We have revealed that even in humans, activated intrarenal renin–angiotensin–aldosterone system (RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (UN aV) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 ± 15 years) underwent 24‐h ambulatory BP monitoring before and during two‐day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate (UAGTV, μg/gCre) was measured as intrarenal RAAS; urinary dopamine excretion rate (UDAV, pg/gCre) as intrarenal dopaminergic system; heart rate variabilities (HRV, calculated from 24‐h Holter‐ECG) of non‐Gaussianity index λ 25s as sympathetic nerve activity; and power of high‐frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with UAGTV (r = −0.47, P = 0.04) and positively with UDAV (r = 0.58, P = 0.009). HF was a determinant of night/day BP ratio (β = −0.50, F = 5.8), rather than DC or λ 25s. During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime UN aV preceded restoration of BP rhythm, accompanied by decreased UAGTV (r = −0.88, P = 0.05) and increased UDAV (r = 0.87, P = 0.05), but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm.

Introduction:Increased sympathetic nerve activity has been suggested in patients with chronic kidney disease (CKD). Pathologic sympathetic activity can alter heart rate variability (HRV), and the altered HRV has prognostic importance, so that reducing sympathetic activity may be an important strategy. Novel nonlinear HRVs, including deceleration capacity (DC), have greater predictive power for mortality. We have recently proposed an increase in a non-Gaussianity index of HRV, λ25s, which indicates the probability of volcanic heart rate deviations of departure from each standard deviation level, as a marker of sympathetic cardiac overdrive. L/T-type calcium channel blocker (L/T-CCB), azelnidipine, decreases sympathetic nerve activity in experimental and clinical studies.Methods:In 43 hypertensive patients with CKD under treatment with an angiotensin receptor blocker (ARB), we investigated whether 8-week add-on L/T-CCB treatment could restore HRV.Results:Means of all normal-to-normal intervals over 24 h (p<0.0001) and DC (p=0.002) increased, and λ25s (p=0.001) decreased regardless of gender, age, renal function or blood pressure, while no significant changes were observed in the other HRVs.Conclusions:Reduction of λ25s is useful to assess the effect of sympathoinhibitory treatment. Further studies are needed to investigate if the restoration of HRV is directly associated with the improvement of prognosis in patients with CKD.

Introduction:We have reported that the circadian rhythm of urinary potassium excretion (U K V) is determined by the rhythm of urinary sodium excretion (U Na V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U Na V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U K V during ARB treatment has not been reported. Materials and methods: Circadian rhythms of U Na V and U K V were examined in 44 patients with CKD undergoing treatment with ARB. Results: Whole-day U Na V was not altered by ARB whereas whole-day U K V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U Na V and U K V (r=0.56, p<0.0001). Whole-day U K V/ U Na V ratio (p=0.0007) and trans-tubular potassium concentration gradient (p=0.002) were attenuated but their night/ day ratios remained unchanged. The change in the night/day U K V ratio correlated directly with the change in night/day U Na V ratio (F=20.4) rather than with the changes in aldosterone, BP or creatinine clearance. Conclusions: The circadian rhythm of U K V was determined by the rhythm of U Na V even during ARB treatment. Changes in the circadian U K V rhythm were not determined by aldosterone but by U Na V.

Horike K, Takeda A, Yamaguchi Y, Ogiyama Y, Yamauchi Y, Murata M, Kawaguchi T, Suzuki T, Otsuka Y, Inaguma D, Goto N, Watarai Y, Uchida K, Morozumi K. Is arteriolar vacuolization a predictor of calcineurin inhibitor nephrotoxicity?
Clin Transplant 2011: 25 (Suppl. 23): 23–27.
© 2011 John Wiley & Sons A/S. Abstract:  Calcineurin inhibitors (CNI) have been commonly used as pivotal immunosuppressive agents to renal transplant recipients and have contributed significantly to improving short‐term allograft survival. However, long‐term administration of CNI may cause an adverse effect on kidney function, known as chronic nephrotoxicity. Chronic CNI nephrotoxicity (CNI‐NT) shows characteristic histopathological findings that involve arteriolar hyalinosis. Recently, the term alternative arteriolar hyalinosis (aah) is used to discriminate CNI‐specific arteriolar hyaline deposition from non‐specific arteriolar hyalinosis. We studied whether arteriolar vacuolization represents an early lesion of aah as a predictor of CNI‐NT. We retrospectively studied the 79 patients under treatment with a CNI immunosuppressant, who underwent living‐related renal transplantation (RTx) from January 2007 to March 2009. We examined serial protocol graft biopsies at one h, one, six, and 12 months after RTx. We classified histological findings into two groups on the basis of aah lesion (with or without aah) in serial biopsies for 12 months. Arteriolar vacuolization was more frequently observed in the aah group than in the non‐aah group with a significant difference. Arteriolar vacuolization was found even in the one‐h biopsy specimens, indicating a non‐specific histopathological finding. But in the aah group, arteriolar vacuolization tended to be more frequently observed later on. Aah can be a predictor of CNI‐NT.

Objective Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events.