• Korean Journal of Clinical Pharmacy
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• v.21 no.4
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• pp.364-375
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• 2011

Given that single blockade with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can achieve only partial and undurable suppression of the Renin Angiotensin System (RAS), it has been hypothesized that dual blockage would be more beneficial in the management of blood pressure (BP) reduction and prevention of progressive chronic kidney disease (CKD) than either agent alone. Thus, it has been suggested that the combination of an ACEI and an ARB might provide renal benefits to hypertensive patients over and above BP reduction. However, this might also expose patients to additive or synergistic side effects. We attempted to conduct a systematic review to evaluate the benefits and harms of combination therapy in hypertensive patients with or without kidney diseases. MEDLINE and KoreaMed were searched for relevant randomized clinical trials in adult hypertensive patients with or without diabetes (restricted to 1997, limited to trials published in English). Results were summarized using the random-effects model, and between-studies heterogeneity was estimated with $I^2$. A final analysis of ten trials (23,928 patients) revealed that the combination of an ACEI and an ARB reduced blood pressure (SBP/DBP) by 3.95/2.02 mmHg (95% confidence interval [CI], -4.38 to -3.53/-2.33 to -1.71) compared with ACEI monotherapy, and 2.83/2.64 mmHg (95% CI, -3.25 to -2.41/-4.95 to -0.33) compared with ARB monotherapy. Eight trials (391 patients) demonstrated a significant reduction in 24h-proteinuria (weighted mean difference, 0.16 g/day, 95% CI, -0.26-0.05), but they did not translate into an improvement in GFR. Tests for heterogeneity showed no difference in effect among the studies. The combination therapy reduced proteinuria by 30% (95% CI, 23% to 37%) and 39% (95% CI, 31% to 48%) compared with ACEI monotherapy and ARB monotherapy, respectively. However, in patients who had proteinuria more than 0.5 g/day, the combination therapy failed to show significant reduction in urinary protein excretion. The current cumulative evidence suggests that diabetic patients with proteinuria on dual RAS blockade have an increase risk of adverse events such as hyperkalemia, hypotension, and so on, compared with ACEI or ARB alone. It is, therefore, proposed that the combination therapy should not be routinely used for the treatment of hypertension with or without compelling indications.

• Childhood Kidney Diseases
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• v.14 no.2
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• pp.132-142
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• 2010

Hypokalemia usually reflects total body potassium deficiency, but less commonly results from transcellular potassium redistribution with normal body potassium stores. The differential diagnosis of hypokalemia includes pseudohypokalemia, cellular potassium redistribution, inadequate potassium intake, excessive cutaneous or gastrointestinal potassium loss, and renal potassium wasting. To discriminate excessive renal from extrarenal potassium losses as a cause for hypokalemia, urine potassium concentration or TTKG should be measured. Decreased values are indicative of extrarenal losses or inadequate intake. In contrast, excessive renal potassium losses are expected with increased values. Renal potassium wasting with normal or low blood pressure suggests hypokalemia associated with acidosis, vomiting, tubular disorders or increased renal potassium secretion. In hypokalemia associated with hypertension, plasam renin and aldosterone should be measured to differentiated among hyperreninemic hyperaldosteronism, primary hyperaldosteronism, and mineralocorticoid excess other than aldosterone or target organ activation. Hypokalemia may manifest as weakness, seizure, myalgia, rhabdomyolysis, constipation, ileus, arrhythmia, paresthesias, etc. Therapy for hypokalemia consists of treatment of underlying disease and potassium supplementation. The evaluation of hyperkalemia is also a multistep process. The differential diagnosis of hyperkalemia includes pseudohypokalemia, redistribution, and true hyperkalemia. True hyperkalemia associated with decreased glomerular filtration rate is associated with renal failure or increased body potassium contents. When glomerular filtration rate is above 15 mL/min/$1.73m^2$, plasma renin and aldosterone must be measured to differentiate hyporeninemic hypoaldosteronism, primary aldosteronism, disturbance of aldosterone action or target organ dysfunction. Hyperkalemia can cause arrhythmia, paresthesias, fatigue, etc. Therapy for hyperkalemia consists of administration of calcium gluconate, insulin, beta2 agonist, bicarbonate, furosemide, resin and dialysis. Potassium intake must be restricted and associated drugs should be withdrawn.

