Shinsuke Isobe

Circadian rhythm of blood pressure and the renin–angiotensin system in the kidney

Activation of the intrarenal renin–angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.

Alogliptin improves steroid-induced hyperglycemia in treatment-naïve Japanese patients with chronic kidney disease by decrease of plasma glucagon levels

Background Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular disease, and a strategy to counteract CKD must be established. CKD caused by immunological abnormalities is treated by steroids, frequently resulting in steroid diabetes. Although insulin is the most effective drug against steroid diabetes, administering it to patients can be difficult. Dipeptidyl peptidase-4 (DPP-4) inhibitors were developed for diabetes mellitus with a new mechanism of action. However, their efficacies and mechanisms of action for steroid diabetes are unclear. Material/Methods We studied 11 CKD patients treated with steroids admitted to our hospital (3 men and 8 women; age, 66.0±15.9 years). DPP-4 inhibitor alogliptin was administered for steroid diabetes. Levels of markers related to glucose metabolism were measured before alogliptin treatment and after alogliptin treatment, before the prednisolone dose was reduced. Results Alogliptin treatment significantly increased plasma glucagon-like peptide-1 (GLP-1) levels from 1.16±1.71 pmol/L to 4.48±1.53 pmol/L and significantly reduced levels of plasma glucose recorded 2 h after lunch and hemoglobin A1c (HbA1c). No significant differences were seen in insulin secretory ability of homeostasis model assessment (HOMA) (HOMA-β) and insulin resistance index of HOMA (HOMA-R) before and after alogliptin treatment. In contrast, alogliptin treatment significantly decreased plasma glucagon levels, from 116.1±38.7 pg/mL to 89.6±17.3 pg/mL. Moreover, there were significant correlations among HbA1c, GLP-1, and glucagon levels. Conclusions Alogliptin improves steroid-induced hyperglycemia by decrease of glucagon levels through an increase in plasma GLP-1 levels.

Plasma Soluble (Pro)renin Receptor Reflects Renal Damage.

Background (Pro)renin receptor [(P)RR], a specific receptor for renin and prorenin, was identified as a member of the renin-angiotensin system (RAS). (P)RR is cleaved by furin, and soluble (P)RR [s(P)RR] is secreted into the extracellular space. Previous reports have indicated that plasma s(P)RR levels show a significant positive relationship with urinary protein levels, which represent renal damage. However, it is not fully known whether plasma s(P)RR reflects renal damage. Methods We recruited 25 patients who were admitted to our hospital to undergo heminephrectomy. Plasma s(P)RR levels were examined from blood samples drawn before nephrectomy. The extent of renal damage was evaluated by the levels of tubulointerstitial fibrosis. Immunohistochemical analysis of intrarenal (P)RR and cell surface markers (cluster of differentiation [CD]3, CD19, and CD68) was performed on samples taken from the removed kidney. Moreover, double staining of (P)RR and cell surface markers was also performed. Results There were significant positive relationships between plasma s(P)RR and tubulointerstitial fibrosis in all the patients and those not receiving RAS blocker therapy. Significant positive relationships were found between plasma s(P)RR levels and the extent of tubulointerstitial fibrosis after adjustment for age, sex, body weight, blood pressure, and plasma angiotensin II, in all the patients and those not receiving RAS blockers. Moreover, (P)RR expression was elevated in infiltrated mononuclear cells but not connecting tubules or collecting ducts and vessels. Infiltrated cells positive for (P)RR consisted of CD3 and CD68 but not CD19. Conclusions These data suggest that plasma s(P)RR levels may reflect (P)RR expression levels in infiltrated mononuclear cells, which can be a surrogate marker of renal damage.

Augmented circadian rhythm of the intrarenal renin-angiotensin systems in anti-thymocyte serum nephritis rats.

We report that disturbance to the circadian rhythm of urinary angiotensinogen (AGT) excretion may lead to renal damage, hypertension and diurnal blood pressure (BP) variations. We aim to clarify the circadian rhythm of the intrarenal renin–angiotensin system (RAS) and its contribution to renal damage, hypertension and BP variations, and to evaluate whether the administration of RAS blockers influences the circadian rhythms of intrarenal RAS components. Anti-thymocyte serum (ATS) nephritis rats were used as a chronic progressive glomerulonephritis model (group A) and compared with control rats (group C). Other rats with ATS nephritis received olmesartan medoxomil (an angiotensin II (AngII) type 1 receptor (AT1R) blocker; group AO) or hydralazine (a vasodilator; group AH). The levels of intrarenal RAS components were evaluated every 6 h. The expression levels of intrarenal AGT, AngII and AT1R were increased in group A and peaked at the same time as BP and urinary protein excretion during the rest phase. The amplitude of the circadian fluctuation of these proteins was more increased in group A than in group C. The circadian fluctuation of these proteins was reduced in groups AO and AH. However, renal function, proteinuria and augmentation of intrarenal RAS components were reduced only in group AO. Intrarenal RAS components, such as AGT, AngII and AT1R proteins, were increased and the amplitude of the oscillations of these proteins was augmented in ATS nephritis rats. Interestingly, renal damage may be linked to the activation of the intrarenal RAS independent of the amplitude of its oscillations and BP.

Acquired Fanconi syndrome in patients with Legionella pneumonia

BackgroundHyponatremia is often observed in patients with Legionella pneumonia. However, other electrolyte abnormalities are uncommon and the mechanism remains to be clarified.Case presentationWe experienced two male cases of acquired Fanconi syndrome associated with Legionella pneumonia. The laboratory findings at admission showed hypophosphatemia, hypokalemia, hypouricemia and/or hyponatremia. In addition, they had the generalized dysfunction of the renal proximal tubules presenting decreased tubular reabsorption of phosphate (%TRP), increased fractional excretion of potassium (FEK) and uric acid (FEUA), low-molecular-weight proteinuria, panaminoaciduria and glycosuria. Therefore, they were diagnosed as Fanconi syndrome. Treatment for Legionella pneumonia with antibiotics resulted in the improvement of all serum electrolyte abnormalities and normalization of the %TRP, FEK, FEUA, low-molecular-weight proteinuria, panaminoaciduria and glycosuria, suggesting that Legionella pneumophila infection contributed to the pathophysiology of Fanconi syndrome.ConclusionTo the best of our knowledge, this is the first report demonstrating Fanconi syndrome associated with Legionella pneumonia.

Intrarenal renin–angiotensin system activity is augmented after initiation of dialysis

Circulating renin–angiotensin system (RAS) activation is maintained after renal function has deteriorated. The activation of the intrarenal RAS plays a critical role in the pathophysiology of chronic kidney disease (CKD), independently of the circulating RAS. However, the activation of intrarenal RAS and the chymase-dependent pathway after initiation of dialysis has not been clarified. We recruited 19 CKD patients (10 without dialysis and 9 with dialysis) who underwent a heminephrectomy. Circulating RAS was investigated before nephrectomy. The levels of intrarenal RAS components and chymase-positive cells were investigated using radioimmunoassay or immunoblot analysis on samples collected from the removed kidney. Renal damage was evaluated by the extent of tubulointerstitial fibrosis. No significant differences in circulating RAS between nondialysis and dialysis patients were found. However, intrarenal angiotensin II (AngII) and the extent of tubulointerstitial fibrosis in dialysis patients were significantly increased when compared with nondialysis patients. Prorenin and angiotensin-converting enzyme (ACE) levels were dramatically decreased in accordance with renal dysfunction. On the other hand, chymase-positive cells and AngII type 1 receptor (AT1R) expression was significantly increased in dialysis patients when compared with nondialysis patients. In multiple linear regression analyses, there were significant positive and negative relationships between the extent of interstitial fibrosis and angiotensinogen (β=0.45, P=0.042) and prorenin levels (β=−0.85, P<0.01), respectively. In summary, a decrease in prorenin and ACE expression and an increase in chymase, angiotensinogen and AT1R expression in the kidney may augment the intrarenal RAS activation and be associated with renal damage, even after initiation of dialysis.

Increased nocturnal blood pressure variability is associated with renal arteriolar hyalinosis in normotensive patients with IgA nephropathy

Abnormal blood pressure (BP) variability (BPV), occurring as beat-to-beat, 24 h, and day-to-day fluctuations, is related to target organ damage. However, the associations between abnormal BPV and renal structural changes have not been clearly investigated. We evaluated the day time and night time BP s.d. and average real variability (ARV), which reflected short-term BPV, the night time to day time (N/D) ratio of systolic BP (SBP), and the 7-day BPV, in 29 normotensive IgA nephropathy (IgAN) patients. We further compared the results with renal structural changes. The degree of arteriosclerosis was positively correlated with age, s.d. of night time SBP and the N/D ratio of SBP, and was negatively correlated with the estimated glomerular filtration rate (eGFR). The degree of arteriolar hyalinosis was positively correlated with age, night time SBP, s.d. of day time and night time SBP, day time and night time ARV, the N/D ratio of SBP and 7-day SBP, and was negatively correlated with the eGFR. A multiple linear regression analysis revealed that the level of arteriolar hyalinosis, but not arteriosclerosis, was associated with the s.d. of night time SBP (β=0.63, P<0.01) or night time ARV (β=0.61, P<0.01) after adjustment for age, sex, body mass index, the eGFR and night time SBP. Multiple linear regression analyses indicated no significant correlation between the degree of arteriolar hyalinosis and the N/D ratio of SBP or 7-day SBP s.d. or between the degree of arteriosclerosis and any of the BPV parameters. In conclusion, short-term night time BPV was found to be associated with arteriolar hyalinosis in normotensive IgAN patients.

Hyperuricaemia is associated with renal damage independently of hypertension and intrarenal renin-angiotensin system activation, as well as their circadian rhythms.

Both hyperuricaemia and activation of the intrarenal renin‐angiotensin system (RAS) play an important role in the development of hypertension and renal damage. However, it has not been clear whether hyperuricaemia is associated with renal damage due to hypertension or intrarenal RAS activation, as well as their circadian rhythms.

Relationship between urinary fractional excretion of sodium and life prognosis in liver cirrhosis patients

Renal vasoconstriction in generalized vasodilatation with blood pooling and the consequent reduction in effective arterial volume is the pathophysiological basis of liver cirrhosis (LC). Low levels of fractional excretion of sodium (FENa) are an effective marker of hypoperfusion of the renal artery. However, the relationship between levels of FENa, LC severity and life prognosis has not yet been elucidated.

Membranous Nephropathy with an Enhanced Granular Expression of Thrombospondin Type-1 Domain-containing 7A in a Pregnant Woman

A 30-year-old woman with proteinuria first noted at 26 weeks of gestation was admitted to undergo further evaluation. A renal biopsy revealed membranous nephropathy (MN). There was no evidence of any secondary MN. Prednisolone was initiated 6 months after delivery. Four months later, her urine protein became negative. Enhanced granular staining for thrombospondin type-1 domain-containing 7A (THSD7A) in the glomeruli was retrospectively detected in a biopsy specimen. A literature review revealed that 60% of cases of THSD7A-related MN occurred in women of childbearing age. Therefore, THSD7A-related MN should be considered in female patients presenting with idiopathic MN in childbearing age.