Evaluating the feasibility of the KDIGO CKD referral recommendations

Abstract Background In 2012, the international nephrology organization Kidney Disease Improving Global Outcomes (KDIGO) released recommendations for nephrology referral for chronic kidney disease (CKD) patients. The feasibility of adhering to these recommendations is unknown. Methods We conducted a retrospective analysis of the primary care population at Brigham and Women’s Hospital (BWH). We translated referral recommendations based upon serum creatinine, estimated glomerular filtration rate (eGFR), and albuminuria into a set of computable criteria in order to project referral volume if the KDIGO referral recommendations were to be implemented. Using electronic health record data, we evaluated each patient using the computable criteria at the times that the patient made clinic visits in 2013. We then compared the projected referral volume with baseline nephrology clinic volume. Results Out of 56,461 primary care patients at BWH, we identified 5593 (9.9%) who had CKD based on albuminuria or estimated GFR. Referring patients identified by the computable criteria would have resulted in 2240 additional referrals to nephrology. In 2013, this would represent a 38.0% (2240/5892) increase in total nephrology patient volume and 67.3% (2240/3326) increase in new referral volume. Conclusions This is the first study to examine the projected impact of implementing the 2012 KDIGO referral recommendations. Given the large increase in the number of referrals, this study is suggestive that implementing the KDIGO referral guidelines may not be feasible under current practice models due to a supply-demand mismatch. We need to consider new strategies on how to deliver optimal care to CKD patients using the available workforce in the U.S. health care system.https://deepblue.lib.umich.edu/bitstream/2027.42/137675/1/12882_2017_Article_646.pd

Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression

The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease

Comparison of Urine Output among Patients Treated with More Intensive Versus Less Intensive RRT: Results from the Acute Renal Failure Trial Network Study

Intensive RRT may have adverse effects that account for the absence of benefit observed in randomized trials of more intensive versus less intensive RRT. We wished to determine the association of more intensive RRT with changes in urine output as a marker of worsening residual renal function in critically ill patients with severe AKI

Dialysate sodium, serum sodium and mortality in maintenance hemodialysis

Abstract Background. Individuals with end-stage kidney disease appear to have stable pre-dialysis serum sodium concentrations over time, with lower values associating with increased mortality. Dialysate sodium concentrations have increased over many years in response to shorter treatments, but the relationship between serum sodium, dialysate sodium and outcomes in chronic hemodialysis patients has not yet been systematically examined. Methods. We studied a cohort of 2272 individuals receiving thrice-weekly hemodialysis treatment. Available data included demographics, laboratory and clinical measures, details of the dialysis prescription and 30-month follow-up. We examined the distribution of serum and dialysate sodium among subjects and compared mortality according to dialysate and serum sodium concentrations using Cox regression models. Results. Dialysate sodium concentration varied within and among dialysis centers. The pre-dialysis serum sodium concentration (mean 136.1 mmol/L) did not differ across dialysate sodium concentrations. There was evidence for effect modification for mortality according to differing serum sodium and dialysate sodium concentrations (P ¼ 0.05). For each 4 mmol/L increment in serum sodium, the hazard ratio for death was 0.72 [95% confidence interval (CI) 0.63-0.81] with lower dialysate sodium compared to 0.86 (95% CI 0.75-0.99) for higher dialysate sodium. Higher dialysate sodium concentration was associated with mortality at higher, but not lower, pre-dialysis serum sodium concentrations. Conclusions. The pre-dialysis serum sodium concentration appears to be unaffected by the dialysate sodium concentration. The relationship between serum and dialysate sodium and mortality appears to be variable. Further research is warranted to determine the biological mechanisms of these associations and to re-examine total body sodium handling in hemodialysis

Erythropoiesis-stimulating Agent Use among Patients with Lupus Nephritis Approaching End-stage Renal Disease

Objectives: Little is known about erythropoiesis-stimulating agents (ESAs) utilization among lupus nephritis (LN) patients with incipient ESRD. We aimed to identify sociodemographic and clinical factors associated with ESA use among incident LN ESRD patients. Methods: Among all individuals age ≥18 with incident ESRD from 1995-2008 in the U.S. Renal Data System (USRDS), we identified those with systemic lupus erythematosus (ICD-9 code 710.0) as the cause of ESRD. ESA use at ESRD onset was ascertained from the Medical Evidence Report. Year of onset, age, sex, race/ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered potentially associated with ESA use in multivariable-adjusted logistic regression analyses. Results: We identified 12,533 individuals with incident LN ESRD (1% of entire population). Of those, 4,288 (34%) received an ESA preceding ESRD. In multivariable-adjusted models, ESA users had higher serum albumin and hemoglobin concentrations, were more likely to be women, and to live in the Northeast. Conversely, Medicaid beneficiaries, the uninsured, unemployed, African Americans, Hispanics, and those with IV drug use, congestive heart failure and obesity had lower ESA use. Conclusion: Among all U.S. patients and those with LN who developed ESRD, approximately one third received ESAs. Patient sex, race, age, medical insurance, residential region and clinical factors were significantly associated with ESA therapy. While there are no guidelines for ESA use in LN patients approaching ESRD, there has been wide sociodemographic variation, raising questions about ESA prescription practices

