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Significance Statement: Segmentation of multiple structures in cross-sectional imaging is time-consuming and impractical to perform manually, especially if the end goal is clinical implementation. In this study, we developed, validated, and demonstrated the capability of a deep learning algorithm to segment individual medullary pyramids in a rapid, accurate, and reproducible manner. The results demonstrate that cortex volume, medullary volume, number of pyramids, and mean pyramid volume is associated with patient clinical characteristics and microstructural findings and provide insights into the mechanisms that may lead to CKD., Background: The kidney is a lobulated organ, but little is known regarding the clinical importance of the number and size of individual kidney lobes., Methods: After applying a previously validated algorithm to segment the cortex and medulla, a deep-learning algorithm was developed and validated to segment and count individual medullary pyramids on contrast-enhanced computed tomography images of living kidney donors before donation. The association of cortex volume, medullary volume, number of pyramids, and mean pyramid volume with concurrent clinical characteristics (kidney function and CKD risk factors), kidney biopsy morphology (nephron number, glomerular volume, and nephrosclerosis), and short- and long-term GFR <60 or <45 ml/min per 1.73 m 2 was assessed., Results: Among 2876 living kidney donors, 1132 had short-term follow-up at a median of 3.8 months and 638 had long-term follow-up at a median of 10.0 years. Larger cortex volume was associated with younger age, male sex, larger body size, higher GFR, albuminuria, more nephrons, larger glomeruli, less nephrosclerosis, and lower risk of low GFR at follow-up. Larger pyramids were associated with older age, female sex, larger body size, higher GFR, more nephrons, larger glomerular volume, more nephrosclerosis, and higher risk of low GFR at follow-up. More pyramids were associated with younger age, male sex, greater height, no hypertension, higher GFR, lower uric acid, more nephrons, less nephrosclerosis, and a lower risk of low GFR at follow-up., Conclusions: Cortex volume and medullary pyramid volume and count reflect underlying variation in nephron number and nephron size as well as merging of pyramids because of age-related nephrosclerosis, with loss of detectable cortical columns separating pyramids., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

A 16-year-old Japanese girl developed a fever, thrombocytopenia, and renal dysfunction. Treatment was started with steroids, but cervical lymphadenopathy and ascites developed. A lymph node biopsy indicated TAFRO syndrome. The patient's renal function deteriorated, and dialysis was started. Refractory hypertension and subsequent encephalopathy developed. Treatment was started with an anti-IL-6 receptor antibody and an anti-CD20 monoclonal antibody. A kidney biopsy showed malignant nephrosclerosis-like microangiopathy and glomerular collapse due to narrowing of the small arteries. The majority of TAFRO syndrome cases are adult-onset, with glomerular microangiopathy. To our knowledge, this is the first report of adolescent-onset TAFRO syndrome presenting with malignant nephrosclerosis-like lesions associated with hypertension.

Significance Statement: Nephrosclerosis (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) is the defining pathology of both kidney aging and CKD. Optimal thresholds for nephrosclerosis that identify persons with a progressive disease are unknown. This study determined a young-age threshold (18-29 years) and age-based 95th percentile thresholds for nephrosclerosis on the basis of morphometry of kidney biopsy sections from normotensive living kidney donors. These thresholds were 7.1-fold to 36-fold higher in older (70 years or older) versus younger (aged 18-29 years) normotensive donors. Age-based thresholds, but not young-age threshold, were prognostic for determining risk of progressive CKD among patients who underwent a radical nephrectomy or a for-cause native kidney biopsy, suggesting that age-based thresholds are more useful than a single young-age threshold for identifying CKD on biopsy., Background: Nephrosclerosis, defined by globally sclerotic glomeruli (GSG) and interstitial fibrosis and tubular atrophy (IFTA), is a pathology of both kidney aging and CKD. A comparison of risk of progressive CKD using aged-based thresholds for nephrosclerosis versus a single young-adult threshold is needed., Methods: We conducted morphometric analyses of kidney biopsy images for %GSG, %IFTA, and IFTA foci density among 3020 living kidney donors, 1363 patients with kidney tumor, and 314 patients with native kidney disease. Using normotensive donors, we defined young-age thresholds (18-29 years) and age-based (roughly by decade) 95th percentile thresholds. We compared age-adjusted risk of progressive CKD (kidney failure or 40% decline in eGFR) between nephrosclerosis that was "normal compared with young," "normal for age but abnormal compared with young," and "abnormal for age" in patients with tumor and patients with kidney disease., Results: The 95th percentiles in the youngest group (18-29 years) to the oldest group (70 years or older) ranged from 1.7% to 16% for %GSG, 0.18% to 6.5% for %IFTA, and 8.2 to 59.3 per cm 2 for IFTA foci density. Risk of progressive CKD did not differ between persons with nephrosclerosis "normal compared with young" versus "normal for age but abnormal compared with young." Risk of progressive CKD was significantly higher with %GSG, %IFTA, or IFTA foci density that was abnormal versus normal for age in both cohorts., Conclusions: Given that increased risk of progressive CKD occurs only when nephrosclerosis is abnormal for age, age-based thresholds for nephrosclerosis seem to be better than a single young-age threshold for identifying clinically relevant CKD., (Copyright © 2023 by the American Society of Nephrology.)

Malignant nephrosclerosis is a thrombotic microangiopathy associated with abnormal local activation of the complement alternative pathway (AP). However, the mechanism underlying local AP activation is not fully understood. We hypothesized that complement factor D (CFD) secreted by endothelial cells triggers vascular dysfunction in malignant nephrosclerosis via local complement activation. We investigated the deposition of CFD in human kidney biopsy tissues and the function of endothelial-derived CFD in endothelial cell cultures. Immunofluorescence microscopy and laser microdissection-targeted mass spectrometry revealed significant deposition of CFD in the kidneys of patients with malignant nephrosclerosis. Conditionally immortalized human glomerular endothelial cells (CiGEnCs) continuously expressed and secreted CFD in vitro. CFD knockdown in CiGEnCs by small interfering RNA reduced local complement activation and attenuated the upregulation of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), von Willebrand factor (VWF), and endothelin-1 (ET-1) induced by Ang II. The expression of CFD in CiGEnCs was significantly higher than that in other types of microvascular endothelial cells. Our findings suggest that (i) glomerular endothelial cells are an important source of local renal CFD, (ii) endothelial-derived CFD can activate the local complement system, and (iii) endothelial-derived CFD mediates endothelial dysfunction, which may play a role in the pathogenesis of malignant nephrosclerosis., (© 2023. The Author(s).)

Nephroangiosclerosis or kidney disease that accompanies chronic essential arterial hypertension has been known for more than a hundred years. The definitive diagnosis is established by renal biopsy, which is reserved for doubtful cases or atypical presentation, being in most cases a presumptive clinical diagnosis. The objective of this review is to analyse the main controversies that currently exist related to nephroangiosclerosis: inaccuracy in epidemiological aspects (prevalence and incidence unknown), diagnostic difficulties and lack of correlation studies between clinical data and histopathology, progression factors in Caucasians. Currently, with advances in genetic studies in hypertension, not using or redefining the term hypertensive kidney disease for another condition such as nephropathy related to the present genetic alteration is being considered., (Copyright © 2022 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.)

Non-alcoholic fatty liver disease is the most common chronic liver disease and is associated with chronic kidney disease. The fibrosis-4 index and non-alcoholic fatty liver disease score are widely used as non-invasive diagnostic methods for non-alcoholic fatty liver disease. However, the relationship between these markers and specific renal histopathologies in chronic kidney disease remain unclear. This study included 179 patients aged between 16 and 80 years who underwent renal biopsy. We examined the association between the fibrosis-4 index or non-alcoholic fatty liver disease score and change in estimated glomerular filtration rate 12 months after kidney biopsy for each renal histopathology. Renal histopathologies were determined by renal biopsy. Our results showed that there was a significant negative correlation between the fibrosis-4 index and estimated glomerular filtration rate. In nephrosclerosis, the non-alcoholic fatty liver disease score and estimated glomerular filtration rate tended to have a negative correlation, albeit without significance. In IgA nephropathy, both the fibrosis-4 index and non-alcoholic fatty liver disease score were significantly negatively correlated with estimated glomerular filtration rate. Furthermore, the fibrosis-4 index was not associated with urinary protein-to-creatinine ratio or renal function markers such as urinary b2 microglobulin and urinary N-acetyl-D-glucosamine. Our kidney biopsy-based study showed that the liver fibrosis markers fibrosis-4 index and non-alcoholic fatty liver disease score were negatively correlated with the estimated glomerular filtration rate in nephrosclerosis and IgA nephropathy., (© 2022. The Author(s).)

