The role of biomarkers in early identification of acute kidney injury among non-critically ill patients.

BACKGROUND: Prediction and/or early identification of acute kidney injury (AKI) and individuals at greater risk remains of great interest in clinical medicine. Acute kidney injury continues to be a common complication among hospitalized patients, with an incidence ranging from 6 to 58%, depending on the setting. Aim of this study was to determine the performance of Insulin-like growth factor binding protein-7 (IGFBP7), tissue metallopeptidase inhibitor 2 (TIMP2), and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in early detection of AKI among non-critically ill patients. METHODS: In this prospective observational study at Mayo Clinic Hospitals in Rochester, Minnesota, USA, non-critically ill patients admitted from the emergency department between October 31st, 2016 and May 1st, 2018, who had an acute kidney injury (AKI) probability of 5% or higher were included. Biomarkers were measured in residual urine samples collected in the emergency department. The primary outcome was biomarker performance in predicting AKI development within the first 72 h. RESULTS: Among 368 included patients, the mean age was 79 ± 12 years, and 160 (43%) were male. Acute kidney injury occurred in 62 (17%) patients; 11.5% stage 1, 2.5% stage 2, and 3% stage 3. Twelve patients (3%) died during hospitalization and 102 (28%) within nine months after admission. The median uNGAL and IGFBP7-TIMP2 were 57 [20-236 ng/ml], and 0.3 [0.1-0.8], respectively. The C-statistic of uNGAL and IGFBP7-TIMP2 of > 0.3 and > 2.0 for AKI prediction were 0.56, 0.54, and 0.53, respectively. In a model where one point is assigned to each marker of AKI (elevated serum creatinine, IGFBP7-TIMP2 > 0.3, and uNGAL), a higher score correlated with higher nine-month mortality [OR of 1.32 per point (95% CI 1.02-1.71)]. CONCLUSION: Among non-critically ill hospitalized patients, the performance of uNGAL and IGFBP7-TIMP2 for AKI prediction within 72 h of admission was modest. This suggests a limited role for these biomarkers in AKI risk stratification among non-critically ill patients. Key learning points What was known Acute kidney injury (AKI) is a common complication among hospitalized patients. It is associated with increased morbidity and mortality. Various clinical prediction models and biomarkers have been developed to identify patients in special populations (such as ICU and cardiac surgery) who are at risk of AKI and diagnose AKI early. This study adds The performance of the biomarkers uNGAL, TIMP-2, and IGFBP-7 in predicting AKI within 72 h of admission in non-critically ill patients was modest. However, these biomarkers were found to have a prognostic value for predicting 9-month mortality. One potential application of these biomarkers is identifying patients at higher AKI risk before exposing them to nephrotoxic agents. Potential impact This study provides evidence regarding the real-world performance of current FDA-approved biomarkers (uNGAL, TIMP-2, and IGFBP-7) for predicting acute kidney injury (AKI) within 72 h of hospital admission among noncritically ill patients. While the performance of these biomarkers for predicting short-term AKI was modest, they may have a prognostic value for predicting 9-month mortality.

Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies.

BACKGROUND: Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment. METHODS: We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria. RESULTS: Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD. CONCLUSION: Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.

Risk Factors for Acute Kidney Injury in Hospitalized Non-Critically Ill Patients: A Population-Based Study.

OBJECTIVE: To develop and validate an acute kidney injury (AKI) risk prediction model for hospitalized non-critically ill patients. PATIENTS AND METHODS: We retrospectively identified all Olmsted County, Minnesota, residents admitted to non-intensive care unit (ICU) wards at Mayo Clinic Hospital, Rochester, Minnesota, in 2013 and 2014. The cohort was divided into development and validation sets by year. The primary outcome was hospital-acquired AKI defined by Kidney Disease: Improving Global Outcomes criteria. Cox regression was used to analyze mortality data. Comorbid risk factors for AKI were identified, and a multivariable model was developed and validated. RESULTS: The development and validation cohorts included 3816 and 3232 adults, respectively. Approximately 10% of patients in both cohorts had AKI, and patients with AKI had an increased risk of death (hazard ratio, 3.62; 95% CI, 2.97-4.43; P<.001). Significant univariate determinants of AKI were preexisting kidney disease, diabetes mellitus, hypertension, heart failure, vascular disease, coagulopathy, pulmonary disease, coronary artery disease, cancer, obesity, liver disease, and weight loss (all P<.05). The final multivariable model included increased baseline serum creatinine value, admission to a medical service, pulmonary disease, diabetes mellitus, kidney disease, cancer, hypertension, and vascular disease. The area under the receiver operating characteristic curves for the development and validation cohorts were 0.71 (95% CI, 0.69-0.75) and 0.75 (95% CI, 0.72-0.78), respectively. CONCLUSION: Hospital-acquired AKI is common in non-ICU inpatients and is associated with worse outcomes. Patient data at admission can be used to identify increased risk; such patients may benefit from more intensive monitoring and earlier intervention and testing with emerging biomarkers.

Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment.

Globally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age.

The Incidence of Primary vs Secondary Focal Segmental Glomerulosclerosis: A Clinicopathologic Study.

