Validation of a Risk Prediction Equation for Incident Chronic Kidney Disease in a Hypertensive Non-Diabetes Cohort in Singapore Primary Care Patients.

BACKGROUND: Accurate identification of individuals at risk of developing chronic kidney disease (CKD) may improve clinical care. Nelson et al. developed prediction equations to estimate the risk of incident eGFR of less than 60 mL/min/1.73 m2 in diabetic and non-diabetes patients using data from 34 multinational cohorts. We aim to validate the non-diabetes equation in our local multi-ethnic cohort and develop further prediction models. METHODS: Demographics, clinical and laboratory data of hypertensive non-diabetes patients with baseline eGFR ≥60 mL/min/1.73 m2 on follow-up with primary care clinics between 2010 and 2015 were collected. Follow-up was 5 years from entry to study. We validated Nelson's equation and developed our own model which we subsequently validated. The developmental cohort included patients between 2010 and 2014 while the validation cohort included patients in 2015. Variables included age, sex, eGFR, history of cardiovascular disease, ever smoker, body mass index, albuminuria, cholesterol, and treatment. Primary outcome was incident eGFR <60/min/1.73 m2 within 5 years. Model performance was evaluated by C-statistics and calibration was assessed. RESULTS: In the developmental cohort of 27,800 patients, 2823 (10.2%) developed the outcome during a mean follow-up of 4.4 years while 638 (12.8%) patients developed the outcome in the validation cohort of 4,994 patients. Applicability of Nelson's equation was limited by missing albuminuria, absence of black race, and exclusion of non-hypertensive patients in our cohort. Nonetheless, the modified Nelson's model demonstrated C-statistic of 0.85 (95% CI: 0.84-0.86). The C-statistic of our bespoke model was 0.85 (0.85-0.86) and 0.87 (0.85-0.88) for the developmental cohort and validation cohort, respectively. Calibration was suboptimal as the predicted risk exceeded the observed risk. CONCLUSIONS: The modified Nelson's equation and our locally derived novel model demonstrated high discrimination. Both models may potentially be used in predicting risk of CKD in hypertensive patients who are managed in primary care, allowing for early interventions in high-risk population.

An Update on Current Therapeutic Options in IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) remains the leading cause of primary glomerular disease worldwide. Outcomes are poor with high rates of progressive chronic kidney disease and kidney failure, which contributes to global healthcare costs. Although this disease entity has been described, there were no disease-specific treatments until recently, with the current standard of care focusing on optimal supportive measures including lifestyle modifications and optimization of the renin-angiotensin-aldosterone blockade. However, with significant advances in the understanding of the pathogenesis of IgAN in the past decade, and the acceptance of surrogate outcomes for accelerated drug approval, there have been many new investigational agents tested to target this disease. As these agents become available, we envision a multi-pronged treatment strategy that simultaneously targets the consequences of ongoing nephron loss, stopping any glomerular inflammation, inhibiting pro-fibrotic signals in the glomerulus and tubulo-interstitium, and inhibiting the production of pathogenic IgA molecules. This review is an update on a previous review published in 2021, and we aim to summarize the developments and updates in therapeutic strategies in IgAN and highlight the promising discoveries that are likely to add to our armamentarium.

Complements and Their Role in Systemic Disorders.

The complement system is critical to the body's innate defense against exogenous pathogens and clearance of endogenous waste, comprising the classical, alternative, and lectin pathways. Although tightly regulated, various congenital and acquired diseases can perturb the complement system, resulting in specific complement deficiencies. Systemic rheumatic, neurological, ophthalmological, renal, and hematological disorders are some prototypical complement-mediated diseases. An adequate understanding of the mechanisms of the normal complement system and the pathophysiology of complement dysregulation is critical for providing diagnostic clues and appropriately managing these conditions. This review guides clinicians in understanding the role of complement factors in systemic diseases and what diagnostic and therapeutic options are available for complement-mediated disorders.

Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial.

BACKGROUND: IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression. METHODS: In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. RESULTS: Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%). CONCLUSIONS: These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

Cost-effectiveness of screening for chronic kidney disease in the general adult population: a systematic review.

Introduction: Chronic kidney disease (CKD) is a significant public health problem, with rising incidence and prevalence worldwide, and is associated with increased morbidity and mortality. Early identification and treatment of CKD can slow its progression and prevent complications, but it is not clear whether CKD screening is cost-effective. The aim of this study is to conduct a systematic review of the cost-effectiveness of CKD screening strategies in general adult populations worldwide, and to identify factors, settings and drivers of cost-effectiveness in CKD screening. Methods: Studies examining the cost-effectiveness of CKD screening in the general adult population were identified by systematic literature search on electronic databases (MEDLINE OVID, Embase, Cochrane Library and Web of Science) for peer-reviewed publications, hand-searched reference lists and grey literature of relevant sites, focusing on the following themes: (i) CKD, (ii) screening and (iii) cost-effectiveness. Studies comprising health economic evaluations performed for CKD screening strategies, compared with no CKD screening or usual-care strategy in adult individuals, were included. Study characteristics, model assumptions and CKD screening strategies of selected studies were identified. The primary outcome of interest is the incremental cost-effectiveness ratio (ICER) of CKD screening, in cost per quality-adjusted life year (QALY) and life-year gained (LYG), expressed in 2022 US dollars equivalent. Results: Twenty-one studies were identified, examining CKD screening in general and targeted populations. The cost-effectiveness of screening for CKD was found to vary widely across different studies, with ICERs ranging from $113 to $430 595, with a median of $26 662 per QALY and from $6516 to $38 372, with a median of $29 112 per LYG. Based on the pre-defined cost-effectiveness threshold of $50 000 per QALY, the majority of the studies found CKD screening to be cost-effective. CKD screening was especially cost-effective in those with diabetes ($113 to $42 359, with a median of $27 471 per QALY) and ethnic groups identified to be higher risk of CKD development or progression ($23 902 per QALY in African American adults and $21 285 per QALY in Canadian indigenous adults), as indicated by a lower ICER. Additionally, the cost-effectiveness of CKD screening improved if it was performed in older adults, populations with higher CKD risk scores, or when setting a higher albuminuria detection threshold or increasing the interval between screening. In contrast, CKD screening was not cost-effective in populations without diabetes and hypertension (ICERs range from $117 769 to $1792 142, with a median of $202 761 per QALY). Treatment effectiveness, prevalence of CKD, cost of CKD treatment and discount rate were identified to be the most common influential drivers of the ICERs. Conclusions: Screening for CKD is especially cost-effective in patients with diabetes and high-risk ethnic groups, but not in populations without diabetes and hypertension. Increasing the age of screening, screening interval or albuminuria detection threshold, or selection of population based on CKD risk scores, may increase cost-effectiveness of CKD screening, while treatment effectiveness, prevalence of CKD, cost of CKD treatment and discount rate were influential drivers of the cost-effectiveness.

The contribution of a proliferation-inducing ligand (APRIL) and other TNF superfamily members in pathogenesis and progression of IgA nephropathy.

Advances in our understanding of the pathogenesis of immunoglobulin A nephropathy (IgAN) have led to the identification of novel therapeutic targets and potential disease-specific treatments. Specifically, a proliferation-inducing ligand (APRIL) has been implicated in the pathogenesis of IgAN, mediating B-cell dysregulation and overproduction of pathogenic galactose-deficient IgA1 (Gd-IgA1). Animal and clinical studies support the involvement of APRIL in the pathogenesis and progression of IgAN. An elevated level of APRIL is found in IgAN when compared with controls, which correlates with the level of Gd-IgA1 and associates with more severe disease presentation and worse outcomes. Conversely, anti-APRIL therapy reduces pathogenic Gd-IgA1 and IgA immune complex formation and ameliorates the severity of kidney inflammation and injury. Genome-wide association studies in IgAN have identified TNFSF13 and TNFRSF13B, a cytokine ligand-receptor gene pair encoding APRIL and its receptor, respectively, as risk susceptibility loci in IgAN, further supporting the causal role of the APRIL signalling pathway in IgAN. Several novel experimental agents targeting APRIL, including atacicept, telitacicept, zigakibart and sibeprenlimab, are currently under investigation as potential therapies in IgAN. Preliminary results suggest that these agents are well-tolerated, and reduce levels of Gd-IgA1, with corresponding improvement in proteinuria. Further studies are ongoing to confirm the safety and efficacy of anti-APRIL approaches as an effective therapeutic strategy in IgAN.

Ocular manifestations in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a rare but important systemic disease with or without ocular manifestations. We describe 4 cases of IgAN presenting with scleritis and review the various ocular manifestations in patients with IgAN. We found 55 cases with ocular manifestations in patients with prior or newly-diagnosed IgAN described in 38 publications. The most common ocular manifestations of IgAN were episcleritis (23.6%), scleritis (16.4%), hypertensive retinopathy or retinal vasculopathy (20.0%), and uveitis (14.5%). The median age at presentation was 36.5 years, with 54.5% female patients. 61.8% had history of IgAN prior to ocular involvement, while 29.1% had ocular presentations as the first manifestation of IgAN. The majority received systemic corticosteroids and/or immunosuppressants. Additionally, we report 4 women with anterior scleritis and previous diagnosis of IgAN. All 4 were treated with topical and systemic corticosteroids. Three out of 4 patients had no recurrence for at least 1 year since the first presentation. IgAN is a rare but important systemic association to be considered in ocular inflammatory conditions. Timely recognition and comanagement of the disease with nephrologist could reduce disease morbidity.

Sustainable kidney care delivery and climate change - a call to action.

The delivery of kidney care, particularly haemodialysis treatment, can result in substantial environmental impact through greenhouse emissions, natural resources depletion and waste generation. However, strategies exist to mitigate this impact and improve long term environmental sustainability for the provision of haemodialysis treatment. The nephrology community has begun taking actions to improve the environmental sustainability of dialysis, but much work remains to be done by healthcare professionals, dialysis providers and professional organisations.

Impact of variant of concern and vaccination status on COVID-19 infection virological dynamics in end stage kidney disease patients receiving haemodialysis.

AIM: It is unclear if variant of concern and vaccination status impact COVID-19 infection virological dynamics in haemodialysis patients and affect de-isolation protocol for dialysis centres. METHOD: We performed a retrospective observational cohort study between February 2020 to September 2021, to examine the virological kinetics of vaccinated and unvaccinated haemodialysis patients with polymerase chain reaction (PCR)-confirmed COVID-19 infection of the delta and pre-delta variants. RESULTS: Of the 38 subjects with PCR-confirmed COVID-19 infection, we found that individuals infected during the delta-variant period had higher viral load at presentation and required longer duration to achieve a negative PCR swab, compared to those infected in the pre-delta variant period. Time to achieve negative PCR swab was longest in unvaccinated individuals infected during delta-variant period. However, vaccinated and unvaccinated individuals achieved high PCR cycle threshold value of ≥25 and ≥30 at similar timing. CONCLUSION: Our study suggests that patients infected during delta-variant period of COVID-19 illness, have higher viral load at presentation and prolonged viral shedding, especially in the unvaccinated cohort. However, prolonged time to negative PCR is likely due to inactive virus shedding, and that conversion to negative PCR may not be a necessary pre-requisite for de-isolation.

Dialysis circuit clotting in critically ill patients with COVID-19 infection.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) infection has been associated with a hypercoagulable state with increased reports of thrombotic events. Acute kidney injury requiring dialysis is common in critically ill patients and circuit clotting compromises efficacy of treatment. This study aims to analyze the circuit life and circuit clotting during continuous kidney replacement therapy (CKRT) and intermittent hemodialysis in patients with and without COVID-19. METHODS: This is a single-center, retrospective cohort study in critically ill patients undergoing CKRT or intermittent hemodialysis between 1 February 2020 to 22 May 2020. Patients in the intensive care unit (ICU) with COVID-19 infection and contemporary controls who tested negative were included. Co-primary outcomes were functional circuit life for patients on CKRT and all circuit clotting events for patients on CKRT and/or intermittent hemodialysis. RESULTS: Seventy CKRT circuits and 32 intermittent hemodialysis sessions for 12 COVID-19 cases and 22 CKRT circuits and 18 intermittent hemodialysis sessions for 15 controls were analyzed. CKRT circuit clotting was more common in the COVID-19 group compared to the control group (64% vs 36%, p = 0.02), despite higher anticoagulation use in the COVID-19 group (41% vs 14%, p = 0.02). Functional CKRT circuit life was similar in COVID-19 patients and controls (median 11 vs 12 h, p = 0.69). On Cox regression analysis, circuit clotting was similar with hazard ratio (HR) 1.90 [95% confidence interval (CI): 0.89-4.04]; however, clotting was increased in COVID-19 patients after adjustment for anticoagulation use (HR: 3.31 [95% CI 1.49-7.33]). In patients with COVID-19, CKRT circuits with anticoagulation had a longer circuit life compared to CKRT circuits without anticoagulation (median 22 versus 7 h respectively, p <  0.001). Circuit clotting was similar in both groups undergoing intermittent hemodialysis. CONCLUSION: Dialysis clotting amongst COVID-19 patients is increased despite more anticoagulation use and the hazard for clotting is greater especially after adjusting for anticoagulation use. Circuit life was suboptimal in COVID-19 patients on circuits without anticoagulation and therefore routine use of anticoagulation amongst COVID-19 patients should be considered whenever possible.

Risk Factors for Development of Acute Kidney Injury in COVID-19 Patients: A Retrospective Observational Cohort Study.

INTRODUCTION: Acute kidney injury (AKI) in coronavirus infection disease (COVID-19) is associated with disease severity. We aimed to evaluate risk factors associated with AKI beyond COVID-19 severity. METHODS: A retrospective observational study of COVID-19 patients admitted to a tertiary hospital in Singapore. Logistic regression was used to evaluate associations between risk factors and AKI (based on Kidney Disease Improving Global Outcomes criteria). Dominance analysis was performed to evaluate the relative importance of individual factors. RESULTS: Seven hundred seven patients were included. Median age was 46 years (interquartile range [IQR]: 29-57) and 57% were male with few comorbidities (93%, Charlson Comorbidity Index [CCI] <1). AKI occurred in 57 patients (8.1%); 39 were in AKI stage 1 (68%), 9 in stage 2 (16%), and 9 in stage 3 (16%). Older age (adjusted odds ratio [aOR] 1.04; 95% confidence interval [CI]: 1.01-1.07), baseline use of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) (aOR 2.86; 95% CI: 1.20-6.83), exposure to vancomycin (aOR 5.84; 95% CI: 2.10-16.19), use of nonsteroidal anti-inflammatory drugs (NSAIDs) (aOR 3.04; 95% CI: 1.15-8.05), and severe COVID-19 with hypoxia (aOR 13.94; 95% CI: 6.07-31.98) were associated with AKI in the multivariable logistic regression model. The 3 highest ranked predictors were severe COVID-19 with hypoxia, vancomycin exposure, and age, accounting for 79.6% of the predicted variance (41.6, 23.1, and 14.9%, respectively) on dominance analysis. CONCLUSION: Severe COVID-19 is independently associated with increased risk of AKI beyond premorbid conditions and age. Appropriate avoidance of vancomycin and NSAIDs are potentially modifiable means to prevent AKI in patients with COVID-19.

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.