Larger Nephron Size and Nephrosclerosis Predict Progressive CKD and Mortality after Radical Nephrectomy for Tumor and Independent of Kidney Function.

BACKGROUND: Nephron hypertrophy and nephrosclerosis may be important determinants of CKD and mortality. However, studies of outcomes associated with these microstructural features have been limited to small tissue specimens from patients selected for either good kidney health or known kidney disease. METHODS: To determine whether microstructural features are predictive of progressive CKD and mortality outcomes, we studied patients who underwent a radical nephrectomy for a tumor. Large wedge sections of renal parenchyma distal to the tumor were stained and scanned into high-resolution images; we annotated the cortex and all glomeruli to calculate glomerular volume, cortex volume per glomerulus, and percentage of globally sclerotic glomeruli. Morphometric measurements also included percentages of artery luminal stenosis and interstitial fibrosis/tubular atrophy (IF/TA) of the cortex. At follow-up visits every 6-12 months, we determined which patients experienced progressive CKD (defined as dialysis, kidney transplantation, or a 40% decline from postnephrectomy eGFR). Cox models for these outcomes were adjusted for age, sex, body mass index, hypertension, diabetes, smoking, eGFR, and proteinuria. RESULTS: Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73 m2), 117 progressive CKD events, 183 noncancer deaths, and 116 cancer deaths occurred during a median follow-up of 6.4 years. Larger glomerular volume, larger cortex per glomerulus, and higher percentage of globally sclerotic glomeruli or IF/TA predicted progressive CKD. Higher percentage IF/TA also predicted noncancer mortality. Microstructural features did not predict cancer mortality or recurrence. CONCLUSIONS: After a radical nephrectomy, larger nephrons and nephrosclerosis predicted progressive CKD, and IF/TA predicted noncancer mortality. Morphometric analysis of renal parenchyma can predict noncancer clinical events in patients long after their radical nephrectomy.

In-vivo techniques for determining nephron number.

PURPOSE OF REVIEW: Many studies have suggested low nephron endowment at birth contributes to the risk of developing hypertension and chronic kidney disease (CKD) later in life. Loss of nephrons with age and disease is largely a subclinical process. New technologies are needed to count nephrons as glomerular filtration rate (GFR) is a poor surrogate for nephron number. RECENT FINDINGS: Cortical volume, glomerular density, and percent globally sclerotic glomeruli are imperfect surrogates for nephron number. The disector-fractionator method is the most accurate method to count nephrons but is limited to autopsy settings. Glomerular density combined with kidney imaging and ultrafiltration coefficient-based methods require a kidney biopsy, and have been applied in living humans (kidney donors). Low nephron number predicts a higher postdonation urine albumin. Contrast-enhanced MRI has detected glomeruli without a biopsy, but so far, not in living humans. SUMMARY: Currently, there is no accurate and well tolerated method for determining nephron number in living humans. A clinically useful method may allow GFR to be replaced by its more relevant determinants: nephron number and single nephron GFR. This could revolutionize nephrology by separating the measurement of chronic disease (nephron loss) from more reversible hemodynamic effects (nephron hyperfiltration/hypofiltration).

Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study.

BACKGROUND: Global glomerulosclerosis is characteristic of chronic kidney disease and also occurs with normal aging. Our goal was to determine the upper limit of normal for number of globally sclerotic glomeruli. METHODS: Core-needle biopsies of the renal cortex were obtained at the time of living kidney transplantation at three centers between 1998 and 2011. The number of globally sclerotic glomeruli was averaged across two biopsy sections. Quantile regression was used to estimate the 95th percentile for globally sclerotic glomeruli as the upper reference limit. There were 2052 donors (mean age 43 years, 41% male, 10% hypertensive), with a mean (SD) of 16.0 (9.7) glomeruli and 0.47 (0.99) globally sclerotic glomeruli on biopsy; only 2.6% had >5% fibrosis. RESULTS: In a multivariable model excluding hypertensive donors, independent predictors of the number of globally sclerotic glomeruli were age, total number of glomeruli and cortex area. A simplified model was used to estimate the 95th percentile for number of globally sclerotic glomeruli by total number of glomeruli and age. For a biopsy section with 17-32 total glomeruli, the 95th percentile ranged from 1 for a 20-year old to 5.5 for a 70-year old donor. Hypertensive donors were more likely to have an abnormal number of globally sclerotic glomeruli (OR = 1.79, P = 0.035). CONCLUSIONS: We have derived the 95% reference limit for number of globally sclerotic glomeruli in ostensibly healthy individuals accounting for age and the biopsy characteristics. Numbers of globally sclerotic glomeruli in a kidney biopsy that exceed these thresholds suggest chronic pathological injury in excess of that expected with normal aging.

Quantification of asymptomatic kidney stone burden by computed tomography for predicting future symptomatic stone events.

