Live-donor kidney transplant outcome prediction (L-TOP) using artificial intelligence.

Outcome prediction for live-donor kidney transplantation improves clinical and patient decisions and donor selection. However, the concurrently used models are of limited discriminative or calibration power and there is a critical need to improve the selection process. We aimed to assess the value of various artificial intelligence (AI) algorithms to improve the risk stratification index. We evaluated pre-transplant variables among 66 914 live-donor kidney transplants (performed between 01/12/2007-01/06/2021) from the United Network of Organ Sharing database, randomized into training (80%) and test (20%) sets. The primary outcome measure was death-censored graft survival. We tested four machine learning models for discrimination (time-dependent concordance index, CTD, and area under the ROC curve) and calibration (integrated Brier score, IBS). We used decision curve analysis to assess the potential clinical utility. Among the models, the deep Cox mixture model showed the best discriminative performance (AUC = 0.70, 0.68, and 0.68 at 5, 10, and 13 years post-transplant, respectively). CTD reached 0.70, 0.67, and 0.66 at 5, 10, and 13 years post-transplant. The IBS score was 0.09, indicating good calibration. In comparison, applying the Living Kidney Donor Profile Index (LKDPI) on the same cohort produced a CTD of 0.56 and an AUC of 0.55-0.58 only. Decision curve analysis showed an additional net benefit compared to the LKDPI, 'Treat all' and 'Treat None' approaches. Our AI-based deep Cox mixture model, termed Live-Donor Kidney Transplant Outcome Prediction outperforms existing prediction models, including the LKDPI, with the potential to improve decisions for optimum live donor selection by ranking potential transplant pairs based on graft survival. This model could be adopted to improve the outcomes of paired exchange programs.

Dynamic Behaviour of Donor Specific Antibodies in the Early Period Following HLA Incompatible Kidney Transplantation.

In HLA-incompatible kidney transplantation, monitoring donor-specific antibodies (DSA) plays a crucial role in providing appropriate treatment and increases kidney survival times. This work aimed to determine if early post-transplant DSA dynamics inform graft outcome over and above other predictive factors. Eighty-eight cases were classified by unsupervised machine learning into five distinct DSA response groups: no response, fast modulation, slow modulation, rise to sustained and sustained. Fast modulation dynamics gave an 80% rate for early acute rejection, whereas the sustained group was associated with the lowest rejection rates (19%). In complete contrast, the five-year graft failure was lowest in the modulation groups (4-7%) and highest in the sustained groups (25-31%). Multivariable analysis showed that a higher pre-treatment DSA level, male gender and absence of early acute rejection were strongly associated with a sustained DSA response. The modulation group had excellent five-year outcomes despite higher rates of early rejection episodes. This work further develops an understanding of post-transplant DSA dynamics and their influence on graft survival following HLA-incompatible kidney transplantation.

CORRECTED ARTICLE: Effect of Dietary Potassium Restriction on Serum Potassium, Disease Progression, and Mortality in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. METHODS: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. RESULTS: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I2 = 0%). Higher (4,558 mg/d) versus lower (1,725 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14, 95% CI: [0.77, 1.70] I² = 57%). Higher (4,414 mg/d) compared with lower (1,670 mg/d) dietary potassium intake was not significantly associated with reduced mortality risk (HR: 0.80, 95% CI: [0.46, 1.41] I² = 78%). CONCLUSIONS: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia but whether this is associated with risk of death in those with CKD is uncertain. High-quality randomized controlled trials are needed.

C3d-positive donor-specific antibodies have a role in pretransplant risk stratification of cross-match-positive HLA-incompatible renal transplantation: United Kingdom multicentre study.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

Effect of Dietary Potassium Restriction on Serum Potassium, Disease Progression, and Mortality in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. METHODS: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. RESULTS: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I2 = 0%). Lower (1,725 mg/d) versus higher (4,558 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14; 95% CI: 0.77, 1.70; I2 = 57%). Lower (1,670 mg/d), compared with higher (4,414 mg/d) dietary potassium intake was associated with a 40% reduction in mortality hazard (HR: 0.60; 95% CI: 0.40, 0.89; I2 = 56%). CONCLUSIONS: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia and is associated with a reduced risk of death in those with CKD. High-quality randomized controlled trials are needed.

Spanish adaptation and validation of the Child Food Security Survey Module (CFSSM-S).