Background: Patients with nephrosclerosis display heterogenous clinical phenotypes, often leading to a clinical diagnosis discordant with pathological nephrosclerosis diagnosis. However, little is known about clinical factors associated with clinicopathological discordance of biopsy-proven nephrosclerosis., Methods: In a cross-sectional study of 891 patients with biopsy-proven nephrosclerosis registered in the Japan Renal Biopsy Registry (J-RBR) between July 2007 and June 2016, we examined clinical characteristics associated with a pre-biopsy clinical diagnosis discordant with pathological nephrosclerosis diagnosis using multivariable logistic regression with adjustment for relevant clinical characteristics., Results: Overall, the mean (SD) age was 58.6 (13.7) years; 67.6% of patients were male; and 63.2% were on antihypertensive drugs. The median estimated glomerular filtration rate (eGFR) was 43.8 mL/min/1.73 m 2 and the median proteinuria was 0.5 g/day. Of the 891 patients, 497 (55.8%) had a clinical diagnosis discordant with pathological nephrosclerosis diagnosis, with chronic nephritic syndrome being the most common (> 75%) discordant clinical diagnosis. After multivariable adjustment, age (odds ratio 1.34, [95% confidence interval, 1.16-1.55], per 10 years increase), eGFR (1.10 [1.00-1.21], per 10 mL/min/1.73 m 2 increase), and proteinuria (1.20 [1.03-2.16], per 1 g/day decrease) were found to be significantly associated with the clinicopathological discordance., Conclusions: Patients with older age, higher eGFR, and lower proteinuria had significantly higher likelihood of being clinically diagnosed with other glomerular disease in patients with biopsy-proven nephrosclerosis. Our findings highlight the heterogeneous clinical phenotypes of nephrosclerosis and suggest the need for continuous improvement of clinical diagnostic accuracy as well as for wider kidney biopsy indications for nephrosclerosis., (© 2021. The Author(s).)

In a retrospective study of a western pygmy marmoset ( Cebuella pygmaea ) colony, postmortem examination of 1/8 juvenile and 29/47 adult animals identified vascular, cardiac, and renal lesions consistent with systemic hypertension. This included frequent renal arteriolar hypertrophy, hyaline and proliferative arteriolosclerosis, fibrinoid necrosis of arterioles, glomerulosclerosis, and nephrosclerosis. Affected animals ranged from 0.6 to 12 years of age (mean 6 years) and had an observed male predominance. Genealogical relatedness was evident in several breeding pairs and spanned multiple generations. Concurrent cardiac and renal disease was commonly identified, although frequently subclinical, and both were important causes of morbidity and mortality in affected animals. Cardiomegaly and hypertrophy were typical features and were accompanied by left atrial thrombosis in 10 animals. Signs of heart failure included chronic pulmonary edema in 20 cases and body cavity effusions in 17. In the kidneys, 19 cases had glomerular disease and hypertensive vasculopathy, and 26 cases had nephrosclerosis or glomerulosclerosis. Common extrarenal secondary causes of hypertension were excluded by necropsy examination. The pathogenesis is suggested to involve primary hypertension leading to renal and cardiac disease. Elevated sympathetic activity might be an underlying factor in the frequent development of primary systemic hypertension in the pygmy marmoset, as for the owl monkey.

Current research on hypertension utilizes more than fifty animal models that rely mainly on stable increases in systolic blood pressure. In experimental hypertension, grading or scoring of glomerulopathy in the majority of studies is based on a wide range of opinion-based histological changes that do not necessarily comply with lesional descriptors for glomerular injury that are well-established in clinical pathology. Here, we provide a critical appraisal of experimental hypertensive glomerulopathy with the same approach used to assess hypertensive glomerulopathy in humans. Four hypertensive models with varying pathogenesis were analyzed-chronic angiotensin II infused mice, mice expressing active human renin in the liver (TTRhRen), spontaneously hypertensive rats (SHR), and Goldblatt two-kidney one-clip rats (2K1C). Analysis of glomerulopathy utilized the same criteria applied in humans-hyalinosis, focal segmental glomerulosclerosis (FSGS), ischemic, hypertrophic and solidified glomeruli, or global glomerulosclerosis (GGS). Data from animal models were compared to human reference values. Kidneys in TTRhRen mice, SHR and the nonclipped kidneys in 2K1C rats had no sign of hyalinosis, FSGS or GGS. Glomerulopathy in these groups was limited to variations in mesangial and capillary compartment volumes, with mild increases in collagen deposition. Histopathology in angiotensin II infused mice corresponded to mesangioproliferative glomerulonephritis, but not hypertensive glomerulosclerosis. The number of nephrons was significantly reduced in TTRhRen mice and SHR, but did not correlate with severity of glomerulopathy. The most substantial human-like glomerulosclerotic lesions, including FSGS, ischemic obsolescent glomeruli and GGS, were found in the clipped kidneys of 2K1C rats. The comparison of affected kidneys to healthy control in animals produces lesion values that are numerically impressive but correspond to mild damage if compared to humans. Animal studies should be standardized by employing the criteria and classifications established in human pathology to make experimental and human data fully comparable for comprehensive analysis and model improvements., Competing Interests: The authors have declared that no competing interests exist.

Abstract: The 2019 novel coronavirus disease (COVID-19) has spread worldwide, infiltrating, infecting, and devastating communities in all locations of varying demographics. An overwhelming majority of published literature on the pathologic findings associated with COVID-19 is either from living clinical cohorts or from autopsy findings of those who died in a medical care setting, which can confound pure disease pathology. A relatively low initial infection rate paired with a high biosafety level enabled the New Mexico Office of the Medical Investigator to conduct full autopsy examinations on suspected COVID-19-related deaths. Full autopsy examination on the first 20 severe acute respiratory syndrome coronavirus 2-positive decedents revealed that some extent of diffuse alveolar damage in every death due to COVID-19 played some role. The average decedent was middle-aged, male, American Indian, and overweight with comorbidities that included diabetes, ethanolism, and atherosclerotic and/or hypertensive cardiovascular disease. Macroscopic thrombotic events were seen in 35% of cases consisting of pulmonary thromboemboli and coronary artery thrombi. In 2 cases, severe bacterial coinfections were seen in the lungs. Those determined to die with but not of severe acute respiratory syndrome coronavirus 2 infection had unremarkable lung findings., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Activation of renal fibroblasts is a critical mechanism in the process of renal fibrosis. As a commonly used herbal formula, Shenkang (SK) has been found to attenuate renal fibrosis and renal parenchyma destruction. However, the effect of SK on renal fibroblast activation in unilateral ureteral obstruction (UUO) mice and its molecular mechanism remain undetermined. The present study was performed to elucidate the effect of SK on renal fibroblast activation and renal fibrosis, as well as the potential underlying mechanism, in both NRK-49F cells and UUO mice., Methods: NRK-49F cells were stimulated with 10 ng/ml TGF-β1 for 48 h. After SK treatment, the CCK-8 method was used to evaluate cell viability. Thirty-six C57BL/6 mice were randomly divided into the sham group, UUO group, angiotensin receptor blocker (ARB) group, and SK high-, moderate- and low-dose groups. UUO was induced in mice except those in the sham group. Drugs were administered 1 day later. On the 13th day, the fractional anisotropy (FA) value was determined by MRI to evaluate the degree of renal fibrosis. After 14 days, serum indexes were assessed. Hematoxylin and eosin (HE) and Sirius red staining were used to observe pathological morphology and the degree of fibrosis of the affected kidney. Western blotting and PCR were used to assess the expression of related molecules in both cells and animals at the protein and gene levels., Results: Our results showed that SK reduced extracellular matrix (ECM) and α-smooth muscle actin (α-SMA) expression both in vitro and in vivo and attenuated renal fibrosis and the pathological lesion degree after UUO, suppressing JAK2/STAT3 activation. Furthermore, we found that SK regulated the JAK2/STAT3 pathway regulators peroxiredoxin 5 (Prdx5) in vitro and suppressor of cytokine signaling protein 1 (SOCS1) and SOCS3 in vivo., Conclusions: These results indicated that SK inhibited fibroblast activation by regulating the JAK2/STAT3 pathway, which may be a mechanism underlying its protective action in renal fibrosis.

