Deep learning identified pathological abnormalities predictive of graft loss in kidney transplant biopsies.

Interstitial fibrosis, tubular atrophy, and inflammation are major contributors to kidney allograft failure. Here we sought an objective, quantitative pathological assessment of these lesions to improve predictive utility and constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte infiltrates. Periodic acid- Schiff stained slides of transplant biopsies (60 training and 33 testing) were used to quantify pathological lesions specific for interstitium, tubules and mononuclear leukocyte infiltration. The pipeline was applied to the whole slide images from 789 transplant biopsies (478 baseline [pre-implantation] and 311 post-transplant 12-month protocol biopsies) in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss. Our model accurately recognized kidney tissue compartments and mononuclear leukocytes. The digital features significantly correlated with revised Banff 2007 scores but were more sensitive to subtle pathological changes below the thresholds in the Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of one-year graft loss, while a Composite Damage Score in 12-month post-transplant protocol biopsies predicted later graft loss. ITASs and Composite Damage Scores outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITASs or Composite Damage Scores also demonstrated significantly higher incidence of estimated glomerular filtration rate decline and subsequent graft damage. Thus, our deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies and demonstrated superior ability for prediction of post-transplant graft loss with potential application as a prevention, risk stratification or monitoring tool.

Recent evidence on the effect of treatment of metabolic acid on the progression of kidney disease.

PURPOSE OF REVIEW: Preclinical and epidemiological studies have shown an association between acidosis and progression of chronic kidney disease (CKD) and kidney fibrosis. This review discusses the recent trials evaluating the effect of treatment of metabolic acidosis on kidney outcomes. RECENT FINDINGS: The emerging evidence suggests that bicarbonate treatment may slow the progression of CKD and reduce the risk of kidney failure. However, high-certainty evidence on the efficacy and safety of alkali therapy is still lacking. Ongoing studies are evaluating the effect of veverimer, a novel nonabsorbable polymer, on clinical kidney outcomes. SUMMARY: Recent studies indicate a potential benefit from reduction in acid load in patients with CKD. Whilst it is reasonable that clinicians institute acid-lowering interventions in CKD patients with acidosis, adequately powered trials are required to evaluate the benefit of correction of metabolic acidosis to delay kidney disease progression.

Histological diagnosis of immune checkpoint inhibitor induced acute renal injury in patients with metastatic melanoma: a retrospective case series report.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become the standard of care in many oncological conditions but are associated with a spectrum of renal immune-related adverse events (IrAEs). We aimed to describe the spectrum, histology, management and outcomes of renal IrAE in patients with metastatic melanoma undergoing ICI therapy. METHODS: We conducted a retrospective review of 23 patients with a diagnosis of metastatic melanoma treated with ICI between January 2017 and April 2019 who developed a renal IrAE. Baseline demographic data, biochemical and histopathological results, management and outcomes were analyzed. RESULTS: The majority of patients who developed renal irAE were male and received combination immunotherapy. The median time of onset from initiation of ICI therapy to renal IrAE was 4 months. 52% of the treated renal IrAE had histopathologically confirmed renal IrAE. The most common histological pattern of injury was acute tubulo-interstitial nephritis (92%). One patient developed anti-GBM disease with non-dialysis dependent stage 5 CKD. In tubulointerstitial injury, there was no association between peak creatinine, renal recovery and histologically reported inflammation or fibrosis. Patients with renal IrAE demonstrated persisting renal dysfunction at 3, 6 and 12 months with a mean baseline, 3 and 12 month creatinine of 90.0 µmol/L, 127.0 µmol/L and 107.5 µmol/L respectively. CONCLUSION: Renal IrAE is most commonly attributable to steroid responsive acute tubulointerstitial nephritis. The outcome of rarer pathologies such as anti-GBM disease may be adversely affected by a delayed diagnosis. There is persisting renal dysfunction following an episode of renal IrAE that may have impact on future renal and overall survival outcomes.

A Systematic Review and Meta-Analysis on Effects of Bicarbonate Therapy on Kidney Outcomes.

AIM: Preclinical studies suggest treatment of metabolic acidosis may slow chronic kidney disease (CKD) progression. This systematic review aimed to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of bicarbonate therapy on kidney outcomes. METHODS: Medline, EMBASE, and Cochrane databases were searched for RCTs with ≥3 months' follow-up in patients with CKD (estimated glomerular filtration rate [eGFR] ≤60 ml/min per 1.73 m2 and/or proteinuria) comparing the effects of sodium bicarbonate with placebo/no study medication on kidney outcomes. The primary outcome was change from baseline to last measurement in kidney function measured as either eGFR or creatinine clearance. Treatment effects were summarized using random-effects meta-analysis. RESULTS: Fifteen trials (2445 participants, median follow-up 12 months) were eligible for inclusion. Compared with placebo or no study medication, sodium bicarbonate retarded the decline in kidney function (standardized mean difference [SMD]: 0.26; 95% confidence interval [CI]: 0.13-0.40; I 2 = 50%, low certainty evidence), and reduced the risk of end-stage kidney failure (risk ratio [RR]: 0.53; 95% CI 0.32-0.89; I 2 = 69%, low certainty evidence). The effect of sodium bicarbonate on proteinuria (SMD: -0.09; 95% CI -0.27 to 0.09; I 2 = 28%, very low certainty evidence), systolic blood pressure (weighted mean difference [WMD]: -0.57 mm Hg; 95% CI -2.32 to 1.18; I 2 = 0%, low certainty evidence), all-cause death (RR: 0.81; 95% CI: 0.39-1.68; I 2 = 30%; very low certainty evidence) and edema (RR: 1.16; 95% CI: 0.90-1.50; I 2 = 28%; low certainty evidence) were uncertain. CONCLUSION: Sodium bicarbonate may slow CKD progression. Adequately powered randomized trials are required to evaluate the benefits and risks of sodium bicarbonate in CKD.

