The Number and Size of Individual Kidney Medullary Pyramids is Associated with Clinical Characteristics, Kidney Biopsy Findings, and CKD Outcomes among Kidney Donors.

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.

Age-Based Versus Young-Adult Thresholds for Nephrosclerosis on Kidney Biopsy and Prognostic Implications for CKD.

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.

The spectrum of glomerular and vascular kidney pathology associated with myeloproliferative neoplasms.

A high prevalence of chronic kidney disease (CKD) occurs in patients with myeloproliferative neoplasms (MPN). However, MPN-related glomerulopathy (MPN-RG) may not account for the entirety of CKD risk in this population. The systemic vasculopathy encountered in these patients raises the hypothesis that vascular nephrosclerosis may be a common pattern of injury in patients with MPN and with CKD. In an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four different pathology departments, we now describe glomerular and vascular lesions and establish clinicopathologic correlations. Our study encompassed 47 patients with MPN who underwent a kidney biopsy that included 16 patients with chronic myeloid leukemia (CML) and 31 patients with non-CML MPN. Fourteen cases met a proposed definition of MPN-RG based on mesangial sclerosis and hypercellularity, as well as glomerular thrombotic microangiopathy. MPN-RG was significantly associated with both myelofibrosis and poorer kidney survival. Thirty-three patients had moderate-to-severe arteriosclerosis while 39 patients had moderate-to-severe arteriolar hyalinosis. Multivariable models that included 188 adult native kidney biopsies as controls revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension. Therefore, MPN-RG is associated with myelofibrosis and has a poor kidney prognosis. Thus, our findings suggest that the kidney vasculature is a target during MPN-associated vasculopathy and establish a new link between MPN and CKD. Hence, these results may raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

Mesangial Injury and Capillary Ballooning Precede Podocyte Damage in Nephrosclerosis.

The development of focal and segmental glomerulosclerosis (FSGS) as a consequence of glomerular hypertension resulting from arterial hypertension is widely considered a podocyte disease. However, the primary damage is encountered in the mesangium. In acute settings, mesangial cells disconnect from their insertions to the glomerular basement membrane, causing a ballooning of capillaries and severe changes of the folding pattern of the glomerular basement membrane, of the arrangement of the capillaries, and thereby of the architecture of the tuft. The displacement of capillaries led to contact of podocytes and parietal epithelial cells, initiating the formation of tuft adhesions to Bowman's capsule, the committed lesion to progress to FSGS. In addition, the displacement of capillaries also caused an abnormal stretching of podocytes, resulting in podocyte damage. Thus, the podocyte damage that starts the sequence to FSGS is predicted to develop secondary to the mesangial damage. This sequence was found in two hypertensive rat models of FSGS and in human hypertensive nephrosclerosis.

Nephrosclerosis in young patients with malignant hypertension.

BACKGROUND: Nephrosclerosis is one of the histopathological consequences of severe or malignant hypertension (MH), some of the pathophysiology of which has been extrapolated from essential polygenetic arterial hypertension. Despite our recent description of unsuspected ciliopathies with MH, causes of MH in young patients with severe renal impairment are poorly understood. METHODS: To refine and better describe the MH phenotype, we studied clinical and prognostic factors in young patients receiving a kidney biopsy following their first episode of MH. Patients were identified retrospectively and prospectively from eight centres over a 35-year period (1985-2020). Keywords were used to retrospectively enrol patients irrespective of lesions found on renal biopsy. RESULTS: A total of 114 patients were included, 77 (67%) of whom were men, average age 34 years, 35% Caucasian and 34% African origin. An isolated clinical diagnosis of severe nephrosclerosis was suggested in only 52% of cases, with 24% primary glomerulopathies. Only 7% of patients had normal renal function at diagnosis, 25% required emergency dialysis and 21% were eventually transplanted. Mortality was 1% at the last follow-up. Independent prognostic factors significantly associated with renal prognosis (6-month dialysis) and predictive of end-stage renal disease were serum creatinine on admission {odds ratio [OR] 1.56 [95% confidence interval (CI) 1.34-1.96], P < .001} and renal fibrosis >30% [OR 10.70 (95% CI 1.53-112.03), P = .03]. Astonishingly, the presence of any thrombotic microangiopathy lesion on renal biopsy was an independent, protective factor [OR 0.14 (95% CI 0.02-0.60), P = .01]. The histopathological hallmark of nephrosclerosis was found alone in only 52% of study patients, regardless of ethnicity. CONCLUSIONS: This suggests that kidney biopsy might be beneficial in young patients with MH.