Clinical Background: Older age has been associated with higher prevalence and progression of chronic kidney disease (CKD). The presence of CKD leads to an increased risk of end-stage renal disease, cardiovascular diseases, and death. Epidemiology: Progressive aging of the population is accompanied by an increase in the prevalence of CKD worldwide. The high prevalence of CKD in the aged population would result in a considerably greater social burden. Challenges: Structural and functional changes are often observed in the aged kidney. The main pathological feature of the aged kidney is nephrosclerosis such as arteriosclerosis, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. As a consequence of renal aging, the nephron number decreases. A lower nephron number approximately parallels with the decline in glomerular filtration rate (GFR), and GFR declines with aging. Recent studies have highlighted several pathological mechanisms involved in renal aging, that can serve as targets for intervention. Decreased renal oxygen levels, mitochondrial dysfunction, and inflammation drive renal fibrosis, one of the hallmarks of renal aging. Prevention and Treatment: Novel therapeutic approaches that target these functional changes are now being developed to prevent an aging-associated inevitable loss of renal function. For example, calorie restriction, Sirtuin 1 activator and peroxisome proliferator-activated receptor-γ agonists have the potential to ameliorate renal deterioration. This chapter provides an overview of the aged kidney and summarizes the current knowledge on therapeutic strategies to attenuate renal aging., (© 2021 S. Karger AG, Basel.)

Background: Hypertensive nephrosclerosis is the presumed underlying cause in many end-stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy., Objective: To evaluate and improve the diagnostic process for nephrosclerosis patients., Methods: We included adults from the population-based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988-2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve-based methods of optimal cut-offs were used to improve clinical nephrosclerosis criteria., Results: Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney-related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy-verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (<0.75 g d -1 ), systolic blood pressure (>155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false-positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk-tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy., Conclusion: Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Endoplasmic reticulum (ER) stress is considered an important factor in the formation of fibrosis. Therefore, modulation of ER stress may represent a promising therapeutic strategy in renal fibrosis. MiR-185-5p has been identified to be implicated in TGF-β1-induced renal fibrosis; however, it is largely unknown whether and how miR-185-5p regulates ER stress in renal fibrosis. In this study, we demonstrated that miR-185-5p directly bound to ATF6, an ER stress-related protein, and downregulated the expression thereof. We subsequently constructed an in vitro model of renal fibrosis using HK2 cells treated with TGF-β1, and found that miR-185-5p attenuated ER stress and dedifferentiation of tubular epithelia by suppression of ATF6. In addition, we constructed an in vivo mouse model using unilateral urethral obstruction (UUO). Our in vivo findings showed that miR-185-5p reduced the expression of ER stress-related proteins and inhibited epithelial dedifferentiation via downregulation of ATF6, thereby improving UUO-induced renal fibrosis. Overall, our findings revealed that miR-185-5p exerts beneficial effects in renal fibrosis. Thus, the miR-185-5p/ATF6 regulatory pathway may be a potential target for therapeutic intervention in renal fibrosis.

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 m 2 ), 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., (Copyright © 2020 by the American Society of Nephrology.)

Two major studies of structural changes associated with aging in human kidneys are reviewed and new information presented. The studies are the Monash University stereologically analyzed series of 319 autopsy kidneys from the United States in which 44% were white and the Mayo Clinic CT angiogram/biopsy analysis of 1,388 US kidney donors in which 97% were white. Hypertension rates in the Monash series were 48% and included moderate and severe hypertension. In the Mayo Clinic study, 12% had mild hypertension. The studies showed no relationship between glomerular number and hypertension except for a weak relationship with older white women in the Monash series. An inverse relationship was present between glomerular number and glomerular volume, a reciprocity that tended to enhance glomerular mass and by inference filtration capacity with lower nephron numbers. This relationship seemed to be present whether low nephron numbers were intrinsic or acquired. In the Mayo Clinic studies, pretransplant iothalamate clearances demonstrated that single nephron (SN) glomerular filtration rates (GFR) were similar throughout the range of glomerular number in subjects younger than 70 years, but that increased SNGFR correlated with nephron hypertrophy and increased nephrosclerosis particularly at 70 years of age and over. Hypertension at least through middle age cannot be related to a deficiency of glomeruli, but glomeruli are lost with later aging in association with adaptive nephron hypertrophy that can maintain GFR near normal. These studies help define an age-related nephropathy that overlaps with hypertension as a potential cause of end-stage renal disease when glomerulosclerosis is advanced., (© 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.)

Background: Aberrant microRNA (miRNA) expression affects biologic processes and downstream genes that are crucial to CKD initiation or progression. The miRNA miR-204-5p is highly expressed in the kidney but whether miR-204-5p plays any role in the development of chronic renal injury is unknown., Methods: We used real-time PCR to determine levels of miR-204 in human kidney biopsies and animal models. We generated Mir204 knockout mice and used locked nucleic acid-modified anti-miR to knock down miR-204-5p in mice and rats. We used a number of physiologic, histologic, and molecular techniques to analyze the potential role of miR-204-5p in three models of renal injury., Results: Kidneys of patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy exhibited a significant decrease in miR-204-5p compared with controls. Dahl salt-sensitive rats displayed lower levels of renal miR-204-5p compared with partially protected congenic SS.13 BN26 rats. Administering anti-miR-204-5p to SS.13 BN26 rats exacerbated interlobular artery thickening and renal interstitial fibrosis. In a mouse model of hypertensive renal injury induced by uninephrectomy, angiotensin II, and a high-salt diet, Mir204 gene knockout significantly exacerbated albuminuria, renal interstitial fibrosis, and interlobular artery thickening, despite attenuation of hypertension. In diabetic db/db mice, administering anti-miR-204-5p exacerbated albuminuria and cortical fibrosis without influencing blood glucose levels. In all three models, inhibiting miR-204-5p or deleting Mir204 led to upregulation of protein tyrosine phosphatase SHP2, a target gene of miR-204-5p, and increased phosphorylation of signal transducer and activator of transcription 3, or STAT3, which is an injury-promoting effector of SHP2., Conclusions: These findings indicate that the highly expressed miR-204-5p plays a prominent role in safeguarding the kidneys against common causes of chronic renal injury., (Copyright © 2020 by the American Society of Nephrology.)

As early detection and advances in the treatment for renal cell carcinoma continue to lead to excellent oncologic outcomes, the preservation of renal function in kidney cancer patients has emerged as an increasingly important clinical objective. Given that diabetes, hypertension, obesity, cigarette smoking, and aging are independent risk factors for renal cell carcinoma, the corresponding non-neoplastic kidney diseases frequently are present, but often undiagnosed. In addition, the subsequent clinical management of the ensuing chronic kidney disease historically has not included nephrologists. Awareness of these practice gaps remain low among nephrologists, surgeons, and pathologists. This article discusses the common non-neoplastic kidney diseases that are encountered in cancer nephrectomy specimens. The accurate and timely diagnosis of these disorders will result in additional gains in clinical outcomes. There is a unique opportunity for the nephrology community to play a central role in the management of chronic kidney disease that often is present in kidney cancer patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Two types of global glomerulosclerosis, glomerular obsolescence and solidification, have been identified. A clinicopathological correlation between these glomerular changes and hypertensive nephrosclerosis has been reported; however, clinicopathological correlations with other kidney diseases are unknown. The aim of this study was to evaluate the correlation between the two glomerulosclerosis types and the clinical IgA nephropathy presentation. Methods: A single center, cross-sectional study of patients with IgA nephropathy was performed. Correlations between glomerulosclerosis and body mass index, mean blood pressure, creatinine-based estimated glomerular filtration rate (eGFR), total cholesterol, urinary protein corrected by urinary creatinine, and anti-hypertensive agent use were investigated using univariate and multivariate analyses. Results: Overall, 116 patients were enrolled (male/female, 59/57; mean age, 40.5 ± 15.0 years). Separate analyses were performed for solidification and obsolescence glomerulosclerosis. Univariate analysis demonstrated a significant correlation between the percentage of solidification glomerulosclerosis and patient age, mean blood pressure, eGFR, and use of antihypertensive drugs. Multivariate analysis showed that only eGFR and use of antihypertensive drugs maintained their independent predictive value. The amount of urinary protein emerged as a significant factor based on the multivariate analysis. However, although the univariate analysis demonstrated a statistically significant correlation between the percentage of obsolescence and eGFR for obsolescence glomerulosclerosis, a multivariate analysis indicated that none of the factors maintained their independent predictive value. Conclusions: The incidence of solidification was better correlated with some nephritis-related clinical parameters compared with the incidence of obsolescence. The emergence of solidification may influence the clinical activities that are associated with IgA nephropathy.

