METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution.

RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin).

METHODS: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110.

FINDINGS: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62-0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16-1·59), representing a 50% (42-58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1).

INTERPRETATION: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease.

METHODS: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.

FINDINGS: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83-2·41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2·75 to -1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36-136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19-38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001).

INTERPRETATION: Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.

MATERIALS AND METHODS: The CKD-CHECK (CKD-CHECK EGFR Chart in Kidney disease) is a toolkit that was developed to auto-generate patients' eGFR trend using a line graph, displaying the trend visually over a year. It identifies patients with rapid CKD progression, triggers the doctors to order appropriate tests (proteinuria quantification or renal imaging) and helps in decision making (continued monitoring at primary care level or referral to nephrologist). The toolkit was piloted among medical officers practising in a hospital-based primary care clinic treating patients with eGFR<60ml/min/1.73m2 using an interventional before-after study design from February to May 2022. In the preintervention period, the CKD patients were managed based on standard practice. The doctors then used the CKDCHECK toolkit on the same group of CKD patients during the intervention period. The feasibility and acceptability of the toolkit was assessed at the end of the study period using the Acceptability of Intervention Measure (AIM) and Feasibility of Intervention Measure (FIM) questionnaires. All patients' clinical data and referral rate were collected retrospectively through medical files and electronic data systems. Comparison between the pre- and post-intervention group were analysed using paired t-test and McNemar test, with statistical significance p value of <0.05.

RESULTS: A total of 25 medical officers used the toolkit on 60 CKD patients. The medical officers found the CKD-CHECK toolkit to be highly acceptable and feasible in primary care setting. The baseline characteristics of the patients were a mean age of 72 years old, predominantly females and Chinese ethnicity. Majority of the CKD patients had diabetes mellitus, hypertension and dyslipidemia. The numbers of CKD rapid progressors was similar (26.7% in the preintervention group vs 33.3% in the post-intervention group). There were no significant differences in terms of proteinuria assessment and ultrasound kidney for CKD rapid progressors before and after the intervention. However, a significant number of CKD rapid progressors were referred to nephrologists after the use of CKD-CHECK toolkit (p=0.016).

METHODS: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes.

RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups.

MATERIALS AND METHODS: This is a cross-sectional study of patients referred for 99mTc-DTPA scan at the Nuclear Medicine Centre of International Islamic University Malaysia. The record was taken from patients visiting the centre from January 2016 to December 2019.

RESULTS: The mean measured GFR by 99mTc-DTPA scan was 42.2 ± 20.38 ml/min. These were lower than that estimated by CG, MDRD, and CKD-EPI equations. CKD-EPI had the highest correlation of 0.72, least bias (mean bias of 11.08 ± 23.08) and was more precise (r2 = 0.4) as compared to MDRD and CG. In patients < 65 years old, CKD-EPI had the highest correlation; however, MDRD had the least bias and highest accuracy. In terms of BMI, CKD-EPI had the least bias and highest accuracy for BMI >30 and with the highest correlation for all classes of BMI.

MATERIALS AND METHODS: Participants with an estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of >300-5,000 mg/g were randomized to 100 mg of canagliflozin or a placebo. The effects of canagliflozin treatment on pre-specified efficacy and safety outcomes were examined using Cox proportional hazards regression between participants from EA countries (China, Japan, Malaysia, the Philippines, South Korea and Taiwan) and the remaining participants.

RESULTS: Of 4,401 participants, 604 (13.7%) were from EA countries; 301 and 303 were assigned to the canagliflozin and placebo groups, respectively. Canagliflozin lowered the risk of primary outcome (composite of end-stage kidney disease, doubling of serum creatinine level, or renal or cardiovascular death) in EA participants (hazard ratio 0.54, 95% confidence interval 0.35-0.84). The effects of canagliflozin on renal and cardiovascular outcomes in EA participants were generally similar to those of the remaining participants. Safety outcomes were similar between the EA and non-EA participants.

METHODS: In this 24-month, open-label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids.