Trends in the incidence of renal replacement therapy by type of primary kidney disease in Japan, 2006-2020.

AIM: Age-standardized incidence of end stage kidney disease requiring renal replacement therapy (RRT) has stabilized in men and declined in women in Japan since 1996. However, recent trends by primary kidney disease are unknown. The present study aimed to examine recent trends in incidence rates of RRT by primary kidney disease in Japan. METHODS: Numbers of incident RRT patients aged ≥20 years by sex and primary kidney disease from 2006 to 2020 were extracted from the Japanese Society of Dialysis Therapy registry. Using the census population as the denominator, annual incidence rates of RRT were calculated and standardized to the WHO World Standard Population (2000-2025). Average annual percentage change (AAPC) and corresponding 95% confidence intervals (CIs) were calculated for trends using Joinpoint regression analysis. RESULTS: From 2006 to 2020, the crude number of incident RRT patients due to nephrosclerosis increased by 132% for men and 62% for women. Age-standardized incidence rates of RRT due to nephrosclerosis increased significantly, by 3.3% (95% CI: 2.9-3.7) and 1.4% (95% CI: 0.8-1.9) per year for men and women, respectively. The AAPC of chronic glomerulonephritis (-4.4% [95% CI: -5.3 to -3.8] for men and -5.1% [95% CI: -5.5 to -4.6] for women) and diabetic nephropathy (-0.6% [95% CI: -0.9 to -0.3] for men and -2.8% [95% CI: -3.1 to -2.6] for women) significantly decreased from 2006 to 2020. CONCLUSION: Incident RRT due to chronic glomerulonephritis and diabetic nephropathy decreased, while the number and incident rates of RRT due to nephrosclerosis increased, from 2006 to 2020 in Japan.

Serum Uric Acid Levels and Nephrosclerosis in a Population-Based Autopsy Study: The Hisayama Study.

INTRODUCTION: Information regarding the influence of serum uric acid (SUA) levels on pathological changes in the kidney is limited. In this study, we examined the association between SUA levels and pathological findings of nephrosclerosis in population-based autopsy samples. METHODS: A total of 923 deceased individuals in a Japanese community underwent autopsy examinations between 1974 and 1994. Of these, 547 individuals with available kidney tissues and health examination data within a median of 3 years before death were eligible for the present study. SUA levels were categorized into quintiles (Q1, 107-237; Q2, 238-279; Q3, 280-326; Q4, 327-380; Q5, 381-755 µmol/L). Advanced degrees of glomerular sclerosis, kidney arteriolar hyalinosis, and kidney arteriosclerosis were defined as the 90th percentile or more of a glomerular sclerosis index and an arteriolar hyalinosis index, and the 10th percentile or less of a wall-lumen ratio, respectively. A logistic regression model was used to evaluate odds ratios (ORs) and their 95% confidence intervals (CIs) of SUA levels on each kidney lesion. RESULTS: Higher SUA levels were significantly associated with higher values of the age- and sex-adjusted glomerular sclerosis index and lower values of the wall-lumen ratio (both p for trend <0.01). Individuals in the Q5 group had a significantly greater likelihood of advanced glomerular sclerosis (OR 7.19, 95% CI 2.42-21.38) and advanced kidney arteriosclerosis (OR 5.28, 95% CI 1.77-15.80) than individuals in the Q1 group after adjusting for potential covariates. There was no evidence of significant associations of SUA levels with either the arteriolar hyalinosis index or the presence of advanced arteriolar hyalinosis. CONCLUSIONS: Elevated SUA levels were significantly associated with advanced glomerular sclerosis and advanced kidney arteriosclerosis, but not with advanced arteriolar hyalinosis in community-based autopsy samples of Japanese.

Clinicopathological discordance in biopsy-proven nephrosclerosis: a nationwide cross-sectional study of the Japan Renal Biopsy Registry (J-RBR).

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 m2 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 m2 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.

Autopsy study examining non-chronic kidney disease versus chronic kidney disease caused by hypertensive-nephrosclerosis in elderly subjects.

BACKGROUND: The aim of this autopsy study was to clarify the differences of renal histopathology between non-chronic kidney disease (CKD) and CKD caused by hypertensive-nephrosclerosis in the elderly and during the aging process. METHODS: We examined autopsy specimens from 105 elderly patients (53 male subjects; mean age, 86.2 years) including 44 patients with CKD as a result of nephrosclerosis. The analysis was divided into two groups depending on whether they had CKD. RESULTS: The incidences of arterial intimal thickening (AIT), obsolescent-type global glomerulosclerosis (OB), and interstitial fibrosis and tubular atrophy (IF/TA) were higher in the CKD group than in the non-CKD group (all p < 0.01). These factors were all correlated with each other (AIT vs. OB, r = 0.43; AIT vs. IF/TA, r = 0.25; OB vs. IF/TA, r = 0.53). IF/TA had the strongest association with hypertension and decreased eGFR. In the non-CKD group, the frequency of OB was more than 20% in subjects aged 90 years or older. However, the individuals in the non-CKD group tended to have compensatory glomerular hypertrophy with increasing age and a retained eGFR, while the CKD group was unable to obtain compensatory hypertrophy and had a lower eGFR. We also found that AIT, OB and IF/TA occurred independently of systemic atherosclerosis. CONCLUSIONS: Non-CKD in the elderly refers to the so-called aging kidney. The progression from aging kidney to CKD caused by nephrosclerosis was influenced by increases in AIT, OB and IF/TA. IF/TA was thought to be the most important downstream factor in the progression of aging kidney to CKD.

Page kidney following spontaneous subcapsular hematoma immediately after kidney transplantation: a case report.

BACKGROUND: Page kidney (PK) is the occurrence of kidney hypoperfusion and ischemia due to pressure on the kidney by a subcapsular hematoma (SH), a mass, or fluid collection. SH after renal transplantation may result in kidney ischemia and graft loss. CASE PRESENTATION: We present a rare case of early spontaneous SH in an allograft kidney that led to a decrease in renal function. A 56-year-old male patient underwent deceased donor kidney transplantation. After declamping, appropriate renal perfusion and immediate diuresis were observed, with no evidence of SH. However, his urinary output abruptly decreased 6 h postoperatively. Abdominal ultrasonography showed 28 mm deep SH on transplant and the resistive index (RI) increased to 0.98-1 and diastolic flow reversal was observed. Surgical interventions were performed 2 days after transplantation, following a further decrease in urinary output. Serum creatinine decreased to 2.2 mg/dL, urinary output increased to an average of 200 cc per hour and the RI value was decreased to 0.7 on POD 7. CONCLUSION: In patients with abrupt decreased renal function after transplantation, SH should be suspected and the presence of PK should be determined using Doppler USG. In these cases, surgical intervention may avoid allograft dysfunction.

Study protocol and baseline characteristics of newly induced dialysis patients: a prospective multi-center cohort study with a biological sample bank, the Ibaraki Dialysis Initiation Cohort (iDIC) study.

