Multi-photon microscopy for the evaluation of interstitial fibrosis in extended criteria donor kidneys: A proof-of-concept study.

INTRODUCTION: To evaluate the initial use of label-free second harmonic generation (SHG) imaging with two-photon excitation (2PE) auto-fluorescence in multiphoton microscopy (MPM) for the quantification of collagen/fibrosis on preimplantation biopsies of extended criteria donors (ECD). MATERIALS AND METHODS: Twenty preimplantation core biopsies were extracted from 10 donor kidney samples, of which originated from seven donors. Kidney Donor Profile Index (KDPI) and Remuzzi scores of biopsies were calculated. Collagen parameters measured included quantification by the Collagen Area Ratio in Total Tissue (CART) and qualitative measurements by Collagen Reticulation Index (CRI). RESULTS: Biopsies classified with > 85% KDPI scores had significantly higher CART (p = .011) and lower CRI values (p = .025) than biopsies with ≤ 85% KDPI scores. Increase in CRI values correlated significantly with rise in recipient creatinine levels 1-year post-transplant (p = .027; 95% CI: 4.635-66.797). CONCLUSION: MPM is an evolving technology that enables the quantification of the amount (CART) and quality (CRI) of collagen deposition in unstained preimplantation biopsies of donor kidneys stratified by KDPI scores. This initial evaluation found significant differences in both parameters between donor kidneys with more or less than 85% KDPI.

Cumulative iodinated contrast exposure for computed tomography during acute kidney injury and major adverse kidney events.

OBJECTIVES: To determine if contrast-enhanced CT imaging performed in patients during their episode of AKI contributes to major adverse kidney events (MAKE). METHODS: A propensity score-matched analysis of 1127 patients with AKI defined by KDIGO criteria was done. Their mean age was 63 ± 16 years with 56% males. A total of 419 cases exposed to CT contrast peri-AKI were matched with 798 non-exposed controls for 14 covariates including comorbidities, acute illnesses, and initial AKI severity; outcomes including MAKE and renal recovery in hospital were compared using bivariate analysis and logistic regression. MAKE was a composite of mortality, renal replacement therapy, and doubling of serum creatinine on discharge over baseline; renal recovery was classified as early versus late based on a 7-day timeline from AKI onset to nadir creatinine or cessation of renal replacement therapy in survivors. RESULTS: Sixty-two patients received cumulatively > 100 mL of CT contrast, 143 patients had > 50-100 mL, and 214 patients had 50 mL or less; MAKE occurred in 34%, 17%, and 21%, respectively, as compared with 20% in non-exposed controls (p = 0.008 for patients with > 100 mL contrast versus none). More contrast-exposed patients experienced late renal recovery (27% versus 20%) and longer hospital days (median 10 versus 8) than non-exposed patients (all p < 0.01). On multivariate analysis, cumulative CT contrast > 100 mL was independently associated with MAKE (odds ratio 2.39 versus non-contrast, adjusted for all confounders, p = 0.005); cumulative CT contrast under 100 mL was not associated with MAKE. CONCLUSIONS: High cumulative volume of CT contrast administered to patients with AKI is associated with worse short-term renal outcomes and delayed renal recovery. KEY POINTS: • Cumulative intravenous iodinated contrast for CT imaging of more than 100 mL, during an episode of acute kidney injury, was independently associated with worse renal outcomes and less renal recovery. • These adverse outcomes including renal replacement therapy were not more frequent in similar patients who received cumulatively 100 mL or less of CT contrast, compared with non-exposed patients. • More patients with CT contrast exposure during acute kidney injury experienced delayed renal recovery.

A meta-analysis on the prevalence of chronic kidney disease in liver transplant candidates and its associated risk factors and outcomes.

