Gut Microbiome and Microbiome-Derived Metabolites in Patients with End-Stage Kidney Disease.

The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis.

Efficacy and safety of pemafibrate in patients with chronic kidney disease: A retrospective study.

Hypertriglyceridemia and chronic kidney disease (CKD) are known risk factors for cardiovascular disease. However, treatment with statins, which control low-density lipoprotein cholesterol levels, increases the risk of estimated glomerular filtration rate (eGFR) reduction. Although conventional fibrates, such as bezafibrate (Beza-F) and fenofibrate (Feno-F), are the mainstay for hypertriglyceridemia treatment, they may be associated with a risk of increased serum creatinine level and renal dysfunction. Pemafibrate (Pema) is pharmacologically defined as a selective peroxisomal proliferator-activated receptor α modulator which is excreted in bile and not likely to cause renal dysfunction. We evaluated the efficacy and safety of switching from Beza-F or Feno-F to Pema in CKD patients with hypertriglyceridemia. We recruited 47 CKD patients with hypertriglyceridemia who were receiving Beza-F, Feno-F, or eicosapentaenoic acid (EPA) but were switched to Pema from 2018 to 2021. A retrospective analysis of renal function and lipid profiles was performed before and 24 weeks after switching. CKD patients switching from EPA to Pema were used as study control. The effect of Pema on hypertriglyceridemia was equivalent to that of Beza-F or Feno-F. However, after switching to Pema, eGFR showed a marked average improvement of 10.2 mL/min/1.73 m2 (P < .001). Improvement in eGFR and levels of n-acetyl-ß-d-glucosaminidase and ß-2-microglobulin was observed only in cases of switching from Beza-F or Feno-F but not from EPA. Although Beza-F and Feno-F are useful medications for the treatment of hypertriglyceridemia, these are associated with a high risk of renal dysfunction. We also found that the deterioration in eGFR due to Beza-F or Feno-F is reversible with drug withdrawal and may not increase the risk for long-term renal dysfunction. We suggest that Pema may be an effective and safe treatment for hypertriglyceridemia in CKD patients.

Development of an In-House EphA2 ELISA for Human Serum and Measurement of Circulating Levels of EphA2 in Hypertensive Patients with Renal Dysfunction.

Identifying novel biomarkers of kidney function in patients with chronic kidney disease (CKD) has strong clinical value as current measures have limitations. This study aims to develop and validate a sensitive and specific ephrin type-A receptor 2 (EphA2) enzyme-linked immunosorbent assay (ELISA) for human serum, and determine whether its results correlate with traditional renal measures in patients with hypertension. The novel ELISA of the current study was validated and used to measure circulating EphA2 levels in 80 hypertensive patients with and without kidney function decline (eGFR less than 60 mL/min/1.73 m2). Validation of the EphA2 ELISA showed good recovery (87%) and linearity (103%) and no cross-reactivity with other Eph receptors. Patients with kidney function decline had lower diastolic blood pressure, and higher UPCR and EphA2 than those without kidney function decline. The association of age and eGFR with EphA2 was maintained in the stepwise multiple regression analysis. In a multivariate logistic model, EphA2 was associated with a lower eGFR (<60 mL/min/1.73 m2) after adjustment for age, sex, and UPCR. High circulating EphA2 levels have potential application as a clinical biomarker for the presence of CKD in patients with hypertension.

Progranulin and Its Receptor Predict Kidney Function Decline in Patients With Type 2 Diabetes.

Progranulin (PGRN), a growth factor, is abundantly expressed in a broad range of tissues and cell types with pleiotropic functions including inflammation, neurodegeneration, and facilitating lysosome acidification. PGRN binds to TNF receptors (TNFR) and inhibits downstream inflammatory signaling pathways. TNFR is a well-known predictor of glomerular filtration rate (GFR) decline in a variety of diseases. Therefore, we measured circulating PGRN in addition to TNFR using an enzyme-linked immunosorbent assay and explored whether it predicted renal prognosis in 201 Japanese patients with type 2 diabetes. During a median follow-up of 7.6 years, 21 participants reached primary renal endpoint, which involves a decline of at least 57% in eGFR from baseline, or the onset of end-stage renal disease. Univariate Cox regression analysis revealed that classical renal measures (GFR and albuminuria), two TNF-related biomarkers (PGRN and TNFR), and BMI were associated with this outcome. Multivariate analysis demonstrated that high levels of PGRN [HR 2.50 (95%CI 2.47-2.52)] or TNFR1 [HR 5.38 (95%CI 5.26-5.50)] were associated with this outcome after adjusting for relevant covariates. The high levels of PGRN as well as TNFR1 were associated with a risk of primary renal outcome in patients with type 2 diabetes after adjusting for established risk factors.

Fractional excretion of tumor necrosis factor receptor 1 and 2 in patients with type 2 diabetes and normal renal function.

AIMS/INTRODUCTION: Increased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin-to-creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear. MATERIALS AND METHODS: This was a cross-sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 . The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured. RESULTS: Serum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60-89 mL/min/1.73 m2 , and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60-89 mL/min/1.73 m2 ) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model. CONCLUSIONS: The pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.

