Randomized Trial to Assess the Clinical Utility of Renal Allograft Monitoring by Urine CXCL10 Chemokine.

SIGNIFICANCE STATEMENT: This study is the first randomized controlled trial to investigate the clinical utility of a noninvasive monitoring biomarker in renal transplantation. Although urine CXCL10 monitoring could not demonstrate a beneficial effect on 1-year outcomes, the study is a rich source for future design of trials aiming to explore the clinical utility of noninvasive biomarkers. In addition, the study supports the use of urine CXCL10 to assess the inflammatory status of the renal allograft. BACKGROUND: Urine CXCL10 is a promising noninvasive biomarker for detection of renal allograft rejection. The aim of this study was to investigate the clinical utility of renal allograft monitoring by urine CXCL10 in a randomized trial. METHODS: We stratified 241 patients, 120 into an intervention and 121 into a control arm. In both arms, urine CXCL10 levels were monitored at three specific time points (1, 3, and 6 months post-transplant). In the intervention arm, elevated values triggered performance of an allograft biopsy with therapeutic adaptations according to the result. In the control arm, urine CXCL10 was measured, but the results concealed. The primary outcome was a combined end point at 1-year post-transplant (death-censored graft loss, clinical rejection between month 1 and 1-year, acute rejection in 1-year surveillance biopsy, chronic active T-cell-mediated rejection in 1-year surveillance biopsy, development of de novo donor-specific HLA antibodies, or eGFR <25 ml/min). RESULTS: The incidence of the primary outcome was not different between the intervention and the control arm (51% versus 49%; relative risk (RR), 1.04 [95% confidence interval, 0.81 to 1.34]; P = 0.80). When including 175 of 241 (73%) patients in a per-protocol analysis, the incidence of the primary outcome was also not different (55% versus 49%; RR, 1.11 [95% confidence interval, 0.84 to 1.47]; P = 0.54). The incidence of the individual end points was not different as well. CONCLUSIONS: This study could not demonstrate a beneficial effect of urine CXCL10 monitoring on 1-year outcomes (ClinicalTrials.gov_ NCT03140514 ).

Urine CXCL10 as a biomarker in kidney transplantation.

PURPOSE OF REVIEW: Urine CXCL10 is a promising biomarker for posttransplant renal allograft monitoring but is currently not widely used for clinical management. RECENT FINDINGS: Large retrospective studies and data from a prospective randomized trial as well as a prospective cohort study demonstrate that low urine CXCL10 levels are associated with a low risk of rejection and can exclude BK polyomavirus replication with high certainty. Urine CXCL10 can either be used as part of a multiparameter based risk assessment tool, or as an individual biomarker taking relevant confounders into account. A novel Luminex-based CXCL10 assay has been validated in a multicenter study, and proved to be robust, reproducible, and accurate. SUMMARY: Urine CXCL10 is a well characterized inflammation biomarker, which can be used to guide performance of surveillance biopsies. Wide implementation into clinical practice depends on the availability of inexpensive, thoroughly validated assays with approval from regulatory authorities.

Short- and long-term impact of neutropenia within the first year after kidney transplantation.

The aim of this retrospective single-center study was to investigate the short- and long-term impact of neutropenia occurring within the first year after kidney transplantation, with a special emphasis on different neutropenia grades. In this unselected cohort, 225/721 patients (31%) developed 357 neutropenic episodes within the first year post-transplant. Based on the nadir neutrophil count, patients were grouped as neutropenia grade 2 (<1.5-1.0*109 /l; n = 105), grade 3 (<1.0-0.5*109 /l; n = 65), and grade 4 (<0.5*109 /l; n = 55). Most neutropenia episodes were presumably drug-related (71%) and managed by reduction/discontinuation of potentially responsible drugs (mycophenolic acid [MPA] 51%, valganciclovir 25%, trimethoprim/sulfamethoxazole 19%). Steroids were added/increased as replacement for reduced/discontinued MPA. Granulocyte colony-stimulating factor was only used in 2/357 neutropenia episodes (0.6%). One-year incidence of (sub)clinical rejection, one-year mortality, and long-term patient and graft survival were not different among patients without neutropenia and neutropenia grade 2/3/4. However, the incidence of infections was about 3-times higher during neutropenia grade 3 and 4, but not increased during grade 2. In conclusion, neutropenia within the first year after kidney transplantation represents no increased risk for rejection and has no negative impact on long-term patient and graft survival. Adding/increasing steroids as replacement for reduced/discontinued MPA might supplement management of neutropenia.

