Three-dimensional convolutional neural network-based classification of chronic kidney disease severity using kidney MRI.

A three-dimensional convolutional neural network model was developed to classify the severity of chronic kidney disease (CKD) using magnetic resonance imaging (MRI) Dixon-based T1-weighted in-phase (IP)/opposed-phase (OP)/water-only (WO) imaging. Seventy-three patients with severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2, CKD stage G4-5); 172 with moderate renal dysfunction (30 ≤ eGFR < 60 mL/min/1.73 m2, CKD stage G3a/b); and 76 with mild renal dysfunction (eGFR ≥ 60 mL/min/1.73 m2, CKD stage G1-2) participated in this study. The model was applied to the right, left, and both kidneys, as well as to each imaging method (T1-weighted IP/OP/WO images). The best performance was obtained when using bilateral kidneys and IP images, with an accuracy of 0.862 ± 0.036. The overall accuracy was better for the bilateral kidney models than for the unilateral kidney models. Our deep learning approach using kidney MRI can be applied to classify patients with CKD based on the severity of kidney disease.

Development of a prognostic risk score to predict early mortality in incident elderly Japanese hemodialysis patients.

BACKGROUND: Information of short-term prognosis after hemodialysis (HD) introduction is important for elderly patients with chronic kidney disease (CKD) and their families choosing a modality of renal replacement therapy. Therefore, we developed a risk score to predict early mortality in incident elderly Japanese hemodialysis patients. MATERIALS AND METHODS: We analyzed data of incident elderly HD patients from a nationwide cohort study of the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) to develop a prognostic risk score. Candidate risk factors for early death within 1 year was evaluated using multivariate logistic regression analysis. The risk score was developed by summing up points derived from parameter estimate values of independent risk factors. The association between risk score and early death was tested using Cox proportional hazards models. This risk score was validated twice by using an internal validation cohort derived from the JRDR and an external validation cohort collected for this study. RESULTS: Using the development cohort (n = 2,000), nine risk factors were retained in the risk score: older age (>85), yes = 2, no = 0; sex, male = 2, female = 0; lower body mass index (<20), yes = 2, no = 0; cancer, yes = 1, no = 0; dementia, yes = 3, no = 0; lower creatinine (<6.5 mg/dL), yes = 1, no = 0; lower albumin (<3.0 g/dL), yes = 3, no = 0; normal or high calcium (≥8.5 mg/dL), yes = 1, no = 0; and higher C reactive protein (>2.0 mg/dL), yes = 2, no = 0. In the internal and external validation cohorts (n = 739, 140, respectively), the medium- and high-risk groups (total score, 6 to 10 and 11 or more, respectively) showed significantly higher risk of early death than the low-risk group (total score, 0 to 5) (p<0.001). CONCLUSION: We developed a prognostic risk score predicting early death within 1 year in incident elderly Japanese HD patients, which may help detect elderly patients with a high-risk of early death after HD introduction.

Successful Treatment of Diffuse Large B-cell Lymphoma Involving Multiple Renal and Bone Infiltrations Presenting with Giant Cell Arteritis-like Manifestations: A Case Report.

We herein report a case of diffuse large B-cell lymphoma (DLBCL) involving multiple renal and bone infiltrations presenting with giant cell arteritis-like (GCA)-like manifestations. One month prior, the present patient had left-sided temporal headache, jaw claudication, and renal failure. The patient was diagnosed with DLBCL based on a renal biopsy. After rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus intrathecal methotrexate/cytarabine/prednisone and rituximab, high-dose methotrexate, and cytarabine (R-MA) chemotherapy, the patient's clinical manifestations improved, and complete remission was achieved. DLBCL rarely but occasionally presents with GCA-like manifestations or multiple renal and bone infiltrations, highlighting the need for prompt and aggressive combination chemotherapy.

The utility of automatic segmentation of kidney MRI in chronic kidney disease using a 3D convolutional neural network.

