CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m² and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m²) and linear mixed effects models to analyze the effects on eGFR slope.

At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m², respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin’s lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m², canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m². Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (–1.72 versus –4.33 ml/min per 1.73 m²; between-group difference 2.61 ml/min per 1.73 m²).

Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m². Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.

Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

To investigate PKC’s potential role in injury during cold storage–associated transplantation, we incubated rat kidney proximal tubule cells in University of Wisconsin (UW) solution at 4°C for cold storage, returning them to normal culture medium at 37°C for rewarming. We also stored kidneys from donor mice in cold UW solution for various durations, followed by transplantation into syngeneic recipient mice.

We observed PKC activation in both in vitro and in vivo models of cold-storage rewarming or transplantation. In the mouse model, PKC was activated and accumulated in mitochondria, where it mediated phosphorylation of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), at serine 616. Drp1 activation resulted in mitochondrial fission or fragmentation, accompanied by mitochondrial damage and tubular cell death. Deficiency of PKC in donor kidney ameliorated Drp1 phosphorylation, mitochondrial damage, tubular cell death, and kidney injury during cold storage–associated transplantation. PKC deficiency also improved the repair and function of the renal graft as a life-supporting kidney. An inhibitor of PKC, V1-1, protected kidneys against cold storage–associated transplantation injury.

These results indicate that PKC is a key mediator of mitochondrial damage and renal tubular injury in cold storage–associated transplantation and may be an effective therapeutic target for improving renal transplant outcomes.

To explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines.

Our findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells.

STAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

We subjected SerpinB2 knockout mice to ischemia-reperfusion injury or unilateral ureteral obstruction. We performed phagocyte depletion to study SerpinB2’s role beyond the effects of macrophages and transplanted bone marrow from knockout mice to wild-type mice and vice versa to dissect cell type–dependent effects. Primary tubular cells and macrophages from SerpinB2 knockout and wild-type mice were used for functional studies and transcriptional profiling.

Cultured senescent tubular cells, kidneys of aged mice, and renal stress models exhibited upregulation of SerpinB2 expression. Functionally, lack of SerpinB2 in aged knockout mice had no effect on the magnitude of senescence markers but associated with enhanced kidney damage and fibrosis. In stress models, inflammatory cell infiltration was initially lower in knockout mice but later increased, leading to an accumulation of significantly more macrophages. SerpinB2 knockout tubular cells showed significantly reduced expression of the chemokine CCL2. Macrophages from knockout mice exhibited reduced phagocytosis and enhanced migration. Macrophage depletion and bone marrow transplantation experiments validated the functional relevance of these cell type–specific functions of SerpinB2.

SerpinB2 influences tubule-macrophage crosstalk by supporting tubular CCL2 expression and regulating macrophage phagocytosis and migration. In mice, SerpinB2 expression seems to be needed for coordination and timely resolution of inflammation, successful repair, and kidney homeostasis during aging. Implications of SerpinB2 in human kidney disease deserve further exploration.

To address a lack of good human-based cell culture models for studying cystinosis, we generated the first human induced pluripotent stem cell (iPSC) and kidney organoid models of the disorder. We used a variety of techniques to examine hallmarks of cystinosis—including cystine accumulation, lysosome size, the autophagy pathway, and apoptosis—and performed RNA sequencing on isogenic lines to identify differentially expressed genes in the cystinosis models compared with controls.

Compared with controls, these cystinosis models exhibit elevated cystine levels, increased apoptosis, and defective basal autophagy. Cysteamine treatment ameliorates this phenotype, except for abnormalities in apoptosis and basal autophagy. We found that treatment with everolimus, an inhibitor of the mTOR pathway, reduces the number of large lysosomes, decreases apoptosis, and activates autophagy, but it does not rescue the defect in cystine loading. However, dual treatment of cystinotic iPSCs or kidney organoids with cysteamine and everolimus corrects all of the observed phenotypic abnormalities.

These observations suggest that combination therapy with a cystine-depleting drug such as cysteamine and an mTOR pathway inhibitor such as everolimus has potential to improve treatment of cystinosis.

We transplanted kidney organoids under the renal capsule of the left kidney in immunodeficient mice followed by the implantation of a titanium imaging window on top of the kidney organoid. To assess glomerular function in the transplanted human pluripotent stem cell–derived kidney tissue 1, 2, and 3 weeks after transplantation, we applied high-resolution intravital multiphoton imaging through the imaging window during intravenous infusion of fluorescently labeled low and high molecular mass dextran molecules or albumin.

After vascularization, glomerular structures in the organoid displayed dextran and albumin size selectivity across their glomerular filtration barrier. We also observed evidence of proximal tubular dextran reuptake.

Our results demonstrate that human pluripotent stem cell–derived glomeruli can develop an appropriate barrier function and discriminate between molecules of varying size. These characteristics together with tubular presence of low molecular mass dextran provide clear evidence of functional filtration. This approach to visualizing glomerular filtration function will be instrumental for translation of organoid technology for clinical applications as well as for disease modeling.

This review provides insight in cross-species developmental differences of absorption, distribution, metabolism, and excretion properties in the kidney, which should be considered in neonate/juvenile study interpretation, hypotheses generation, and experimental design.

A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m²) at baseline, participants were classified into the four DKD phenotypes—no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR—to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline.

During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher.

Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.

We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006–2014) that linked the Sax Institute’s 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement <60 mL/min/1.73 m² recorded during the follow-up period. Participants with eGFR < 60 mL/min/1.73 m² at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR <60 mL/min/1.73 m² and multivariable Cox regression to examine factors associated with the study outcome.

Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR <60 mL/min/1.73 m² over a median follow-up time of 5.7 years (interquartile range, 3.0–5.9 years). The eGFR <60 mL/min/1.73 m² incidence rate per 100 person-years was 6.0 (95% CI 5.7–6.3) overall, 1.5 (1.3–1.9) in participants aged 45–54 years, 3.7 (3.4–4.0) for 55–64 year olds, 7.6 (7.1–8.1) for 65–74 year olds, 15.0 (13.0–16.0) for 75–84 year olds, and 26.0 (22.0–32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase; 95% CI 1.19–1.26), geography (outer regional and remote versus major city: 1.36; 1.17–1.58), obesity (obese class III versus normal: 1.44; 1.16–1.80), and the presence of hypertension (1.52; 1.33–1.73), coronary heart disease (1.13; 1.02–1.24), cancer (1.30; 1.14–1.50), and depression/anxiety (1.14; 1.01–1.27).

In participants with diabetes, the incidence of an eGFR <60 mL/min/1.73 m² was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.

We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that patients with less severe disease were prescribed metformin, propensity score matching (PSM) was conducted.

All-cause mortality and incident ESRD were lower in the metformin group according to the multivariate Cox analysis. Because the two groups had significantly different baseline characteristics, PSM was performed. After matching, metformin usage was still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57–0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58–0.77; P < 0.001). Only one event of metformin-associated lactic acidosis was recorded. In both the original and PSM groups, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668–1.276; P = 0.629).

In the present retrospective study, metformin usage in advanced chronic kidney disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. However, considering the remaining biases even after PSM, further randomized controlled trials are needed to change real-world practice.

Community-dwelling, nondisabled adults (n=330) ≥65 years of age underwent quantitative gait analysis, including walking while talking. Differences in walking-while-talking performance by CKD status were evaluated, and relative changes between walking-while-talking and walking alone performance were computed to quantify cognitive-motor interference (dual-task cost). Associations were tested using multivariable linear spline regression models, and independent gait domains were derived using factor analysis. CKD was defined as an eGFR<60 ml/min per 1.73 m².

CKD was present in 134 (41%) participants. Participants with CKD had slower gait speed along with various gait cycle abnormalities during walking while talking: among those with CKD, every 10-ml/min per 1.73 m² lower eGFR was associated with 3.3-cm/s (95% confidence interval, 0.4 to 6.1) slower gait speed, 1.8-cm (95% confidence interval, 0.6 to 3.0) shorter step length, 1.1% (95% confidence interval, 0.6 to 1.7) less time in the swing phase, and 1.4% (95% confidence interval, 0.5 to 2.3) greater time in double support after multivariable adjustment. When comparing walking while talking with walking alone, every 10-ml/min per 1.73 m² lower eGFR was associated with 1.8% (95% confidence interval, 0.5 to 3.2) greater decrease in time in the swing phase and 0.9% (95% confidence interval, 0.2 to 1.5) greater increase in time in the stance phase. Factor analysis identified three walking-while-talking domains and three dual-task cost domains: eGFR was associated specifically with the rhythm domain for both walking-while-talking and dual-task cost. Every 10-ml/min per 1.73 m² lower eGFR was associated with a poorer performance of 0.2 SD (95% confidence interval, 0.1 to 0.3) for walking while talking and 0.2 SD (95% confidence interval, 0.03 to 0.3) for dual-task cost.

During walking while talking, CKD is associated with gait abnormalities, possibly due to increased cognitive-motor interference.

The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone.

No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference –2.4%; 95% confidence interval, –11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; –7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3x upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; –2.0% to 4.7%).

Tolvaptan has been used safely in combination with statins in clinical trials.

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3

We measured serum uromodulin in 5143 participants enrolled in the German CKD (GCKD) study. The associations of baseline serum uromodulin with all-cause mortality, major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, nonfatal myocardial infarction or stroke, or incident peripheral vascular disease), and kidney failure (dialysis or transplantation) were evaluated using multivariable Cox proportional hazard regression analyses in a cohort study design, adjusting for demographics, eGFR, albuminuria, cardiovascular risk factors, and medication.

The mean age of participants was 60±12 years, 60% were male. Mean serum uromodulin concentration was 98±60 ng/ml, eGFR was 49±18 ml/min per 1.73 m², and 78% had eGFR <60 ml/min per 1.73 m². Participants in lower serum uromodulin quartiles had lower eGFR and higher albuminuria, prevalence of diabetes, hypertension, coronary artery disease, and more frequent history of stroke at baseline. During a follow-up of 4 years, 335 participants died, 417 developed MACE, and 229 developed kidney failure. In multivariable analysis, the highest serum uromodulin quartile was associated with lower hazard for mortality (hazard ratio [HR], 0.57; 95% CI, 0.38 to 0.87), MACE (HR, 0.63; 95% CI, 0.45 to 0.90), and kidney failure (HR, 0.24; 95% CI, 0.10 to 0.55) compared with the lowest quartile.

Higher serum uromodulin is independently associated with lower risk for mortality, cardiovascular events, and kidney failure in white patients with CKD.

Deutsches Register für Klinische Studien (DRKS; German national database of clinical studies), DRKS00003971.

This retrospective observational study evaluated adults (18 years of age or older) with ischemic stroke who underwent CTA and cerebral angiography sequentially between 2010 and 2018. The incidence of postcontrast acute kidney injury was determined using the baseline estimated glomerular filtration rate. The value of the baseline estimated glomerular filtration rate at which the occurrence of postcontrast acute kidney injury increased was also determined.

Postcontrast acute kidney injury occurred in 57/601 (9.5%) patients. Those with a baseline estimated glomerular filtration rate of <30 mL/min/1.73 m² showed a higher incidence of acute kidney injury. Age, chronic kidney disease, medication (nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, statins, and insulin) use following contrast media exposure, and serum albumin affected the incidence of postcontrast acute kidney injury. The incidence of postcontrast acute kidney injury increased when the baseline estimated glomerular filtration rate was <43 mL/min/1.73 m².

Patients with low baseline renal function had the highest incidence of postcontrast acute kidney injury after CTA and cerebral angiography, but no fatal adverse effects were documented. Thus, patients suspected of having a stroke should be actively managed with respect to neurovascular function.