Kazunobu Ichikawa

Clinical utility of trace proteinuria for microalbuminuria screening in the general population

BackgroundThe urine dipstick test that regards > 1+ proteinuria as positive is unsuitable for microalbuminuria screening owing to its low sensitivity in the general population. We conducted a cross-sectional survey to examine whether trace proteinuria could be an indicator of microalbuminuria.MethodsThe subjects were 2321 participants in a community-based health check-up in Takahata, Japan. Dipstick tests for proteinuria and the urine albumin–creatinine ratio (UACR) measurement were performed with single-spot urine specimens collected early in the morning. The results of the dipstick tests were recorded as (−), trace, (1+), (2+), and (3+). Micro- and macroalbuminuria were defined as UACR 30–300 mg/g and > 300 mg/g, respectively.ResultsOverall, the prevalence and median UACR levels of urine protein (−), trace, (1+), (2+), and (3+) were 92.0% (8.8 mg/g), 3.5% (43 mg/g), 2.6% (81 mg/g), 1.4% (315 mg/g), and 0.5% (1073 mg/g), respectively. Within the trace proteinuria category, the prevalence of microalbuminuria in all subjects, men, subjects ≥60 years, diabetic subjects, and hypertensive subjects was 59.3%, 73.8%, 71.2%, 88.9%, and 68.0%, respectively. By regarding trace proteinuria as positive, the sensitivity of the urine protein dipstick test for micro- and macroalbuminuria was improved (from 23.3% to 37.1%), while its specificity was not significantly changed (from 98.9% to 97.3%).ConclusionTrace proteinuria could be a useful indicator of microalbuminuria in the general population, and especially in subjects at high risk of cardiovascular disease.

Increases in urinary albumin and beta2-microglobulin are independently associated with blood pressure in the Japanese general population: the Takahata Study

Essential hypertension is a multifactorial disorder and a risk factor for renal failure and cardiovascular disease. Recently it was hypothesized that subtle acquired renal injury such as renal microvascular and tubulointerstitial damage induces salt-sensitive hypertension. The objective of this study was to examine the relationship between blood pressure and renal abnormalities in the Japanese general population. The participants in this community-based, cross-sectional study were 1,965 subjects over 40 years old, without renal insufficiency and antihypertensive medication. Urine albumin–creatinine ratio (UACR) and beta2-microglobulin–creatinine ratio (UBCR) were measured in single spot urine samples, as markers of renal microvascular and tubulointerstitial damage, respectively. Multiple linear regression analysis showed a significant positive correlation of blood pressure with UACR and UBCR, but not with estimated glomerular filtration rate. In multiple logistic regression analysis, the increases in UACR and UBCR were independently associated with hypertension, after adjustment for possible confounders. Higher levels of UACR (⩾5.9 mg g−1) and UBCR (⩾145 μg g−1) were associated with a significantly higher risk of hypertension, compared with UACR ⩽5.8 mg g−1 and UBCR ⩽84.5 μg g−1, respectively. Furthermore, there was a positive relationship between urinary sodium excretion and blood pressure in subjects with high UBCR tertile. This study showed that the increases in urinary albumin and beta2-microglobulin were independently associated with blood pressure in a general population. These renal abnormalities may be differentially related to the development of hypertension.

Genetic polymorphisms of paraoxonase-1 are associated with chronic kidney disease in Japanese women

Paraoxonase-1 (PON1) is an HDL cholesterol-associated antioxidant enzyme, and some of its polymorphisms are linked with systemic oxidative stress and cardiovascular events. In this study, we genotyped seven single nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease in 2,968 individuals from the general Japanese population. We found that a missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]), was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. In contrast, such relationships were not detected in men. Multivariate regression analysis found that the A/A genotype was an independent and significant factor for albuminuria and renal insufficiency (eGFR less than 60 ml/min/1.73 m(2)). The serum PON1 activity was lowest in subjects with the A/A genotype. In biopsy specimens, immunohistochemical analysis found increased PON1 expression on the endothelial surface of sclerotic renal arterioles and glomerular capillaries in patients with hypertension or diabetes. Our study shows that this PON1 G-to-A substitution may be a key player in a common pathway to chronic kidney and cardiovascular diseases in women.

An angiotensin II type-I receptor blocker, olmesartan medoxomil, attenuates lipid peroxidation in renal injury induced by subtotal nephrectomy

BackgroundLipid-related oxidative stress, such as that caused by malondialdehyde (MDA), acrolein, and 4-hydroxynonenal (4-HNE), is involved in vascular injury in diabetes and hypertension. Olmesartan medoxomil, a blocker of angiotensin II type-I receptor, is an antihypertensive drug with antioxidant properties. In this study, we examined the involvement of oxidative lipids and the effect of olmesartan on lipid peroxidation in the progressive renal injury induced by renal mass reduction in rats.MethodsRats were treated with vehicle or olmesartan (0.5 mg/kg or 10 mg/kg) for up to 8 weeks after subtotal nephrectomy. The expression of oxidative lipids and the effect of olmesartan on lipid peroxidation were evaluated by Western blotting and immunostaining of renal tissue.ResultsImmunohistochemical examination revealed that MDA, acrolein, and 4-HNE were scarcely detected in renal cortex in sham-operated rats. On the contrary, these oxidative lipids were observed in injured glomeruli and dilated renal tubules in the ablated kidneys. Western blotting of renal cortical tissue revealed that MDA- or acrolein-bound proteins were mainly detected in the range of 30–90 kDa. Treatment with olmesartan attenuated lipid peroxidation and glomerulosclerosis. The renoprotective and antioxidative effect was higher in rats that received a high dose of olmesartan than in rats in the low-dose group.ConclusionsThese results indicate that oxidative lipids reflect the progression of renal injury induced by subtotal nephrectomy in rats. Olmesartan may have a renoprotective effect, with attenuation of lipid peroxidation.

Comparison of Mortality between Japanese Peritoneal Dialysis and Hemodialysis Patients: A 5-Year Multicenter Follow-Up Study

To examine the relationship between dialysis modality and prognosis in Japanese patients, we conducted a prospective multicenter observational study. We recruited 83 background-matched peritoneal dialysis (PD) and 83 hemodialysis (HD) patients (average age, 64.9 years; men, 53.6%; diabetic patients, 22.9%; median duration of dialysis, 48 months in all patients) and followed them for 5 years. During the follow-up period, 27 PD patients (16 cardiovascular and 11 non-cardiovascular deaths) and 27 HD patients died (14 cardiovascular and 13 non-cardiovascular deaths). There were 8 PD patients switched to HD, and 6 PD patients received renal transplantation. Kaplan-Meier analysis revealed that the crude survival rate was not significantly different at the end of 5 years (PD 67.5% versus 67.5%, log-rank P = 0.719). The difference in cardiovascular and non-cardiovascular mortalities between PD and HD was not statistically significant. Multivariate Cox analysis showed that the independent predictors for death were age and serum albumin levels, but not the dialysis modality. This study showed that the overall mortality was not significantly different between PD and HD patients, which suggests that dialysis modality might not be an independent factor for survival in Japanese patients.

The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: The Takahata study

Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP. To investigate the association between single-point single-nucleotide polymorphism (SNP) of NPHP4 gene and renal function, we conducted a cross-sectional study in Japanese population. The subjects of this study were non-diabetic general population consisting of 2604 individuals >40 years in Takahata town, Japan. We genotyped 11 SNPs within NPHP4 gene that displayed frequent minor allele frequencies (>0.1) in Japanese general population. Among 11 SNPs in NPHP4 gene, only rs1287637 that induces amino acid substitution (A (Gln)/T (Leu)), located in the acceptor site of exon 21, showed a significant association with estimated glomerular filtration rate (eGFR; T/T: 81.3±15.6 (n=1886), A/T: 82.0±15.5 (n=652) and A/A: 87.4±21.4 ml min−1 per 1.73m2 (n=66); mean±s.d., P=0.006). This SNP was not in linkage disequilibrium with the surrounding SNPs. The multivariate analysis adjusted with possible confounders showed that the A/T+T/T genotype of rs1287637 was independently associated with reduced renal function (eGFR <90 ml min−1 per 1.73m2; odds ratio (OR) 1.75, 95% confidence interval (CI) 1.05–2.94, P=0.033). These results indicate the novel and independent association between single-point SNP rs1287637 in NPHP4 gene and renal function in non-diabetic Japanese population.

Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group

Abstract Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Rapid decline in renal function after acute myocardial infarction

AIM To investigate the long term effects of cardiac events on renal function, a prospective study of patients with acute myocardial infarction was conducted. METHODS A total of 137 patients with acute myocardial infarction were followed for 1 year. The change of estimated glomerular filtration rate (eGFR) in cardiac patients was compared with that in background-matched controls, and the factors associated with eGFR changes were analyzed. RESULTS The eGFR decrease was much larger after myocardial infarction, from 73.7 ± 1.9 ml/min/1.73 m2 (mean ± SEM) at baseline to 64.7 ± 1.7 at 1 year, (p < 0.001), compared with that of controls (from 72.8 ± 1.2 to 72.1 ± 1.3, p = 0.305). Multiple regression analysis showed that eGFR change was associated negatively with age, baseline eGFR, proteinuria, and positively with the administration of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, but not the severity of cardiac damage and comorbidities. Longitudinal analysis 1 year before and 2 years after myocardial infarction showed that eGFR decrease was larger during baseline and 6 months after the event (-7.0 ± 1.0). CONCLUSIONS Renal decline was rapid after myocardial infarction and was affected by clinical characteristics of patients. Careful follow-up of renal function is recommended to prevent the progression of renal and cardiac disease.

The clinical and pathological characteristics of nephropathies in connective tissue diseases in the Japan Renal Biopsy Registry (J-RBR)

BackgroundIn connective tissue diseases, a wide variety of glomerular, tubulointerstitial, and vascular lesions of the kidney are observed. Nonetheless, recent information is limited regarding renal lesions in connective tissue diseases, except in systemic lupus erythematosus (SLE).MethodsIn this study, we used a nationwide database of biopsy-confirmed renal diseases in Japan (J-RBR) (UMIN000000618). In total, 20,523 registered patients underwent biopsy between 2007 and 2013; from 110 patients with connective tissue diseases except SLE, we extracted data regarding the clinico-pathological characteristics of the renal biopsy.ResultsOur analysis included patients with rheumatoid arthritis (RA) (n = 52), Sjögren’s syndrome (SjS) (n = 35), scleroderma (n = 10), mixed connective tissue disease (MCTD; n = 5), anti-phospholipid syndrome (APS; n = 3), polymyositis/dermatomyositis (PM/DM; n = 1), Behçet’s disease (n = 1) and others (n = 3). The clinico-pathological features differed greatly depending on the underlying disease. The major clinical diagnosis was nephrotic syndrome in RA; chronic nephritic syndrome with mild proteinuria and reduced renal function in SjS; rapidly progressive nephritic syndrome in scleroderma. The major pathological diagnosis was membranous nephropathy (MN) and amyloidosis in RA; tubulointerstitial nephritis in SjS; proliferative obliterative vasculopathy in scleroderma; MN in MCTD. In RA, most patients with nephrosis were treated using bucillamine, and showed membranous nephropathy.ConclusionsUsing the J-RBR database, our study revealed that biopsy-confirmed cases of connective tissue diseases such as RA, SjS, scleroderma, and MCTD show various clinical and pathological characteristics, depending on the underlying diseases and the medication used.

Polymorphism of proinflammatory cytokine genes and albuminuria in the Japanese general population: the Takahata study

BACKGROUND A cluster of proinflammatory cytokines plays an important role in the development of various renal diseases, and the expression of these cytokines is genetically modified. To examine the association between polymorphisms of proinflammatory cytokine genes and albuminuria, a cross-sectional study was conducted in the general population. METHODS Single nucleotide polymorphisms (SNPs) in six proinflammatory cytokine genes, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, CC chemokine ligand 1 (CCL1) and monocyte chemoattractant protein-1 (MCP-1), were genotyped in 2927 Japanese subjects. Urine albumin-creatinine ratio (UACR) was measured in morning spot urine samples. RESULTS Albuminuria (UACR ≥ 30 mg/g) was significantly associated with the A/A + A/G genotype at rs2069852 in the IL-6 gene (P = 0.01) and the A/A genotype at rs228269 in the CCL1 gene (P = 0.002). Multivariate analysis with adjustment for traditional risk factors showed that these genotypes independently predicted albuminuria [odds ratio (OR) 1.782, 95% confidence interval (CI) 1.171-2.712, P = 0.007 for the A/A + A/G genotype at rs2069852 in IL-6, and OR 1.432, 95% CI 1.128-1.770, P = 0.003 for the A/A genotype at rs228269 in CCL1]. The prevalence of albuminuria and the UACR were increased along with the increase of risk genotypes. CONCLUSIONS This study revealed that SNPs in the IL-6 and CCL1 genes were associated with albuminuria, and the combination of these genotypes had an additive effect on the prevalence and severity of albuminuria. This indicates that genetic factors influencing inflammatory responses may affect the development of renal injury in the Japanese general population.