The sodium-glucose cotransporter 2 inhibitor tofogliflozin prevents diabetic kidney disease progression in type 2 diabetic mice.

Trials on cardiovascular and renal outcomes in patients with type 2 diabetes have consistently demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of diabetic kidney disease (DKD) progression. However, their renal protective mechanisms have yet to be completely understood and the effect on albuminuria reduction in animal models is controversial. We investigated these issues using KK and KK-Ay mice as a control (CTRL) and as a model for type 2 diabetes (DKD), respectively. KK-Ay mice were treated with 0.015% tofogliflozin, which is an SGLT2 inhibitor, starting at seven weeks of age for eight weeks. Compared with the CTRL mice, the DKD mice had higher HbA1c levels and albuminuria. Although tofogliflozin treatment significantly lowered HbA1c levels, it did not reverse albuminuria. Tofogliflozin treatment enhanced damage in both the glomerular (i.e., enlarged mesangial area, increased foot process effacement rate, and decreased number of WT-1-positive cells) and tubulointerstitial (increased protein levels of KIM-1 and MCP-1, increased number of macrophages, and abnormal mitochondrial morphology) areas. Our results suggest that tofogliflozin may prevent glomerular and tubulointerstitial damage, partly by ameliorating hyperglycemia, renal inflammation, and abnormal mitochondrial morphology.

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta-Ins2Akita (KK-Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l-aspartic acid) levels in diabetic KK-Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK-Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK-Akita mice (DKD group), and (c) treated (double-volume Asp diet) KK-Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate-labeled lectins, wheat germ agglutinin (WGA), and anti-endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

Circulating kidney injury molecule-1 as a biomarker of renal parameters in diabetic kidney disease.

AIMS/INTRODUCTION: Urinary kidney injury molecule-1 (KIM-1) has been associated with proximal tubular damage in human and animal studies. Although it has been recognized as a biomarker of acute kidney injury and chronic kidney disease, its significance in the serum remains unclear. Therefore, we examined the relationship of serum and urinary KIM-1 levels with renal parameters in patients with type 2 diabetes. MATERIALS AND METHODS: Serum and urinary KIM-1 levels, together with urinary liver-type fatty acid-binding protein, were measured in 602 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 . These were then compared with the urinary albumin-to-creatinine ratio and eGFR. RESULTS: The serum and urinary KIM-1 levels were significantly different among the three (eGFR ≥60, 45-59, <45 mL/min/1.73 m2 ) groups. These levels were positively associated with the albumin-to-creatinine ratio and negatively associated with eGFR. In a multivariate logistic model, both serum and urinary KIM-1 were associated with an increased albumin-to-creatinine ratio (>30 mg/g Cr), but only the serum KIM-1 was associated with a lower eGFR (<60 mL/min/1.73 m2 ), after adjustment for covariates. CONCLUSIONS: Renal parameters appear to be strongly associated with serum KIM-1, and not urinary KIM-1, in patients with type 2 diabetes and an eGFR ≥30 mL/min/1.73 m2 .

Transcriptional activation of long terminal repeat of bovine leukemia virus by bovine heat shock factor 1.

Bovine leukemia virus (BLV) causes enzootic bovine leukosis (EBL). The BLV genome encodes Tax protein, a transcriptional activator of viral gene expression that binds to the BLV long terminal repeat (LTR). Heat shock factor 1 (HSF1) is a known regulator of the heat shock response proteins, including heat shock proteins. In the present study, the BLV LTR was investigated for interaction of heat shock element (HSE) with HSF1 and the viral Tax protein. It could be confirmed that a functional HSE is well conserved in different BLV strains. The LTR transcriptional activity, as measured by luciferase reporter assay, was upregulated by bovine HSF1 - without Tax expression - in feline CC81 cells. The HSF1 activated LTR transcription by binding to the HSE. LTR-activation was lost upon HSE removal from the LTR and upon expression of a mutant HSF1 lacking the DNA-binding domain. We conclude that BLV LTR is activated to a basal level by host transcriptional factor HSF1, but without Tax protein involvement.

A rare case with a solitary fibrous tumour of the colon and an epithelioid angiomyolipoma of the kidney.

Solitary fibrous tumour is a soft tissue tumour composed of a subset of fibroblast-like cells and frequently needs immunohistochemical staining for final diagnosis. Epithelioid angiomyolipoma is a variant of angiomyolipoma but characterized by the absence of both adipocytes and abnormal blood vessels. We introduce a very rare case with the combination of these two tumours. A Japanese female patient without significant symptom was hospitalized and operated due to multiple uterine leiomyomas. During the operation, the surgeons found another tumour attaching to serosa of sigmoid colon. This tumour was resected and interpreted as solitary fibrous tumour, suspicious of malignancy. After 13 months of treatment, she was hospitalized again due to hematuria. The doctors detected a tumour in her right kidney. After consultation, laparoscopic right nephrectomy was done. The pathological result of this tumour was epithelioid angiomyolipoma. This is the first report on this very rare combination of tumours with extensive immunohistochemical demonstration of both tumours. Hereby, we review clinical information and histopathological findings together with discussion on each tumour.