Revisiting cytomegalovirus serostatus and replication as risk factors for inferior long-term outcomes in the current era of renal transplantation.

BACKGROUND: Cytomegalovirus (CMV) serostatus and CMV replication are considered as risk factors for inferior graft and patient survival after renal transplantation, but long-term outcome data are limited. The aim of this retrospective single-centre study was to investigate the impact of CMV serostatus and CMV replication/disease on long-term outcomes in a well-defined cohort managed by a standardized CMV prevention/treatment protocol. METHODS: We investigated 599 consecutive kidney transplantations having a CMV prevention protocol consisting of either prophylaxis (D+/R- and R+ with ATG induction) or screening/deferred therapy (R+ without ATG induction). Patients were grouped according to CMV serostatus [high risk (D+/R-): n = 122; intermediate risk (R+): n = 306; low risk (D-/R-): n = 171] and occurrence of CMV replication/disease (no CMV replication: n = 419; asymptomatic CMV replication: n = 110; CMV syndrome: n = 39; tissue-invasive CMV disease: n = 31). The median follow-up time was 6.5 years. RESULTS: Graft and patient survival were not different among the three CMV serostatus groups as well as the four CMV replication/disease groups (P ≥ 0.44). Eighty-seven patients died, 17 due to infections (21%), but none was attributable to CMV. The overall hospitalization incidence for CMV-related infection was 3% (17/599 patients). The incidence of clinical and (sub)clinical rejection was similar among the groups (P ≥ 0.17). In a multivariate Cox proportional hazard model, neither CMV serostatus, nor CMV replication, nor CMV disease were independent predictors for patient death or graft failure, respectively. CONCLUSIONS: This retrospective single-centre study suggests that the negative impact of CMV infection on long-term patient and allograft survival as well as on allograft rejection can be largely eliminated with current diagnostic/therapeutic management.

Reducing calcineurin inhibitor first for treating BK polyomavirus replication after kidney transplantation: long-term outcomes.

BACKGROUND: Reducing immunosuppression is the mainstay of treating BK polyomavirus (BKPyV) viraemia after kidney transplantation, but the best approach, efficacy and impact are undefined. We established a standard operating procedure (SOP) treating BKPyV viraemia based on first reducing calcineurin inhibitor ('CNI first'). The aim of this study was to investigate long-term outcomes in 644 consecutive transplantations using this SOP. METHODS: Patients were monitored for active BKPyV infection by urinary decoy cells and, if positive, by BKPyV viraemia. In case of sustained BKPyV viraemia >1000 copies/mL, immunosuppression was reduced stepwise according to the SOP. Patients were classified as 'no decoy cells' [n = 432 (66%)], 'decoy cells/no viraemia' [n = 107 (17%)] and 'viraemia' [n = 105 (17%)]. RESULTS: At 6-years post-transplant, graft survival was ∼84%, the clinical rejection rate was ∼25% and they were not different among the three groups (P = 0.14; P = 0.91). The median estimated glomerular filtration rate at the last follow-up was similar (range 49-53 mL/min, P = 0.08). Of 105 viraemic patients, 101 (96%) cleared BKPyV viraemia. In 39% of patients, viraemia clearance followed a tacrolimus reduction. A reduction of mycophenolic acid was required in 43% and discontinuation in 3%. No short-term graft loss was directly attributable to BKPyV-associated nephropathy. After a median follow-up of 5 years after clearance of BKPyV viraemia, 11/101 patients (11%) developed clinical rejection: 7 (7%) T-cell-mediated rejection and 4 (4%) antibody-mediated rejection (ABMR). CONCLUSIONS: Immunosuppression reduction based on 'CNI first' leads to similar long-term outcomes in patients with/without BKPyV viraemia and is associated with a low risk for ABMR after clearance of BKPyV viraemia. Randomized trials are needed to compare the risks and benefits of immunosuppression reduction strategies in kidney transplant patients with BKPyV viraemia.