Pre-liver transplant (LT) chronic kidney disease (CKD) has emerged as a leading cause of post-operative morbidity. We aimed to report the prevalence, associated risk factors, and clinical outcomes in patients with pre-LT CKD. Meta-analysis and systematic review were conducted for included cohort and cross-sectional studies. Studies comparing healthy and patients with s pre-LT CKD were included. Outcomes were assessed with pooled hazard ratios. 15 studies were included, consisting of 82,432 LT patients and 26,754 with pre-LT CKD. Pooled prevalence of pre-LT CKD was 22.35% (CI: 15.30%-32.71%). Diabetes mellitus, hypertension, viral hepatitis, and non-alcoholic fatty liver disease, and older age were associated with increased risk of pre-LT CKD: (OR 1.72 CI: 1.15-2.56, P = 0.01), (OR 2.23 CI: 1.76-2.83, P < 0.01), (OR 1.09; CI: 1.05-1.13, P < 0.01), (OR 1.73; CI: 1.10-2.71 P = 0.03), and (MD: 2.92 years; CI: 1.29-4.55years; P < 0.01) respectively. Pre-LT CKD was significantly associated with increased mortality (HR 1.38; CI: 1.2-1.59; P < 0.01), post-LT end-stage renal disease and post-LT CKD. Almost a quarter of pre-LT patients have CKD and it is significantly associated with post-operative morbidity and mortality. However, long-term outcomes remain unclear due to a lack of studies reporting such outcomes.

A meta-analysis of the cumulative incidence, risk factors, and clinical outcomes associated with chronic kidney disease after liver transplantation.

Chronic kidney disease (CKD) remains a relatively common complication after liver transplantation (LT), and significantly impacts overall survival. We sought to assess the cumulative incidence, risk factors and mortality associated with post-LT CKD. CKD was defined as eGFR <60 ml/min/1.73 m2 as estimated by the Modified Diet in Renal Disease (MDRD) formula. Single-arm meta-analysis was done to evaluate the cumulative incidence of CKD at 1-, 3-, and 5-year timepoints post-LT. Risk factors for CKD were evaluated using hazard ratios (HR). Twenty-one studies involving 44 383 patients were included. Cumulative incidence of stage 3-5 CKD was 31.44% (CI 0.182-0.447), 36.71% (CI 0.188-0.546), and 43.52% (CI 0.296-0.574) at 1, 3, and 5 years after LT, respectively. Stage 5 CKD cumulative incidence increased from 0.274% (CI 0.001-0.005) at 1 year to 2.06% (CI 0.009-0.045) at 5 years post-LT. Age, female sex, diabetes, and peri-operative acute kidney injury (AKI) were significant risk factors for CKD. Stage 4-5 CKD was associated with a decrease in overall survival (HR 3.23, 95% CI 1.74-5.98, P < 0.01). CKD after LT is relatively common, and is associated with significantly reduced overall survival. Identification of patients at high risk of developing CKD allows physicians to prophylactically use renal-sparing immunosuppression which may be crucial in achieving desirable clinical outcomes.

Health Care Analytics With Time-Invariant and Time-Variant Feature Importance to Predict Hospital-Acquired Acute Kidney Injury: Observational Longitudinal Study.

BACKGROUND: Acute kidney injury (AKI) develops in 4% of hospitalized patients and is a marker of clinical deterioration and nephrotoxicity. AKI onset is highly variable in hospitals, which makes it difficult to time biomarker assessment in all patients for preemptive care. OBJECTIVE: The study sought to apply machine learning techniques to electronic health records and predict hospital-acquired AKI by a 48-hour lead time, with the aim to create an AKI surveillance algorithm that is deployable in real time. METHODS: The data were sourced from 20,732 case admissions in 16,288 patients over 1 year in our institution. We enhanced the bidirectional recurrent neural network model with a novel time-invariant and time-variant aggregated module to capture important clinical features temporal to AKI in every patient. Time-series features included laboratory parameters that preceded a 48-hour prediction window before AKI onset; the latter's corresponding reference was the final in-hospital serum creatinine performed in case admissions without AKI episodes. RESULTS: The cohort was of mean age 53 (SD 25) years, of whom 29%, 12%, 12%, and 53% had diabetes, ischemic heart disease, cancers, and baseline eGFR <90 mL/min/1.73 m2, respectively. There were 911 AKI episodes in 869 patients. We derived and validated an algorithm in the testing dataset with an AUROC of 0.81 (0.78-0.85) for predicting AKI. At a 15% prediction threshold, our model generated 699 AKI alerts with 2 false positives for every true AKI and predicted 26% of AKIs. A lowered 5% prediction threshold improved the recall to 60% but generated 3746 AKI alerts with 6 false positives for every true AKI. Representative interpretation results produced by our model alluded to the top-ranked features that predicted AKI that could be categorized in association with sepsis, acute coronary syndrome, nephrotoxicity, or multiorgan injury, specific to every case at risk. CONCLUSIONS: We generated an accurate algorithm from electronic health records through machine learning that predicted AKI by a lead time of at least 48 hours. The prediction threshold could be adjusted during deployment to optimize recall and minimize alert fatigue, while its precision could potentially be augmented by targeted AKI biomarker assessment in the high-risk cohort identified.