OBJECTIVE: To find the optimal characterization of asymptomatic radiographic stone burden on computed tomography (CT) scans. METHODS: A survey was sent to stone formers who underwent a CT scan while asymptomatic during a stone clinic evaluation. Symptomatic stone passage events after CT scan were detected by survey and medical record review. Radiographic stone burden was quantified by number of stones, largest stone diameter, automated total stone volume (TSV), and bilateral stones and then compared as predictors of stone events. RESULTS: There were 550 stone formers; 43% had a stone event for a median of 4.7 years after the CT scan. Stone burden by quartiles was 0-1, 2-3, 4-6, and ≥7 for number of stones; 0-2, 3-4, 5-7, and ≥8 mm for largest stone diameter; and 0-8, 9-78, 79-280, and ≥281 mm(3) for TSV; 48% had bilateral stones. The hazard ratios (HRs) for symptomatic event was 1.30 (P <.001) for the number of stones per quartile, 1.26 (P <.001) for largest stone diameter per quartile, 1.38 (P <.001) for TSV per quartile, and 1.80 (P <.001) for bilateral stones. On multivariate analysis, only TSV was an independent predictor of symptomatic events (HR, 1.35 per quartile; P = .01). This risk of events with TSV was also independent of demographics, urine chemistries, and stone composition. Among the 53 patients with interim events between CT scans, a rapid increase in TSV between CT scans (>570 mm(3) per year) predicted subsequent events (HR, 2.8; P = .05). CONCLUSION: Automated TSV is more predictive of symptomatic events than manual methods for quantifying stone burden on CT scan.

Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors.

BACKGROUND AND OBJECTIVES: The relationship of kidney function and CKD risk factors to structural changes in the renal parenchyma of normal adults is unclear. This study assessed whether nephron hypertrophy and nephrosclerosis had similar or different associations with kidney function and risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From 1999 to 2009, 1395 living kidney donors had a core needle biopsy of their donated kidney during transplant surgery. The mean nonsclerotic glomerular volume and glomerular density (globally sclerotic and nonsclerotic) were estimated using the Weibel and Gomez stereologic methods. All tubules were counted in 1 cm(2) of cortex to determine a mean profile tubular area. Nephron hypertrophy was identified by larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density. Nephrosclerosis was identified by higher globally sclerotic glomerular density. RESULTS: The mean (± SD) age was 44 ± 12 years, 24-hour urine albumin excretion was 5 ± 7 mg, measured GFR was 103 ± 17 ml/min per 1.73 m(2), uric acid was 5.2 ± 1.4 mg/dl, and body mass index was 28 ± 5 kg/m(2). Of the study participants, 43% were men, 11% had hypertension, and 52% had a family history of ESRD. Larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density were correlated. Male sex, higher 24-hour urine albumin excretion, family history of ESRD, and higher body mass index were independently associated with each of these measures of nephron hypertrophy. Higher uric acid, higher GFR, and older age were also independently associated with some of these measures of nephron hypertrophy. Hypertension was not independently associated with measures of nephron hypertrophy. However, hypertension and older age were independently associated with higher globally sclerotic glomerular density. CONCLUSIONS: Nephron hypertrophy and nephrosclerosis are structural characteristics in normal adults that relate differently to clinical characteristics and may reflect kidney function and risk factors via separate but inter-related pathways.

Automated assessment of renal cortical surface roughness from computerized tomography images and its association with age.

RATIONALE AND OBJECTIVES: Nephrosclerosis occurs with aging and is characterized by increased kidney subcapsular surface irregularities at autopsy. Assessments of cortical roughness in vivo could provide an important measure of nephrosclerosis. The purpose of this study was to develop and validate an image-processing algorithm for quantifying renal cortical surface roughness in vivo and determine its association with age. MATERIALS AND METHODS: Renal cortical surface roughness was measured on contrast-enhanced abdominal computed tomography (CT) images of potential living kidney donors. A roughness index was calculated based on geometric curvature of each kidney from three-dimensional images and compared to visual observation scores. Cortical roughness was compared between the oldest and youngest donors, and its interaction with cortical volume and age assessed. RESULTS: The developed quantitative roughness index identified significant differences in kidneys with visual surface roughness scores of 0 (minimal), 1 (mild), and 2 (moderate; P < .001) in a random sample of 200 potential kidney donors. Cortical roughness was significantly higher in the 94 oldest (64-75 years) versus 91 youngest (18-25 years) potential kidney donors (P < .001). Lower cortical volume was associated with older age but not with roughness (r = -0.03, P = .75). The association of oldest age group with roughness (odds ratio [OR] = 1.8 per standard deviation [SD] of roughness index) remained significant after adjustment for total cortex volume (OR = 2.0 per SD of roughness index). CONCLUSIONS: A new algorithm to measure renal cortical surface roughness from CT scans detected rougher surface in older compared to younger kidneys, independent of cortical volume loss. This novel index may allow quantitative evaluation of nephrosclerosis in vivo using contrast-enhanced CT.