[Kidney Biopsies - the Basics and Recent Developments]. / Nierenbiopsie-Diagnostik: Was muss ich wissen und was ist neu?

Kidney Biopsies - the Basics and Recent Developments Abstract. Renal biopsies are taken to clarify the differential diagnosis of glomerular hematuria, proteinuria, and renal insufficiency. Nephropathology services are usually available at larger pathology units only because of the special equipment needed for light microscopy, immunohistology, and electron microscopy, the low number of biopsies processed compared to other fields, and the special expertise needed to read and sign out the cases. Biopsy diagnosis crucially contributes to the diagnostic workup and therapy of patients with kidney diseases. Increasingly, new immunohistochemical markers allow an etiological classification. We discuss paraprotein-associated kidney diseases in more detail because they are relatively common. Many of these patients do not fulfil the diagnostic criteria of plasma cell myeloma. Several years ago, the term «monoclonal gammopathy of renal significance¼ (MGRS) and a more aggressive therapeutic approach was introduced for these patients, with an improvement in mortality and morbidity. We also review the new group of complement C3-glomerulopathies. Although relatively rare, they have a very interesting pathophysiology and novel anti-complement therapies may provide new therapeutic approaches.

Successful steroid withdrawal guided by surveillance biopsies-A single-center experience.

Steroid withdrawal following renal transplantation is challenging and widely debated. This retrospective study aimed at investigating the frequency and determinants of successful steroid withdrawal guided by surveillance biopsies. We analyzed 156 pretransplant DSA-negative renal transplants receiving basiliximab induction and maintenance immunosuppression with tacrolimus-mycophenolate-steroids. The absence of rejection in surveillance biopsies at 3 or 6 months post-transplant initiated steroid withdrawal, which was monitored by subsequent indication and/or surveillance biopsies. The primary outcome was the frequency of successful (i.e., rejection-free) steroid withdrawal at 1 year post-transplant. In the whole study population, successful steroid withdrawal was achieved in 73 of 156 patients (47%). Steroid withdrawal was initiated in 98 of 156 patients (63%) and successful in 73 of 98 patients (74%). Subsequent clinical rejection occurred in only one of 98 patients (1%), whereas 24 of 98 patients (24%) experienced subclinical rejection. Steroid withdrawal was not initiated in 58 of 156 patients (37%) mainly due to current or prior severe (Banff TCMR ≥IA) subclinical rejection. Prediction of successful steroid withdrawal by pretransplant or early post-transplant parameters was poor. In conclusion, (sub)clinical rejection-free steroid withdrawal can be expected in about half of pretransplant DSA-negative patients. As successful steroid withdrawal cannot be well predicted by pre- and early post-transplant parameters, guidance by surveillance biopsies is an attractive strategy.

New developments in transplant proteomics.