Ensuring Sustainability of Continuous Kidney Replacement Therapy in the Face of Extraordinary Demand: Lessons From the COVID-19 Pandemic.

With the exponential surge in patients with coronavirus disease 2019 (COVID-19) worldwide, the resources needed to provide continuous kidney replacement therapy (CKRT) for patients with acute kidney injury or kidney failure may be threatened. This article summarizes subsisting strategies that can be implemented immediately. Pre-emptive weekly multicenter projections of CKRT demand based on evolving COVID-19 epidemiology and routine workload should be made. Corresponding consumables should be quantified and acquired, with diversification of sources from multiple vendors. Supply procurement should be stepped up accordingly so that a several-week stock is amassed, with administrative oversight to prevent disproportionate hoarding by institutions. Consumption of CKRT resources can be made more efficient by optimizing circuit anticoagulation to preserve filters, extending use of each vascular access, lowering blood flows to reduce citrate consumption, moderating the CKRT intensity to conserve fluids, or running accelerated KRT at higher clearance to treat more patients per machine. If logistically feasible, earlier transition to intermittent hemodialysis with online-generated dialysate, or urgent peritoneal dialysis in selected patients, may help reduce CKRT dependency. These measures, coupled to multicenter collaboration and a corresponding increase in trained medical and nursing staffing levels, may avoid downstream rationing of care and save lives during the peak of the pandemic.

Extended Mortality and Chronic Kidney Disease After Septic Acute Kidney Injury.

PURPOSE: To evaluate 1-year mortality in patients with septic acute kidney injury (AKI) and to determine association between initial AKI recovery patterns (reversal within 5 days, beyond 5 days but recovery, or nonrecovery) and chronic kidney disease (CKD) progression. METHODS: Prospective observational study, with retrospective evaluation of initial nonconsenters, of critically ill patients with septic AKI. RESULTS: We studied 207 patients (age, mean [SD]: 64 [16] years, 39% males), of which 56 (27%), 18 (9%), and 9 (4%) died in intensive care unit (ICU), post-ICU in hospital, and posthospitalization, respectively. Infections (including pneumonia) and major adverse cardiac events accounted for 64% and 12% of deaths, respectively. Factors independently associated with 1-year mortality include older age, ischemic heart disease, higher Simplified Acute Physiology Score II, central nervous system or musculoskeletal primary infections, higher daily fluid balance (FB), and frusemide administration during ICU stay (all P < .05). Among 63 patients receiving renal replacement therapy (RRT), hospital mortality was higher with cumulative median FB >8 L versus ≤8 L at RRT initiation (57% vs 24%; P = .009); there was trend for less ICU- and RRT-free days at day 28 in patients with higher FB pre-RRT (P = NS). Chronic kidney disease progression over 1 year developed in 21%, 30%, and 79% of 105 initial survivors with AKI reversal, recovery, and nonrecovery, respectively (P < .001). Acute kidney injury nonrecovery during hospitalization independently predicted CKD progression (P = .001). CONCLUSIONS: Patients with septic AKI had 40% 1-year mortality, mainly associated with infections. High FB and frusemide administration were modifiable risk factors. Risk of CKD progression is high especially with initial AKI nonrecovery.

Visceral obesity in Asian living kidney donors significantly impacts early renal function after donor nephrectomy.