OBJECTIVE: The present study aimed to assess the: (i) internal structure of the Spanish Child Food Security Survey Module (CFSSM-S) with exploratory and confirmatory factor analysis (EFA and CFA); (ii) measurement invariance by gender, grade, weight status, socio-economic status (SES) and family affluence; and (iii) relationships with these external variables. DESIGN: A cross-sectional study was conducted. The CFSSM-S and other tools were employed to assess food insecurity, weight status, SES and family affluence, respectively. SETTING: A secondary school (grades 7-10) in the city of Terrassa in Catalonia, Spain. SUBJECTS: Participants included adolescent boys and girls (n 426) aged 12-17 years. RESULTS: The cross-validation design with EFA and CFA captured a single factor, 'food insecurity'. The goodness-of-fit for the one-factor model with CFA (root-mean-square error of approximation=0·038, comparative fit index=0·984, Tucker-Lewis index=0·979) and internal consistency (ω=0·95) were excellent. The measurement invariance indicated that CFSSM-S could be used across genders, grades, weight status, SES and family affluence. Only mean differences for SES and family affluence were found which showed a linear trend, indicating higher CFSSM-S scores for participants with lower SES and family affluence. Of participants, 1·9 % experienced very low food security, 16·4 % low food security and 81·7 % were food secure. CONCLUSIONS: The CFSSM-S is the first validated instrument to assess food insecurity with psychometric guarantees in Spanish adolescents. Researchers and health practitioners in Spain could use this self-reported questionnaire to gain more information about adolescent health in relation to food insecurity.

Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study.

BACKGROUND: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (VO(2peak)). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. STUDY DESIGN: Prospective matched-cohort study. SETTING & PARTICIPANTS: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. PREDICTOR: CKF versus essential hypertension without cardiovascular disease. MEASUREMENTS & OUTCOMES: VO(2peak) was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in VO(2peak) between study groups, statistically significant predictors of VO(2peak) in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. RESULTS: VO(2peak) was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P<0.001). Independent predictors of VO(2peak) for CKF included left ventricular (LV) filling pressure (E/mean e'; unstandardized regression coefficient: change in VO(2peak) [in mL/min·kg] per 1-unit change of variable = -5.1) and pulse wave velocity (-4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (-8.8). The interaction effect of VO(2peak) between patient groups with LV mass index (P<0.001), LV end-diastolic volume index (P<0.001), and peak heart rate (P<0.01) were significantly stronger in the hypertension group, whereby higher values led to greater VO(2peak). LIMITATIONS: Skeletal muscle strength was not assessed. CONCLUSION: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension.

Subclass analysis of donor HLA-specific IgG in antibody-incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure.

Donor HLA-specific antibodies (DSAs) can cause rejection and graft loss after renal transplantation, but their levels measured by the current assays are not fully predictive of outcomes. We investigated whether IgG subclasses of DSA were associated with early rejection and graft failure. DSA levels were determined pretreatment, at the day of peak pan-IgG level and at 30 days post-transplantation in eighty HLA antibody-incompatible kidney transplant recipients using a modified microbead assay. Pretreatment IgG4 levels were predictive of acute antibody-mediated rejection (P = 0.003) in the first 30 days post-transplant. Pre-treatment presence of IgG4 DSA (P = 0.008) and day 30 IgG3 DSA (P = 0.03) was associated with poor graft survival. Multivariate regression analysis showed that in addition to pan-IgG levels, total IgG4 levels were an independent risk factor for early rejection when measured pretreatment, and the presence of pretreatment IgG4 DSA was also an independent risk factor for graft failure. Pretreatment IgG4 DSA levels correlated independently with higher risk of early rejection episodes and medium-term death-censored graft survival. Thus, pretreatment IgG4 DSA may be used as a biomarker to predict and risk stratify cases with higher levels of pan-IgG DSA in HLA antibody-incompatible transplantation. Further investigations are needed to confirm our results.

Exaggerated blood pressure response to dynamic exercise despite chronic refractory hypotension: results of a human case study.