Background: Biopsy-based studies on nephrosclerosis are lacking and the clinicopathological predictors for progression of chronic kidney disease (CKD) are not well established., Methods: We retrospectively assessed 401 patients with biopsy-proven nephrosclerosis in Japan. Progression of CKD was defined as new-onset end-stage renal disease, decrease of estimated glomerular filtration rate (eGFR) by  ≥50% or doubling of serum creatinine, and the sub-distribution hazard ratio (SHR) with 95% confidence interval (CI) for CKD progression was determined for various clinical and histological characteristics in competing risks analysis. The incremental value of pathological information for predicting CKD progression was assessed by calculating Harrell's C-statistics, the Akaike information criterion (AIC), net reclassification improvement and integrated discrimination improvement., Results: During a median follow-up period of 5.3 years, 117 patients showed progression of CKD and 10 patients died before the defined kidney event. Multivariable sub-distribution hazards model identified serum albumin (SHR 0.48; 95% CI 0.35-0.67), hemoglobin A1c (SHR 0.71; 95% CI 0.54-0.94), eGFR (SHR 0.98; 95% CI 0.97-0.99), urinary albumin/creatinine ratio (UACR) (SHR 1.18; 95% CI 1.08-1.29), percentage of segmental/global glomerulosclerosis (%GS) (SHR 1.01; 95% CI 1.00-1.02) and interstitial fibrosis and tubular atrophy (IFTA) (SHR 1.52; 95% CI 1.20-1.92) as risk factors for CKD progression. The C-statistic of a model with only clinical variables was improved by adding %GS (0.790 versus 0.796, P < 0.01) and IFTA (0.790 versus 0.811, P < 0.01). The reclassification statistic was also improved after adding the biopsy data to the clinical data. The model including IFTA was superior, with the lowest AIC., Conclusions: The study implies that in addition to the traditional markers of eGFR and UACR, we may explore the markers of serum albumin and hemoglobin A1c, which are widely available but not routinely measured in patients with nephrosclerosis, and the biopsy data, especially the data on the severity of interstitial damage, for the better prediction of CKD progression in patients with nephrosclerosis., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

It is unclear whether structural findings in the kidneys of living kidney donors predict postdonation kidney function. We studied living kidney donors who had a kidney biopsy during donation. Nephron size was measured by glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area. Age-specific thresholds were defined for low nephron number (calculated from CT and biopsy measures) and nephrosclerosis (global glomerulosclerosis, interstitial fibrosis/tubular atrophy, and arteriosclerosis). These structural measures were assessed as predictors of postdonation measured GFR, 24-hour urine albumin, and hypertension. Analyses were adjusted for baseline age, gender, body mass index, systolic and diastolic blood pressure, hypertension, measured GFR, urine albumin, living related donor status, and time since donation. Of 2673 donors, 1334 returned for a follow-up visit at a median 4.4 months after donation, with measured GFR <60 mL/min/1.73 m 2 in 34%, urine albumin >5 mg/24 h in 13%, and hypertension in 5.3%. Larger glomerular volume and interstitial fibrosis/tubular atrophy predicted follow-up measured GFR <60 mL/min/1.73 m 2 . Larger cortex volume per glomerulus and low nephron number predicted follow-up urine albumin >5 mg/24 h. Arteriosclerosis predicted hypertension. Microstructural findings predict GFR <60 mL/min/1.73 m 2 , modest increases in urine albumin, and hypertension shortly after kidney donation., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We previously reported that rats treated with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), during lactation developed hypertension in adult life, without apparent functional or structural damage to kidneys, providing a new model of essential hypertension. Here, we investigated whether uninephrectomy associated with salt overload would unveil a latent renal dysfunction in this model, aggravating arterial hypertension and promoting renal injury. Male Munich-Wistar rat pups received PDTC from maternal milk (PDTC Lact ) from 0 to 20 days after birth. Another group received no treatment during lactation. All offspring underwent uninephrectomy (UNx) at 10 weeks of age and then were subdivided into NS, receiving a normal salt (0.5% Na + ) diet, PDTC Lact  + NS, HS, receiving a high-salt diet (2% Na + chow + 0.5% saline to drink), and PDTC Lact +HS. Twelve weeks later, HS rats were moderately hypertensive with mild albuminuria and renal injury. In contrast, severe hypertension, glomerulosclerosis, and cortical collagen deposition were prominent in PDTC Lact  + HS animals, along with "onion-skin" arteriolar lesions, evidence of oxidative stress and intense renal infiltration by macrophages, and lymphocytes and angiotensin II-positive cells, contrasting with low circulating renin. The NF-κB pathway was also activated. In a separate set of PDTC Lact +HS rats, Losartan treatment prevented NF-κB activation and strongly attenuated glomerular injury, cortical fibrosis, and renal inflammation. NF-κB activity during late nephrogenesis is essential for the kidneys to properly maintain sodium homeostasis in adult life. Paradoxically, this same system contributed to renal injury resembling that caused by malignant hypertension when renal dysfunction caused by its inhibition during lactation was unmasked by uninephrectomy associated with HS.

Introduction: In patients with diabetes mellitus (DM), non-diabetic renal disease (NDRD) can also occurs, as well as diabetic nephropathy. NDRD is most accurately diagnosed using kidney biopsy., Aim: The aim of the study was to investigate the incidence and type of NDRD diagnosed by kidney biopsy in patients with type 2 DM and the correlation of clinical and laboratory findings with histopathological diagnosis., Material and Methods: From April 2007 to October 2018, 290 kidney biopsies were performed at the Department of Nephrology, Internal Medicine Clinic in Banja Luka, out of which 18 patients (males 9, mean age 59.8 years) were with type 2 DM. The US-guided (ultrasound device: Toshiba Famio 5) kidney biopsy was performed using an automatic biopsy instrument FAST-GUN® with needle 16G. Kidney tissue samples were analyzed by light microscopy and immunofluorescence., Results: In 18 patients with type 2 DM, the average duration of the disease was 5.9 years, 5 patients had a retinopathy, and 16 patients had hypertension. Biopsy indications were: nephrotic syndrome in 11 patients, asymptomatic urinary abnormalities in 3 patients, and rapid chronic renal failure progression. Unsatisfactory quality sample for pathohistological analysis was obtained in one patient, and out of the other 17, 6 (35.3%) had NDRD, 3 (17.6%) had NDRD superimposed with the diabetic nephropathy, and 8 (47.1%) had diabetic nephropathy. Of the patients who had NDRD, 3 had membranous glomerulonephritis, 1 had focal segmental glomerulosclerosis, and two had hypertensive nephroangiosclerosis. Out of patients with coexisting NDRD and diabetic nephropathy, 2 had hypertensive nephroangiosclerosis and one diabetic nephropathy and lupus nephritis., Conclusion: NDRD was diagnosed using kidney biopsy in 9/17 patients with type 2 DM, which confirms the significance of the kidney biopsy in patients with DM with properly indications. Accurate diagnosis provides disease specific treatment and thus significantly improves the long-term prognosis of the patient.