PURPOSE OF REVIEW: Despite modern immunosuppression, renal allograft rejection remains a major contributor to graft loss. Novel biomarkers may help improve posttransplant outcomes through the early detection and treatment of rejection. Our objective is to provide an overview of proteomics, review recent discovery-based rejection studies, and explore innovative approaches in biomarker development. RECENT FINDINGS: Urine MMP7 was identified as a biomarker of subclinical and clinical rejection using two-dimensional liquid chromatography tandem-mass spectrometry (LC-MS/MS) and improved the overall diagnostic discrimination of urine CXCL10 : Cr alone for renal allograft inflammation. A novel peptide signature to classify stable allografts from acute rejection, chronic allograft injury, and polyoma virus (BKV) nephropathy was identified using isobaric tag for relative and absolute quantitation (TRAQ) and label-free MS, with independent validation by selected reaction monitoring mass spectrometry (SRM-MS). Finally, an in-depth exploration of peripheral blood mononuclear cells identified differential proteoform expression in healthy transplants versus rejection. SUMMARY: There is still much in the human proteome that remains to be explored, and further integration of renal, urinary, and exosomal data may offer deeper insight into the pathophysiology of rejection. Functional proteomics may be more biologically relevant than protein/peptide quantity alone, such as assessment of proteoforms or activity-based protein profiling. Discovery-based studies have identified potential biomarker candidates, but external validation studies are required.

First Successful Treatment of a Patient with a Primary Immune Complex-Membranoproliferative Glomerulonephritis with Iptacopan: A Case Report.

Introduction: Nowadays, there is insufficient evidence for the recommendation of management patients with a primary membranoproliferative glomerulonephritis (MPGN). A better understanding of the pathogenesis has led to the reclassification of primary MPGN and distinction into the two main entities of either primary immune complex-MPGN or C3 glomerulopathy. Both entities share overlapping pathophysiological features with complement alternative pathway (AP) dysregulation. Iptacopan is an oral inhibitor of the complement factor B that effectively blocks the complement AP. Case Presentation: We report the first successful treatment of a 47-year-old man suffering from a primary immune complex-MPGN with iptacopan. So far established immunosuppressive therapies with prednisone and mycophenolate mofetil failed to control the current flare of the disease, mainly presenting with impaired kidney function and proteinuria within the nephrotic range. However, 3 months after starting the treatment with iptacopan urine protein-creatinine ratio decreased impressively to a level of 100-150 mg/mmol. Thereafter, low-level proteinuria and kidney function remained stable during follow-up. Do date, the treatment with iptacopan is continued as a monotherapy and is well tolerated. Conclusion: To the best of our knowledge, this is the first case report which suggests that iptacopan may be an interesting treatment option for primary immune complex-MPGN.

Soluble CD30 correlates with clinical but not subclinical renal allograft rejection.

Soluble CD30 (sCD30) has been proposed as a promising noninvasive biomarker for clinical renal allograft rejection, but its diagnostic characteristics regarding detection of subclinical rejection have not been assessed. We investigated sCD30 in 146 consecutive kidney allograft recipients under tacrolimus-mycophenolate-based immunosuppression having 250 surveillance biopsies at 3 and 6 months as well as 52 indication biopsies within the first year post-transplant. Allograft histology results were classified as (i) acute Banff score zero or interstitial infiltrates only, (ii) tubulitis t1, (iii) tubulitis t2-3 and (iv) isolated vascular compartment inflammation. sCD30 correlated well with the extent of clinical (P < 0.0001), but not subclinical tubulointerstitial rejection (P = 0.06). To determine diagnostic characteristics of sCD30, histological groups were assigned to two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (tubulitis t1-3 and isolated vascular compartment inflammation). For clinical allograft inflammation, AUC was 0.87 (sensitivity 89%, specificity 79%; P = 0.0006); however, for subclinical inflammation, AUC was only 0.59 (sensitivity 50%, specificity 69%; P = 0.47). In conclusion, sCD30 correlated with clinical, but not subclinical renal allograft rejection limiting its clinical utility as a noninvasive rejection screening biomarker in patients with stable allograft function receiving tacrolimus-mycophenolate-based immunosuppression.

[Not Available]. / Proteinurie - Bedeutung und diagnostisches Vorgehen.