We developed a 3D convolutional neural network (CNN)-based automatic kidney segmentation method for patients with chronic kidney disease (CKD) using MRI Dixon-based T1-weighted in-phase (IP)/opposed-phase (OP)/water-only (WO) images. The dataset comprised 100 participants with renal dysfunction (RD; eGFR < 45 mL/min/1.73 m2) and 70 without (non-RD; eGFR ≥ 45 mL/min/1.73 m2). The model was applied to the right, left, and both kidneys; it was first evaluated on the non-RD group data and subsequently on the combined data of the RD and non-RD groups. For bilateral kidney segmentation of the non-RD group, the best performance was obtained when using IP image, with a Dice score of 0.902 ± 0.034, average surface distance of 1.46 ± 0.75 mm, and a difference of - 27 ± 21 mL between ground-truth and automatically computed volume. Slightly worse results were obtained for the combined data of the RD and non-RD groups and for unilateral kidney segmentation, particularly when segmenting the right kidney from the OP images. Our 3D CNN-assisted automatic segmentation tools can be utilized in future studies on total kidney volume measurements and various image analyses of a large number of patients with CKD.

A case of hemophagocytic lymphohistiocytosis in a hemodialysis patient with coronavirus disease 2019.

During the treatment of a patient on hemodialysis with severe coronavirus disease 2019 (COVID-19), the patient was weaned from extracorporeal membrane oxygenation, which was used to treat severe COVID-19 pneumonia. However, the patient's condition worsened after the peak infection phase of COVID-19 because of acute respiratory distress syndrome with suspected hemophagocytic lymphohistiocytosis (HLH). After a bone marrow biopsy confirmed the diagnosis, methylprednisolone pulse therapy, followed by combination therapy (including oral prednisolone and cyclosporine) was immediately administered, and the patient survived. Because HLH can occur a month or more after the onset of COVID-19, even if the viral load is reduced to the point of being undetectable by reverse transcriptase-polymerase chain reaction, it can be considered to correspond to the "post-acute COVID-19 syndrome," which has recently been proposed. Early intervention is necessary, because HLH can be fatal. Therefore, it is important to know that HLH can occur at any stage of COVID-19 and to pay attention to the patient's progress over time, including checking the HScore.

Prognosis of Patients with Acute Kidney Injury due to Type 1 Cardiorenal Syndrome Receiving Continuous Renal Replacement Therapy.

INTRODUCTION: The prognosis of patients with acute kidney injury (AKI) caused by type 1 cardiorenal syndrome (CRS) requiring continuous renal replacement therapy (CRRT) is unclear. We investigated the in-hospital mortality and prognostic factors in these patients. METHODS: We retrospectively identified 154 consecutive adult patients who received CRRT for AKI caused by type 1 CRS between January 1, 2013, and December 31, 2019. We excluded patients who underwent cardiovascular surgery and those with stage 5 chronic kidney disease. The primary outcome was in-hospital mortality. Cox proportional hazards analysis was performed to analyze independent predictors of in-hospital mortality. RESULTS: The median age of patients at admission was 74.0 years (interquartile range: 63.0-80.0); 70.8% were male. The in-hospital mortality rate was 68.2%. Age ≥80 years (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.21-2.87; p = 0.004), previous hospitalization for acute heart failure (HR, 1.67; 95% CI, 1.13-2.46; p = 0.01), vasopressor or inotrope use (HR, 5.88; 95% CI, 1.43-24.1; p = 0.014), and mechanical ventilation at CRRT initiation (HR, 2.24; 95% CI, 1.46-3.45; p < 0.001) were associated with in-hospital mortality. CONCLUSION: In our single-center study, the use of CRRT for AKI due to type 1 CRS was associated with high in-hospital mortality.

A Case of Anti-vascular Endothelial Growth Factor Therapy-Related Nephrotic Syndrome With Marked Intraglomerular Macrophage Infiltration.

