Kiyomi Koike

Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice

BACKGROUND Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. METHODS Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. RESULTS Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-D-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. CONCLUSIONS Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.

Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD)

AIMS Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been reported to be a novel marker for the progression of chronic kidney disease (CKD). We have recently found that accumulation of ADMA could trigger peritubular capillary loss, thus contributing to tubulointerstitial ischemia and fibrosis in a rat model of CKD. However, effects of ADMA on glomerular capillary loss and sclerosis remain to be elucidated. MAIN METHODS In this study, we investigated whether lowering of ADMA by overexpression of dimethylarginine dimethylaminohydrolase (DDAH), a main enzyme that degrades ADMA, could ameliorate glomerular capillary loss and sclerosis in a rat model of CKD. Four weeks after 5/6 subtotal nephrectomy (Nx), animals were given tail vein injections with recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ), or orally administered with 20 mg/kg/day of hydralazine (Hyz) which served as a blood pressure control model. KEY FINDINGS Plasma levels of ADMA were associated with decreased number of glomerular capillaries as well as severity of glomerular sclerosis in Nx-rats. These glomerular changes progressed in Adv-LZ- or Hyz-treated Nx-rats, while they were ameliorated by the treatment with DDAH overexpression. SIGNIFICANCE Our present data suggest that ADMA may be involved in glomerular capillary loss and sclerosis, thus contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.

Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats.

BACKGROUND Pigment epithelium-derived factor (PEDF) is a glycoprotein with potent neuronal differentiating activity. We, along with others, have recently found that PEDF inhibits retinal hyperpermeability by counteracting the biological effects of vascular endothelial growth factor (VEGF). However, the protective role of PEDF against nephrotic syndrome (NS), a condition of hyperpermeability in the glomerular capillaries, remains to be elucidated. In this study, we investigated whether and how PEDF reduced proteinuria in rats with adriamycin (ADR)-induced nephropathy (ADN), an experimental model of NS. METHODS ADN was induced by a single intravenous injection of doxorubicin hydrochloride (n = 12). Half the ADN rats were intravenously administrated human recombinant PEDF; the other half were given vehicle everyday for up to 14 days. Control rats (n = 6) received vehicle only. RESULTS In ADN, expression levels of PEDF in isolated glomeruli were significantly decreased, which were associated with a marked proteinuria and increased urinary excretion of nephrin, an index of podocyte damage. Loss of nephrin and decreased podocyte cell number and fusion of foot processes of podocytes with nuclear factor-kappa B (NF-kappaB) activation and VEGF overexpression were also observed in the glomeruli of rats with ADN. Intravenous administration of PEDF ameliorated all of these changes in ADN rats. CONCLUSION The present findings suggest that PEDF could reduce proteinuria by suppressing podocyte damage and decreased nephrin as well as increased VEGF expression in the glomeruli of ADN rats. Pharmacological up-regulation or substitution of PEDF may offer a promising therapeutic strategy for the treatment of nephrotic syndrome.

Adult-onset acute tubulointerstitial nephritis and uveitis with Fanconi syndrome. Case report and review of the literature.

We report a case of tubulointerstitial nephritis and uveitis (TINU syndrome) with full type Fanconi syndrome. A 32-year-old woman presented with fatigue, anorexia and weight loss. Laboratory findings showed anemia, polyclonal hypergammaglobulinemia and moderate renal dysfunction. Tubular function abnormalities were normoglycemic glucosuria, panaminoaciduria, phosphaturia and kaliuresis leading to hypokalemia. Renal tubular acidosis and hypouricemia were also evident. Serum antistreptolysin O titer was high. Ocular symptoms (bilateral anterior uveitis) emerged soon after admission. Renal biopsy showed diffuse tubulointerstitial infiltration by lymphocytes and plasma cells without granuloma. Treatment with systemic steroids was given and renal function, and ocular symptom returned to normal with 3 months. Although tubular abnormalities involving TINU syndrome has already been reported, the disease associated with full type Fanconi syndrome has rarely been seen, and systemic steroid may be beneficial in reducing the development of tubulointerstitial injury.

Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction.

Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-β and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.

A new vasculitis activity score for predicting death in myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis patients.

Background/Aims: Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive microscopic polyangiitis patients with renal involvement have been shown to have a progressive clinical course. In this study, we compared the clinical utility of the Japanese Vasculitis Activity Score (JVAS) with the Birmingham Vasculitis Activity Score (BVAS) for predicting death in patients with MPO-ANCA-associated renal involvement. Methods: Sixty-nine patients with MPO-ANCA-associated vasculitis with renal involvement (22 males and 47 females, age 69.8 ± 8.7 years) were enrolled in this study. We retrospectively investigated which score was better for predicting the poor prognosis of patients. Results: The mortality rate of the patients within 2 years after disease onset was 33% (23/69). JVAS was not correlated with BVAS. Univariate logistic regression analysis for death showed that the odds ratio (OR) of JVAS was statistically significant (OR 1.76, 95% confidence interval, CI, 1.29–2.41, p < 0.001), while that of BVAS was not (OR 1.07, 95% CI 0.98–1.16, p = 0.14). Moreover, a multivariate model showed that JVAS was an independent determinant of death (OR 1.59, 95% CI 1.12–2.25, p = 0.009). The area under the receiver operating characteristic curve for JVAS was 0.778, which was significantly larger (p = 0.02) than that for BVAS (0.586). The estimated optimal cut-off point of JVAS for the prediction of death was 5. At this point, the sensitivity was 82.6% and the specificity was 60.9%. Conclusion: We demonstrated that compared with BVAS, JVAS was a simpler and more reliable measure for predicting death in patients with MPO-ANCA-associated vasculitis with renal involvement.

Interstitial Foxp3-positive T cells may predict renal survival in patients with myeroperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

1. Regulatory T cells (Treg) and cytotoxic T cells (CTL) are involved in various immune diseases. However, the prognostic impact of Treg and CTL in patients with myeroperoxidase anti‐neutrophil cytoplasmic antibody‐associated glomerulonephritis (MPO‐ANCA‐GN) is not well known. Therefore, in the present study, we examined the relationship between expression of forkhead box P3 (Foxp3) and T cell intracytoplasmic antigen (TIA)‐1, Treg and CTL markers and renal survival in patients with MPO‐ANCA‐GN.

Ferrokinetics is associated with the left ventricular mass index in patients with chronic kidney disease

Abstract Background Patients with chronic kidney disease (CKD) often have the complication of anaemia. Usage of an erythropoietin-stimulating agent accelerates iron deficiency because it promotes iron utilization. Recently, iron administration was reported to be effective for patients with cardiac failure. We examined the association between ferrokinetics and cardiac function in patients with CKD. Methods In this cross-sectional study, we examined 558 patients (424 men and 134 women; mean age, 68.9 ± 13.1 years) with CKD who were admitted to our hospital. We assessed cardiac function by ultrasonography and ferrokinetics through transferrin saturation (TSAT) and ferritin levels. Results The primary diseases of CKD were nephrosclerosis (n = 247), diabetic nephropathy (n = 154), chronic glomerulonephritis (n = 73), and others. The mean estimated glomerular filtration rate was 16.9 ± 9.3 mL/min/1.7 m2, and the haemoglobin (Hb) level was 11.0 ± 1.7 g/dL. The median of TSAT was 28.05%, and patients were divided into two groups: below (L-Ts) and above (H-Ts) the median. The median of ferritin was 122 ng/mL, and patients were divided into two groups: below (L-f) and above (H-f) the median. We categorized four groups as H-Ts + H-F, H-Ts + L-F, L-Ts + H-F, and L-Ts + L-F. The Hb levels were 11.1 ± 1.8, 11.3 ± 1.4, 10.9 ± 1.6, and 10.8 ± 1.5 g/dL, respectively, and there was no difference between groups. However, the left ventricular mass indices (LVMIs) were 122.6 ± 46.6, 110.8 ± 32.0, 118.3 ± 36.0, 126.7 ± 46.9, respectively (P = 0.0291). This tendency was stronger in patients without cardiovascular events. Conclusion In patients with CKD, there is an association between ferrokinetics and LVMI. We have to be mindful not only of anaemia but also of ferrokinetics.

Hepatitis B Virus Infection Among Patients With Chronic Kidney Disease Who Attended an Educational Program in Japan: HBV in Patients With CKD in Japan

The rate of hepatitis B infection among hemodialysis patients is high. However, it is not clear if this rate reflects the infection rate among patients with chronic kidney disease (CKD). Therefore, we evaluated the rate of hepatitis B infection among patients with CKD. This is an important clinical issue when considering the risk of infection to medical staff when performing invasive procedures in this clinical population. A retrospective, observational study was conducted among stable, non‐dialysis patients with CKD who attended a CKD educational program at our hospital, between August 2012 and October 2017. We collected patients’ background and markers of hepatitis infection (HBsAg, HBcAb and HBsAb, as well as HBV‐DNA when available) from medical records. The data from 496 patients (373 men and 123 women, with a mean age of 69.3 ± 13.0 years and mean level of creatinine of 3.15 ± 1.72 mg/dL, AST of 21.6 ± 10.5 IU/L, and ALT of 17.3 ± 12.5 IU/L), were included in the analysis. The rate of positive testing for hepatitis B virus infection was as follows: HBsAg, 1.6%; HBsAb, 16.5%; and HBcAb, 21.4%. Of the patients with a negative HBsAg test, 20.1% tested positive for HBcAb. Of the 66 patients in whom HBV‐DNA testing was performed, 10.6% tested positive. The rate of hepatitis B virus infection was specifically higher among patients ≥71‐years‐old. In patients with CKD, the rate of HBsAg positivity is high. Rate of HBcAb positivity is higher particularly in older individuals.

Relationship Between Mortality and Cancer-Bearing Status in Patients With Chronic Kidney Disease Who Attended an Educational Program

Patients with malignancy have a poorer prognosis than others do, which must be taken into consideration when treating them for chronic kidney disease (CKD). However, there are few studies investigating their prognosis. This was an observational study of 515 (394 men and 121 women) stable non‐dialysis patients with CKD who attended a CKD educational program. Mean age was 68.8 ± 13.0 years. Median follow‐up was 968.5 days. Mean creatinine was 3.4 ± 1.6 mg/dL. Of these, 63 had malignancy and 452 did not; 20.6% of the former and 11.9% of the latter group died by the end of the study period (P = 0.0548). Malignancy was not associated with all‐cause mortality (HR: 1.3475, 95% CI: 0.7202–2.5214, P = 0.3507) but with malignancy‐associated mortality (HR: 3.9477, 95% CI: 1.6348–9.5331, P = 0.0023). Renal replacement therapy was not associated with mortality. Since malignancy greatly affects the prognosis, it must be taken into consideration when treating these patients.