A 61-year-old man was diagnosed with sarcoidosis involving the lungs, eyes, parotid gland and extrathoracic lymph nodes complicated by chronic kidney injury and hypercalcemia. Kidney biopsy showed non-specific interstitial nephritis and nephrosclerosis. However, immunohistochemical staining of cell surface markers revealed a multinucleated giant macrophage surrounded by T-cells, suggesting granulomatous interstitial nephritis. Corticosteroid improved the kidney function, and reduced the serum levels of calcium and angiotensin-converting enzyme. Sarcoid nephropathy may be caused by the combination of several sarcoidosis-associated pathophysiological conditions and a comprehensive kidney examination should be performed to assess the type of injury when determining a treatment strategy.

Background: The concomitant appearance of glomerular collapse and enlargement is characteristic of the histological findings in nephrosclerosis. However, no previous study quantitatively examined the clinicopathological significance of this feature in patients with biopsy-proven nephrosclerosis., Methods: Renal biopsy specimens and follow-up data from nephrosclerosis patients with estimated glomerular filtration rates >30 ml/min/1.73 m2 at diagnosis were retrospectively reviewed. Mean volumes for glomerular tufts (GV) and Bowman capsules (BV) were separately calculated, based on the measurement of all areas of glomerular tufts and Bowman capsules in a cross-section of biopsy specimens. The G/B ratio was defined as the ratio of GV to BV. The doubling of serum creatinine levels (DSC) and the initiation of renal replacement therapies (end-stage renal disease (ESRD)) were examined as renal outcome indices., Results: A total of 67 patients with biopsy-proven nephrosclerosis were included. Clinicopathological findings at biopsy, other than GV, were comparable among all patients, irrespective of G/B ratio. Overall, 25 patients (37%) developed DSC and 9 (13%) developed ESRD during the median observation periods of 7.8 and 8.5 years, respectively. Renal survival curve analyses indicated a significantly worse prognosis for patients with a low G/B ratio, as compared with those with a high G/B ratio. Cox hazard analyses for DSC identified low G/B ratio as a significant predictor, but not low GV or BV., Conclusions: These results suggest that the quantitative evaluation of G/B ratio may detect subtle abnormalities in the glomerulus, indicating the subsequent renal outcomes of nephrosclerosis patients.

Background: Urinary mitochondrial DNA (mtDNA) fragment level has been proposed as a biomarker of chronic kidney disease (CKD). In this study, we determine the relation between urinary mtDNA level and rate of renal function deterioration in non-diabetic CKD., Methods: We recruited 102 non-diabetic CKD patients (43 with kidney biopsy that showed non-specific nephrosclerosis). Urinary mtDNA level was measured and compared to baseline clinical and pathological parameters. The patients were followed 48.3 ± 31.8 months for renal events (need of dialysis or over 30% reduction in estimated glomerular filtration rate [eGFR])., Results: The median urinary mtDNA level was 1519.42 (inter-quartile range 511.81-3073.03) million copy/mmol creatinine. There were significant correlations between urinary mtDNA level and baseline eGFR (r = 0.429, p < 0.001), proteinuria (r = 0.368, p < 0.001), severity of glomerulosclerosis (r = - 0.537, p < 0.001), and tubulointerstitial fibrosis (r = - 0.374, p = 0.014). The overall rate of eGFR decline was - 2.18 ± 5.94 ml/min/1.73m 2 per year. There was no significant correlation between the rate of eGFR decline and urinary mtDNA level. By univariate analysis, urinary mtDNA level predicts dialysis-free survival, but the result became insignificant after adjusting for clinical and histological confounding factors., Conclusion: Urinary mtDNA levels have no significant association with the rate of renal function decline in non-diabetic CKD, although the levels correlate with baseline renal function, proteinuria, and the severity of histological damage. Urinary mtDNA level may be a surrogate marker of permanent renal damage in non-diabetic CKD.

Purpose: To investigate the association of renal elasticity to microscopic findings of nephron hypertrophy and nephrosclerosis., Methods: Patients who underwent renal biopsy were enrolled. Renal elasticity was measured by acoustic radiation force impulse, and nephron size (glomerular volume, non-sclerotic glomerular density, and mean profile tubular area) and nephrosclerosis (globally sclerotic glomeruli and interstitial fibrosis) were estimated. Nephron hypertrophy was indicated by larger glomerular volume, larger tubular area, and lower non-sclerotic glomerular density. Nephrosclerosis was indicated by a higher percentage of globally sclerotic glomeruli and higher severity of fibrosis., Results: Renal elasticity was negatively correlated with glomerular volume (r = - 0.480, P = 0.024) and mean tubular area (r = - 0.469, P = 0.028), but it was not correlated with non-sclerotic glomerular density (r = 0.205, P = 0.359), percentage of globally sclerotic glomeruli (r = 0.057, P = 0.800), and severity of fibrosis (r = 0.014, P = 0.950). In a multiple linear regression analysis, glomerular volume and mean tubular area were independently associated with renal elasticity (std β = - 0.454, P = 0.015 and std β = - 0.577, P = 0.007, respectively)., Conclusion: Renal elasticity was correlated with microstructural findings of nephron hypertrophy. Measuring renal elasticity could help in detecting kidney disease.

Background Glomerular volume increases when demand exceeds nephron supply, which may lead to glomerulosclerosis. It is unclear if determinants of glomerular volume are consistent between populations that differ by severity of comorbidities. Methods We studied kidney biopsy specimens from living kidney donors ( n =2453) and patients who underwent radical nephrectomy for a renal tumor ( n =780). We scanned specimen sections into high-resolution digital images, manually traced glomerular profiles, and calculated mean glomerular volumes using the Weibel-Gomez stereologic formula (separately for nonsclerosed glomeruli and globally sclerosed glomeruli). We then assessed the relationship of glomerular volume with age, clinical characteristics, and nephrosclerosis on biopsy specimen. Results Compared with kidney donors, patients with tumors were older and more frequently men, obese, diabetic, or hypertensive, had more glomerulosclerosis and interstitial fibrosis on biopsy specimen, and had 12% larger nonsclerosed glomeruli ( P <0.001). In both populations, male sex, taller height, obesity, hypertension, and proteinuria associated with larger nonsclerosed glomeruli to a similar extent. In patients with tumors, diabetes, glomerulosclerosis >25%, and interstitial fibrosis >25% also associated with larger nonsclerosed glomeruli. Independent clinical predictors of larger nonsclerotic glomeruli were family history of ESRD, male sex, taller height, obesity, diabetes, and proteinuria. After adjustment for these characteristics, nonsclerotic glomerular volume did not differ between populations and was stable up to age 75 years, after which it decreased with age. Many of these findings were also evident with globally sclerotic glomerular volume. Conclusions Characteristics associated with glomerular volume are consistent between patient populations with low and high levels of comorbidity., (Copyright © 2018 by the American Society of Nephrology.)

Background: Nephrosclerosis is an increasingly reason for dialysis in Japan. However, kidney biopsy specimens for hypertensive nephrosclerosis are very limited; thus, the pathologic evaluation of hypertensive nephrosclerosis currently remains unclear., Methods: Clinical and pathologic data of a total of 184 biopsy-confirmed hypertensive nephrosclerosis patients were collected from 13 centers throughout Japan. Seven pathological findings were assessed in this study. The outcomes of interest for this study were dialysis, composite kidney events, cardiovascular events, and all-cause mortality., Results: The Green and Yellow (G&Y), Orange, and Red groups of the chronic kidney diseases (CKD) heat map contained 36, 57, and 91 cases, respectively. The mean observation period was 7.3 ± 5.2 (median, IQR; 6.1, 2.6-9.7) years. Global glomerulosclerosis (GScle), interstitial fibrosis and tubular atrophy (IFTA), arteriolar hyalinosis in Red exhibited higher scores than those in G&Y and Orange. The incidence rates of the composite kidney end points in 100 person-years for the G&Y, Orange, and Red groups were 1.42, 2.16, and 3.98, respectively. In the univariate Cox analysis for the composite kidney end points, GScle, IFTA and interstitial cell infiltration exhibited statistically significant high hazard ratios (1.18, 1.84, 1.69, respectively). However, after adjustment for clinical and medication data, the Red group in the CKD heat map category was risk factor for the composite kidney end points (HR 9.51)., Conclusions: In summary, although pathologic findings had minor impacts on the prediction of composite outcomes in this study, the clinical stage of the CKD heat map is a good predictor of composite kidney events.

