Acute Kidney Disease (AKD) commonly affects disadvantaged populations in low-resourced areas with poor access to kidney care. Here, barriers to management include a lack of AKD education alongside an inability to measure serum creatinine (SCr) to identify kidney disease. The Kidney Care Network (KCN) is a service improvement initiative which aims to implement a novel strategy for the management of AKD into routine clinical care in low- and low-middle income countries (LLMICs). The strategy includes the development of a scoring system to screen patients for risk of AKD and the use of a device to measure SCr at the point-of-care (POC). This approach is underpinned by dedicated AKD training activities for healthcare workers providing front line clinical care. We report feasibility in the implementation of the KCN approach in adults in 4 LLMICs. Between 2018-2020, 4311 patients at project sites in Bolivia, Brazil, Nepal, and South Africa were deemed at risk of kidney disease and underwent SCr testing, predominantly with the POC device. AKD was identified in 2922 (67.8%) patients. AKD was most commonly due to infections and hypovolemia, and as such was treatable by relatively simple means. Most patients with AKD were treated at the site of patient presentation, including rural primary healthcare facilities, and with early AKD identification the need for kidney replacement therapy was low. In-hospital mortality was only 2.9% and follow-up occurred at 3 months in 1865 (62.3%) patients discharged post AKD diagnosis. Hence, we show the KCN approach is a feasible and effective mechanism for improving AKD management in LLMICs.

Genome editing technologies, particularly clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, have transformed biomedical research by enabling precise genetic modifications. Due to its efficiency, cost-effectiveness, and versatility, CRISPR has been widely applied across various stages of research, from fundamental biological investigations in preclinical models to potential therapeutic interventions. In nephrology, CRISPR represents a groundbreaking tool for elucidating the molecular mechanisms underlying kidney diseases and developing innovative therapeutic approaches. This review synthesizes the latest advancements in CRISPR-based gene editing within nephrology, highlighting its applications in genetic kidney disorders, polygenic nephropathies, and functional genomic studies. Preclinical studies utilizing CRISPR-engineered kidney organoids and animal models have provided crucial insights into disease pathophysiology, offering platforms for drug discovery and precision medicine. Additionally, CRISPR-based functional screens have identified novel disease-associated pathways, particularly in diabetic nephropathy and glomerular disorders. Beyond experimental research, the therapeutic potential of CRISPR in nephrology is emerging, with recent advances in base editing and prime editing demonstrating the feasibility of correcting pathogenic mutations in conditions such as Alport syndrome and autosomal dominant polycystic kidney disease. Moreover, CRISPR plays a pivotal role in xenotransplantation, with gene-edited porcine kidneys addressing key immunological and virological barriers. Despite its promise, clinical translation faces challenges, including delivery efficiency, off-target effects, and ethical considerations. This review provides an overview of the current state and future directions of CRISPR-based gene editing in nephrology, underscoring its transformative potential in advancing kidney disease research and therapeutics.

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium < 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) > 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value < 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

Background The International Society of Nephrology proposes an acute kidney disease (AKD) management strategy that includes a risk score to aid AKD identification in low- and low-middle-income countries (LLMICs). We investigated the performance of the risk score and determined kidney and patient outcomes from AKD at multiple LLMIC sites. Methods and findings Adult patients presenting to healthcare facilities in Bolivia, Brazil, South Africa, and Nepal were screened using a symptom-based risk score and clinical judgment. Those at AKD risk underwent serum creatinine testing, predominantly with a point-of-care (POC) device. Clinical data were collected prospectively between September 2018 and November 2020. We analyzed risk score performance and determined AKD outcomes at discharge and over follow-up of 90 days. A total of 4,311 patients were at increased risk of AKD, and 2,922 (67.8%) had AKD confirmed. AKD prevalence was 80.2% in patients enrolled based on the risk score and 32.5% when enrolled on clinical judgment alone (p < 0.0001). The area under the receiver operating characteristic curve was 0.73 for the risk score to detect AKD. Death during admission occurred in 84 (2.9%) patients with AKD and 3 (0.2%) patients without kidney disease (p < 0.0001). Death after discharge occurred in 206 (9.7%) AKD patients, and 1865 AKD patients underwent reassessment of kidney function after discharge; 902 (48.4%) patients had persistent kidney disease including 740 (39.7%) patients reclassified with de novo or previously undiagnosed chronic kidney disease (CKD). The study was pragmatically designed to assess outcomes as part of routine healthcare, and there was heterogeneity in clinical practice and outcomes between sites, in addition to selection bias during cohort identification. Conclusions The use of a risk score can aid AKD identification in LLMICs. High rates of persistent kidney disease and mortality after discharge highlight the importance of AKD follow-up in low-resource settings.

Abstract Background Immunoglobulin G4-related disease is an inflammatory disease affecting multiple organs including the kidney. Immunoglobulin G4-related kidney disease most commonly manifests as a tubulointerstitial nephritis and is associated with glomerular disease in a proportion of cases. Membranous nephropathy is the most frequent glomerular lesion. Herein, we report the first documented case of immunoglobulin G4-related disease presenting with nephrotic syndrome owing to minimal change disease. Case presentation A 67-year-old South Asian male presented to our service with systemic upset and leg swelling. He had heavy proteinuria (urine protein:creatinine ratio 1042 mg/mmol) and was hypoalbuminemic (17 g/L) and hypercholersterolemic (9.3 mmol/L), consistent with the nephrotic syndrome. His serum creatinine was 140 μmol/L, and he was hypocomplementemic (C3 0.59 g/L, C4 < 0.02 g/L) with raised immunoglobulin G4 subclass levels (5.29 g/L). Kidney biopsy demonstrated minimal change disease alongside a plasma-cell-rich tubulointerstitial nephritis with strong positive staining for immunoglobulin G4. A diagnosis of minimal change disease in the setting of immunoglobulin G4-related disease was made. He was commenced on oral prednisolone at 60 mg daily but suffered infectious complications, including necrotizing fasciitis within 3 weeks of starting treatment, ultimately resulting in his death 52 days after initial presentation. Conclusion This case highlights the potential for immunoglobulin G4-related disease to be associated with a spectrum of glomerular pathologies including minimal change disease. It adds to the differential diagnosis of secondary causes of minimal change disease, and moreover, aids as an important reminder of the potential complications of high-dose steroids used in its treatment.

OBJECTIVES:Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation. METHODS:We stimulated purified monocytes and whole peripheral blood mononuclear cells (PBMCs) from patients with GPA, patients with MPA or healthy controls with PR3 or MPO and visualised MGC and granuloma-like structure formation using light, confocal and electron microscopy, as well as measuring the cell cytokine production. We investigated the expression of PR3 binding partners on monocytes and tested the impact of their inhibition. Finally, we injected zebrafish with PR3 and characterised granuloma formation in a novel animal model. RESULTS:In vitro, PR3 promoted monocyte-derived MGC formation using cells from patients with GPA but not from patients with MPA, and this was dependent on soluble interleukin 6 (IL-6), as well as monocyte MAC-1 and protease-activated receptor-2, found to be overexpressed in the cells of patients with GPA. PBMCs stimulated by PR3 formed granuloma-like structures with central MGC surrounded by T cells. This effect of PR3 was confirmed in vivo using zebrafish and was inhibited by niclosamide, a IL-6-STAT3 pathway inhibitor. CONCLUSIONS:These data provide a mechanistic basis for granuloma formation in GPA and a rationale for novel therapeutic approaches.

The International Society of Nephrology (ISN) 0by25 Initiative calls for global strategies to diagnose and treat kidney disease (KD) in patients with potentially reversible causes, especially in Low- and Low-middle income countries (LLMICs). Based on outcomes from the 0by25 Pilot Feasibility Study, the Kidney Care Network (KCN) project aims to implement a strategy to identify and manage KD as part of routine clinical care. We report the results from this implementation project in 4 LLMICs.

Background: Many low-resource settings have limited access to serum creatinine tests necessary for kidney disease identification. Among Malawian patients who are hospitalized after trauma, we evaluated the use of point-of-care saliva urea nitrogen (SUN) dipsticks to predict acute kidney injury (AKI). Methods: In a nested prospective cohort study, we enrolled hospitalized acute trauma patients aged ≥6 months to evaluate AKI (defined by KDIGO criteria) and the test characteristics of SUN to predict AKI. Results: Among 335 participants (approximately three-quarters able to expectorate and 34% aged ≤18 years), 12.5% (n = 42) developed AKI. At a SUN threshold of ≥40 mg/dL, a positive dipstick test was specific (99.3%) but insensitive (14.3%) in predicting AKI, with a positive predictive value of 75% and negative predictive value of 89%. At this threshold, 2.4% of participants were dipstick-positive (SUN+), and 75% of those had AKI. Reducing the SUN threshold to ≥30 mg/dL increased participants who were SUN+ to 5.0% (n = 16) but also increased the false positive rate and missed 79% (n = 33) of AKI cases. Stratified results showed better performance among adults than children and similar results when comparing participants who could and could not expectorate. There was moderate correlation between categorized BUN values and SUN (r = 0.53) but less agreement (weighted kappa 0.27; 95% CI 0.17–0.37). Conclusions: SUN dipstick testing has good specificity and negative predictive value for ruling out AKI, but poor sensitivity. We found similar results among those who could or could not expectorate a saliva sample.

Journal of the American Society of Nephrology 33(11S):p 475, November 2022. | DOI: 10.1681/ASN.20223311S1475a

Stages of CKD are currently defined by eGFR and require measurement of serum creatinine concentrations. Previous studies have shown a good correlation between salivary and serum urea levels and the stage of CKD. However, quantitative salivary urea assays in current clinical use require costly and labor-intensive commercial kits, which restricts the advantage of using saliva and limits wider applicability as a quick and easy means of assessing renal function. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy has been shown to provide a potentially straightforward, reagent-free method for the identification of a range of disease-related biomarkers and is in current clinical use for analyses of the chemical composition of kidney stones. We assessed the feasibility of ATR-FTIR spectroscopy as an alternative method to measure salivary urea in patients with different stages of CKD. The ATR-FTIR spectra of dried saliva samples from six healthy controls and 20 patients with CKD (stages 1-5) were analyzed to provide their urea concentrations. The lower limit of detection of salivary urea by the ATR-FTIR spectroscopy method was 1-2 mM, at the lower end of the clinically relevant range. Statistically significant differences in salivary urea concentrations were demonstrated between healthy subjects (4.1±0.5 mM) and patients with CKD stages 3-5 (CKD stage 3, 6.8±0.7 mM; CKD stage 4, 9.1±1 mM; CKD stage 5, 14.8±1.6 mM). These salivary urea concentrations correlated well with serum urea levels in the same patients measured by an automated analyzer (Spearman rank correlation coefficient of 0.71; P<0.001). The ability of the method to detect and stage CKD was assessed from the sensitivity and specificity parameters of a receiver operating characteristics (ROC) curve analysis. This proof-of-concept study demonstrates that quantitation of salivary urea by ATR-FTIR spectroscopy could provide a viable tool for rapid and cost-effective diagnosis of stages 3-5 CKD.

Background and objectives The optimal induction treatment in low–immune risk kidney transplant recipients is uncertain. We therefore investigated the use and outcomes of induction immunosuppression in a low-risk cohort of patients who were well matched with their donor at HLA-A, -B, -DR, -DQB1 on the basis of serologic typing. Design, setting, participants, & measurements Our study was an observational study of first adult kidney-only transplant recipients in the United States recorded by the Organ Procurement and Transplant Network. Results Among 2976 recipients, 57% were treated with T cell–depleting antibodies, 28% were treated with an IL-2 receptor antagonist, and 15% were treated without induction. There was no difference in allograft survival, death-censored graft survival, or death with function between patients treated with an IL-2 receptor antagonist and no induction therapy. In multivariable models, patients treated with T cell–depleting therapy had a similar risk of graft loss from any cause, including death (hazard ratio, 1.19; 95% confidence interval, 0.98 to 1.45), compared with patients treated with an IL-2 receptor antagonist or no induction. The findings were consistent in subgroup analyses of Black recipients, patients grouped by calculated panel reactive antibody, and donor source. The incidence of acute rejection at 1 year was low (≤5%) and did not vary between treatment groups. Conclusions Use of induction therapy with T cell–depleting therapy or IL-2 receptor antagonists in first kidney transplant recipients who are well matched with their donor at the HLA-A, -B, -DR, -DQB1 gene loci is not associated with improved post-transplant outcomes.