MATERIALS AND METHODS: An e-mail invitation to participate in an online survey was sent to hospital laboratories in Malaysia (n=140). Questions regarding methods for measuring creatinine, equations for calculating eGFR, eGFR reporting, the terminology used in reporting urine albumin, types of samples and the cut-off values used for normal albuminuria.

RESULTS: A total of 42/140 (30%) laboratories answered the questionnaire. The prevalent method used for serum creatinine measurement was the Jaffé method (88.1%) traceable to isotope-dilution mass spectrometry. eGFR was reported along with serum creatinine by 61.9% of laboratories while 33.3% of laboratories report eGFR on request. The formula used for eGFR reporting was mainly MDRD (64.3%) and results were reported as exact numbers even when the eGFR was <60 ml/min/1.73m2. The term microalbumin is still used by 83.3% of laboratories. There is a large heterogeneity among the labs regarding the type of sample recommended for measuring urine albumin, reference interval and reporting units.

Methods: This cross-sectional study included all gout patients who attended the rheumatology clinic from January 2013 to June 2018 and had received febuxostat as a second-line ULT. Analysis focused on the proportion of gout patients who achieved target serum urate (sUA) of <360 μmol/L, duration taken to achieve target sUA, and febuxostat dosage at achievement of target sUA. Safety assessments included comparison of serum creatinine, estimated glomerular filtration rate (eGFR), and serum alanine aminotransferase (ALT) at baseline, at achievement of target sUA, and at 12-monthly intervals.

Results: Majority (90.9%) of patients achieved target sUA. Median duration required to achieve target sUA was 5.5 months with IQR (interquartile range) of 8.5. Five (22.7%) patients achieved target sUA within one month of therapy with febuxostat 40 mg per day. Eleven (55%) patients achieved target sUA within six months and 16 (80%) by 12 months. Equal proportion of patients achieved target sUA with febuxostat 40 mg per day and 80 mg per day, respectively. There was no significant difference in the changes in serum creatinine level, eGFR and ALT from baseline and at achievement of target sUA, nor at 12-monthly intervals throughout the duration of febuxostat therapy. Apart from three patients who developed hypersensitivity reactions to febuxostat, no other adverse events were reported.

Methods: We evaluated commonly used surrogate and imputed baseline creatinine values against a "reference" creatinine measured during follow-up in an adult clinical trial cohort. Known AKI incidence (Kidney Disease: Improving Global Outcomes [KDIGO] criteria) was compared with AKI incidence classified by (1) back-calculation using the Modification of Diet in Renal Disease (MDRD) equation with and without a Chinese ethnicity correction coefficient; (2) back-calculation using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation; (3) assigning glomerular filtration rate (GFR) from age and sex-standardized reference tables; and (4) lowest measured creatinine during admission. Back-calculated distributions were performed using GFRs of 75 and 100 ml/min.

Results: All equations using an assumed GFR of 75 ml/min underestimated AKI incidence by more than 50%. Back-calculation with CKD-EPI and GFR of 100 ml/min most accurately predicted AKI but misclassified all AKI stages and had low levels of agreement with true AKI diagnoses. Back-calculation using MDRD and assumed GFR of 100 ml/min, age and sex-reference GFR values adjusted for good health, and lowest creatinine during admission performed similarly, best predicting AKI incidence (area under the receiver operating characteristic curves [AUC ROCs] of 0.85, 0.87, and 0.85, respectively). MDRD back-calculation using a cohort mean GFR showed low total error (22%) and an AUC ROC of 0.85.

AIMS: We explored if the association is explained by shared risk factors or is independent and whether there are regional or stroke subtype variations.

METHODS: INTERSTROKE is a case-control study and the largest international study of risk factors for first acute stroke, completed in 27 countries. We included individuals with available serum creatinine values and calculated estimated glomerular filtration rate (eGFR). Renal impairment was defined as eGFR <60 mL/min/1.73 m2. Multivariable conditional logistic regression was used to determine the association of renal function with stroke.