BACKGROUND: Patients with end-stage kidney disease (ESKD) face higher risks of life-threatening events including cardiovascular disease. Various risk factors are identified as agents influencing the life prognosis of ESKD patients. Herein, we evaluated the risk factors related to the outcomes of Japanese patients with dialysis induction. We present the study protocol, the patients' baseline characteristics, and their outcomes. METHODS: The Ibaraki Dialysis Initiation Cohort (iDIC) Study is a prospective multi-center cohort study in collaboration with 60 tertiary-care facilities in Ibaraki Prefecture, Japan. We collected baseline data from clinical records and analyzed blood and urine samples of these facilities' patients with diabetic nephropathy, hypertensive nephrosclerosis, and chronic glomerulonephritis (CGN). The study's primary outcome was the survival rate at 24 months after dialysis induction. We performed a Kaplan-Meier analysis for cumulative survival and a Cox proportional hazards analysis for all-cause mortality and hospitalization. RESULTS: We analyzed 636 patients' cases (424 males, 212 females, age 67.4 ± 13.1 yrs. [mean ± SD]). We compared the patients' baseline data with those of similar cohort studies. As the primary kidney disease, 327 cases (51.4%) were diagnosed as diabetic nephropathy, 101 (15.9%) as hypertensive nephrosclerosis, and 114 (17.9%) as CGN. The mean serum creatinine value was 9.1 ± 2.9 mg/dL. The mean estimated glomerular filtration rate was 5.6 ± 1.8 mL/min/1.73m2. The cumulative survival rates at 6 months and 24 months after dialysis induction were 95.2 and 87.7%, respectively. The cumulative survival rate was significantly lower with increasing age. A Cox proportional hazards regression analysis demonstrated that high age was significantly associated with all-cause mortality. CONCLUSIONS: Regarding the clinical characteristics of these newly induced dialysis patients, the same trend as in other cohort studies was observed. Another study is underway to explore prognostic factors based on the iDIC Study's findings.

Vascular, cardiac, and renal lesions attributed to primary systemic hypertension in western pygmy marmosets (Cebuella pygmaea).

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.

In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

Transient receptor potential canonical type 6 (TRPC6) is a nonselective receptor-operated cation channel that regulates reactive fibrosis and growth signaling. Increased TRPC6 activity from enhanced gene expression or gain-of-function mutations contribute to cardiac and/or renal disease. Despite evidence supporting a pathophysiological role, no orally bioavailable selective TRPC6 inhibitor has yet been developed and tested in vivo in disease models. Here, we report an orally bioavailable TRPC6 antagonist (BI 749327; IC50 13 nM against mouse TRPC6, t1/2 8.5-13.5 hours) with 85- and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7. TRPC6 calcium conductance results in the stimulation of nuclear factor of activated T cells (NFAT) that triggers pathological cardiac and renal fibrosis and disease. BI 749327 suppresses NFAT activation in HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants (P112Q, M132T, R175Q, R895C, and R895L) and blocks associated signaling and expression of prohypertrophic genes in isolated myocytes. In vivo, BI 749327 (30 mg/kg/day, yielding unbound trough plasma concentration ∼180 nM) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice subjected to sustained pressure overload. Additionally, BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction. These results provide in vivo evidence of therapeutic efficacy for a selective pharmacological TRPC6 inhibitor with oral bioavailability and suitable pharmacokinetics to ameliorate cardiac and renal stress-induced disease with fibrosis.

Structural and Functional Changes in Aging Kidneys.

The renal condition is one of the crucial predictors of longevity; therefore, early diagnosis of any dysfunction plays an important role. Kidneys are highly susceptible to the aging process. Unfavorable conditions may lead to a significant disturbance of the body's homeostasis. Apart from physiological changes, there are some conditions such as hypertension, diabetes or obesity which contribute to the acceleration of the aging process. A determination of macroscopic and microscopic changes is essential for assessing the progression of aging. With age, we observe a decrease in the volume of renal parenchyma and an increase in adipose tissue in the renal sinuses. Senescence may also be manifested by the roughness of the kidney surface or simple renal cysts. The main microscopic changes are a thickening of the glomerular basement membrane, nephrosclerosis, an accumulation of extracellular matrix, and mesangial widening. The principal aspect of stopping unfavorable changes is to maintain health. Studies have shown many useful ways to mitigate renal aging. This review is focused especially on medications such as renin-angiotensin-aldosterone system blockers or resveratrol, but even eating habits and lifestyle.