Chronic kidney disease (CKD) is an important problem throughout the world, associated with the increase of blood urea nitrogen (BUN) and serum creatinine (sCre) and with renal tubular injuries. It is crucial to elucidate the molecular mechanisms of renal injuries to identify the new therapeutics and early diagnostic methods. We focused on cell adhesion molecule-1 (CADM1) protein. CADM1, its isoform SP4, is expressed in the epithelial cells of various tissues, including renal distal tubules, localized on the lateral cell membrane, mediates cell-cell adhesion via trans-homophilic binding, and interacts with various proteins. We previously reported that its expression was downregulated by post-proteolytic cleavage (α- and β-shedding) in pulmonary diseases. To investigate whether CADM1 α-shedding occurs in human nephropathies, we performed Western blotting and immunohistochemical analysis of specimens with arterionephrosclerosis (AS) and diabetic nephropathy (DN) from autopsied kidneys. CADM1 α-shedding was induced in AS and DN kidneys and derived from the decrease in full-length CADM1 (FL-CADM1) and increase of the COOH-terminal fragment (α-CTF). In particular, the reduced FL-CADM1 level was correlated with tubular and tubulointerstitial injuries and the increases in BUN and sCre levels. Apoptosis of renal tubular epithelial cells (TECs) was promoted in both nephropathies, and it was significantly correlated with the decrease in the FL-CADM1. Furthermore, FL-CADM1 knockdown by small interfering RNA downregulated anti-apoptotic Bcl-2 protein and promoted apoptosis of cultured renal TECs. The present study suggests that the reduction of FL-CADM1 leads to renal TEC apoptosis and could exacerbate renal tubular and tubulointerstitial injuries, which contribute to the development of CKD.

Background: The glomerular filtration rate (GFR) assesses the function of all nephrons, and the single-nephron GFR assesses the function of individual nephrons. How the single-nephron GFR relates to demographic and clinical characteristics and kidney-biopsy findings in humans is unknown., Methods: We identified 1388 living kidney donors at the Mayo Clinic and the Cleveland Clinic who underwent a computed tomographic (CT) scan of the kidney with the use of contrast material and an iothalamate-based measurement of the GFR during donor evaluation and who underwent a kidney biopsy at donation. The mean single-nephron GFR was calculated as the GFR divided by the number of nephrons (calculated as the cortical volume of both kidneys as assessed on CT times the biopsy-determined glomerular density). Demographic and clinical characteristics and biopsy findings were correlated with the single-nephron GFR., Results: A total of 58% of the donors were women, and the mean (±SD) age of the donors was 44±12 years. The mean GFR was 115±24 ml per minute, the mean number of nephrons was 860,000±370,000 per kidney, and the mean single-nephron GFR was 80±40 nl per minute. The single-nephron GFR did not vary significantly according to age (among donors <70 years of age), sex, or height (among donors ≤190 cm tall). A higher single-nephron GFR was independently associated with larger nephrons on biopsy and more glomerulosclerosis and arteriosclerosis than would be expected for age. A higher single-nephron GFR was associated with a height of more than 190 cm, obesity, and a family history of end-stage renal disease., Conclusions: Among healthy adult kidney donors, the single-nephron GFR was fairly constant with regard to age, sex, and height (if ≤190 cm). A higher single-nephron GFR was associated with certain risk factors for chronic kidney disease and certain kidney-biopsy findings. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Malignant hypertension can occasionally be associated with microangiopathic haemolytic anaemia. A 38-year-old male presented with nausea, vomiting, loss of appetite and oliguria for 2 weeks. He was diagnosed with hypertensive emergency with cardiac and renal dysfunction. Interestingly, further workup was diagnostic for the presence of thrombotic microangiopathy (TMA): haemoglobin =12.7 g/dL, indirect bilirubin =2.0 mg/dL, haptoglobin ≤6 mg/dL, platelet count =121 000/μL and schistocytes on peripheral smear. At the outset, the cause of TMA was unclear. Patient denied having diarrhoea, making haemolytic uremic syndrome less likely. A normal ADAMTS13 activity test ruled out thrombotic thrombocytopaenic purpura. Malignant hypertension induced TMA was highest on the differential and plasma exchange was deferred. Renal biopsy revealed features of TMA and malignant nephrosclerosis. Patient eventually became dialysis dependent. Aggressive blood pressure control was obtained with multiple medications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Endoplasmic reticulum (ER) stress is implicated in chronic kidney disease (CKD) development in patients and in animal models. Here we show that ER stress inhibition through 4-phenylbutyric acid (4-PBA) administration decreases blood pressure, albuminuria, and tubular casts in an angiotensin II/deoxycorticosterone acetate/salt murine model of CKD. Lower albuminuria in 4-PBA-treated mice was associated with higher levels of cubilin protein in renal tissue membrane fractions. 4-PBA decreased renal interstitial fibrosis, renal CD3 + T-cell and macrophage infiltration, mRNA expression of TGFβ1, Wnt signaling molecules, and ER stress-induced pro-inflammatory genes. CHOP deficient mice that underwent this model of CKD developed hypertension comparable to wild type mice, but had less albuminuria and tubular casts. CHOP deficiency resulted in higher nephrin levels and decreased glomerulosclerosis compared to wild type mice; this effect was accompanied by lower macrophage infiltration and fibrosis. Our findings portray ER stress inhibition as a means to alleviate hypertensive CKD by preserving glomerular barrier integrity and tubular function. These results demonstrate ER stress modulation as a novel target for preserving renal function in hypertensive CKD., Competing Interests: The authors declare no competing financial interests.

The renal microvasculature is targeted during aging, sometimes producing chronic kidney disease (CKD). Overdiagnosis of CKD in older persons is concerning. To prevent it, a new concept of "healthy aging" is arising from a healthy renal donor study. We investigated the renal microcirculatory changes of three older persons and compared them with that of one patient with nephrosclerosis using a three-dimensional (3D) reconstruction technique that we previously developed. This method uses a virtual slide system and paraffin-embedded serial sections of surgical material that was double-immunostained by anti-CD34 and anti-α smooth muscle actin (SMA) antibodies for detecting endothelial cells and medial smooth muscle cells, respectively. In all cases, the 3D images proved that arteriosclerotic changes in large proximal interlobular arteries did not directly induce distal arterial change or glomerulosclerosis. The nephrosclerotic patient showed severe hyalinosis with luminal narrowing of small arteries directly inducing glomerulosclerosis. We also visualized an atubular glomerulus and intraglomerular dilatation of an afferent arteriole during healthy aging on the 3D image and showed that microcirculatory changes were responsible for them. Thus, we successfully visualized healthy aged kidneys on 3D images and confirmed the underlying pathology. This method has the ability to investigate renal microcirculatory damage during healthy aging., Competing Interests: The authors declare no conflict of interest.