Temporal Change in Blood Group after Bone Marrow Transplant: A Case of Successful ABO-Incompatible Deceased Donor Transplant.

ABO-incompatible kidney transplantation has been successfully utilised in a deceased donor and living donor kidney transplantation to improve organ utilisation and decrease waiting times. We describe a case of a successful, unanticipated ABO-incompatible donation after cardiac death (DCD) kidney transplant in a patient who had a previous ABOi haematopoietic stem cell transplant (HSCT) and had reverted to his original blood group B, after matching as a blood group A recipient with a blood group A donor. The recipient was unsensitized with a cPRA which was 0% and no donor-specific antibodies and zero HLA mismatch. An urgent anti-A titre was 1 : 2. Given the low antibody titres, we proceeded to transplantation. The patient developed delayed graft function and required dialysis on postoperative day 1 and day 2. The creatinine fell spontaneously on day 5, with progressively increased urine output and stable graft function on discharge at day 6. Anti-A titres were 1 : 1 on serial postoperative measurements. There were no rejection episodes, and the patient has a functioning graft at 16 months posttransplant. We describe a rare case in which the blood group can change after stem cell transplant and should be checked. We also demonstrate that a DCD ABOi transplant in the context of low anti-A titres for a patient with previous ABOi stem cell transplant can be performed successfully with standard immunosuppression.

Orthostatic Renal Transplant Compression Following Weight Gain Leading to Acute Kidney Injury.

BACKGROUND: We present a first case of orthostatic renal graft compression and acute kidney injury following weight gain. CASE REPORT: A 61-year-old male with a second cadaveric transplant presented with acute kidney injury - creatinine rise from 80 to 210 µmol/L (0.90 to 2.38 mg/dL). His medical history included diabetes, hypertension, ischemic heart disease, and obesity despite bariatric surgery. Renal biopsy was consistent with acute tubular necrosis. Serial renovascular duplex studies showed absence of diastolic flow and reduced renal perfusion despite a patent renal transplant artery and vein. Raising the fatty apron cephalad normalized renal blood flow with resistive indices throughout the kidney. Subsequent laparascopy ruled out adhesional obstruction and carbon dioxide angiogram confirmed normal transplant vessels, anastomotic sites, and intrarenal branches. He was treated with bedrest and an abdominal support belt with improvement of creatinine to 100 to 110 µmol/L (1.1-1.2 mg/dL). CONCLUSIONS: Transplant physicians and surgeons need to be aware of positional renal graft compression from an enlarged bulky omentum and fatty apron. Diagnosis requires positional sonography.

Specialized Roles of Human Natural Killer Cell Subsets in Kidney Transplant Rejection.

Background: Human natural killer (NK) cells are key functional players in kidney transplant rejection. However, the respective contributions of the two functionally distinct human NK cell subsets (CD56bright cytokine-producing vs. CD56dim cytotoxic effector) in episodes of allograft rejection remain uncertain, with current immunohistochemical methods unable to differentiate these discrete populations. We report the outcomes of an innovative multi-color flow cytometric-based approach to unequivocally define and evaluate NK cell subsets in human kidney allograft rejection. Methods: We extracted renal lymphocytes from human kidney transplant biopsies. NK cell subsets were identified, enumerated, and phenotyped by multi-color flow cytometry. Dissociation supernatants were harvested and levels of soluble proteins were determined using a multiplex bead-based assay. Results were correlated with the histopathological patterns in biopsies-no rejection, borderline cellular rejection, T cell-mediated rejection (TCMR), and antibody-mediated rejection (AMR). Results: Absolute numbers of only CD56bright NK cells were significantly elevated in TCMR biopsies. In contrast, both CD56bright and CD56dim NK cell numbers were significantly increased in biopsies with histopathological evidence of AMR. Notably, expression of the activation marker CD69 was only significantly elevated on CD56dim NK cells in AMR biopsies compared with no rejection biopsies, indicative of a pathogenic phenotype for this cytotoxic NK cell subset. In line with this, we detected significantly elevated levels of cytotoxic effector molecules (perforin, granzyme A, and granulysin) in the dissociation supernatants of biopsies with a histopathological pattern of AMR. Conclusions: Our results indicate that human NK cell subsets are differentially recruited and activated during distinct types of rejection, suggestive of specialized functional roles.