INTRODUCTION: Obesity may be a risk factor for kidney donors to develop reduced renal function. The Framingham heart study suggested that visceral adipose tissue (VAT) confers a more adverse metabolic profile compared with subcutaneous adipose tissue (SAT). Asians tend to have a higher VAT composition and it is unclear if their kidney function is affected differently. We hypothesized that Asian living kidney donors who have visceral obesity are at a higher risk of renal function deterioration 1 year after donation. METHODS: Between 2011 and 2014, we retrospectively evaluated data from 73 consecutive patients (52% male; mean age 44.9 ± 11.7 years) before they underwent donor nephrectomy and at their 1 year routine follow-up. VAT and SAT were measured at the level of the umbilicus on pre-operative computerized tomography (CT). Visceral obesity (VO) was defined as a VAT > 100 cm [2] and patients were then further divided and compared in two subgroups: VAT > 100 and < 100 cm [2]. Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m [2]) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation pre-operatively and 1 year post-operatively. RESULTS: Both subgroups had similar baseline kidney function (P = NS) pre-operatively. At the 1 year follow-up, patients with VO experienced a more significant decline of renal function (109 ± 9 to 89 ± 8 mL/min per 1.73 m2), compared to those without VO (111 ± 12 to 96 ± 11 mL/min per 1.73 m2, P = 0.013). VO was associated with a body mass index (BMI) > 25 kg/m2 (P < 0.001), male gender (P < 0.001) and older age at the time of donor nephrectomy (48.0 vs 39.5 years, P = 0.01). The presence of hypertension or hyperlipidaemia pre-operatively, choice of surgical approach, and post-operative complication rates, did not differ significantly between the subgroups. CONCLUSIONS: Visceral obesity as defined by VAT > 100 cm2 at the level of the umbilicus on cross-sectional imaging, may have a significant impact on early renal function after donor nephrectomy. Adiposity markers, as measured by cross-sectional CT imaging, may be incorporated into routine pre-operative kidney donor workup.

Electronic health records accurately predict renal replacement therapy in acute kidney injury.

BACKGROUND: Electronic health records (EHR) detect the onset of acute kidney injury (AKI) in hospitalized patients, and may identify those at highest risk of mortality and renal replacement therapy (RRT), for earlier targeted intervention. METHODS: Prospective observational study to derive prediction models for hospital mortality and RRT, in inpatients aged ≥18 years with AKI detected by EHR over 1 year in a tertiary institution, fulfilling modified KDIGO criterion based on serial serum creatinine (sCr) measures. RESULTS: We studied 3333 patients with AKI, of 77,873 unique patient admissions, giving an AKI incidence of 4%. KDIGO AKI stages at detection were 1(74%), 2(15%), 3(10%); corresponding peak AKI staging in hospital were 61, 20, 19%. 392 patients (12%) died, and 174 (5%) received RRT. Multivariate logistic regression identified AKI onset in ICU, haematological malignancy, higher delta sCr (sCr rise from AKI detection till peak), higher serum potassium and baseline eGFR, as independent predictors of both mortality and RRT. Additionally, older age, higher serum urea, pneumonia and intraabdominal infections, acute cardiac diseases, solid organ malignancy, cerebrovascular disease, current need for RRT and admission under a medical specialty predicted mortality. The AUROC for RRT prediction was 0.94, averaging 0.93 after 10-fold cross-validation. Corresponding AUROC for mortality prediction was 0.9 and 0.9 after validation. Decision tree analysis for RRT prediction achieved a balanced accuracy of 70.4%, and identified delta-sCr ≥ 148 µmol/L as the key factor that predicted RRT. CONCLUSION: Case fatality was high with significant renal deterioration following hospital-wide AKI. EHR clinical model was highly accurate for both RRT prediction and for mortality; allowing excellent risk-stratification with potential for real-time deployment.

Nephrectomy-induced reduced renal function and the health-related quality of life of living kidney donors.