OBJECTIVES: To describe the change in the incidence rates of primary and secondary focal segmental glomerulosclerosis (FSGS) from 1994 through 2013 in Olmsted County, Minnesota, and to identify the clinical and biopsy characteristics that distinguish primary from secondary FSGS. PATIENTS AND METHODS: Olmsted County adult residents with native kidney biopsy from January 1, 1994, through December 31, 2013, and FSGS as the only glomerulopathy were identified. The clinical and pathologic characterstics of primary and secondary FSGS were described and compared, and incidence rates were calculated. RESULTS: Of 370 adults biopsied, 281 had glomerular diseases, of which 46 (16%) had FSGS. From 1994-2003 to 2004-2013, there were significant increases in kidney biopsy rates (14.7 [95% CI, 12.1-17.3] vs 22.9 [95% CI, 20.0-25.7] per 100,000 person-years, 17% increase per 5 years; P<.001) and total FSGS rates (1.4 [95% CI, 0.6-2.2] vs 3.2 [95% CI, 2.1-4.3] per 100,000 person-years, 41% increase per 5 years; P=.02). Compared with patients with limited foot process effacement (<80%), patients with diffuse effacement (≥80%) without an identifiable cause had lower serum albumin levels (P<.001), had higher proteinuria (P<.001), and were more likely to have nephrotic syndrome (100% vs 4%; P<.001). Patients with diffuse effacement without an identifiable cause were classified as primary FSGS, which accounted for 3 of 12 patients (25%) during 1994-2003 and 9 of 34 (26%) during 2004-2013. CONCLUSION: Although the incidence of FSGS has increased, the proportions of primary and secondary FSGS have remained stable.

Renal Outcomes in Patients With IgA Nephropathy Undergoing Liver Transplant: A Retrospective Cohort Study.

BACKGROUND: End-stage liver disease (ESLD) is the most common cause of secondary immunoglobulin A nephropathy (IgAN). Multiple mechanisms have been proposed to explain the association between liver disease and IgAN. Although some mechanisms are expected to reverse in patients after liver transplant, the long-term renal prognosis is unclear for these patients. METHODS: This observational retrospective cohort study examined the renal outcomes of 14 patients who had IgAN with end-stage liver disease and subsequently underwent either liver transplant alone or combined liver and kidney transplant at a single tertiary care center. RESULTS: Of the 7 patients who underwent liver transplant alone, hematuria persisted in 2, 4 had progressive loss of kidney function with worsening proteinuria in 3 but only 1 reached end-stage renal disease 5 years posttransplant. Among 7 combined liver and kidney transplant recipients, 1 had histologic and 1 had histologic and clinical recurrence of IgAN without kidney allograft loss. CONCLUSIONS: IgAN in patients with advanced liver disease does not necessarily resolve after liver transplant but has overall favorable renal outcomes.

Structural and Functional Changes in Human Kidneys with Healthy Aging.

Aging is associated with significant changes in structure and function of the kidney, even in the absence of age-related comorbidities. On the macrostructural level, kidney cortical volume decreases, surface roughness increases, and the number and size of simple renal cysts increase with age. On the microstructural level, the histologic signs of nephrosclerosis (arteriosclerosis/arteriolosclerosis, global glomerulosclerosis, interstitial fibrosis, and tubular atrophy) all increase with age. The decline of nephron number is accompanied by a comparable reduction in measured whole-kidney GFR. However, single-nephron GFR remains relatively constant with healthy aging as does glomerular volume. Only when glomerulosclerosis and arteriosclerosis exceed that expected for age is there an increase in single-nephron GFR. In the absence of albuminuria, age-related reduction in GFR with the corresponding increase in CKD (defined by an eGFR<60 ml/min per 1.73 m2) has been shown to associate with a very modest to no increase in age-standardized mortality risk or ESRD. These findings raise the question of whether disease labeling of an age-related decline in GFR is appropriate. These findings also emphasize the need for a different management approach for many elderly individuals considered to have CKD by current criteria.

The Development and Evaluation of a Novel Instrument Assessing Residents' Discharge Summaries.

PURPOSE: To develop and determine the reliability of a novel measurement instrument assessing the quality of residents' discharge summaries. METHOD: In 2014, the authors created a discharge summary evaluation instrument based on consensus recommendations from national regulatory bodies and input from primary care providers at their institution. After a brief pilot, they used the instrument to evaluate discharge summaries written by first-year internal medicine residents (n = 24) at a single U.S. teaching hospital during the 2013-2014 academic year. They conducted a generalizability study to determine the reliability of the instrument and a series of decision studies to determine the number of discharge summaries and raters needed to achieve a reliable evaluation score. RESULTS: The generalizability study demonstrated that 37% of the variance reflected residents' ability to generate an adequate discharge summary (true score variance). The decision studies estimated that the mean score from six discharge summary reviews completed by a unique rater for each review would yield a reliability coefficient of 0.75. Because of high interrater reliability, multiple raters per discharge summary would not significantly enhance the reliability of the mean rating. CONCLUSIONS: This evaluation instrument reliably measured residents' performance writing discharge summaries. A single rating of six discharge summaries can achieve a reliable mean evaluation score. Using this instrument is feasible even for programs with a limited number of inpatient encounters and a small pool of faculty preceptors.

Should We Always Defer Treatment of Kidney Disease When There Is Extensive Interstitial Fibrosis on Biopsy?

Severity of interstitial fibrosis and tubular atrophy (IFTA) seen on kidney biopsy has been used by nephrologist as prognostic marker of kidney disease. While IFTA is a very strong predictor of kidney failure, some patients with severe fibrosis will still not progress to kidney failure within 5 years. Treatment of underlying kidney disease in select patients with severe IFTA should be considered when risks of treatment are reasonable despite the low potential for benefit.