Rule, Andrew D.

Objective Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD. Research design and methods In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin. Results Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r s =−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r s =0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased. Conclusions Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 . This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 . Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Significance Statement Research investigating glomerular morphology in different cortical regions has been limited to animal models and a small number of human autopsy kidneys. In this study, the authors used tissue from living patients who underwent a radical nephrectomy (for a renal tumor) to characterize glomerular morphology and glomerulosclerosis by cortical depth. They found that glomerular volume and glomerulosclerosis differed by depth across three cortical regions (superficial, middle, and deep). Although most clinical associations with glomerulosclerosis and glomerulomegaly did not differ by cortical depth, there were important exceptions. Age-related glomerulosclerosis appeared to be an ischemic process and was more evident in the superficial (subcapsular) region. Diabetes-related glomerulosclerosis was more evident in the deep (juxtamedullary) region. Obesity more strongly associated with larger glomeruli in the superficial region. Background Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited. Methods To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions. Results The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µ m 3 , respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex. Conclusions Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.

Significance Statement Kidney stone recurrence can manifest with symptoms from stone passage or with asymptomatic changes in kidney stone burden revealed by radiography. In a multicenter, prospective cohort study, the authors demonstrate that substantially more asymptomatic and self-managed symptomatic kidney stone recurrence occur in stone formers than has been appreciated, as many studies consider only symptomatic recurrence that results in clinical care. Among first-time symptomatic stone formers, 54% had an asymptomatic kidney stone; half of those with such a stone passed it within 5 years (but only half who did so experienced symptoms). The findings also show that when a more comprehensive definition of recurrence that includes all symptomatic and radiological manifestations is used, risk factors better predict kidney stone recurrence, thus supporting a comprehensive assessment of recurrence in clinical trials. Background Meaningful interpretation of changes in radiographic kidney stone burden requires understanding how radiographic recurrence relates to symptomatic recurrence and how established risk factors predict these different manifestations of recurrence. Methods We recruited first-time symptomatic stone formers from the general community in Minnesota and Florida. Baseline and 5-year follow-up study visits included computed tomography scans, surveys, and medical record review. We noted symptomatic recurrence detected by clinical care (through chart review) or self-report, and radiographic recurrence of any new stone, stone growth, or stone passage (comparing baseline and follow-up scans). To assess the prediction of different manifestations of recurrence, we used the Recurrence of Kidney Stone (ROKS) score, which sums multiple baseline risk factors. Results Among 175 stone formers, 19% had symptomatic recurrence detected by clinical care and 25% detected by self-report; radiographic recurrence manifested as a new stone in 35%, stone growth in 24%, and stone passage in 27%. Among those with a baseline asymptomatic stone (54%), at 5 years, 51% had radiographic evidence of stone passage (accompanied by symptoms in only 52%). Imaging evidence of a new stone or stone passage more strongly associated with symptomatic recurrence detected by clinical care than by self-report. The ROKS score weakly predicted one manifestation—symptomatic recurrence resulting in clinical care ( c -statistic, 0.63; 95% confidence interval, 0.52 to 0.73)—but strongly predicted any manifestation of symptomatic or radiographic recurrence (5-year rate, 67%; c -statistic, 0.79; 95% confidence interval, 0.72 to 0.86). Conclusions Recurrence after the first stone episode is both more common and more predictable when all manifestations of recurrence (symptomatic and radiographic) are considered.

AbstractBackgroundReliable and valid tools to screen for malnutrition in the intensive care unit (ICU) remain elusive. The sarcopenia index (SI) [(serum creatinine/serum cystatin C) × 100], could be an inexpensive, objective tool to predict malnutrition. We evaluated the SI as a screening tool for malnutrition in the ICU and compared it with the modified‐NUTRIC score.Materials and MethodsThis was a historical cohort study of ICU patients with stable kidney function admitted to Mayo Clinic ICUs between 2008 and 2015. Malnutrition was defined by the Subjective Global Assessment. Diagnostic performance was evaluated with the area under the receiver operating characteristic curve (AUC) and multivariable logistic regression.ResultsOf the 398 included patients, 181 (45%) had malnutrition, with 34 (9%) scored as severely malnourished. The SI was significantly lower in malnourished patients than in well‐nourished patients (64 ± 27 vs 72 ± 25; P = 0.002), and reductions in SI corresponded to increased malnutrition severity (P = 0.001). As a screening tool, the SI was an indicator of malnutrition risk (AUC 0.61) and performed slightly better than the more complex modified‐NUTRIC score (AUC = 0.57). SI cutoffs of 101 and 43 had >90% sensitivity and >90% specificity, respectively, for the prediction of malnutrition. Patients with a low SI (≤43) had a significantly higher risk of mortality (HR = 2.61, 95% CI 1.06–6.48, P = 0.038).ConclusionThe frequency of malnutrition was high in this critically ill population, and it was associated with a poor prognosis. The SI could be used to assess nutrition risk in ICU patients.

Abstract Background High glomerular filtration rate (GFR) is often used as a surrogate for single-nephron hyperfiltration. Our objective was to determine the definition for high GFR that best reflects clinical and structural characteristics of hyperfiltration. Methods We studied living kidney donors at the Mayo Clinic and Cleveland Clinic. Potential donors underwent evaluations that included measured GFR (mGFR) by iothalamate clearance and estimated GFR (eGFR) by the serum creatinine–based Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI) equation. High GFR was defined by the 95th percentile for each method (mGFR or eGFR) using either overall or age-specific thresholds. High mGFR was defined as both corrected and uncorrected for body surface area. The association of high GFR by each definition with clinical characteristics and radiologic findings (kidney volume) was assessed. In the subset that donated, the association of high GFR with kidney biopsy findings (nephron number and glomerular volume) and single-nephron GFR was assessed. Results We studied 3317 potential donors, including 2125 actual donors. The overall 95th percentile for corrected mGFR was 134 mL/min/1.73 m2 and for eGFR was 118 mL/min/1.73 m2. The age-based threshold for uncorrected mGFR was 198 mL/min − 0.943×Age, for corrected mGFR it was 164 mL/min/1.73 m2 − 0.730×Age and for eGFR it was 146 mL/min/1.73 m2 − 0.813×Age. High age-based uncorrected mGFR had the strongest associations with higher single-nephron GFR, larger glomerular volume, larger kidney volume, male gender, higher body mass index and higher 24-h urine albumin, but also had the strongest association with high nephron number. A high age-height-gender–based uncorrected mGFR definition performed almost as well but had a weaker association with nephron number and did not associate with male gender. Conclusions High age-based uncorrected mGFR showed the most consistent associations reflective of hyperfiltration. However, high age-based uncorrected mGFR has limited clinical utility because it does not distinguish between hyperfiltration and high nephron number.

AbstractBackgroundNephrotoxins contribute to 20%–40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations.MethodsThe study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups.ResultsThe overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85–1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71–1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09).ConclusionShort courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.