A 75-year-old woman with colon cancer and distant metastases was treated with fluorouracil, levofolinate, and irinotecan (FOLFIRI) plus bevacizumab postoperatively. During the 32nd course, the patient developed massive proteinuria, and only bevacizumab was discontinued; the proteinuria improved rapidly over time. However, more than six months later, the patient developed massive proteinuria again, and her renal function declined. Renal biopsy revealed glomerular microangiopathy with prominent foam cell infiltration into the glomerulus, which was thought to be caused by chronic endothelial cell damage to the glomerular capillaries. Endothelial cell damage is thought to be caused not only by the inhibition of vascular endothelial growth factor action of bevacizumab in the glomerular capillary but also by the cytotoxicity of the concomitant anticancer drugs and coexisting clinical conditions such as dyslipidemia and hypertension. After discontinuing anticancer agents and intensifying diet and antihypertensive therapy, proteinuria and dyslipidemia slowly improved; however, it became difficult to continue adequate chemotherapy, and the tumor marker levels worsened. Combination therapies, including molecular targeted agents, have become common, and the side effects of anticancer agents are expected to continue to be complicated. To prevent the onset and severity of renal complications, management of blood pressure, lipid level, and glucose metabolism, as well as multidisciplinary medical management, including dietary therapy, is required.

The utility of texture analysis of kidney MRI for evaluating renal dysfunction with multiclass classification model.

We evaluated a multiclass classification model to predict estimated glomerular filtration rate (eGFR) groups in chronic kidney disease (CKD) patients using magnetic resonance imaging (MRI) texture analysis (TA). We identified 166 CKD patients who underwent MRI comprising Dixon-based T1-weighted in-phase (IP)/opposed-phase (OP)/water-only (WO) images, apparent diffusion coefficient (ADC) maps, and T2* maps. The patients were divided into severe, moderate, and control groups based on eGFR borderlines of 30 and 60 mL/min/1.73 m2. After extracting 93 texture features (TFs), dimension reduction was performed using inter-observer reproducibility analysis and sequential feature selection (SFS) algorithm. Models were created using linear discriminant analysis (LDA); support vector machine (SVM) with linear, rbf, and sigmoid kernels; decision tree (DT); and random forest (RF) classifiers, with synthetic minority oversampling technique (SMOTE). Models underwent 100-time repeat nested cross-validation. Overall performances of our classification models were modest, and TA based on T1-weighted IP/OP/WO images provided better performance than those based on ADC and T2* maps. The most favorable result was observed in the T1-weighted WO image using RF classifier and the combination model was derived from all T1-weighted images using SVM classifier with rbf kernel. Among the selected TFs, total energy and energy had weak correlations with eGFR.

Hatching stimulation activity of steroidal glycoalkaloids toward the potato cyst nematode, Globodera rostochiensis.

Cyst nematodes (Globodera spp. and Heterodera spp.) are highly evolved sedentary endoparasites that are considered as harmful pests worldwide. The hatching of the dormant eggs of cyst nematodes occurs in response to hatching factors (HFs), which are compounds that are secreted from the roots of host plants. Solanoeclepin A (SEA), a triterpene compound, has been isolated as HF for potato cyst nematode (PCN) eggs, whereas other compounds, such as steroidal glycoalkaloids (SGAs), are also known to show weak hatching stimulation (HS) activity. However, the structures of both compounds are different and the HF-mediated hatching mechanism is still largely unknown. In the present study, we observed specific hatching of PCN eggs stimulated by the hairy root culture media of potato and tomato, revealing the biosynthesis and secretion of HFs. SGAs, such as α-solanine, α-chaconine, and α-tomatine, showed significant HS activity, despite being remarkably less activities than that of SEA. Then, we evaluated the contribution of SGAs on the HS activities of the hairy root culture media. The estimated SGAs content in the hairy root culture media were low and nonconcordant with the HS activity of those, suggesting that the HS activity of SGAs did not contribute much. The analysis of structure-activity relationship revealed that the structural requirements of the HS activity of SGAs are dependent on the sugar moieties attached at the C3-hydoroxyl group and the alkaloid property of their aglycones. The stereochemistry in the EF rings of their aglycone also affected the strength of the HS activity.

Klotho supplementation ameliorates blood pressure and renal function in DBA/2-pcy mice, a model of polycystic kidney disease.

Klotho interacts with various membrane proteins such as receptors for transforming growth factor-ß (TGF-ß) and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. Recombinant human klotho protein (10 µg·kg-1·day-1) or a vehicle was administered daily by subcutaneous injection to 6-wk-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, mice were killed, and the kidneys were harvested for analysis. Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-PGF2α excretion (P < 0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expression of superoxide dismutase, and klotho itself (P < 0.05). Klotho supplementation attenuated renal expressions of TGF-ß and collagen type I and diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of rapamycin (P < 0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys (P < 0.05). Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

Glomerular solidification is associated with nephritis-related clinical parameters in IgA nephropathy.