BACKGROUND: Chronic refractory hypotension is a rare but significant mortality risk in renal failure patients. Such aberrant physiology usually deems patient unfit for renal transplant surgery. Exercise stimulates the mechano-chemoreceptors in the skeletal muscle thereby modulating the sympathetic effects on blood pressure regulation. The haemodynamic response to dynamic exercise in such patients has not been previously investigated. We present a case with severe chronic hypotension who underwent exercise testing before and after renal transplantation, with marked differences in blood pressure response to exercise. CASE PRESENTATION: A 40-year old haemodialysis-dependent patient with a 2 year history of refractory hypotension (≤80/50 mmHg) was referred for living donor renal transplantation at our tertiary centre. Each dialysis session was often less than 2 h and 30 min due to symptomatic hypotension. As part of the cardiovascular assessment, she underwent haemodynamic evaluation with cardiopulmonary exercise testing. Blood pressure normalized during unloaded pedalling but was exaggerated at maximal workload whereby it rose from 82/50 mmHg to a peak of 201/120 mmHg. Transthoracic echocardiography, tonometric measure of central vascular compliance and myocardial perfusion scan were normal. She subsequently underwent an antibody-incompatible renal transplantation and was vasopressor reliant for 14 days during the post-operative period. Eight weeks following transplant, resting blood pressure was normal and a physiological exercise-haemodynamic response was observed during a repeat cardiopulmonary exercise testing. CONCLUSION: This case highlights the potential therapeutic role of unloaded leg cycling exercise during dialysis session to correct chronic hypotension, allowing patients to have greater tolerance to fluid shift. It also adds to existing evidence that sympathetic dysfunction is reversible with renal transplant. Furthermore chronic hypotension with preserved exercise-haemodynamic response and cardiovascular reserve should not preclude these patients from renal transplant surgery.

Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation.

Exercise intolerance is an important comorbidity in patients with CKD. Anaerobic threshold (AT) determines the upper limits of aerobic exercise and is a measure of cardiovascular reserve. This study investigated the prognostic capacity of AT on survival in patients with advanced CKD and the effect of kidney transplantation on survival in those with reduced cardiovascular reserve. Using cardiopulmonary exercise testing, cardiovascular reserve was evaluated in 240 patients who were waitlisted for kidney transplantation between 2008 and 2010, and patients were followed for ≤5 years. Survival time was the primary endpoint. Cumulative survival for the entire cohort was 72.6% (24 deaths), with cardiovascular events being the most common cause of death (54.2%). According to Kaplan-Meier estimates, patients with AT <40% of predicted peak VO2 had a significantly reduced 5-year cumulative overall survival rate compared with those with AT ≥40% (P<0.001). Regarding the cohort with AT <40%, patients who underwent kidney transplantation (6 deaths) had significantly better survival compared with nontransplanted patients (17 deaths) (hazard ratio, 4.48; 95% confidence interval, 1.78 to 11.38; P=0.002). Survival did not differ significantly among patients with AT ≥40%, with one death in the nontransplanted group and no deaths in the transplanted group. In summary, this is the first prospective study to demonstrate a significant association of AT, as the objective index of cardiovascular reserve, with survival in patients with advanced CKD. High-risk patients with reduced cardiovascular reserve had a better survival rate after receiving a kidney transplant.

Deceased-Donor Kidney Transplant Outcome Prediction Using Artificial Intelligence to Aid Decision-Making in Kidney Allocation.

In kidney transplantation, pairing recipients with the highest longevity with low-risk allografts to optimize graft-donor survival is a complex challenge. Current risk prediction models exhibit limited discriminative and calibration capabilities and have not been compared to modern decision-assisting tools. We aimed to develop a highly accurate risk-stratification index using artificial intelligence (AI) techniques. Using data from the UNOS database (156,749 deceased kidney transplants, 2007-2021), we randomly divided transplants into training (80%) and validation (20%) sets. The primary measure was death-censored graft survival. Four machine learning models were assessed for calibration (integrated Brier score [IBS]) and discrimination (time-dependent concordance [CTD] index), compared with existing models. We conducted decision curve analysis and external validation using UK Transplant data. The Deep Cox mixture model showed the best discriminative performance (area under the curve [AUC] = 0.66, 0.67, and 0.68 at 6, 9, and 12 years post-transplant), with CTD at 0.66. Calibration was adequate (IBS = 0.12), while the kidney donor profile index (KDPI) model had lower CTD (0.59) and AUC (0.60). AI-based D-TOP outperformed the KDPI in evaluating transplant pairs based on graft survival, potentially enhancing deceased donor selection. Advanced computing is poised to influence kidney allocation schemes.

Can eHealth applications improve renal transplant outcomes for adolescents and young adults? A systematic review.