Background: This study aimed to investigate renal outcomes and their predictors in biopsy-proven hypertensive nephrosclerosis (HN) patients and to compare clinico-pathological characteristics and prognoses between benign nephrosclerosis (BN) and malignant nephrosclerosis (MN) patients., Methods: Data for biopsy-proven HN patients were retrospectively analyzed. Renal survival rates and relationships between clinico-pathological characteristics and outcomes were assessed., Results: A total of 194 patients were enrolled; the mean age at biopsy was 43.8 years, and male gender predominated (82.5 %). The median duration of hypertension was 5.0 years, and the mean systolic and diastolic blood pressures were 195 ± 37 and 126 ± 26 mmHg, respectively. The median serum creatinine (Scr) level, estimated glomerular filtration rate (eGFR), and proteinuria level were 1.61 mg/dl, 49.6 ml/min/1.73 m(2), and 0.80 g/24 h, respectively. BN and MN were found by renal biopsy in 55.2 % and 44.8 % of patients, respectively. At biopsy, MN patients were younger, and had higher median Scr and proteinuria levels, higher incidences of anemia, hypertensive heart disease and hypertensive retinopathy, and worse renal outcomes than BN patients. During a median follow-up period of 3.0 years, 36 patients (18.6 %) reached end-stage renal disease (ESRD), and the 5- and 10-year cumulative renal survival rates for HN patients were 84.5 % and 48.9 %, respectively. A decreased baseline eGFR, an increased baseline proteinuria level, anemia, increased percentage of global glomerulosclerosis and tubular atrophy and interstitial fibrosis (TAIF) were independent predictors of future ESRD., Conclusions: The clinico-pathological characteristics and prognoses were significantly different between the MN and BN patients. The renal outcomes of HN patients were independently associated with the baseline eGFR and proteinuria level, anemia, percentage of global glomerulosclerosis and TAIF.

Background: Reduced estimated glomerular filtration rate (eGFR) and proteinuria are risk factors for end-stage renal disease (ESRD), of which benign nephrosclerosis is a common cause. However, few biopsy-based studies have assessed these associations., Methods: We performed retrospective cohort study of 182 Japanese patients who underwent renal biopsy from June 1985 through March 2014 and who were diagnosed with benign nephrosclerosis. Competing risk regression analyses were used to investigate the effect of eGFR and proteinuria levels at the time of renal biopsy on the risk for renal events (ESRD or a 50% decline in eGFR from baseline)., Results: During a median 5.8-year follow-up, 63 (34.6%) patients experienced renal events. The incidence of renal events increased with lower baseline eGFR and greater baseline proteinuria levels. After adjustment for baseline covariates, lower eGFR levels (subhazard ratios [SHRs], 1.30; 95% confidence interval [CI], 1.01-1.67, per 10 mL/min/1.73 m2) and higher proteinuria levels (SHR, 1.52; 95% CI, 1.23-1.87, per 1.0 g/day) at the time of renal biopsy were associated independently with higher risk for renal events. Lower levels of serum albumin (SHR, 2.07; 95% CI, 1.20-3.55 per 1.0 g/dL) were also associated with renal events. Patients with both eGFR <30 mL/min/1.73 m2 and proteinuria ≥0.5 g/day had a 26.7-fold higher risk (95% CI, 3.97-179.4) of renal events than patients with both eGFR ≥60 mL/min/1.73 m2 and proteinuria <0.5 g/day., Conclusions: Reduced eGFR and increased proteinuria as well as lower serum albumin at the time of renal biopsy are independent risk factors for renal events among patients with biopsy-proven benign nephrosclerosis.

Background: Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats., Methods: Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin. Urine was collected every 2-4 weeks for biomarker analysis. Renal tissue was examined histologically for fibrosis and for levels of inflammatory and fibrotic genes., Results: Male obese ZSF-1 rats demonstrated metabolic syndrome and proteinuria. Female counterparts were hyperlipidemic with delayed proteinuria, but were not hyperglycemic. Kidney hyperfiltration was observed in male obese rats in weeks 2-4 after surgery, and subsequently declined to levels significantly lower than controls. Tubulointerstitial/glomerular fibrosis in male obese rats was significantly elevated by week 12 post surgery and continued to expand in the ensuing weeks, particularly in uninephrectomized rats. Female rats had less severe fibrosis. Except for epidermal growth factor which decreased, the levels of several key inflammatory, injury and fibrotic factors were elevated in both tissue (mRNA) and urine (protein) of male obese rats., Conclusion: Male obese ZSF-1 rats represent an important DN model, manifesting key pathophysiological features including metabolic syndrome, proteinuria, progressive tubular and glomerular fibrosis, and transient hyperfiltration followed by progressive decline in renal function. Uninephrectomy significantly accelerated disease progression. Females were less severe in disease manifestation. Several urinary and tissue biomarkers were identified in the male obese rats that tracked with disease progression., (© 2016 S. Karger AG, Basel.)

The term "kidney shrinkage", which is used in both pathological anatomy and clinical contexts, is not uniformly defined. In medicolegal practice, it is particularly important whether or not a cause of death can be inferred from this diagnosis. If this were the case, a shrunken kidney determined in a forensic autopsy would obtain the same significance as a competing cause of death. International medical journals and German-language textbooks were searched for definitions of the various terms used to denote this condition, and the definitions were reassessed. The term "kidney shrinkage" was found to have historical roots and has further evolved since the 19th century. Although the first use of the term could not be determined with certainty, Bright (1789-1858) appears to be one of the first to use it in describing kidney disease. Definitions given in modern textbooks are based on kidney function, size, or macromorphology. However, these definitions lack uniformity and are often unsubstantiated. Because of its evocative power, the use of the historically coined term "kidney shrinkage" appears justified, at least as part of the medicolegal practitioner's jargon, to describe kidneys that have an uneven surface, decreased renal parenchyma, and a weight of less than 80 g, even if the term does not allow deductions about the degree of renal insufficiency and, thus, the significance of kidney shrinkage as the cause of death. The evaluation of such aspects requires histological analysis or referral to the results of clinical chemistry analyses that may have been performed while the individual was still alive.

Nephrosclerosis is an umbrella term defining changes in all compartments of the kidney, changes caused by hypertension and by ageing. Among other lesions, arteriolosclerosis and arteriolohyalinosis play a major role in inducing glomerular ischaemic shrinking and sclerosis along with glomerulomegaly and focal-segmental glomerulosclerosis (FSGS). These lesions are accompanied by tubulointerstitial inflammation and fibrosis that predict the decline of renal function. Nephrosclerosis is a major cause of renal insufficiency in blacks of African descent with a severe, early form of renovasculopathy and a rapid course to renal failure with predominant lesions of FSGS. It seems that in blacks, separate genetic factors independently lead to vascular lesions and to hypertension with a different time-scale of their onset and of their progression, nephroangiosclerosis preceding the onset of hypertension. Conversely, true and histologically identified nephrosclerosis in white Europeans rarely leads to end-stage renal disease in the absence of malignant hypertension. Various animal models demonstrate that renal vascular lesions may exist in the absence of hypertension. These experiments also point to a major role of angiotensin II and of a number of independent and overlapping cellular and molecular pathways in a cascade of inflammatory events that end in renal fibrosis. Two pathophysiologic mechanisms are at work in inducing glomerular lesions and tubulointerstitial fibrosis: a loss of autoregulation of the renal blood flow caused by an arteriolohyalinosis of the glomerular afferent arteriole and ischaemia that fosters the generation of hypoxia inducible-fibrosing factors. Not all antihypertensive drugs equally protect the kidney from nephrosclerosis. Angiotensin II antagonists exert a favourable effect on hyperfiltration. Conversely, dihydropyridine calcium-channel blockers and vasodilators do not withstand the derangement of renal autoregulation., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Previous autopsy studies suggested that a reduced nephron number is associated with increased risk of hypertension and chronic kidney disease. However, the significance of the nephron number estimated from a renal biopsy in patients with hypertensive nephrosclerosis (HNS) has not yet been elucidated., Methods: In this cross-sectional study, we examined the clinicopathological findings of biopsy-proven HNS patients with preserved renal function (estimated glomerular filtration rate ≥ 60 ml/min/1.73 m(2)). The glomerular density (GD; the number of glomeruli per total renal cortical area) in biopsy specimens was evaluated as a surrogate of the nephron number. Renal biopsies from kidney transplant donors were used as healthy controls., Results: A total of 58 HNS patients were enrolled. The GD value in the HNS patients was low compared with those in the kidney transplant donors (2.0 vs. 3.2 /mm(2)). These differences remained significant when globally sclerotic glomeruli were included in the calculation of the GD. Of note, the GD in HNS patients with overt proteinuria (≥1 g/day) was significantly lower than that of HNS patients with mild proteinuria (<1g/day; 1.8 vs. 2.2/mm(2), P = 0.014). In contrast, other histopathological parameters, including the severity of global glomerulosclerosis, interstitial fibrosis/tubular atrophy and arterial and arteriole lesions were comparable between the 2 HNS subgroups. In addition, the GD was identified as a factor that was associated with the amount of urinary protein excretion at biopsy, independent of other clinicopathological factors., Conclusions: These results suggest that a low GD is a renal histological characteristic of HNS patients, especially those with overt proteinuria., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: We studied the urinary sediment mRNA level of Th9- and Th22-related cytokines in patients with systemic lupus erythematosus (SLE)., Methods: We quantified urinary mRNA levels of interleukin (IL) 9, IL-10, IL-22, and their corresponding transcription factors in 73 patients with active lupus nephritis, 13 patients with hypertensive nephrosclerosis (HTN), and 25 healthy subjects., Results: There was no detectable IL-9 mRNA in all samples. Patients with proliferative lupus nephritis had significantly lower urinary IL-22 mRNA levels than those with nonproliferative nephritis (2.2 ± 5.4 vs 8.6 ± 20.0 copies, p = 0.019), and urinary IL-22 mRNA level inversely correlated with the histological activity index (r = -0.427, p < 0.0001). In contrast, patients with lupus nephritis had significantly higher urinary IL-10 mRNA levels than patients with HTN (7.8 ± 18.5 vs 1.9 ± 4.0 copies, p = 0.012), and urinary IL-10 mRNA levels correlated with its intrarenal mRNA levels (r = 0.337, p = 0.004) and SLE disease activity index (r = 0.277, p = 0.018). Urinary IL-10 mRNA level was significantly lower among patients who achieved complete remission than those with partial remission or no response (4.1 ± 6.5 vs 14.1 ± 28.0 copies, p = 0.036)., Conclusion: Urinary IL-22 mRNA level is decreased in patients with SLE with proliferative nephritis, while urinary IL-10 mRNA levels correlates with its intrarenal mRNA level and disease activity. Urinary IL-10 mRNA levels may also predict treatment response. These results suggest that urinary mRNA levels of IL-10 and IL-22 might be used as biomarkers for assessing disease activity and risk stratification in lupus nephritis.

