Citations

Abstract Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. Methods In a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation. Results 7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%. Conclusions None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.

Significance Statement The quality of a kidney obtained from a living donor is often inferred from the donor’s age, risk factors, and kidney function. Little is known about the influence of a donated kidney’s structural features on the risk of death-censored graft failure in the recipient. In an analysis of 2293 kidney donor-recipient pairs, the authors identified subclinical nephrosclerosis, larger nephron size (but not nephron number), and smaller medullary volume as structural predictors of death-censored graft failure that were independent of both donor and recipient clinical characteristics. These findings provide important insights into the factors that define the “intrinsic quality” of the living kidney donor graft at the time of donation, and support use of intraoperative biopsies to identify donor kidneys that are at higher risk for failure. Background Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. Methods Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. Results The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. Conclusions Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft’s “intrinsic quality” at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

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.