Glomerular Volume and Glomerulosclerosis at Different Depths within the Human Kidney

Denic, Aleksandar; Ricaurte, Luisa; Lopez, Camden L.; Narasimhan, Ramya; Lerman, Lilach O.; Lieske, John C.; Thompson, R. Houston; Kremers, Walter K.; Rule, Andrew D.

doi:10.1681/asn.2019020183

Cited by 43 publications

(63 citation statements)

References 35 publications

(39 reference statements)

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“…The study sample was an expansion of a previously described cohort of patients who are part of the Mayo Clinic Nephrectomy Registry. 10,11 This cohort has undergone a radical nephrectomy for a renal tumor at Mayo Clinic Minnesota from 2000 to 2015. We only studied patients who underwent a complete unilateral nephrectomy for a renal tumor (usually renal cancer) with no metastatic lesions or positive lymph nodes at the time of surgery.…”

Section: Study Populationmentioning

confidence: 99%

“…Segmental sclerosis was rare and minimal in this cohort. 11 The study was approved by the Mayo Clinic Institutional Review Board.…”

Section: Study Populationmentioning

confidence: 99%

“…10,18 Arteriosclerosis was assessed by the average percentage luminal stenosis (from intimal thickening) using the three most orthogonal small-to mediumsized arteries on the wedge section. 11 The percentage luminal stenosis was determined from the area of intima divided by the area of intima and lumen ( Figure 2C). IF/TA was assessed for the entire cortex.…”

Section: Kidney Microstructurementioning

confidence: 99%

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

Denic

Elsherbiny

Mullan

et al. 2020

JASN

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BackgroundNephron 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.MethodsTo 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.ResultsAmong 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.ConclusionsAfter 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.

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Section: Study Populationmentioning

confidence: 99%

“…Segmental sclerosis was rare and minimal in this cohort. 11 The study was approved by the Mayo Clinic Institutional Review Board.…”

Section: Study Populationmentioning

confidence: 99%

Section: Kidney Microstructurementioning

confidence: 99%

See 1 more Smart Citation

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

Denic

Elsherbiny

Mullan

et al. 2020

JASN

Self Cite

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“…Puelles et al (2012) found no correlation between glomerular location and volume in human kidneys. However, Denic et al (2019) examined 812 human nephrectomy kidneys and concluded that glomerular volume was highest in the middle cortical region, and lowest superficially, whereas the presence of glomeruli sclerosis was highest in the superficial region.…”

Section: Discussionmentioning

confidence: 99%

Kidney structural characteristics based on a kidney biopsy and contrast‐enhanced computed tomography in healthy living kidney donors

Nielsen

Skov

Buus

et al. 2020

The Anatomical Record

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The demands for kidney transplantations are increasing, and so is the number of live kidney donors (LKDs). Recent studies show that LKDs have an increased risk of developing end‐stage renal disease compared with healthy non‐donors. However, the knowledge about factors predicting renal disease in kidney donors is sparse. Some evidence points to increased glomerular sclerosis and kidney fibrosis, as well as a low number of glomeruli as associated with a worse renal outcome. This methodological study investigated that which estimates are obtainable with a standard kidney biopsy taken from the donated kidney during the transplantation, and a standard contrast‐enhanced computed tomography (CT) in kidney donors. CT‐scans were used to obtain total volume of the kidney and kidney cortex using the Cavalieri estimator and 2D‐nucleator. Glomerular number density in the biopsies was estimated by a model‐based method, and was multiplied by total cortex volume in order to estimate the total number of glomeruli in the kidney. Glomerular volume was estimated by the 2D‐nucleator and a model‐based stereological technique. Kidney fibrosis (point‐counting), glomerular sclerosis (evaluation of glomerular profiles), and arteriole dimensions (2D‐nucleator) were also estimated in the biopsy sections from the donated kidney. Various studies have attempted to identify predictors of renal outcome in LKDs. There is no consensus yet, and further studies are needed to elucidate if and how the estimates described in this study are associated with renal outcome in LKDs.

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“…Secondly, while we analyzed 10 whole glomeruli per kidney, we could not determine whether individual glomeruli were located in the inner or outer cortex. This would have been preferable because pathology is often more prevalent in one cortical zone than the other (Denic et al, 2019;Kanzaki et al, 2013;Samuel, Hoy, Douglas-Denton, Hughson, & Bertram, 2005). However, when using the 20x BABB lens to image mouse kidneys it is not possible to be confident about the zonal location of glomeruli.…”

Section: Discussionmentioning

confidence: 99%

Maternal hypoxia developmentally programs low podocyte endowment in male, but not female offspring

Gonçalves

Walton

Gazzard

et al. 2020

The Anatomical Record

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Fetal hypoxia is a common complication of pregnancy. We have previously reported that maternal hypoxia in late gestation in mice gives rise to male offspring with reduced nephron number, while females have normal nephron number. Male offspring later develop proteinuria and renal pathology, including glomerular pathology, whereas female offspring are unaffected. Given the central role of podocyte depletion in glomerular and renal pathology, we examined whether maternal hypoxia resulted in low podocyte endowment in offspring. Pregnant CD1 mice were allocated at embryonic day 14.5 to normoxic (21% oxygen) or hypoxic (12% oxygen) conditions. At postnatal day 21, kidneys from mice were immersion fixed, and one mid‐hilar slice per kidney was immunostained with antibodies directed against p57 and synaptopodin for podocyte identification. Slices were cleared and imaged with a multiphoton microscope for podometric analysis. Male hypoxic offspring had significantly lower birth weight, nephron number, and podocyte endowment than normoxic male offspring (podocyte number; normoxic 62.86 ± 2.26 podocytes per glomerulus, hypoxic 53.38 ± 2.25; p < .01, mean ± SEM). In contrast, hypoxic female offspring had low birth weight but their nephron and podocyte endowment was the same as normoxic female offspring (podocyte number; normoxic 62.38 ± 1.86 podocytes per glomerulus, hypoxic 61.81 ± 1.80; p = .88). To the best of our knowledge, this is the first report of developmentally programmed low podocyte endowment. Given the well‐known association between podocyte depletion in adulthood and glomerular pathology, we postulate that podocyte endowment may place offspring at risk of renal disease in adulthood, and explain the greater vulnerability of male offspring.

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Glomerular Volume and Glomerulosclerosis at Different Depths within the Human Kidney

Cited by 43 publications

References 35 publications

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

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

Kidney structural characteristics based on a kidney biopsy and contrast‐enhanced computed tomography in healthy living kidney donors

Maternal hypoxia developmentally programs low podocyte endowment in male, but not female offspring

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