Fluorescence Imaging Using Enzyme-Activatable Probes for Detecting Diabetic Kidney Disease and Glomerular Diseases.

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes.

Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics.

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.

Early elimination of uremic toxin ameliorates AKI-to-CKD transition.

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.

Prevalence of latent tuberculosis infection and its risk factors in Japanese hemodialysis patients.

BACKGROUND: The majority of active tuberculosis (TB) cases develop from latent tuberculosis infection (LTBI). Since the risk of TB in hemodialysis (HD) patients is particularly high, interferon-gamma release assay (IGRA) for LTBI screening in HD patients is considered important. However, the prevalence and characteristics of LTBI in Japanese HD patients remain obscure. METHODS: We performed an observational cross-sectional study of LTBI using IGRA QFT-3G tests in 118 HD outpatients enrolled at 3 hospitals of varying location and function. RESULTS: Of the 118 patients, 96 were QFT negative, 7 were QFT indeterminate, 14 were QFT positive, and 1 was QFT judgment impossible. No patient had active TB. Confirmed (QFT positive) and possible (QFT positive + indeterminate) LTBI patients totaled 14 (11.9%) and 21 (17.8%), respectively. The LTBI possible group was significantly older and had a significantly higher rate of nephrosclerosis versus the QFT-negative group. The indeterminate group had a significantly longer HD period. The QFT results were not remarkably affected by other clinical data, including hospital characteristics. The possible LTBI rate increased age-dependently, with higher values from 60 years of age. CONCLUSIONS: The prevalence of LTBI is high in Japanese HD patients, especially from the age of 60 years. Older age was a significant risk factor for LTBI, with prediction difficult using other clinical data. Extended HD may mask IGRA results. Therefore, aggressive screening for LTBI is advised in all HD patients regardless of hospital region or type, especially in patients over 60 years of age or newly commencing HD.

Clinical Outcomes after Endovascular Therapy Among Hemodialysis Patients with Peripheral Artery Disease Stratified by the Primary Kidney Disease.

OBJECTIVES: The objective of this study was to investigate the clinical characteristics of hemodialysis patients with peripheral artery disease (PAD) and the outcomes after endovascular therapy (EVT) in such patients stratified by the primary kidney disease. METHODS: This retrospective observational study evaluated 142 consecutive hemodialysis patients with symptomatic PAD who underwent EVT (men: n = 103, age: 74 ± 8 years). Patients were divided into 3 groups in accordance with the reason for hemodialysis: hypertensive nephrosclerosis (HTN [n = 26]), diabetic nephropathy (DN [n = 85]), and chronic glomerulosclerosis (CGN [n = 31]). The primary outcome was major adverse event(s) (MAEs), including target lesion revascularization, major amputation, and all-cause death. Clinical characteristics and outcomes were compared among the 3 groups. RESULTS: Patients with HTN were older (81 ± 6 years vs. 72 ± 8 years vs. 74 ± 8 years; P < 0.001) and had a shorter hemodialysis vintage (2.4 years vs. 6.8 years vs. 11.2 years; P < 0.001) than those with DN and CGN. Critical limb ischemia (CLI) affected 15 (58%) patients in the HTN group, 52 (61%) in the DN group, and 10 (32%) in the CGN group. Target lesion length was longer in patients with HTN than in those in the other groups (155 ± 101 mm vs. 108 ± 77 mm [DN] vs. 98 ± 76 mm [CGN]; P = 0.020). During a median follow-up period of 372 days (interquartile range, 198-730 days), Kaplan-Meier curve analysis revealed that HTN was associated with an increased risk for MAEs (χ2 11.6; P = 0.003). Furthermore, multivariate Cox regression analysis revealed that CLI, HTN, and B-type natriuretic peptide levels were independent predictors of MAE (hazard ratio 3.91, 2.88, and 1.00; P < 0.001, P < 0.001, and P = 0.001, respectively). CONCLUSIONS: Among hemodialysis patients with PAD, HTN was associated with an increased risk for MAEs after EVT.

Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes.

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.13BN26 rats. Administering anti-miR-204-5p to SS.13BN26 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.