Proteinuria is a common incidental finding in primary care. A systematic approach is necessary to differentiate benign causes of proteinuria from severe kidney diseases. Glomerular proteinuria is the predominant pathophysiologic mechanism of the three types of proteinuria (i. e. glomerular, tubular and "overflow") and usually corresponds to urinary protein excretion > 1 g per day. When urine dipstick analysis is positive a quantitative measurement of urinary protein excretion is necessary. Therefore, quantification by albumin/creatinine ratio measurement in a random urine specimen is an important and reliable next step. Patients with persistent proteinuria, in whom the underlying aetiology remains unclear, besides extensive analysis or with a proteinuria ≥ 1 g per day should be referred to a nephrologist for further diagnosis and timely therapeutic interventions.

Excellent Clinical Long-Term Outcomes of Kidney Transplantation From Small Pediatric Donors (Age ≤ 5 Years) Despite Early Hyperfiltration Injury.

Background: The use of small pediatric donors (age ≤ 5 years and body weight < 20kg) for adult transplant recipients is still regarded controversially in terms of early complications, long-term outcomes, and development of hyperfiltration injury due to body size mismatch. Objective: To investigate long-term outcomes of adult renal allograft recipients receiving a kidney from small pediatric donor (SPD) in terms of kidney function and early features of hyperfiltration injury such as histological changes and proteinuria. Design: Retrospective, single center study. Settings: Transplant center of the University Hospital of Basel, Switzerland. Patients: Adult renal allograft recipients receiving a kidney from a small pediatric donor at our center between 2005 and 2017. Methods: The outcome of 47 transplants from SPD were compared with 153 kidney transplants from deceased-standard criteria donors (SCD) occurring during the same time period. Incidence of clinical signs of hyperfiltration injury (eg, proteinuria) was investigated. According to our policy, surveillance biopsies were taken at 3 and 6 months post-transplant and were evaluated in terms of signs of hyperfiltration injury. Results: At a median follow-up of 2.3 years post-transplant, death-censored graft survival of SPD was comparable to transplants from SCD (94% vs 93%; P = .54). Furthermore, allograft function at last follow-up (estimated glomerular filtration rate-Modification of Diet in Renal Disease) was significantly higher in pediatric transplant (80 vs 55 ml/min/1.73 m2, P = .002). We found histological signs of early hyperfiltration injury in 55% of SPD. There was an equally low proteinuria in both groups during follow-up. Limitations: It is a single center and retrospective observational study with small sample size. The outcomes were investigated in a well-selected population of recipients with low body mass index, low immunological risk, and well-controlled hypertension and was not compared with equal selected group of recipients. Conclusions: Early histological and clinical signs of hyperfiltration injury in SPD is frequent. Despite the hyperfiltration injury, there is an equal allograft survival and even superior allograft function in SPD compared with SCD during follow-up. This observation supports the concept of high adaptive capacity of pediatric donor kidneys.