For a century, nephrosclerosis was ascribed to nonmalignant hypertension and aging. However, it was intuitively perceived that hypertension may follow rather than explain this nephrovasculopathy. Hypertensive nephrosclerosis was long considered a major cause of end-stage renal failure (ESRD). This is especially true in blacks of African descent but not in other ethnic populations. The term 'nephrosclerosis' is still an easy way out to classify a patient with renal insufficiency. This leads to neglect the possibility of an overlooked nephropathy complicated by hypertension and to believe that drastic blood pressure control may retard the progression to ESRD. Several clinical and experimental lines of evidence lead to the understanding that nephrosclerosis, especially in blacks, is a genetic renovasculopathy that precedes the rise in blood pressure. The identification of coding region variants in APOL1 encoding apolipoprotein L-1 in black but also white and Asians opens new lines of research on the genetics of nephroangiosclerosis and of FSGS. Metabolic derangements, such as obesity, oxidative stress, dyslipidemia and atherosclerosis may be considered confounding factors with regard to nephrosclerosis. Histomorphometric studies led to sorting out the lesions due to aging from those stemming from hypertension. They shed new light not only on glomerular lesions that comprise ischemic obsolescence but also on glomerulomegaly and focal-segmental sclerosis, the latter due to a loss of renal autoregulation. It appears that the control of hypertension is not credited with the expected benefit for slowing the decline of renal function. 'Nephrosclerosis' can be considered an umbrella term of poor significance that should be replaced by its pathologic description, that is, arterionephrosclerosis and incite to elucidate the various genetic and metabolic factors that lead to a lesion in quest of a specific disease., (© 2015 S. Karger AG, Basel.)

Objective: The aim of this study was to evaluate the roles of podocalyxin (PCX) and connective tissue growth factor (CTGF) in spontaneously hypertensive rats., Methods: Spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats were divided into groups referred to as SHR 12W, SHR 24W, WKY 12W and WKY 24W. Systolic blood pressure and 24-hour total uric protein were measured every two weeks in the respective groups. CTGF, PCX, alpha-smooth muscle actin (α-SMA) and collagen-III were evaluated via immunohistochemical staining. In addition, CTGF, PCX, and α-SMA gene expression levels were determined by analyzing mRNA levels., Results: More kidney lesions occurred alongside foot processes effacement in SHR 24W rats than in SHR 12W rats. In SHR 12W rats, blood pressure and 24-hour total uric protein level were elevated and continued to increase thereafter. In the SHR 12W and SHR 24W groups, the expression of CTGF, α-SMA and collagen-III was significantly increased. Immunohistochemical staining showed that PCX expression was significantly reduced in the SHR group and CTGF expression was increased. A significant decrease in PCX mRNA and an increase in CTGF mRNA were observed in SHR 24W rats relative to SHR 12W rats., Conclusion: Both the overexpression of CTGF and the loss of podocalyxin reflect renal damage in spontaneously hypertensive rats. CTGF and PCX may be involved in the mechanisms of podocyte injury and apoptosis induced by hypertension.

Background: African Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis., Methods: Stereological disector/fractionator estimates of glomerular number (N(glom)) and average glomerular volume (V(glom)) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with V(glom) by age, race, gender, body mass index (BMI) and blood pressure., Results: African Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). N(glom) was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased V(glom) with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased V(glom) (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased V(glom) was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of V(glom) was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased., Conclusions: Glomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on V(glom) and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans., (© The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA.)

Recent studies have demonstrated that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblasts in the kidney are incompletely understood. As TGF-β1/Smad3 signaling has been shown to have an important role in the pathogenesis of kidney fibrosis, we investigated the role of Smad3 in the activation of bone marrow-derived fibroblasts in the kidney following obstructive injury using Smad3-knockout mice and Smad3-null monocytes. Compared with wild-type mice, Smad3-knockout mice accumulated significantly fewer bone marrow-derived fibroblasts in the kidney after obstructive injury. Furthermore, Smad3-knockout mice exhibited less myofibroblast activation and expressed less α-SMA in the obstructed kidney. Consistent with these findings, genetic deletion of Smad3 reduced total collagen deposition and suppressed the expression of extracellular matrix proteins. Moreover, wild-type mice engrafted with Smad3(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidney with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with Smad3(+/+) bone marrow cells. In cultured monocytes, TGF-β1 induced phosphorylation of Smad3 and Smad3 deficiency abolished TGF-β1-induced expression of α-SMA and extracellular matrix proteins. Taken together, our results demonstrate that Smad3 signaling has an essential role in the activation of bone marrow-derived fibroblasts in the kidney during the pathogenesis of renal fibrosis.

Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. The interaction of TG2 with the heparan sulfate proteoglycan syndecan-4 (Sdc4) regulates the cell surface trafficking, localization, and activity of TG2 in vitro but remains unstudied in vivo. We tested the hypothesis that Sdc4 is required for cell surface targeting of TG2 and the development of kidney fibrosis in CKD. Wild-type and Sdc4-null mice were subjected to unilateral ureteric obstruction and aristolochic acid nephropathy (AAN) as experimental models of kidney fibrosis. Analysis of renal scarring by Masson trichrome staining, kidney hydroxyproline levels, and collagen immunofluorescence demonstrated progressive fibrosis associated with increases in extracellular TG2 and TG activity in the tubulointerstitium in both models. Knockout of Sdc-4 reduced these effects and prevented AAN-induced increases in total and active TGF-β1. In wild-type mice subjected to AAN, extracellular TG2 colocalized with Sdc4 in the tubular interstitium and basement membrane, where TG2 also colocalized with heparan sulfate chains. Heparitinase I, which selectively cleaves heparan sulfate, completely abolished extracellular TG2 in normal and diseased kidney sections. In conclusion, the lack of Sdc4 heparan sulfate chains in the kidneys of Sdc4-null mice abrogates injury-induced externalization of TG2, thereby preventing profibrotic crosslinking of extracellular matrix and recruitment of large latent TGF-β1. This finding suggests that targeting the TG2-Sdc4 interaction may provide a specific interventional strategy for the treatment of CKD., (Copyright © 2014 by the American Society of Nephrology.)