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.

Regional prescription surveillance of phosphate binders in the western Saitama area: the substantial role of ferric citrate hydrate in improving serum phosphorus levels and erythropoiesis.

BACKGROUND: In April 2015, five types of phosphate binders (PBs) were available by prescription in Japan, namely calcium carbonate, sevelamer hydrochloride, lanthanum carbonate, bixalomer, and ferric citrate hydrate (FeC). FeC reduces serum phosphorus levels and increases the body's iron stores. However, it is unclear whether FeC lowers serum phosphorus relative to other agents in a regional practical setting. METHODS: We performed a retrospective observational cohort study of regional hemodialysis surveillance in the western Saitama area of Japan, which included 1374 hemodialysis patients enrolled from 32 satellite dialysis units. The clinical data and prescribing information were retrospectively collected and analyzed. The difference in serum phosphorus among the groups administered five types of PBs (new or additional) from April to September 2015 was the primary outcome. RESULTS: As of April 2015, the median values of serum phosphorus, corrected calcium, and intact parathyroid hormone were 5.4 mg/dL, 9.1 mg/dL, and 147 pg/dL, respectively (N = 1374). Unexpectedly, with an increase in the number of PBs administered, serum phosphorous levels increased (p < 0.001). The significant changes in the serum phosphorus and hemoglobin levels were associated with the prescription of FeC but not with that of the other PBs. CONCLUSIONS: This regional survey suggests that serum phosphorus is well managed and that FeC has the potential to reduce the serum phosphorus level relative to other PBs and to ameliorates anemia.

Predictors of long-term prognosis in acute kidney injury survivors who require continuous renal replacement therapy after cardiovascular surgery.

The long-term prognosis of patients with postoperative acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) after cardiovascular surgery is unclear. We aimed to investigate long-term renal outcomes and survival in these patients to determine the risk factors for negative outcomes. Long-term prognosis was examined in 144 hospital survivors. All patients were independent and on renal replacement therapy at hospital discharge. The median age at operation was 72.0 years, and the median pre-operative estimated glomerular filtration rate (eGFR) was 39.5 mL/min/1.73 m2. The median follow-up duration was 1075 days. The endpoints were death, chronic maintenance dialysis dependence, and a composite of death and chronic dialysis. Predictors for death and dialysis were evaluated using Fine and Gray's competing risk analysis. The cumulative incidence of death was 34.9%, and the chronic dialysis rate was 13.3% during the observation period. In the multivariate proportional hazards analysis, eGFR <30 mL/min/1.73 m2 at discharge was associated with the composite endpoint of death and dialysis [hazard ratio (HR), 2.1; 95% confidence interval (CI), 1.1-3.8; P = 0.02]. Hypertension (HR 8.7, 95% CI, 2.2-35.4; P = 0.002) and eGFR <30 mL/min/1.73 m2 at discharge (HR 26.4, 95% CI, 2.6-267.1; P = 0.006) were associated with dialysis. Advanced age (≥75 years) was predictive of death. Patients with severe CRRT-requiring AKI after cardiovascular surgery have increased risks of chronic dialysis and death. Patients with eGFR <30 mL/min/1.73 m2 at discharge should be monitored especially carefully by nephrologists due to the risk of chronic dialysis and death.

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys.

Renal expression of klotho is reduced in hypertension. Experiments were performed to examine whether exogenous klotho protein supplementation ameliorates pressure natriuresis in early phase of hypertension, using stroke-prone spontaneously hypertensive rats (sp-SHR). The interactions between klotho protein and renal renin-Ang (angiotensin) system were examined with immunoprecipitation and cell culture methods. Uninephrectomy was performed in sp-SHRs to induce nephrosclerosis, and they were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to sp-SHR decreased blood pressure, renal Ang II levels, AGT (angiotensinogen) expression, HIF (hypoxia-inducible factor)-1α abundance, and medullary fibronectin levels, with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt, and mTOR (mammalian target of rapamycin) abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and enhanced pressure-induced natriuresis in sp-SHR. Klotho protein bound to AT1R (Ang II type-1 receptor) and decreased the presence of AT1R on HK-2 (human proximal tubular) cells, attenuating inositol triphosphate generation. Klotho protein suppressed Ang II-induced increments of AGT expression in HK-2 cells. Collectively, the present data demonstrate that klotho binds with the AT1R to suppress Ang signal transduction, participating in inactivating renal renin-Ang system. Our results also suggest that exogenous klotho supplementation represses Akt-mTOR signaling to reduce renal hypertrophy and restore the autoregulatory ability of glomerular filtration rate in uninephrectomized sp-SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway and medullary fibrosis, contributing to enhancements of pressure natriuresis and reduction in blood pressure.

Quantitative evaluation of interstitial pneumonia using 3D-curved high-resolution CT imaging parallel to the chest wall: A pilot study.

OBJECTIVES: To quantify the imaging findings of patients with interstitial pneumonia (IP) and emphysema using three-dimensional curved high-resolution computed tomography (3D-cHRCT) at a constant depth from the chest wall, and compare the results to visual assessment of IP and each patient's diffusing capacity of the lungs for carbon monoxide (DLco). METHODS: We retrospectively reviewed the axial CT findings and pulmonary function test results of 95 patients with lung cancer (72 men and 23 women, aged 45-84 years) with or without IP, as follows: non-IP (n = 47), mild IP (n = 31), and moderate IP (n = 17). The 3D-cHRCT images of the lung at a 1-cm depth from the chest wall were reconstructed automatically using original software; total area (TA), high-attenuation area (HAA) >-500 HU, and low-attenuation area (LAA) <-950 HU were calculated on a workstation. The %HAA and %LAA were calculated as follows: [Formula: see text], and [Formula: see text]. RESULTS: The %HAA and %LAA respective values were 3.2±0.9 and 27.7±8.2, 3.9±1.2 and 27.6±5.9, and 6.9±2.2 and 25.4±8.7 in non-IP, mild IP, and moderate IP patients, respectively. There were significant differences in %HAA between the 3 groups of patients (P<0.001), but no differences in %LAA (P = 0.558). Multiple linear regression analysis revealed that %HAA and %LAA were negatively correlated with predicted DLco (standard partial regression coefficient [b*] = -0.453, P<0.001; b* = -0.447, P<0.001, respectively). CONCLUSIONS: The %HAA and %LAA values computed using 3D-cHRCT were significantly correlated with DLco and may be important quantitative parameters for both IP and emphysema.

Thoracic Temporal Subtraction Three Dimensional Computed Tomography (3D-CT): Screening for Vertebral Metastases of Primary Lung Cancers.

PURPOSE: We developed an original, computer-aided diagnosis (CAD) software that subtracts the initial thoracic vertebral three-dimensional computed tomography (3D-CT) image from the follow-up 3D-CT image. The aim of this study was to investigate the efficacy of this CAD software during screening for vertebral metastases on follow-up CT images of primary lung cancer patients. MATERIALS AND METHODS: The interpretation experiment included 30 sets of follow-up CT scans in primary lung cancer patients and was performed by two readers (readers A and B), who each had 2.5 years' experience reading CT images. In 395 vertebrae from C6 to L3, 46 vertebral metastases were identified as follows: osteolytic metastases (n = 17), osteoblastic metastases (n = 14), combined osteolytic and osteoblastic metastases (n = 6), and pathological fractures (n = 9). Thirty-six lesions were in the anterior component (vertebral body), and 10 lesions were in the posterior component (vertebral arch, transverse process, and spinous process). The area under the curve (AUC) by receiver operating characteristic (ROC) curve analysis and the sensitivity and specificity for detecting vertebral metastases were compared with and without CAD for each observer. RESULTS: Reader A detected 47 abnormalities on CT images without CAD, and 33 of them were true-positive metastatic lesions. Using CAD, reader A detected 57 abnormalities, and 38 were true positives. The sensitivity increased from 0.717 to 0.826, and on ROC curve analysis, AUC with CAD was significantly higher than that without CAD (0.849 vs. 0.902, p = 0.021). Reader B detected 40 abnormalities on CT images without CAD, and 36 of them were true-positive metastatic lesions. Using CAD, reader B detected 44 abnormalities, and 39 were true positives. The sensitivity increased from 0.783 to 0.848, and AUC with CAD was nonsignificantly higher than that without CAD (0.889 vs. 0.910, p = 0.341). Both readers detected more osteolytic and osteoblastic metastases with CAD than without CAD. CONCLUSION: Our temporal 3D-CT subtraction CAD software easily detected vertebral metastases on the follow-up CT images of lung cancer patients regardless of the osteolytic or osteoblastic nature of the lesions.