• Clinical and Experimental Pediatrics
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• v.52 no.8
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• pp.938-943
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• 2009

Purpose : We performed this study in order to investigate the effect of direct renin inhibition on an experimental animal model with nephrotoxic serum nephritis and tried to give useful information for clinical research and renin inhibitor treatment. Methods : Thirty BALB/c 6-week-old male mice were divided into 4 groups: control group (CO, n=5), control-treatment group with aliskiren (CT, n=5), disease group (DO, n=10), and disease treatment group with aliskiren (DT, n=10). Nephritis was induced by an intravenous injection of 0.25 mg/g weight of rabbit anti-GBM immunoglobulin G. Model 2002 Alzet mini-osmotic pumps (Durect Corp.) for aliskiren infusion were implanted into CT and DT. Each group strain was sacrificed serially one at a time on day 14. We estimated the protein-creatinine ratio in 12-hour-collected urine (UP/Cr) and measured the mesangial matrix score in the PAS-stained kidney of each strain. Results : One strain at CT and DT died on day 6 and 7, respectively. Each group strain was sacrificed serially at a time on day 10 because DO were seriously ill. The UP/Cr of each group is as follows: CO, $31.24{\pm}6.54mg/mg$, CT, $23.38{\pm}13.60mg/mg$, DO, $112.72{\pm}10.97mg/mg$, DT $114.07{\pm}32.30mg/mg$. There was no significant difference between DO and DT. The mesangial matrix score of each group was CO, $0.23{\pm}0.10$; CT, $0.13{\pm}0.03$; DO, $1.90{\pm}0.48$; and DT, $1.28{\pm}0.41$, respectively, and there was a significant difference between DO and DT in the extent of mesangial matrix expansion (P=0.008). Conclusion : We found that renin inhibition was able to suppress the mesangial matrix expansion in experimental mice with acute nephritis, although there were no significant differences in UP/Cr.

• Journal of Periodontal and Implant Science
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• v.30 no.2
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• pp.359-374
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• 2000

Cyclosporine A(CsA) is a widely used immunosuppressant for transplant patients and is also used for the treatment of a wide variety of systemic diseases with immunologic disorders. However, its use is frequently limited because of complications such as nephrotoxicity or gingival hyperplasia. Although several hypotheses have been postulated for CsA-induced gingival hyperplasia, i.e. various cytokine effects of inflammatory cells, existence of plaque or CsA itself, but its pathogenesis is still unclear. For experimental chronic CsA toxicity, salt depletion has been shown to increased susceptibility of rodents to the effects of CsA, and this maneuver facilitates production of arteriolopathy and interstitial fibrosis in kidney that mimic the changes found in human. The purpose of this study was to evaluate pathogenesis of CsA-induced gingival hyperplasia by comparing changes between CsA administration groups of normal standard diet and those of low salt diet group. Specific pathogen-free, 20 to 25 days old(120 to 150 g), male Fisher-344 rats(KIST, Korea), 120 to 150g of body weight, were assigned to four groups of six animals each after one week of adaptation period for powder food. Group 1 received olive oil($300{\mu}l/g\;of\;diet$) with normal standard diet(0.4% of sodium)(NSD). Group 2 received CsA(Cypol-N, Jonggundang, Korea; $300{\mu}g/g\;of\;diet$) with normal standard diet(NSD+CsA). Group 3 received same amount of olive oil with low salt diet(0.05 % of sodium, Teklad Premier, U.S.A.)(LSD). Group 4 received same dose of CsA with low salt diet(LSD+CsA). Rats were pair fed and were sacrificed after six weeks. Renal histologic lesions associated with CsA, consisted of cortical interstitial fibrosis, tubular atrophy and hyalinization of arterioles and the impairment of renal function including increase of serum creatinine and decrease of glomerular filtration rate was more severe in low salt diet group. These were proved as the results of activated of renin-angiotensin system in the kidney by low salt condition. Meanwhile the degree of gingival hyperplasia at incisor and molar tooth was less severe in low salt diet group compared with normal sodium diet group. Hyperplastic gingiva showed mild epithelial hyperplasia and expanded underlyng stroma which consisted of matrix increasement, capillary proliferation and dilatation. While the number and the activation of fibroblasts were increased, inflammatory cells were rare in the stroma. The immunohistochemistry for TGF-${\beta}_1$ in the kidney and gingiva revealed stronger positive in LSD+CsA in kidney but in gingiva of NSD+CsA. These results suggested followings; Gingival hyperplasia can be developed without inflammatory cells infiltration and seemed not induced by CsA by itself. The major role for gingival hyperplasia by CsA would be the secondary effect of TGF-${\beta}$, which maybe upregulated by CsA administration. Low salt diet can attenuate this hyperplasia perhaps by decreasing the activation of $TGF-{\beta}$.

• Toxicological Research
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• v.17
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• pp.117-125
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• 2001

Envenoming by Russells viper causes a broad spectrum of renal impairment. Renal failure is an important complication in patients bitten by Russells viper. Experimental work in animals and in vitro has elucidated pathophysiological mechanisms that contribute to life threatening complications and have suggested possibilities for therapeutic intervention. The evidence in experimental animals regarding mechanisms of venom action in relation to changes in either extrarenal or intrarenal factors is presented. The cardiovascular system and renal hemodynamics are affected by venom. Reductions of renal function including renal hemodynamics are associated directly with changes in general circulation during envenomation. Possible endogenous mechanisms for releasing the hormone inducing renal vasoconstriction after envenomation are evident. Hormonal factor such as the catecholamine, prostaglandin and renin angiotensin systems induce these changes. Direct nephrotoxicity of venom action is studied in the isolated per-fused kidney. Characteristic polarization of the cell membrane, changes of mitochondrial activity and Na-K ATPase in renal tubular cells are observed. Changes in renal function and the cardiovascular system are observed of ter envenomation and are reversed by the administration of Russells viper antivenom (purified equine immunoglobulin, $Fab_2$ fragment). The neutralizing effects are more efficient when the intravenous injection of antivenom is given within 30 min after the envenomation.

• Clinical and Experimental Pediatrics
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• v.49 no.1
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• pp.99-102
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• 2006

A 3-year-old girl presented with polydipsia, polyuria, hyponatremia, hypertension and congestive heart failure. Her polyuria was unresponsive to water restriction and vasopressin challenge tests, and her blood pressure was not effectively controlled by antihypertensive drugs. Radiologic examinations revealed a Wilms' tumor in the right kidney. Her plasma renin activity and aldosterone concentration were greatly increased. After surgical removal of the tumor, the congestive heart failure disappeared. Congestive heart failure due to Wilms' tumor is very rare and we report here on such a case, with a brief review of the literature.

• Childhood Kidney Diseases
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• v.24 no.1
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• pp.58-61
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• 2020

Pseudohypoaldosteronism type 1 (PHA1) is a rare salt-wasting disorder caused by resistance to mineralocorticoid action. PHA1 is of two types with different levels of disease severity and phenotype as follows: systemic type with an autosomal recessive inheritance (caused by mutations of the epithelial sodium channel) and renal type with an autosomal dominant inheritance (caused by mutations in the mineralocorticoid receptor). The clinical manifestations of PHA1 vary widely; however, PHA1 commonly involves hyponatremia, hyperkalemia, metabolic acidosis and elevated levels of renin and aldosterone. The earliest signs of both type of PAH1 also comprise insufficiency weight gain due to chronic dehydration and failure to thrive during infancy. Here, we report a case of renal PAH1 in a 28-day-old male infant harboring a novel heterozygous mutation in NR3C2 gene (c.1341_1345dupAAACC in exon 2), showing only failure to thrive without the characteristic of dehydration.

• YAKHAK HOEJI
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• v.43 no.6
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• pp.843-850
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• 1999

We investigated whether endothelium-derived NO and endothelin-1 might result enhanced vasoconstriction induced by administration of norepinephrien (NE) at the early stage of one-kidney, one-clip (1K1C) renal hypertensive rats. We also studied the relation ship of renin-angiotensin system (RAS) using rat aorta in this hypothesis. L-NMMA (30$\mu$M) and L-NAME(30${\mu}M$) enhanced vasoconstriction induced by NE in thoracic aorta of control rats. However angiotensin converting enzyme (ACE) inhibitor didn't. The aorta of 1KIC rats showed a singnificantly exaggerated contractile response to NE as compared with control rats. Rub-bing the endothelium abolished this difference. Ach and SNP-induced vasorelaxation show no significant difference between 1KIC and control rats. The treatment of phosphoramidon (10${\mu}M$) and oral administration of captopril (0.05, w/v%) abolished the exaggerated contractile response to NE at early stage of 1KIC rats. These results suggest that the increase of contractile response at the early phase in 1KIC rat is partially involved in the activation of ACE.

• The Korean Journal of Physiology
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• v.24 no.2
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• pp.261-268
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• 1990

It has long been suggested that the cardiac atrium is a low pressure volume receptor controlling body fluid volume and blood pressure. Recently, the cardiac atrium has been found to contain a family of powerful peptides. To clarify the relationship between high blood pressure and the biologically active atrial peptides, experiments were done to define the characteristics of atrial natriuretic peptide secretion in the isolated perfused atria of renal hypertensive rats. Higher concentrations of plasma atrial natriuretic peptide and renin activity were observed in the two-kidney, one clip hypertensive rat compared to the normotensive rat. Atrial volume changes in response to pressure elevations were attenuated in hypertensive rats compared to normotensive rats. Incremental response to atrial volume changes in ANP secretion was accentuated in hypertensive rats. These date suggest that the accentuated atrial natriuretic peptide response to volume changes of hypertensive rats may be a physiological or pathphysiological adaptation to the high blood pressure and may be, at least in part, responsible for the elevated levels of plasma atrial natriuretic peptide observed in hypertensive rats.

• The Journal of Dong Guk Oriental Medicine
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• v.1
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• pp.55-80
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• 1992

In order to examine that the effect of Sam Hwa San, circulating the vital energy of Sam Cho and controlling body fluid metabolism, gives any influence on renal function, changes in the urine flow, eletrolytes excretion, plasma aldosterone concentration and renin activity were observed after intravenous infusion of the Sam Hwa San extract in rabbit. Also in vitro effect of the herb extract on oxygen consumption in renal cortical slices and ATPase activity in kidney microsomes was measured. The following results were obtained : 1. The urine flow was markedly increased at 10 min after intravenous infusion of the Sam Hwa San extract($0.134{\pm}0.015$ vs. $0.433{\pm}0.046ml/min.kg$), but return ed to normal value after 40 min of infusion. 2. The glomerular filtration rate was significantly increased at 10 min after in travenous infusion of the Sam Hwa San extract, and the renal plasma flow at 10 and 20 min after infusion of the Sam Hwa San extract, following return to normal value. 3. $Na^+$ excretion was significantly increased during 10-40 min after intravenous infusion of the Sam Hwa San extract, although showed the maximal rate at 10-20 min. The fractional $Na^+$ excretion was also increased during 10-40 min. $K^+$ excretion was rapidly increased at 10 min after the intravenous Infusion of the Sam Hwa San extract and then gradually decreased to normal level at 40 min. The fractional $K^+$ excretion was significantly increased during 10-40 min after the intravenous infusion of the Sam Hwa San extract. 4. The plasma aldosterone concentration and renin activity were not altered by the infusion of the Sam Hwa San extract. 5. The ouabain-sensitive oxygen consumption of renal cortical slices was significantly reduced by the Sam Hwa San extract(0.5 and 1.0 vol.%). 6. The Na-K-ATPase activity of renal microsomes was strongly inhibited by the Sam Hwa San extract(0.5 and 1.0 vol.%). These results suggest that the Sam Hwa San causes a strong diuretic effect which results from reduction of Na reabsorption in renal tubule by a direct inhibition of Na-pump and, in part, from all increase in renal blood flow. In clinic, it is considered to obtain the therapeutic effect in body fluid metabolism disharmony to cause the circular disorder of vital energy.