RESULTS: Of 21,127 participants, 41.0% were female, the mean age was 62.3 ± 13.4 years, and the mean eGFR was 79.9 ± 23.5 mL/min/1.73 m2. The prevalence of renal impairment was higher in cases (22.9% vs. 17.7%, p < 0.001) and differed by region (p < 0.001). After adjustment, lower eGFR was associated with increased odds of stroke. Renal impairment was associated with increased odds of all stroke (OR 1.35; 95% CI: 1.24-1.47), with higher odds for intracerebral hemorrhage (OR 1.60; 95% CI: 1.35-1.89) than ischemic stroke (OR 1.29; 95% CI: 1.17-1.42) (pinteraction 0.12). The largest magnitudes of association were seen in younger participants and those living in Africa, South Asia, or South America (pinteraction < 0.001 for all stroke). Renal impairment was also associated with poorer clinical outcome (RRR 2.97; 95% CI: 2.50-3.54 for death within 1 month).

METHODS: This study included all biopsy-proven IgAN patients with ≥ 1year follow-up. Patients with diabetes mellitus at diagnosis and secondary IgAN were excluded. Medical records were reviewed for demographics, clinical presentation, blood pressure, 24-hour urine protein, serum creatinine, renal biopsy and treatment received. The primary outcome was defined as combined event of 50% estimated glomerular filtration rate (eGFR) reduction or ESRD.

RESULTS: We included 130 (74 females; 56 males) patients of mean age 38.0 ± 14.0 years and median eGFR of 75.2 (interquartile range (IQR) 49.3-101.4) ml/min/1.73m2. Eighty-four (64.6%) were hypertensive at presentation, 35 (26.9%) had nephrotic syndrome and 57 (43.8%) had nephrotic range proteinuria (NRP). Median follow-up duration was 7.5 (IQR 4.0-13.0) years. It was noted that 18 (13.8%) developed ESRD and 34 (26.2%) reached the primary outcome. Annual eGFR decline was -2.1 (IQR -5.3 to -0.1) ml/min/1.73m2/year, with median survival of 20 years. Survival rates from the combined event (50% decrease in eGFR or ESRD) at 10, 20 and 30 years were 80%, 53% and 25%, while survival from ESRD were 87%, 73% and 65%, respectively. In the univariate analysis, time-average proteinuria (hazard ratio (HR) = 2.41, 95% CI 1.77-3.30), eGFR <45ml/min/1.73m2 at biopsy (HR = 2.35, 95% CI 1.03-5.32), hypertension (HR = 2.81, 95% CI 1.16-6.80), mean arterial pressure (HR = 1.02, 95% CI 1.01-1.04), tubular atrophy/interstitial fibrosis score (HR = 3.77, 95% CI 1.84-7.73), and cellular/fibrocellular crescent score (HR = 2.44, 95% CI 1.19-5.00) were found to be significant. Whereas only time-average proteinuria (TA-proteinuria) remained as a significant predictor in the multivariate analysis (HR = 2.23, 95% CI 1.57-3.16).

METHODS: MEDLINE and Embase databases were searched from inception up to September 2019 to identify all studies that compared the predictive performance of cystatin C- and/or creatinine-based eGFR in predicting the clearance of vancomycin. The prediction errors (PEs) (the value of eGFR equations minus vancomycin clearance) were quantified for each equation and were pooled using a random-effects model. The root mean squared errors were also quantified to provide a metric for imprecision.

RESULTS: This meta-analysis included evaluations of seven different cystatin C- and creatinine-based eGFR equations in total from 26 studies and 1,234 patients. The mean PE (MPE) for cystatin C-based eGFR was 4.378 mL min-1 (95% confidence interval [CI], -29.425, 38.181), while the creatinine-based eGFR provided an MPE of 27.617 mL min-1 (95% CI, 8.675, 46.560) in predicting clearance of vancomycin. This indicates the presence of unbiased results in vancomycin clearance prediction by the cystatin C-based eGFR equations. Meanwhile, creatinine-based eGFR equations demonstrated a statistically significant positive bias in vancomycin clearance prediction.