Yoichi Ohno

Short- and long-term prognosis of blood pressure and kidney disease in women with a past history of preeclampsia

Little research has been conducted into the long-term effects of preeclampsia, despite its frequent occurrence. The aim of this review is to examine the association between preeclampsia and the development of hypertension and kidney diseases later in life. To achieve this aim, we evaluated three retrospective studies conducted in our department. In the first study, 52 women who suffered from preeclampsia during their first pregnancy were followed for 2xa0years after delivery for any long-term effects upon blood pressure. In the second study, we evaluated HOMA-R, pulse wave velocity and augmentation index in groups of 48 postmenopausal women with a past history of preeclampsia and 204 postmenopausal women without a past history of preeclampsia. In the third study, we examined the association between a past history of preeclampsia and chronic kidney disease based on biopsy in 127 postmenopausal women. From the first study, although there were no significant differences in age, blood pressure at the onset of preeclampsia, the levels of proteinuria and the birth weight of the child between women who remained hypertensive and those who became normotensive, body mass index was significantly larger in women who remained hypertensive compared to those who were normotensive. In the second study, we found that women with a past history of preeclampsia exhibited insulin resistance combined with reduced vascular elasticity. In the third study, of 32 patients with a past history of preeclampsia, 12 patients exhibited focal segmental glomerulosclerosis, 10 exhibited IgA nephropathy and 10 exhibited nephrosclerosis. In contrast, of the women without a past history of preeclampsia, 26 patients exhibited IgA nephropathy, 20 exhibited a minimal change in nephritic syndrome, 6 exhibited nephrosclerosis, 6 exhibited membranous nephropathy, 5 exhibited lupus nephritis, 5 exhibited diabetic nephropathy, and 27 exhibited various nephropathies. None of the women without a past history of preeclampsia exhibited focal segmental glomerulosclerosis. Taken together with previous results, these findings suggest that hypertension and chronic kidney disease in postmenopausal women are closely associated with a past history of preeclampsia.

Elucidating mechanisms underlying altered renal autoregulation in diabetes

Previous studies have reported that high-salt intake paradoxically activates tubuloglomerular feedback (TGF) in type 1 diabetes. Using Zucker lean (ZL) and diabetic fatty (ZDF) rats on normal and high-salt diets, renal hemodynamics and the renin-angiotensin system (RAS) were characterized. On normal salt diet, glomerular filtration rate (GFR) was higher in ZDF than ZL rats. Autoregulation of GFR was less efficient and lithium clearance was lower in ZDF rats than ZL rats. Salt load reduced GFR in ZDF rats with restoration of lithium clearance and partial improvement in autoregulatory index (AI). The administration of 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine-1 receptor antagonist to ZDF rats on a high-salt diet abolished the improvement of AI in GFR. However, this effect was seen by neither (Cx40)GAP27 nor (Cx37,43)GAP27, which inhibits connexin (Cx) 40 or Cx37. Renal ANG II was higher in ZDF than ZL rats on normal salt diet, but the difference was eliminated by a salt load. The present data provide the first demonstration for a salt paradox in type 2 diabetes and implicate that in addition to Cx alterations, an enhanced proximal reabsorption attenuates TGF, underlying glomerular hyperfiltration and RAS activation. These data suggest that a high-salt diet standardizes distal delivery in diabetes, suppressing the RAS, and improving GFR autoregulation and hyperfiltration through adenosine.

Long-Term Effects of Calcium Antagonists on Augmentation Index in Hypertensive Patients with Chronic Kidney Disease: A Randomized Controlled Study

Background: Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD). Methods: The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure. Results: Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 ± 1 vs. –2 ± 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group (–29 ± 2 vs. –38 ± 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (–4 ± 1 vs. –9 ± 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period. Conclusion: In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection.

Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney diseases

Sir, n nIn 2004, the Japanese Society of Hypertension recommended calcium channel blockers (CCBs) as second line drugs, with the renin–angiotensin (Ang) system (RAS) inhibitor as the first choice, for the treatment of hypertension associated with chronic kidney disease (CKD). We reported that augmentation index (AI) is related to proteinuria in CKD patients, and that RAS inhibition preserves arterial compliance in CKD [1,2]. However, the effects of CCBs on arterial stiffness remain unclear among CKD patients. n nA prospective comparative study was performed between 26 non-diabetic CKD patients treated with amlodipine and 27 patients on benidipine (supplemental methods). Patient backgrounds including the prescription of the RAS inhibitor did not differ between groups (supplemental table). Brachial blood pressure was controlled equally well in both groups for a year (supplemental figure). A year later, body weight (to 59 ± 11 kg, P < 0.05) and estimated glomerular filtration rate (eGFR) were decreased, and AI was increased without changes in proteinuria (Figure u200b(Figure1)1) in the amlodipine group. However, in the benidipine group, either eGFR, body weight or AI was not altered, but proteinuria was reduced. n n n nFig. 1 n nAnnual changes in urinary protein (UP, left panel), estimated glomerular filtration rate (eGFR, middle panel) and augmentation index (AI, right panel). *P < 0.05 from zero. Significant decreases in UP (116 ± 93 to 82 ± 67 mg/g ... n n n nIn renal tissue, L-type calcium channels are only found in afferent arterioles, while N-type and T-type calcium channels are localized in both afferent and efferent arterioles [3]. Amlodipine blocks L-type and N-type calcium channels and dilates afferent arterioles much more than efferent arterioles. In contrast, benidipine that inhibits L-type and T-type calcium channels, dilates both afferent and efferent arterioles and reduces glomerular pressure. We have demonstrated that efferent arteriolar constriction is mediated by inositol trisphosphate-induced calcium mobilization and calcium entry through transient receptor potential (TRP) channels [4]. T-type CCBs inhibited AngII-induced calcium mobilization rather than calcium entry in efferent arterioles [3]. TRP channels possess molecular similarity with voltage-dependent calcium channels, but they lack the structure of voltage-sensor, gating independently of voltage. It is possible that some CCBs including benidipine inhibit calcium entry through TRP channels into efferent arteriole. n nIncreasing AI elevates central blood pressure, worsening glomerular hypertension, proteinuria, renal and cardiovascular prognosis [1,2]. Although we would not deny the other possibilities (supplemental discussion), benidipine could reduce oxidative stress on arterial wall by decreasing proteinuria. Albumin passed through slit diaphragm is absorbed by proximal tubular cells. Although a small amount of protein is cleaved by acidification [5], oxidative process is involved in dealing a large amount of protein, generating reactive oxygen species that appear to leak from the kidney. This escalation of AI should worsen glomerular hypertension further, forming a vicious circle of progressive kidney damage [1,2]. n nOur results provided the evidence that benidipine may be superior to amlodipine in renoprotection as the antihypertensive additional to the RAS inhibitor when similar blood pressure levels are attained. Furthermore, the present data suggest that the influence on AI differs among types of CCBs in patients with CKD. n nConflict of interest statement. None declared.

CD36 single nucleotide polymorphism is associated with variation in low-density lipoprotein-cholesterol in young Japanese men.

Macrophages uptake oxidized low-density lipoprotein (LDL) via a scavenger receptor such as CD36 from plasma, and then become foam cells. We examined the association of CD36 gene single nucleotide polymorphisms (SNPs) with certain metabolic characteristics in a young male Japanese population (nu2009=u2009494). The G allele in a SNP located at +30215 on the 3’-untranslated region (UTR) was significantly correlated with the plasma LDL-cholesterol concentrations (ru2009=u20090.13, pu2009<0.01). The difference in LDL-cholesterol concentrations was 10u2009mg dl−1 between GG- and AA-genotype carriers (pu2009<0.05). The CD36 gene SNP is a novel maker of the variation in the LDL-cholesterol levels in young Japanese men.

Time for Reflection Predicts the Progression of Renal Dysfunction in Patients with Nondiabetic Chronic Kidney Disease

Our previous data indicated that both home blood pressure and arterial stiffness predicted the progression of renal dysfunction in the patients with chronic kidney diseases. In the present study, we examined both home blood pressure and the parameters of arterial stiffness as the indicator to the progression of chronic kidney diseases. Forty-two nondiabetic chronic kidney disease patients were enrolled and followed for 1 year. Anti-hypertensive therapy was adjusted to achieve office blood pressure below 130/80 mmHg. Home blood pressure was examined twice a day in the morning and evening. Pulse wave velocity (PWV) and augmentation index (AI) were measured as the index of arterial stiffness. The time for reflection (TR) was also determined. The relationship of annual changes in serum creatinine (Scr) with the above parameters was assessed. Multivariate regression analysis revealed that TR inversely correlated to annual increase in Scr (β = −0.03, p < 0.05). Home blood pressure did not correlate to annual changes in Scr in the present study. The present data indicated that arterial stiffness is elevated despite good blood pressure control in chronic kidney disease, especially among the dippings. In addition, our data suggest that PWV and AI correlated to each other, while they were influenced differently by hemodynamic factors. Finally, the present findings provide the evidence that the arterial stiffness parameter is more sensitive than home blood pressure as an indicator to the progression of chronic kidney disease.

Telmisartan Lowers Home Blood Pressure and Improves Insulin Resistance Without Correlation Between Their Changes

Telmisartan is an angiotensin type 1 receptor blocker (ARB), which also partially activates liganding peroxisome proliferator-activated receptor gamma. However, the relationship between the effects of telmisartan on hemodynamics and metabolism has not sufficiently been elucidated in clinical settings. We examined the long-term effects of telmisartan on hemodynamics including home blood pressure (BP) and on insulin resistance representing as homeostasis model assessment (HOMA-R). Twenty-seven hypertensive patients were consecutively enrolled at our outpatient department. At entry, all of the participants were previously prescribed another ARB for more than 3 months and then the former ARB were replaced by telmisartan. Hemodynamic and metabolic parameters were measured before treatment and at points 1 and 3 months after treatment with telmisartan. Telmisartan significantly lowered home systolic blood pressure (SBP) and diastolic blood pressure (DBP) (DBP) and improved HOMA-R during the treatment period. However, the changes in home SBP and DBP were not correlated with that of HOMA-R. In conclusion, telmisartan lowers home BP and improves insulin resistance without correlation between their changes.

End-stage renal disease (ESRD) contributes to the increasing prevalence of herpes zoster

Sir, n nVaricella-zoster virus (VZV) causes two clinically distinct diseases: varicella (chickenpox) and herpes zoster (HZ; shingles). The lifetime cumulative incidence is ∼10–20% of the population [1]. The incidence rates progressively increase with age, presumably owing to decline in the VZV-specific cell-mediated immunity [2]. Age is the most important risk factor for the development of HZ; however, immunocompromised patients such as transplant recipients, patients receiving selective immunomodulatory therapy and HIV-infected patients have an increased risk of VZV reactivation [3,4]. Further, immunosuppressed individuals with HZ exhibit a significantly higher rate of complications (e.g. dissemination of the disease and ocular involvement) [5]. n nPatients who have end-stage renal disease (ESRD) with uraemia exhibit an impaired host immune response. The reported immunological abnormalities in ESRD patients include decreased phagocytic function of granulocytes and monocytes/macrophages, defective antigen presentation by monocytes/macrophages, reduced antibody production by B lymphocytes and impaired T-cell-mediated immunity [6]. Physicians working in dialysis facilities generally presume that ESRD contributes to the increase in the prevalence of HZ. Despite this presumption, the morbidity of HZ in ESRD has not been previously reported. n nThis retrospective study includes information on all septuagenarian patients who visited the outpatient clinic of the nephrology division and dialysis centre affiliated to our university. A total of 220 patients were followed up for at least 3 years within the last 3.5 years. Of these 220 patients, 45 were excluded from this study because they exhibited one or more already identified risk factors for HZ (e.g. corticosteroid and/or immunomodulatory therapies, carcinomas and autoimmune disorders). Potential patients were identified by searching the diagnostic and billing codes of hospital records. If HZ was confirmed in a patient, the medical records were reviewed to verify that the case of HZ was indeed a new one. Our results revealed that the incidence of HZ increased with the progression in the stages of chronic kidney disease (CKD) (Table u200b(Table1,1, Figure u200bFigure1).1). In fact, the incidence rate of HZ was 84.8 per 1000 person-years in our outpatients undergoing haemodialysis or continuous ambulatory peritoneal dialysis. However, in patients with CKD stage 1, 2 or 3, the incidence rate (8.2 per 1000 person-years) was as low as that in septuagenarian HZ patients without kidney disease [5]. Diabetic nephropathy is the most important cause of ESRD that requires renal replacement therapy. Diabetes as well as CKD is a risk factor for some infectious diseases because these conditions result in a compromised immune system. However, the incidence of HZ and diabetes was not found to be significantly related as determined by the examinations performed in our hospital followed by analysis with the chi-square test. n n n nTable 1 n nThe number of patients per group and their gender, classified according to their CKD stage n n n n n nFig. 1 n nThe graph shows the incidence (%) of HZ in patients classified by chronic kidney disease (CKD) stage. n n n nWe concluded that ESRD, which requires renal replacement therapy, may contribute to the increased prevalence of HZ. n nConflict of interest statement. None declared.

Possible association of tumor necrosis factor receptor 2 gene polymorphism with severe hypertension using the extreme discordant phenotype design

The tumor necrosis factor (TNF)-α pathway has a key role in regulating insulin resistance. TNF receptor 2 (TNFR2) is an emerging candidate gene for insulin resistance in essential hypertension. We examined the association of insulin resistance and enhanced TNF pathway with severe hypertension and the association of a microsatellite polymorphism of the TNFR2 gene with severe hypertension. Male severe essential hypertensive patients (HT) with the onset before 60 years of age and with genetic predispositions to hypertension were consecutively enrolled at our outpatient department (N=92). Normotensive men (NT) over 50 years of age were randomly registered from the participants in the annual health check program (N=78). Patients were selected as HT and NT who met stringent criteria for systolic/diastolic blood pressure (SBP/DBP) levels ≧180 and/or 110u2009mmu2009Hg and <120/80u2009mmu2009Hg, respectively. HT revealed significantly higher plasma insulin levels, C-reactive protein (CRP) and soluble fraction of TNFR2 concentrations (sTNFR2) than NT. A microsatellite polymorphism of the CA repeat in intron 4 of the TNFR2 gene was analyzed. The allele frequency of CA16 in HT differed significantly from that in NT (66/184 vs. 36/156, P=0.01 by χ2 analysis). In HT, the CA16 carriers showed significantly higher SBP and plasma insulin levels and a higher tendency of sTNFR2 than did those without this allele. In NT, CA16 carriers revealed significantly higher sTNFR2 and CRP levels than did the CA16 non-carriers. These results suggest that the TNFR2 gene locus has a potential effect on developing severe hypertension through the augmented TNF pathway and insulin resistance.

Home hemodialysis and conventional in-center hemodialysis in Japan: a comparison of health-related quality of life.

Health‐related quality of life (HRQOL) is an important measure of how disease affects patients daily life. Conventional in‐center hemodialysis (CHD) patients have been found to have decreased HRQOL. Recent study reported that at‐home hemodialysis (HHD) improved the long‐term HRQOL compared with CHD; however, there have been no data from Japanese HHD patients. A sample of 80 Japanese hemodialysis patients (46 HHD and 34 CHD) was matched for age, sex, and cause of end‐stage renal disease. Patient HRQOL was measured using two health surveys: Medical Outcomes Study 36 Item Short Form Health Survey—Version 2 and Kidney Disease Quality of Life—Short Form. HHD patients reported better scores on seven out of eight domains (all domains except general heath) of the Medical Outcomes Study 36 Item Short Form Health Survey—Version 2, as well as better Kidney Disease Quality of Life—Short Form scores with respect to symptoms and problems, effect of kidney disease, and work status. No significant differences were observed for burden of kidney disease, cognitive function, quality of social interaction, sexual function, or sleep. More than 65% of HHD patients stated that they were not bothered at all by limitations on food and water intake. Japanese HHD patients demonstrate significantly higher HRQOL scores. However, while their HRQOL and employment rate were high and they were able to enjoy fewer dietary restrictions, kidney disease remained a great burden.