Fibrinogen Excretion in the Urine and Immunoreactivity in the Kidney Serves as a Translational Biomarker for Acute Kidney Injury

Fibrinogen (Fg) is significantly up-regulated in the kidney after acute kidney injury (AKI). We evaluated the performance of Fg as a biomarker for early detection of AKI. In rats and mice with kidney tubular damage induced by ischemia/reperfusion (I/R) or cisplatin administration, respectively; kidney tissue and urinary Fg increased significantly and correlated with histopathological injury, urinary kidney injury molecule-1 (KIM-1) and N-acetyl glucosaminidase (NAG) corresponding to the progression and regression of injury temporally. In a longitudinal follow-up of 31 patients who underwent surgical repair of abdominal aortic aneurysm, urinary Fg increased earlier than SCr in patients who developed postoperative AKI (AUC-ROC = 0.72). Furthermore, in a cohort of patients with biopsy-proven AKI (n = 53), Fg immunoreactivity in the tubules and interstitium increased remarkably and was able to distinguish patients with AKI from those without AKI (n = 59). These results suggest that immunoreactivity of Fg in the kidney, as well as urinary excretion of Fg, serves as a sensitive and early diagnostic translational biomarker for detection of AKI

Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing

Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured proximal tubule cells fails to undergo normal repair and assumes a proinflammatory and profibrotic phenotype that may promote fibrosis and chronic kidney disease. The healthy to failed repair change is marked by cell state-specific transcriptomic and epigenomic changes. Single nucleus joint RNA- and ATAC-seq sequencing offers an opportunity to study the gene regulatory networks underpinning these changes in order to identify key regulatory drivers. We develop a regularized regression approach to construct genome-wide parametric gene regulatory networks using multiomic datasets. We generate a single nucleus multiomic dataset from seven adult human kidney samples and apply our method to study drivers of a failed injury response associated with kidney disease. We demonstrate that our approach is a highly effective tool for predicting key cis- and trans-regulatory elements underpinning the healthy to failed repair transition and use it to identify NFAT5 as a driver of the maladaptive proximal tubule state

Assessment of Interobserver Reliability of Nephrologist Examination of Urine Sediment.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadImportance: Urine sediment microscopy is commonly performed during the evaluation of kidney disease. Interobserver reliability of nephrologists' urine sediment examination has not been well studied. Objective: Assess interobserver reliability of the urine sediment examination. Design, setting, and participants: In this diagnostic test study, urine samples were prospectively collected from a convenience sample of adult patients from an academic hospital in the United States undergoing kidney biopsy from July 11, 2018, to March 20, 2019. Digital images and videos of urine sediment findings were captured using a bright-field microscope. These images and videos along with urine dipstick results were incorporated in online surveys and sent to expert nephrologists at 15 US teaching hospitals. They were asked to identify individual sediment findings and the most likely underlying disease process. Exposures: Urine dipstick results and urine sediment images from patients undergoing native kidney biopsy. Main outcomes and measures: Interobserver reliability of urine sediment microscopy findings estimated by overall percent agreement and Fleiss κ coefficients. Secondary outcomes included concordance of diagnoses suspected by nephrologists with corresponding kidney biopsy results. Results: In total, 10 surveys from 10 patients containing 76 study questions on individual features were sent to 21 nephrologists, 14 (67%) of whom completed them all. Their combined 1064 responses were analyzed. Overall percent agreement for casts was an estimated 59% (95% CI, 50%-69%), κ = 0.52 (95% CI, 0.42-0.62). For other sediment findings, overall percent agreement was an estimated 69% (95% CI, 61%-77%), κ = 0.65 (95% CI, 0.56-0.73). The κ estimates ranged from 0.13 (95% CI, 0.10-0.17) for mixed cellular casts to 0.90 (95% CI, 0.87-0.94) for squamous epithelial cells. Conclusions and relevance: In this study, substantial variability occurred in the interpretation of urine sediment findings, even among expert nephrologists. Educational or technological innovations may help improve the urine sediment as a diagnostic tool

ADAM17 substrate release in proximal tubule drives kidney fibrosis

Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates\u27 receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis