF/mIPAQ-SF items, values of correlations between mIPAQ-SF responses and accelerometry records ranged from 0.07 (min in vigorous activity) to 0.35 (min in moderate activity) for criterion validity, and from 0.19 (days with moderate activity) to 0.58 (min in moderate activity) for test-retest reliability. Discussion: Regarding moderate-to-vigorous physical activity, mIPAQ-SF self-reports' correlations to accelerometry records improved considerably on those of the IPAQ-SF (r = 0.18 vs. r = 0.33), i.e., improved criterion validity. We therefore conclude that a pre-measurement oral explanation of key IPAQ-SF/mIPAQ concepts enhances criterion validity regarding self-reported moderate-to-vigorous physical activity.

Association of serum bicarbonate with graft survival and mortality in kidney transplant recipients.

BACKGROUND: Metabolic acidosis is an independent risk factor for kidney disease progression with a high prevalence after kidney transplantation (KTx). Remarkably, it is still unclear if there is an impact of metabolic acidosis on graft function and death after KTx. Thus, we wanted to investigate if serum bicarbonate is associated with long-term graft outcome and mortality after KTx. METHODS: We performed a single-center retrospective study including adult de novo KTx patients between 1999 and 2015. Cox proportional hazard model was used to analyze a possible association between time-dependent serum bicarbonate measurements and graft failure or death. RESULTS: Four hundred thirty KTRs were included in the analysis with a mean age of 50.9 ± 13.4 years. Mean observation time was 4.7 ± 2.8 years. Two hundred eighty-four (66%) patients were male and 318 (74%) had received a deceased donor kidney transplant. Mean bicarbonate and eGFR levels 1 year post-transplant amounted to 22.9 ± 3.1 mEq/L and 61 ± 26 ml/min/1.73 m2, respectively. Prevalence of metabolic acidosis was 31% 1 year after transplantation. Fourteen (3%) patients died and 31 (7%) suffered from graft failure. Higher bicarbonate levels were associated with significantly lower hazards for graft failure (Hazard Ratio (HR) = 0.88; 95% Confidence Interval (CI): 0.79-0.98) and mortality (HR = 0.79; 95% CI 0.66-0.93) after adjusting for potential confounders such as age, donor type and time-varying eGFR. CONCLUSIONS: Our analysis showed that higher serum bicarbonate levels are positively associated with long-term graft and patient survival in kidney transplant recipients. Thus, serum bicarbonate may serve as a predictor and independent risk factor for graft and patient outcome after KTx as has been previously shown for patients with CKD.

PIRCHE-II scores prove useful as a predictive biomarker among kidney transplant recipients with rejection: An analysis of indication and follow-up biopsies.

Background: Indication biopsies for deterioration of kidney allograft function often require follow-up biopsies to assess treatment response or lack of improvement. Immune-mediated injury, namely borderline rejection (BLR), T-cell mediated rejection (TCMR), or antibody-mediated rejection (ABMR), results from preformed or de novo alloreactivity due to donor and recipient HLA-mismatches. The impact of HLA-mismatches on alloreactivity is determined by highly immunogenic HLA-epitopes. Methods: We analyzed 123 kidney transplant recipients (KTRs) from 2009 to 2019 who underwent a first indication and a follow-up biopsy. KTRs were divided into three groups according to the first biopsy: No rejection (NR)/BLR (n=68); TCMR (n=21); ABMR (n=34). The HLA-derived epitope-mismatches were calculated using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm. Results: Group NR/BLR: KTRs with higher total PIRCHE-II scores were more likely to develop TCMR in the follow-up biopsy (p=0.031). Interestingly, these differences were significant for both HLA-class I- (p=0.017) and HLA-class II-derived (p=0.017) PIRCHE-II scores. Group TCMR: KTRs with ongoing TCMR in the follow-up biopsy were more likely to show higher total PIRCHE-II scores (median 101.50 vs. 74.00). Group ABMR: KTRs with higher total PIRCHE-II scores were more likely to show an increase in the microvascular inflammation score in the follow-up biopsy. This difference was more pronounced for the HLA-class II-derived PIRCHE-II scores (median 70.00 vs. 31.76; p=0.086). Conclusions: PIRCHE-II scores may prove useful as a biomarker to predict the histopathological changes of immune-related injury from a first indication to a follow-up biopsy. This immunological risk stratification may contribute to individualized treatment strategies.