Hideaki Nakaya

Prepubertal Treatment with Angiotensin Receptor Blocker Causes Partial Attenuation of Hypertension and Renal Damage in Adult Dahl Salt-Sensitive Rats

Recently, we have shown that treatment of stroke-prone spontaneously hypertensive rats with angiotensin inhibitors for a limited time-window before puberty results in an attenuation of hypertensive nephrosclerosis in later life. The aim of this study was to examine the applicability of this therapeutic paradigm to a low-renin model. Dahl salt-sensitive (Dahl-S) rats were fed a high-salt diet from age 6 weeks. Some rats were treated with the angiotensin receptor blocker (ARB) candesartan cilexetil (2 mg/kg/d) from weaning to puberty (age 3–10 weeks), whereas other rats were treated continuously until overt renal damage was seen (age 3–16 weeks). Dahl-S rats on a high salt diet had increased blood pressure (207 ± 3 vs. 125 ± 2 mm Hg), proteinuria, and glomerular/vascular histological changes. The prepubertal treatment with ARB resulted in a continued suppression of blood pressure (153 ± 2 mm Hg) at 16 weeks. Both proteinuria and renal histological changes were significantly (p < 0.05) attenuated, but not completely prevented by the treatment. No significant differences in plasma renin activity, renin mRNA, or AT1/AT2 mRNA were seen between groups. These results suggest that prepubertal treatment affords sustained renoprotection, even in an animal model with a suppressed renin-angiotensin system, and support the notion that appropriate prepubertal intervention may lead to a partial attenuation in the susceptibility to inherited renal diseases.

Analysis of Gα protein recognition profiles of angiotensin II receptors using chimeric Gα proteins

Abstract Receptors with a heptahelical structure initiate signal transduction by interacting with specific Gα proteins. The aim of this study was to analyze the ability of type 1 (AT1) and type 2 (AT2) angiotensin receptors to recognize the receptor coupling regions of Gα proteins using our previously described technique (Ikezu, T., Okamoto, T., Komatsuzaki, K., Matsui, T., Martyn, J.A.J., Nishimoto, I., 1996. Negative transactivation of cAMP response element by familial Alzheimers mutants of APP. EMBO J. 15, 2468–2475; Komatsuzaki, K., Murayama, Y., Giambarella, U., Ogata, E., Seino, S., Nishimoto, I., 1996. A novel system that reports the G-proteins linked to a given receptor: a study of the type 3 somatostatin receptor. FEBS Lett. 406, 165–170). Chimeric Gαs protein constructs, whose receptor binding regions contained sequences from the four major families of Gα proteins (Gαq, Gαi, Gα12, Gαs), were cotransfected with AT1 or AT2 receptors in COS cells, then stimulated with angiotensin II (Ang II). Changes in cellular cAMP were assayed on cell lysates by enzyme immunoassay. In the case of the Gαq family, cotransfection of AT1 with Gα11/Gαs, Gα14/Gαs, Gα16/Gαs, elicited significant increases in cAMP after agonist stimulation. Confirmatory results were found using an independent [ 35 S]GTPγS binding assay. Further examination using chimeric G proteins for Gα12 proteins and Gαi family proteins provided evidence that the AT1 receptor can recognize sequences from Gα12, Gαi1/i2, Gαz, Gαo, while both receptors interacted with Gαi3. These results provide a Gα protein recognition database for both AT1 and AT2 receptors, which may be important for understanding the full spectrum of cellular responses mediated by the hormone Ang II.

Prevention and regression of hypertension: role of renal microvascular protection

Hypertension is a disease which affects over 26.4% of the world adult population, therefore novel approaches to the prevention and treatment of this disease need to be examined. Previous studies from our and other laboratories have shown that treatment of spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats with a renin–angiotensin system (RAS) inhibitor during the ‘critical period’ in hypertension development results in prevention of the later development of hypertension. In humans, Julius et al. reported similar findings in the landmark TROPHY study. Recently, we reported that ‘pulse’ treatment of SHR with high-dose angiotensin receptor blocker (ARB) is effective in causing sustained reduction of already established hypertension, even when the treatment was started after the ‘critical period’. These results suggest the possibility that ‘regression’ of established hypertension may become feasible, and we have started a prospective, multicenter clinical study (STAR CAST study) to examine this possibility. In our animal studies, we found that treatment of rats during the ‘critical period’ with an ARB inhibits the development of renal arteriolar hypertrophy. Moreover, a high-dose angiotensin blocker caused a remarkable reversal of renal arteriolar hypertrophy in SHR, which was associated with changes in microvascular MMP expression. These results suggest that changes in the renal microvasculature may have an important role in the mechanisms of hypertension prevention and regression by ARB.

Feasibility of regression of hypertension using contemporary antihypertensive agents

BACKGROUND Recently, we reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release (CR) resulted in a sustained regression of hypertension in humans. METHODS Patients aged 30 to 59 years with untreated stage 1 essential hypertension and a family history of hypertension were treated with the antihypertensive agents candesartan (n = 124) or nifedipine CR (n = 120). After 1 year of treatment (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. RESULTS In phase 1, after 1 year of treatment a similarly substantial BP decrease was seen in the candesartan (-24.5/16.1 mm Hg) and nifedipine (-26.8/18.0 mm Hg) groups. In phase 2 there was a substantial reoccurrence of hypertension; at the study end, only 1 patient was able to continue without antihypertensive medication. However, a Kaplan-Meier analysis revealed a significant delay of reoccurrence of hyper tension (P = 0.0001) in the candesartan group. CONCLUSIONS One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard doses used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

Adrenal angiotensin II type 1 and type 2 receptors in Cushing's and Conn's syndromes.

Cushings and Conns syndromes are well recognised endocrine diseases, but the pathobiology of the tumors causing these disorders is unclear. In this study we examined AT1 and AT2 gene expression in adrenal adenomas of Cushings and Conns syndromes. AT1 and AT2 receptor mRNA, as well as alternatively spliced AT1 transcripts, were detected by RT-PCR using adjacent adrenal cortex tissue as controls. Whereas no consistent differences in AT1 mRNA were seen compared to control adrenal cortex, AT2 mRNA levels were significantly decreased in the adenomas of Cushings and Conns syndromes. No changes in alternative splicing of AT1 mRNA were observed in the adrenal tumors. The fact that no consistent changes were seen in AT1 mRNA or its splicing, whereas AT2 mRNA were reduced in both forms of hormone producing adrenal tumor suggests that the AT2 receptor, rather than the AT1 subtype, may be correlated with adrenal tumorigenesis.

ACUTE KIDNEY INJURY WITH KARYOMEGALIC INTERSTITIAL NEPHRITIS AFTER NIVOLUMAB TREATMENT - TWO CASE REPORTS

Objective: Background: Acute kidney injury (AKI) caused by immune checkpoint inhibitors are poorly described. Herein, we present 2 cases of AKI in patients under nivolumab treatment. Each case displayed acute interstitial nephritis (AIN) with karyomegalic interstitial nephritis (KIN), which was successfully treated with the discontinuation of nivolumab or the administration of corticosteroid. Design and method: Case 1: A 76-year old male with pancreatic cancer was admitted for AKI (serum creatinine (SCr) level from 0.84 to 3.08 mg/dL) after a series of nivolumab treatment. Five months after the initiation of nivolumab, he suffered from edema in his lower extremities along with the elevation of blood pressure (BP) to 170/97 mmHg. Kidney biopsy showed AIN where tubular epithelial cells with variably sized nuclei that were massively enlarged, irregularly shaped, and abnormally hyperchromatic, which findings were indicative of KIN. Approximately one year after quitting nivolumab treatment, his renal function improved to SCr level of 1.42 mg/dL, Results: Case 2: A 76-year old female with non-small cell lung cancer started treatment by nivolumab. Two months later, she exhibited AKI (SCr level from 0.81 to 1.54 mg/dL). Kidney biopsy revealed tubular injury with interstitial infiltration of inflammatory cells. Of note, tubular epithelial cells were focally enlarged with hyperchromatic nuclei, which finding was consistent with that of KIN. Since most of the enlarged tubular epithelial cells were positive for Ki-67, karyomegalic changes of tubular epithelia are suggested to be associated with the cell cycle abnormalities of tubular cells. The patient was administrated high dose of corticosteroid, and SCr level returned to that of her baseline. Conclusions: Conclusion: This is the first report of characteristic histological findings of KIN in nivolumab-associated AIN. The association of nivolumab-induced AIN with cell cycle derangement in our patients suggests that the activation of effector T cell by nivolumab may affect the proliferation of tubular epithelial cells, thereby leading to karyomegalic changes. In addition to the discontinuation of nivolumab, the administration of corticosteroid successfully improved renal function.

PS 14-44 FEASIBILITY OF REGRESSION OF HYPERTENSION USING CONTEMPORARY ANTIHYPERTENSIVE MEDICATIONS

Objective: We have reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release(CR) resulted in a sustained regression of hypertension in human. Design and Method: Patients aged 30 to 59 years with untreated stage 1 essential hypertension and family history of hypertension were treated with the antihypertensive agents candesartan or nifedipineCR. After 1 year of treatment phase (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. Results: In phase 1, after 1 year of treatment, a similary substantial blood pressure decrease was seen in the candesartan and nifedipine groups. In phase 2, there was a substantial reoccurrence of hypertension and at the study end, only one patient in the candesartan group was able to continue without antihypertensive medication. A Kaplan Meier analysis revealed a significant delay of reoccurrence of hypertension in the candesartan group. Conclusions: One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard dose used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

502 COST-EFFECTIVENESS ANALYSIS OF AMLODIPINE/ ATORVASTATIN SINGLE-PILL THERAPY FOR PATIENTS WITH HYPERTENSION AND HYPERLIPIDEMIA

Aim: Our aim was to evaluate the cost-effectiveness of Amlodipine/ Atorvastatin single-pill therapy for Japanese patients with hypertension and hyperlipidemia. Methods: We constructed a Markov model consisting of the following states: Absence of cardiovascular disease, initial myocardial infarction, initial stroke, recurrence of myocardial infarction, recurrence of stroke and death. Patients’ adherence to medication was considered in this model. The model of the patients was assumed as follows, 60 years-old male and female, systolic blood pressure of 152 mmHg, total cholesterol of 288.2 mg/dl and HDL cholesterol of 54.5 mg/dl. The following 3 regimens were simulated: Fixed Dose Combination (FDC) regimen (amlodipine 5 mg/ atorvastatin 10 mg), two-pill regimen (amlodipine 5 mg and atorvastatin 10 mg) and no treatment regimen. Quality-adjusted life year (QALY) was used as an indicator of effectiveness. The Markov cycle was defined for 1-year, and the patients were followed until death. Results: Cost –effectiveness was evaluated for the 4 conditions of the simulated patients which could be assumed based on the combinations of the status regarding smoking and diabetes. Under all 4 conditions, the incidence of cardiovascular disease among both male and female patients was the lowest in the FDC regimen compared to the others. The incremental cost-effectiveness ratio (ICER) of the FDC regimen in comparison with no treatment regimen was less than 5 million yen/ QALY for both male and female under all conditions. Conclusion: Among the 3 regimens evaluated in this analysis, The FDC regimen was the most cost-effective treatment strategy for patients with hypertension and hyperlipidemia.

THE SHORT TREATMENT WITH THE ANGIOTENSIN RECEPTOR BLOCKER CANDESARTAN SURVEYED BY TELEMEDICINE (STAR CAST) STUDY: STUDY RATIONALE AND INTERIM REPORT: HT.2.02

Objectives: Previous studies in spontaneously hypertensive rats (SHR) showed that treatment with an angiotensin receptor blocker (ARB) at a prehypertensive stage resulted in a significant prevention of hypertension. These observations in animal models were confirmed clinically by the TROPHY study (N Engl J Med 354:1685-1697, 2006). We have recently found that transient treatment with an ARB may cause regression of established hypertension in hypertensive rats by a mechanism (Hypertension 53:83–89, 2009). The aim of this multi-center study is to examine if regression of established hypertension may be feasible in humans. Methods: The STAR CAST (Short Treatment with the Angiotensin Receptor blocker Candesartan Surveyed by Telemedicine) study is a prospective, randomized, open, blinded end-point study that is conducted in several centers in Japan. Patients aged 30–59 with stage 1 hypertension are treated with the ARB candesartan or the calcium channel blocker (CCB) nifedipine slow-release. After 1 year, tapering and withdrawal of antihypertensive treatment will be attempted, and the patients closely monitored with a home blood pressure monitoring telemedicine system (i-TECHO), and the antihypertensive drug withdrawal success rate of the two groups will be compared. Results: At present, 93 patients have been enrolled in the candesartan (C) group, and 94 patients in the nifedipine (N) group. The patient baseline data are as follows: age (C 50.9 + 0.7, N 51.6 + 0.6 years), office blood pressure (OBP: C 151.7 + 0.5/90.1 + 0.6, N 152.5 + 0.5/90.2 + 0.6 mmHg), home blood pressure (HBP: C 147.1 + 1.5/90.7 + 1.0, N 147.8 + 1.4/91.4 + 0.9 mmHg), body mass index (BMI: C 24.3 + 0.3, N 23.6 + 0.3 kg/m2), HbA1c (C 5.15 + 0.03, N 5.18 + 0.04 %). There is a significant correlation between HBP and OBP (p < 0.0001). Only 6 patients (3.2 %) fulfil the WHO criteria of obesity. Conclusion: Previous studies have suggested that regression of established hypertension may be achievable in animal models, but the possibility in humans is unknown. This study is designed to be the first clinical study to examine if regression from stage 1 hypertension to prehypertension may be feasible using an ARB or CCB.