OBJECTIVE: To evaluate the health impact of nephrectomy on living kidney donors (LKDs) by comparing the health-related quality of life (HrQOL) scores measured by Short Form-36 (SF36) between those with and without postdonation renal function impairment (PRFI). METHODS: Eighty-two LKDs (47 females, mean age=50.2±11.2 years) were prospectively recruited to participate in a SF-36 HrQOL survey. Chart review, individual baseline, and postoperative renal function (eGFR) was determined using the Modification of Diet in Renal Disease formula. PRFI was defined as eGFR<60 mL/min/1.73 m2 or proteinuria. Mean SF-36 domain scores were compared between those with and without PRFI. RESULTS: After a median follow-up of 5.7 years, the prevalence of postdonation comorbidities was 29.3% (n=24) PRFI, 25.6% (n=21) hypertension, 6.1% (n=5) diabetes, and 3.7% (n=3) heart disease, and no LKDs developed end-stage renal disease. Mean eGFR before and after donor nephrectomy was 95.5±23.4 and 71.0±17.3 mL/min/1.73 m2 (P<.01). Mean SF-36 scores of LKDs were not significantly different between those with and without PRFI in all the domains (all P>.05). Similarly, the proportion of LKDs with PRFI did not differ significantly between the patients with SF-36 domain scores above and below the published reference values. CONCLUSION: Nephrectomy-induced PRFI may not have a significant impact on the HrQOL of the LKD population with a low proportion of other major comorbidities such as diabetes and ischemic heart disease.

Association of anemia and mineral and bone disorder with health-related quality of life in Asian pre-dialysis patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor health-related quality of life (HRQoL). The association of CKD-related complications such as anemia and mineral and bone disorders (MBD) with HRQoL in pre-dialysis patients is not well-studied. As such, this study aimed to determine the association of anemia and MBD with HRQoL in pre-dialysis patients. METHODS: This was a cross-sectional study involving 311 adult pre-dialysis patients with stage 3-5 CKD from an acute-care hospital in Singapore. Patients' HRQoL were assessed using Kidney Disease Quality of Life Short Form (KDQOL-SF™) and EuroQol 5 Dimensions-3 levels (EQ5D-3L). HRQoL between patients with and without anemia or MBD were compared by separate hierarchical multiple linear regression analyses using various HRQoL scales as dependent variables, adjusted for sociodemographic, clinical and psychosocial variables. RESULTS: After adjusting for MBD, anemia was associated with lower HRQoL scores on work status (WS), physical functioning (PF) and role physical [ß (SE): -10.9 (4.18), p = 0.010; -3.0 (1.28), p = 0.018; and -4.2 (1.40), p = 0.003, respectively]. However, significance was lost after adjustments for sociodemographic variables. Patients with MBD had poorer HRQoL with respect to burden of kidney disease, WS, PF and general health [(ß (SE): -7.9 (3.88), p = 0.042; -9.5 (3.99), p = 0.018; -3.0 (1.22) p = 0.014; -3.6 (1.48), p = 0.015, respectively]. Although these remained significant after adjusting for sociodemographic variables, significance was lost after adjusting for clinical variables, particularly pill burden. This is of clinical importance due to the high pill burden of CKD patients, especially from medications for the management of multiple comorbidities such as cardiovascular and mineral and bone diseases. CONCLUSIONS: Neither anemia nor MBD was associated with HRQoL in our pre-dialysis patients. Instead, higher total daily pill burden was associated with worse HRQoL. Medication reconciliation should therefore be routinely performed by clinicians and pharmacists to reduce total daily pill burden where possible.

Ethnic disparity in prevalence of diabetic kidney disease in an Asian primary healthcare cluster.