Klotho suppresses the renin-angiotensin system in adriamycin nephropathy.

BACKGROUNDS: Klotho protein interacts with the transforming growth factor ß (TGF-ß) receptor and Wnt, which contribute to the progression of renal disease, inhibiting their signals. Renal and circulating klotho levels are diminished in chronic kidney disease. METHODS: Experiments were performed to assess whether supplementation of klotho protein could have protective effects on the kidney. Rats were injected with adriamycin (5 mg/kg) and divided into three groups: those treated with vehicle, those treated with klotho protein and those treated with klotho plus 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD). Rats without adriamycin treatment were used as a control. RESULTS: Adriamycin reduced the serum klotho concentration and renal expression of klotho and E-cadherin. Adriamycin also increased the renal expression of Wnt, TGF-ß, and angiotensinogen, as well as the renal abundance of ß-catenin and angiotensin II. Klotho supplementation suppressed adriamycin-induced elevations of ß-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of ß-catenin and angiotensin II as well as the expression of TGF-ß and angiotensinogen without affecting E-cadherin. CONCLUSIONS: Our data indicate that Wnt is involved in the pathogenesis of adriamycin nephropathy. Furthermore, klotho supplementation inhibited Wnt signaling, ameliorating renal angiotensin II. Finally, klotho protein appears to suppress epithelial-mesenchymal transition by inhibiting TGF-ß and Wnt signaling.

Patients with biopsy-proven nephrosclerosis and moderately impaired renal function have a higher risk for cardiovascular disease: 15 years' experience in a single, kidney disease center.

BACKGROUND: Nephrosclerosis progresses slowly to end-stage renal disease (ESRD) in only a small percentage of patients. However, because hypertension and nephrosclerosis are normally found simultaneously, nephrosclerosis is a risk factor for cardiovascular disease (CVD). In turn, the onset of CVD may progress to further renal impairment. AIM: To evaluate clinical outcomes and the association between nephrosclerosis and CVD in the long term. DESIGN: Prospective study METHODS: We prospectively assessed 35 patients (male/female: 19/16) with nephrosclerosis aged >30 years at disease onset, attending the Kidney Disease Center, Saitama Medical University, in a single teaching hospital center between 1995 and 2014. Nephrosclerosis was diagnosed in accordance with the criteria outlined in the World Health Organization (WHO) monograph of renal diseases. All patients were followed by means of registries for 10 years to record subsequent events, if any. OUTCOMES: The primary study outcome was correlating the occurrence of CVD, defined as a composite of cardiovascular deaths, nonfatal and fatal myocardial infarction, and stroke, with the development of ESRD or death. RESULTS: The mean age of patients at the time of biopsy was 54.8 ± 12.7 years (range 33-72 years). Of these patients, seven were affected by nonfatal CVD and two died due to CVD. Only one patient developed ESRD during the follow-up period. Using Kaplan-Meier analysis, risk factors for the primary study outcome were estimated to include an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), systolic blood pressure > 130 mmHg and proteinuria > 1 g/g creatinine. Univariate analysis was used for the assessment of the relative risk for the primary study endpoint of several covariates: age, systolic blood pressure, eGFR and proteinuria at time of renal biopsy. eGFR was found to be the strongest factor determining an event-free period [relative risk (RR) =1.931, p = 0.014]. CONCLUSIONS: Patients with nephrosclerosis are at high risk of CVD when they have moderately advanced renal impairment.