Contexte: Le recours à de très jeunes donneurs pédiatriques (âge: ≤ 5 ans; poids < 20 kg), pour des greffes chez des receveurs adultes, suscite encore des préoccupations quant aux complications précoces, aux résultats à long terme et au développement de lésions d'hyperfiltration liées à la disproportion de taille corporelle. Objectif: Examiner les résultats à long terme de patients adultes greffés rénaux ayant reçu l'organe d'un très jeune donneur pédiatrique (TJDP), soit la fonction rénale et les signes précoces de lésions d'hyperfiltration (p. ex. changements histologiques et protéinurie). Type d'étude: Étude rétrospective dans un seul établissement. Cadre: Le centre de transplantation de l'hôpital universitaire de Bâle (Suisse). Sujets: Les adultes ayant reçu une greffe rénale provenant d'un très jeune donneur pédiatrique dans notre centre entre 2005 et 2017. Méthodologie: Les résultats de 47 transplantations impliquant des TJDP ont été comparés à ceux de 153 transplantations rénales survenues au cours de la même période, mais impliquant des donneurs décédés répondant aux critères standard (DDCS). L'incidence des signes cliniques de lésions d'hyperfiltration (p. ex. protéinurie) a été étudiée. Selon notre politique, des biopsies de surveillance ont été réalisées à 3 et 6 mois post-transplantation et évaluées pour les signes d'hyperfiltration. Résultats: Lors d'un suivi médian de 2,3 ans post-transplantation, le pourcentage de survie du greffon (censurée pour les décès) provenant de TJDP était comparable à celui de DDCS (94 % c. 93 %; p = 0,54). De plus, la fonction du greffon lors du dernier suivi (DFGe basé sur l'équation MDRD) était significativement plus élevée dans les cas de transplantation pédiatrique (80 ml/min/1,73 m2 contre 55 ml/min/1,73 m2; p=0,002). Des signes histologiques de lésions précoces dues à une hyperfiltration ont été observés dans 55 % des cas impliquant un TJDP. La protéinurie était peu importante et équivalente dans les deux groupes au cours du suivi. Limites: Il s'agit d'une étude observationnelle et rétrospective menée dans un seul centre et sur un faible échantillon. Les résultats ont été obtenus dans une population bien précise de receveurs avec un IMC peu élevé, un risque immunologique faible et une hypertension bien contrôlée; ces résultats n'ont pas été comparés à un autre groupe de receveurs équivalents. Conclusion: Des signes histologiques et cliniques précoces de lésion d'hyperfiltration sont fréquents chez les TJDP. Malgré cela, pendant la période de suivi, la survie de greffon provenant d'un TJDP s'est avérée comparable à celles d'organes provenant de DDCS et la fonction supérieure. Cette observation appuie l'hypothèse d'une grande capacité d'adaptation des reins provenant de donneurs pédiatriques.

Urine CXCL10 to Assess BK Polyomavirus Replication After Kidney Transplantation.

BACKGROUND: Urine CXCL10 is a biomarker for renal allograft inflammation induced by rejection, urinary tract infection, or BK polyomavirus (BKPyV) replication. This study aimed to compare urine CXCL10 levels in different stages of BKPyV reactivation and to investigate urine CXCL10 as a biomarker for BKPyV replication. METHODS: We included 763 urine samples (235 patients) from an interventional, randomized trial obtained in the context of regular screening for urine CXCL10 levels. All urine samples had a complete urine sediment analysis, no rejection episode noted within 30 d before urine collection, and a urine decoy cell analysis was conducted within ±3 d. RESULTS: Urine CXCL10 levels were 2.31 ng/mmol in samples without BKPyV viruria, slightly rose to 4.35 ng/mmol with BKPyV viruria, and then markedly increased to 16.42 ng/mmol when decoy cells were detectable, but still in the absence of BKPyV DNAemia ( P < 0.001). The highest urine CXCL10 values were observed in samples with BKPyV DNAemia (median 42.59 ng/mmol). The area under the curve of urine CXCL10 levels to detect ≥3 decoy cells was 0.816. At a CXCL10 cutoff of 3 ng/mmol, the negative predictive value was 97%. The area under the curve of urine CXCL10 levels to detect BKPyV DNAemia was 0.882, with a negative predictive value of 99% at a CXCL10 cutoff of 3 ng/mmol. CONCLUSIONS: Urine CXCL10 levels are already significantly elevated in BKPyV viruria (especially with decoy cell shedding) and further increase with BKPyV DNAemia. Low urine CXCL10 values can rule out the presence of ≥3 decoy cells and BKPyV DNAemia with high certainty.

Outcome of kidney transplantation from senior deceased donors: a single centre study.