AIMS: Diabetic kidney disease (DKD) incidence is rising in Singapore. While measures to prevent onset and early detection of diabetes as well as optimal diabetes and blood pressure control are important, early detection and treatment of DKD at primary care are crucial to ameliorate its course. This study aimed to evaluate the prevalence of DKD in a primary care cluster in Singapore and identify its risk factors in a multi-ethnic Asian population. METHODS: A total of 57,594 patients with type 2 diabetes mellitus (T2DM) followed-up at the National Healthcare Group Polyclinics with estimated glomerular filtration rate and at least two urine albumin/creatinine ratio (UACR) were stratified into DKD stages: normoalbuminuria (UACR <30 mg/g), microalbuminuria (MI, UACR 30-299 mg/g), macroalbuminuria (MA, ≥300 mg/g) and renal impairment (RI, estimated glomerular filtration rate eGFR <60 mL/min per 1.73 m(2)). Factors associated with DKD stages were evaluated. RESULTS: Overall DKD prevalence (T2DM with MI, MA or RI) was high at 52.5%; 32.1% had MI, 5.3% had MA and 15.1% had RI. DKD prevalence within ethnic subpopulations was different: 52.2% of Chinese, 60.4% of Malays and 45.3% of Indians had DKD, respectively. Malays had a 1.42-fold higher DKD prevalence, while Indians had a 0.86-fold lower. Other independent risk factors were age, female gender, duration of diabetes and hypertension, HbA1c and body mass index. CONCLUSION: The high prevalence of DKD and its interethnic differences suggest need for additional measures to optimize the care of T2DM at primary care to mitigate its progression.

Drug-induced nephrotoxicity: clinical impact and preclinical in vitro models.

The kidney is a major target for drug-induced toxicity. Drug-induced nephrotoxicity remains a major problem in the clinical setting, where the use of nephrotoxic drugs is often unavoidable. This leads frequently to acute kidney injury, and current problems are discussed. One strategy to avoid such problems would be the development of drugs with decreased nephrotoxic potential. However, the prediction of nephrotoxicity during preclinical drug development is difficult and nephrotoxicity is typically detected only late. Also, the nephrotoxic potential of newly approved drugs is often underestimated. Regulatory approved or validated in vitro models for the prediction of nephrotoxicity are currently not available. Here, we will review current approaches on the development of such models. This includes a discussion of three-dimensional and microfluidic models and recently developed stem cell based approaches. Most in vitro models have been tested with a limited number of compounds and are of unclear predictivity. However, some studies have tested larger numbers of compounds and the predictivity of the respective in vitro model had been determined. The results showed that high predictivity can be obtained by using primary or stem cell derived human renal cells in combination with appropriate end points.

Vitamin D status and its association with mineral and bone disorder in a multi-ethnic chronic kidney disease population.

BACKGROUND: Vitamin D deficiency is associated with secondary hyperparathyroidism and mineral and bone disorder (MBD) in chronic kidney disease (CKD). This study aimed to determine the prevalence of vitamin D insufficiency/deficiency, and the association between vitamin D status and MBD in a multi-ethnic CKD population in Southeast Asia. METHODS: Predialysis CKD patients were included in this cross-sectional study. Patient demographics, medical/medication histories, and laboratory parameters (serum 25-hydroxyvitamin D (25(OH)D), creatinine, phosphate (P), calcium, albumin, and intact-PTH (i-PTH)) were collected and compared among patients with various CKD stages. The association between 25(OH)D and these parameters was determined by multiple linear regression. RESULTS: A total of 196 patients with mean ± SD eGFR of 26.4 ± 11.2 mL/min/1.73 m2 was included. Vitamin D deficiency (25(OH)D concentration < 15 ng/mL) and insufficiency (25(OH)D concentration 16 - 30 ng/mL) was found in 29.1% and 57.7% of the patients, respectively. Mean ± SD serum 25(OH)D was 20.8 ± 9.3 ng/mL. Female patients had lower vitamin D concentrations than males (16.9 ng/mL vs. 23.9 ng/mL; p < 0.001). Vitamin D levels were also higher in Chinese (22.3 ng/mL) than Malay (17.3 ng/mL) and Indian (13.1 ng/mL) patients (p < 0.05). Nonadjusted analyses showed higher i-PTH concentration in vitamin D deficient patients (p < 0.05). CONCLUSION: Despite being a sun-rich country all year round, the majority (86.8%) of predialysis CKD patients in Singapore have suboptimal vitamin D status. Lower vitamin D concentrations were found in females and in those with darker skin tone. Vitamin D deficient patients also tended to have higher i-PTH levels.