Introduction:Home dialysis may minimize SARS-CoV2 exposure risks compared to center-based dialysis. We explored how the pandemic may have introduced challenges related to peritoneal dialysis (PD) supply availability, routine patient care, and how facility practices changed during this time. Methods:The PD/Dialysis Outcomes and Practice Patterns Study (PDOPPS/DOPPS) and International Society of Nephrology (ISN) administered a web-based survey from November 2020 to March 2021. Medical director responses were compared across 10 ISN regions. Results:One hundered sixy-five PD facilities in 51 countries returned surveys. During the initial COVID-19 wave, the reported frequency of in-person patient visits decreased in 9 of 10 ISN regions. Before the pandemic, most facilities required a mask during PD exchanges which continued over the course of the pandemic. Although most facilities in different regions did not report PD supply disruptions, sites in Africa and South Asia reported major disruptions. Reductions in laparoscopic surgical procedures for PD catheters were reported by facilities in 9 of 10 regions whereas nonsurgical percutaneous procedures increased in facilities in 6 regions. Training of new PD patients declined in facilities in each region. Increased use of remote technology by patients to communicate with clinics was observed in all regions compared to prepandemic levels. Conclusion:Marked within-region and across-region variability was noted in PD facility burden, clinical practice, and adaptation to the COVID-19 pandemic. This study highlights opportunities to improve routine PD care, adapt to the ongoing pandemic, and increase preparedness for potential future interruptions in PD care.

Introduction: It is unknown how the COVID-19 pandemic has affected the care of vulnerable chronic hemodialysis (HD) patients across regions, particularly in low and lower-middle income countries (LLMICs). We aimed to identify global inequities in HD care delivery during the COVID-19 pandemic. Methods: The ISN and the Dialysis Outcomes and Practice Patterns Study (DOPPS) conducted a global online survey of HD units between March and November, 2020, to ascertain practice patterns and access to resources relevant to HD care during the COVID-19 pandemic. Responses were categorized according to World Bank income classification for comparisons. Results: Surveys were returned from 412 facilities in 78 countries: 15 (4%) in low-income countries (LICs), 111 (27%) in lower-middle income countries (LMICs), 145 (35%) in upper-middle income countries (UMICs), and 141 (34%) in high-income countries (HICs). Respondents reported that diagnostic tests for SARS-CoV-2 were unavailable or of limited availability in LICs (72%) and LMICs (68%) as compared with UMICs (33%) and HICs (20%). The number of patients who missed HD treatments was reported to have increased during the COVID-19 pandemic in LICs (64%) and LMICs (67%) as compared with UMICs (31%) and HICs (6%). Limited access to HD, intensive care unit (ICU) care, and mechanical ventilation among hospitalized patients on chronic dialysis with COVID-19 were also reportedly higher in LICs and LMICs as compared with UMICs and HICs. Staff in LLMICs reported less routine testing for SARS-CoV-2 when asymptomatic as compared with UMICs and HICs-14% in LICs and 11% in LMICs, compared with 26% and 28% in UMICs and HICs, respectively. Severe shortages of personal protective equipment (PPE) were reported by the respondents from LICs and LMICs compared with UMICs and HICs, especially with respect to the use of the N95 particulate-air respirator masks. Conclusion: Striking global inequities were identified in the care of chronic HD patients during the pandemic. Urgent action is required to address these inequities which disproportionately affect LLMIC settings thereby exacerbating pre-existing vulnerabilities that may contribute to poorer outcomes.

Infection Prevention and Control (IPAC) practices have had to be upscaled and changes made to how dialysis is performed in centres because of the COVID-19 pandemic. We aimed to describe how the pandemic has affected haemodialysis patients, staff, and services around the world.