BACKGROUND: Addressing the current demographic development, the efficacy and safety of kidney transplantations from very senior donors needs to be carefully evaluated. The aim of this study was to analyse patient and graft outcomes of kidney allograft recipients stratified by donor age. METHODS: We retrospectively investigated n = 491 patients from a prospective, observational renal transplant cohort. Patients with kidneys from very old donors (n = 75, aged >70 years), elderly donors (n = 158, between 60-70 years), and regular donors (n = 258, aged <60 years) were investigated. The primary outcome was death-censored graft survival within the predefined donor age groups. RESULTS: Overall, n = 57 death-censored graft losses occurred. Graft loss was proportionally highest in the very old donor group (n = 11/75), but this did not reach statistical significance when compared to the elderly (14/158) and regular donor groups (32/258); (p = 0.37). Kaplan-Meier analysis demonstrated that 3-year/5-year death-censored graft survival in the very old donor group was 96%/86% and did not differ from the other age groups (p = 0.44). Median estimated glomerular filtration rate (eGFR), calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (in ml/min/1.73 m2 of body surface) 12 months post-transplant did not differ between the elderly donor and very old donor groups (p = 0.53). However, patients who received regular donor kidneys had higher median eGFR compared to recipients in both the elderly and very old donor groups (p <0.0001). During follow-up, 31% of patients developed at least one acute rejection episode. Time-to-event analysis demonstrated no difference in occurrence of any acute rejection event across all three groups (p = 0.11). CONCLUSIONS: This study demonstrates that kidney transplantation from carefully selected very old donors seems a valid option with reasonable short- and mid-term outcomes.

Delayed graft function is not associated with an increased incidence of renal allograft rejection.

Delayed graft function (DGF) is considered as a risk factor for renal allograft rejection, but this association might be confounded by diagnostic biases (e.g., higher biopsy frequency in patients with DGF, inclusion of clinically diagnosed rejection episodes, and limited details on the rejection phenotype). This retrospective study including 329 deceased donor transplantations aimed to clarify a causal relationship between DGF and rejection. DGF occurred in 93/329 recipients (28%), whereas immediate graft function (IGF) in 236/329 recipients (72%). The percentage of patients with ≥1 allograft biopsy within the first year post-transplant was similar between the DGF and IGF group (96% vs. 94%; p=0.60). The cumulative one-yr incidence of biopsy-proven clinical (35% vs. 34%; p=0.62) and combined (sub)clinical rejection (58% vs. 60%; p=0.79) was not different between the two groups. Furthermore, there were no differences regarding rejection phenotypes/severities and time frame of occurrence. By multivariable Cox regression analysis, donor-specific HLA antibodies, younger recipient age, and immunosuppressive regimens were independent predictors for clinical rejection, while DGF was not. These results in an intermediate sized, but thoroughly investigated patient population challenge the concept that DGF is a risk factor for rejection and highlights the need for additional studies in this regard.

Differences Between Centers in Psychosocial Evaluations for Living Kidney Donors Do Not Influence Outcome: Results From an Observational Multicenter Study.

Rather little is known about how psychosocial evaluations for living kidney donation (LKD) are performed. We aimed to explore whether Swiss transplant centers (STCs) vary regarding the rate of living kidney donors refused for psychosocial reasons, the psychosocial evaluation process, and the characteristics of the donors. Methods: We investigated 310 consecutive candidates for LKD in 4 of 6 existing STC during mandatory psychosocial evaluations. We registered (i) sociodemographic data, (ii) the type of the decision-making process regarding LKD (ie, snap decision, postponed, deliberate, other), (iii) the evaluator's perception of the donor's emotional bonding and his/her conflicts with the recipient, (iv) the donor's prognosis from a psychosocial perspective, (v) time taken for the psychosocial evaluation, and (vi) its result (eligible, eligible with additional requirements, not eligible). Results: Centers had comparable proportions of noneligible donors (2.9%-6.0%) but differed significantly in the percentage of donors accepted with additional requirements (3.4%-66%, P < 0.001). Significant differences emerged between centers regarding the time needed for evaluation (75-160 min [interquartile range (IQR) 75-180 min] per single exploration, P < 0.001), the perception of the donor's emotional bonding (visual analogue scale [VAS] 8-9 [IQR 6-10], P < 0.001), his/her conflicts with the recipient (VAS 1.5-2 [IQR 0-3], P = 0.006), the donor's psychosocial prognosis (VAS 8-9 [IQR 7-10], P < 0.001), and the type of decision concerning LKD (59%-82% with snap decision "yes," P = 0.008). However, despite differences in the psychosocial evaluation process, the rates of patients accepted for transplantation (eligible and eligible with additional requirements versus noneligible) were comparable across STC (P = 0.72). Conclusions: Our results emphasize that it is more important to establish clear guidelines to identify potential psychosocial risks than to stringently standardize the procedure for psychosocial evaluation of living kidney donors.

Risk stratification by the virtual crossmatch: a prospective study in 233 renal transplantations.

The virtual crossmatch (virtual-XM) has been proposed for accurate identification of donor-specific HLA-antibodies, but large prospective studies assessing its value for pretransplant risk stratification are lacking. A total of 233 consecutive renal allograft recipients were prospectively stratified according to the virtual-XM. In patients with a negative virtual-XM (n=190, 82%), prospective cytotoxicity crossmatches (CDC-XM) were omitted, and they received standard immunosuppression. Virtual-XM positive patients were only transplanted if CDC-XM were negative. They received additional induction with anti-T-lymphocyte-globulin and intravenous immunoglobulins (n=43, 18%). The cumulative incidence of clinical/subclinical antibody-mediated rejection (AMR) at 1 year was lower in the negative virtual-XM than in the positive virtual-XM group [15/190 (8%) vs. 18/43 (42%); P<0.0001]. After a median follow-up of 2.6 years, allograft loss because of AMR occurred less often in the negative virtual-XM group (1% vs. 7%; P=0.04) and death-censored allograft survival at 2 years was higher (98% vs. 91%; P=0.02). Serum creatinine was not different at the last follow-up (129 µm vs. 130 µm; P=0.58). We conclude that a negative virtual-XM defines patients at low risk for AMR and early allograft loss, while a positive virtual-XM represents a significant risk for AMR despite enhanced induction therapy. This supports the utility of the virtual-XM for risk stratification and treatment allocation.

Urinary CXCL10 Measurement in Late Renal Allograft Biopsies Predicts Outcome Even in Histologically Quiescent Patients.

BACKGROUND: CXCL10 is a promising early noninvasive diagnostic marker for allograft rejection and predictive for long-term outcomes. However, its value when measured later in the posttransplant course has not yet been accurately analyzed. METHODS: We investigated urinary CXCL10 in 141 patients from a prospective, observational renal transplant cohort with 182 clinically indicated allograft biopsies performed >12 months posttransplant and corresponding urines. Urinary CXCL10 was retrospectively quantified on stored urines using the MSD V-Plex Chemokine Panel 1 sandwich immunoassay (Meso Scale Discovery). The primary outcome was a composite of allograft loss/renal function decline (>30% estimated glomerular filtration rate [eGFR]-decrease between index biopsy and last follow-up). RESULTS: Seventy-two patients (51%) reached the primary outcome, and their urinary CXCL10 levels were significantly higher at the time of their biopsy compared with patients with stable allograft function (median 9.3 ng/mmol vs 3.3 ng/mmol, P < .0001). Time-to-endpoint analyses according to high/low urinary CXCL10 demonstrated that low urinary CXCL10 (≤7.0 ng/mmol) was associated with 73% 5-year event-free graft survival compared with 48% with high urinary CXCL10 (>7.0 ng/mmol; P = .0001). Even in histologically quiescent patients, high urinary CXCL10 was associated with inferior endpoint-free graft survival (P = .003), and it was an independent predictor of the primary outcome (P = .03). CONCLUSIONS: This study demonstrates that urinary CXCL10 has a promising diagnostic performance for detection of late allograft rejection and is an independent predictor of long-term renal allograft outcomes, even in histologically quiescent patients.