BACKGROUND AND OBJECTIVES: Adherence to medical treatment following a kidney transplant is particularly challenging during adolescence and young adulthood. There is increasing evidence of the benefits of the use of computer and mobile technology (labelled as eHealth hereafter) including serious gaming and gamification in many clinical areas. We aimed to conduct a systematic review of such interventions designed to improve self-management skills, treatment adherence and clinical outcomes in young kidney transplant recipients aged 16 to 30 years. METHOD: The Cochrane Library, MEDLINE, EMBASE, PsychINFO, SCOPUS and CINAHL databases were searched for studies published between 01 January 1990 and 20 October 2020. Articles were short-listed by two independent reviewers based on pre-defined inclusion/exclusion criteria. Reference lists were screened and authors of published conference abstracts contacted. Two reviewers independently appraised selected articles, systematically extracted data and assessed the quality of individual studies (CASP and SORT). Thematic analysis was used for evidence synthesis; quantitative meta-analysis was not possible. RESULTS: A total of 1098 unique records were identified. Short-listing identified four eligible studies, all randomized controlled trials (n = 266 participants). Trials mainly focused on mHealth applications or electronic pill dispensers (mostly for patients >18 years old). Most studies reported on clinical outcome measures. All showed improved adherence but there were no differences in the number of rejections. Study quality was low for all four studies. CONCLUSIONS: The findings of this review suggest that eHealth interventions can improve treatment adherence and clinical outcomes for young kidney transplant patients. More robust and high-quality studies are now needed to validate these findings. Future studies should also extend beyond short-term outcomes, and consider cost of implementation. The review was registered with PROSPERO (CRD42017062469).

Hypoxia during maintenance hemodialysis-the critical role of pH.

Background: The impact and management of subclinical hypoxia during hemodialysis is a significant medical challenge. As key determinants of O2 availability and delivery, proposed mechanisms contributing to hypoxia include ischemia, alkalemia and pulmonary leukocyte sequestration. However, no study has comprehensively investigated and compared these interrelated mechanisms throughout a typical hemodialysis treatment week. This study aimed to comprehensively assess the physiological mechanisms that contribute to hypoxia during hemodialysis. Methods: In 76 patients, we measured arterial blood gases and pH at four time-points during hemodialysis (start, 15 min, 60 min, end) over the course of a standard treatment week. For the mid-week hemodialysis session, we additionally measured central hemodynamics (non-invasive cardiac output monitoring) and white blood cell count. Results: Linear regression modelling identified changes in pH, but not central hemodynamics or white blood cell count, to be predictive of changes in PaO2 throughout hemodialysis (e.g. at 60 min, ß standardized coefficient pH = 0.45, model R2 = 0.25, P < .001). Alkalemia, hypokalemia, decreased calcium and increased hemoglobin-O2 affinity (leftward shift in the oxyhemoglobin dissociation curve) were evident at the end of hemodialysis. pH and hemoglobin-O2 affinity at the start of hemodialysis increased incrementally over the course of a standard treatment week. Conclusion: These data highlight the important role of pH in regulating O2 availability and delivery during hemodialysis. Findings support routine pH monitoring and personalized dialysate bicarbonate prescription to mitigate the significant risk of alkalemia and subclinical hypoxia.

Rapid resolution of severe sustained low blood pressure in haemodialysis patients after successful renal transplantation.

BACKGROUND: Low blood pressure occurring in the absence of volume depletion, anti-hypertensive medication, heart failure or cortisol deficiency occurs in ~5-10% of haemodialysis patients, and can result in serious complications. The pathophysiology of this syndrome is poorly understood. METHODS: We describe eight cases with dialysis-associated hypotension who underwent renal transplantation. Four patients were severely hypotensive with a systolic blood pressure (SBP) <100 mmHg before and during dialysis, and four had a SBP usually <100 mmHg during dialysis, but usually >100 mmHg between sessions. All had donor-specific human leukocyte antigen antibodies. Six patients underwent pre-transplant plasmapheresis, which was curtailed in two because of further falls in blood pressure. Two patients experienced clotting of their arteriovenous fistula. In one patient cryofiltration was used, which was tolerated without severe falls in the BP. The remaining patient, who had hypotension-associated retinal vein thrombosis before transplant, was supported with an epinephrine infusion and did not receive plasmapheresis. RESULTS: Post-transplant, the first patient did not receive pressor therapy and died from bowel ischaemia. The other seven patients were supported with inotropes on critical care. The administration of steroids did not reverse hypotension. The mean pre-treatment SBP was 96 mmHg (range 71-110, SEM 5.0). After inotropes were withdrawn and graft function was established, the mean SBP was 127 mmHg (range 113-149, SEM 4.9) (P < 0.01). CONCLUSIONS: Renal transplantation was performed successfully and safely in patients when pressor therapy was used to treat severe dialysis-associated hypotension and, moreover, the blood pressure normalized rapidly after graft function was established.

STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

STAG2 (Stromal Antigen 2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n=119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n=346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for MIBC patients. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy number variations, or cell cycle distribution. However, unbiased RNA sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a non-canonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC.