장기간 이뇨제 투여에 따른 요 산성화 능력과 집합관 H^(+)-ATPase 발현의 변화

김근호,나기영,한진석,오윤규,이정상,주권욱,엄재호 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.2

목 적 : 저자들은 임상에서 흔히 사용하면서 대사성 알칼리증을 유발할 수 있는 furosemide와 hydrochlorothiazide를 장기간 투여할 때 발생하는 요 산성화능의 변화를 관찰하고, 이에 동반하여 근위세관 및 헨리고리관의 NHE3와 집합관의 H^(+)-ATPase 단백 발현에 변화가 있는지 조사하고자 하였다. 방 법 : Sprague-Dawley rat에서 수분과 전해질 용액을 자유롭게 섭취시키면서 furosemide12 mg/day/rat 혹은 hydrochlorothiazide 7.5 mg/day/rat을 각각 7일간 지속적 피하 주입시킨 후 신장에서 반정량적 immunoblot 분석을 시행하여 대조군과 비교하였다. 결 과 : Furosemide 투여 후 대조군과 실험군 사이에 체중, 혈청 알도스테론 및 크레아티닌청소율은 차이가 없었다. 요량 및 요 소디움 배설은 furosemide 투여 후 현저하게 증가하였다. 요 pH가 furosemide 투여 후 감소하였고, 요 암모늄 배설은 furosemide 투여 후 증가하였다. 반정량적 immunoblot 분석 결과 furosemide 투여 후 신 피질의 NHE3 발현에 유의한 변화는없었으나, 신 외수질의 NHE3 발현은 실험군(182±25%)에서 대조군(100±25%)에 비해 증가하였다(p<0.05). 또한, H^(+)-ATPase B1 subunit 발현은 furosemide 투여 후 신 피질(대조군100±13%, 실험군 178±11%, p<0.01)과 신 외수질(대조군 100±29%, 실험군 239±24%, p<0.05)에서 모두 증가하였다. Hydrochlorothiazide 투여 실험에서도 요량 및 요 소디움 배설의 증가와 요 pH의 감소를 확인하였다. 신 피질과 외수질의 NHE3 발현은 hydrochlorothiazide투여 후 변화 없었으나, H^(+)-ATPase B1 subunit 발현은 신 피질(대조군 100±24%, 실험군212±27%, p<0.05)과 신 외수질(대조군 100±13%, 실험군 194±13%, p<0.01)에서 모두 증가하였다. 결 론 : 장기간 furosemide 혹은 hydrochlorothiazide 투여에 의해 원위 요 산성화 능력의 항진을 확인하였고, 이는 집합관 H^(+)-ATPase 단백 발현이 증가하여 발생한 결과로 설명할 수 있을 것으로 생각한다. Purpose : Commonly used diuretics such as furosemide and hydrochlorothiazide may cause metabolic alkalosis by increasing proton secretion from distal nephron. We evaluated changes in urinary acidification and abundance of proton-secreting transporters in response to chronic subcutaneous infusion of diuretics. Methods : Osmotic minipumps were implanted into Sprague-Dawley rats to deliver 12 mg/day furoemide or hydrochlorothiazide 7.5 mg/day for 7 days. All animals were offered tap water and a solution containing 0.8% NaCl and 0.1% KCl as drinking fluid. Results : Compared with vehicle-infused controls, diuretic and natriuretic responses were evident from furosemide or hydrochlorothiazide infusion. However, there were no changes in body weight, serum aldosterone and creatinine clearance between diureticinfused( n=6) and control(n=6) rats. In both furosemide- infused and hydrochlorothiazide-infused rats, urine pH was significantly lowered compared with controls. Furosemide-infused rats showed significantly larger excretion of urinary ammonium. Semiquantitative immunoblotting was carried out from rat kidneys to investigate abundance of proximal tubule or medullary thick ascending limb Na^(+)/H^(+) exchanger type 3(NHE3) and collecting duct H^(+)- ATPase using specific polyclonal antibodies to NHE3 and H^(+)-ATPase B1 subunit, respectively. The abundance of NHE3 from cortical homogenates was not changed by either furosemide or hydrochlorothiazide infusion. However, the abundance of NHE3 from outer medullary homogenates was increased by furosemide infusion. The H^(+)-ATPase B1 subunit abundance was increased by furosemide or hydrochlorothiazide infusion in both cortical and outer medullary homogenates. Conculsion : These increases in the abundance of proton-secreting transporters may account for the enhanced distal urinary acidification in response to chronic diuretic administration. (Korean J Nephrol 2002;21(2):222-231)

이뇨제의 저항성과 내성 기전

오윤규,나기영,김근호,김소영,한진석 대한신장학회 2001 대한신장학회잡지 Vol.20 No.5

정상인에서 옥시토신의 항이뇨 작용

주권욱,전은실,오윤규,김근호,한진석,김성권,이정상 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.2

배 경 : 옥시토신은 바소프레신과 매우 유사한 구조의 호르몬으로서, 과거부터 항이뇨 효과가 있을 것으로 생각하였으나, 최근에야 체외실험을 통하여 옥시토신의 항이뇨 작용이 증명되었다. 인체에서도 옥시토신이 항이뇨 호르몬으로 작용할 가능성이 있지만 아직 분명하지 않다. 저자들은 정상인에게 옥시토신 또는 desmopressin(dDAVP)을 투여하여 인체에서 옥시토신의 항이뇨 효과를 직접적으로 검증하고자 하였다. 방 법: 신기능 장애의 증거가 없는 건강한 성인 남자 10명을 대상으로 기저상태와 옥시토신(20 mU/hour로 정주) 또는 dDAVP(2 μg을 피하 주사)를 투여한 후 2시간 동안 수집한 요에서 요량, 요 삼투질농도, 자유수분 청소율 등을 측정하였고, 요 전해질 배설의 변화를 함께 관찰하였다. 결 과 : 혈청 전해질이나 삼투질농도는 옥시토신 또는 dDAVP 투여 후에 기저상태에 비해 유의한 변화가 없었다. 2시간 요량은 기저상태 446±75 mL로부터, dDAVP 투여 후 92±9 mL로 감소하였고(p<0.05), 옥시토신 투여 후에는 289±53 mL로 변화하였다. 요 삼투질농도는 기저상태 223±25.0 mOsm/kg에서, dDAVP 투여 후 936±34 mOsm/kg 및 옥시토신 투여 후427±63 mOsm/kg로 모두 증가하였다(p<0.05). 자유수분 청소율은 기저상태 110±51 mL/2hour로부터, dDAVP 투여 후 -218±28 mL/2 hour, 옥시토신 투여 후 -57±51 mL/2 hour로 각각 감소하였다(p<0.05). 요나트륨분획배설율(FENa)을 포함한 다른 요 전해질 배설의 유의한 변화는 없었다. 결 론 : 옥시토신이 정상 성인 남자에서 요 삼투질농도의 증가 및 자유수분 청소율의 저하를유발함을 확인하였으며, 이는 옥시토신이 인체에서도 항이뇨 작용이 있음을 시사하는 결과이다. 그러나 생리적인 농도에서 옥시토신이 어떤 역할을 할 것인가와 그 작용기전은 앞으로 규명되어야 할 과제이다. Background : The antidiuretic action of oxytocin in human has been controversial. To investigate whether oxytocin directly acts on water balance in human, we evaluated the parameters of urinary concentration in response to administration of oxytocin in ten healthy male volunteers. Methods : Oxytocin was infused intravenously at a rate of 20 mU/hour for 2.5 hours and urine was collected during the last 2 hours of oxytocin infusion. Changes in urine volume, urine osmolality, excretions of urine electrolytes and free water clearance after the administrartion of oxytocin were compared with the baseline data. Results : The changes in the levels of serum electrolytes and osmolality after the administration of oxytocin were not significant compared with the baseline data. The volume of 2 hours' urine were 446±75 mL and 289±53 mL in the basal state and after the administration of oxytocin, respectively. The urine osmolality was increased significantly by the infusion of oxytocin(427±63 mOsm/kg) compared with that in the basal state(223±25 mOsm/kg)(p< 0.05). The free water clearance was 110±51 mL/2 hours in the basal state and decreased significantly to -57±51 mL/2 hours(p<0.05). Conclusion : We conclude that administration of oxytocin to normal men enhances urinary concentration, evidenced by increased urinary osmolality and decreased free water clearance. In human, oxytocin may play an important role in the regulation of renal water excretion as an antidiuretic hormone. (Korean J Nephrol 2002;21(2):251-258)

원위부 신세뇨관성 산증에서 산-염기 운반체의 결손

김혜영,한진석,전은실,진호준,주권욱,나기영,정우경,오지은,김현리,이서진,이중건,김근호,엄재호,궁성수,김진,이정상 대한신장학회 2000 대한신장학회잡지 Vol.19 No.5

Reviews : Dialysis Unphysiology and Sodium Balance

Gheun Ho Kim 대한전해질·혈압학회 2009 Electrolytes & Blood Pressure Vol.7 No.2

Dialysis unphysiology was first discussed by Carl Kjellstrand in 1975 for the possible negative effects of the unphysiology of intermittent dialysis treatment. Current hemodialysis practices are still unphysiologic because they cannot keep blood chemistries within normal limits, both before and after dialysis. In addition, the discontinuous nature of hemodialysis causes saw-tooth volume fluctuations, and the extracellular fluid volume expansion during the interdialytic period may lead to hypertension and adverse cardiovascular consequences. Sodium, which is accumulated over the interdialytic period, may be divided into two fractions. The one is the fraction of osmotically active sodium which is mainly confined to the extracellular space, and the other is that of water-free (osmotically inactive) sodium which diffuses into the intracellular space. Both contribute to the pathogenesis of hypertension because the former may act to expand extracellular fluid volume and the latter may cause vasoconstriction in the long run by increasing cytosolic concentration of calcium in the vascular smooth muscle cells. Even in intensive hemodialysis, it may take several weeks to months for water-free sodium storage in the vascular smooth muscle cells to be relieved. This may be an explanation for the lag phenomenon, i.e., the delay of blood pressure decrease after normalization of extracellular fluid volume shown in the Tassin experience. Modest restriction of dietary sodium intake, the dialytic session length long enough to maintain a high ultrafiltration volume, and the reasonably low dialysate sodium concentration are required to avoid unphysiology of positive sodium balance in current hemodialysis practice.

Review : Gaps between Global Guidelines and Local Practices in CKD-MBD

( Gheun Ho Kim ) 대한전해질학회 2014 Electrolytes & Blood Pressure Vol.12 No.2

The term ‘chronic kidney disease-mineral bone disorder’ (CKD-MBD) is a new term that, in contrast to the old term ‘renal osteodystrophy’, implies a systemic syndrome associated with cardiovascular morbidity and mortality. This new terminology is in line with previous studies that show elevated serum calcium, phosphorus, and parathyroid hormone (PTH) levels associated with increased cardiovascular and all-cause mortality. In order to improve outcomes in patients with CKD-MBD, many countries have developed clinical practice guidelines. Globally, the Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines are the most commonly used. However, whether these global guidelines can be successfully implemented on a local level needs to be studied. Differences in medical care and social factors between countries may limit the generalizability of global guidelines. Reports from the Korean registry and the Dialysis Outcomes and Practice Patterns Study (DOPPS) suggest that many dialysis patients are not within the target ranges recommended by the KDOQI and KDIGO guidelines for serum calcium, phosphorus, and PTH, suggesting gaps between global guidelines and local practices. Clinical studies with Korean CKD-MBD patients are necessary to compare Korean practices and outcomes to those suggested by global guidelines and to determine the target serum mineral levels associated with the best local outcomes.

Becoming a high impact journal

( Gheun-ho Kim ) 대한신장학회 2020 Kidney Research and Clinical Practice Vol.39 No.4

Edematous Hyponatremia Treated with Tolvaptan in a Patient with Amyotrophic Lateral Sclerosis

( Gheun-ho Kim ) 대한전해질학회 2017 Electrolytes & Blood Pressure Vol.15 No.2

Amyotrophic lateral sclerosis (ALS) patients rarely present with either syn-drome of inappropriate antidiuretic hormone secretion or generalized edema. Tolvaptan is a selective vasopressin V2 receptor antagonist that produces effective aquaresis, and its use in ALS patients has not been previously reported. A 50-year-old male ALS patient was admitted be-cause of both generalized edema and dilutional hyponatremia. These manifestations were refractory to conventional diuretics and fluid therapy, but a very brisk diuresis was induced by tolvaptan administration. Edema and hyponatremia were also improved, and the patient was able to be discharged without tolvaptan. In this case report, we postulate how edema and dilutional hyponatremia developed in the patient, and discuss the mechanism of tolvaptan in treating hypervolemic hyponatremia. Further experience is necessary to evaluate the usefulness of tolvaptan in pa-tients with neurological disorders.

Renal Effects of Prostaglandins and Cyclooxygenase-2 Inhibitors

( Gheun Ho Kim ) 대한전해질학회 2008 Electrolytes & Blood Pressure Vol.6 No.1

Prostaglandins (PGs) with best-defined renal functions are PGE2 and prostacyclin (PGI2). These vasodilatory PGs increase renal blood flow and glomerular filtration rate under conditions associated with decreased actual or effective circulating volume, resulting in greater tubular flow and secretion of potassium. Under conditions of decreased renal perfusion, the production of renal PGs serves as an important compensatory mechanism. PGI2 (and possibly PGE2) increases potassium secretion mainly by stimulating secretion of renin and activating the renin-angiotensin system, which leads to increased secretion of aldosterone. In addition, PGE2 is involved in the regulation of sodium and water reabsorption and acts as a counterregulatory factor under conditions of increased sodium reabsorption. PGE2 decreases sodium reabsorption at the thick ascending limb of the loop of Henle probably via inhibition of the Na+-K+-2Cl- cotransporter type 2 (NKCC2). Cyclooxygenase inhibitors may enhance urinary concentrating ability in part through effects to upregulate NKCC2 in the thick ascending limb of Henle`s loop and aquaporin-2 in the collecting duct. Thus, they may be useful to treat Bartter`s syndrome and nephrogenic diabetes insipidus.

Pharmacologic Treatment of Chronic Hyperkalemia in Patients with Chronic Kidney Disease

Gheun-Ho Kim 전해질고혈압연구회 2019 Electrolytes & Blood Pressure Vol.17 No.1

Hyperkalemia is frequently complicated in patients with advanced chronic kidney disease(CKD) because kidney is the major route of potassium excretion. Urinary potassium excretion is reduced according to the decline in glomerular filtration rate, and the risk of hyperkalemia is increased in patients with high potassium intake, advanced age, diabetes mellitus, congestive heart failure, and medica- tions such as renin-angiotensin-aldosterone system(RAAS) blockades. On the other hand, the benefits of RAAS blockades and a high-potassium diet should be considered in CKD patients. To overcome these contradictory treatment stra- tegies, potassium binders have emerged as new options to enhance fecal pota- ssium excretion. In different regions of the world, four types of potassium binders are preferentially used. Whereas sodium polystyrene sulfonate(SPS) exchanges sodium for potassium, calcium polystyrene sulfonate(CPS) has the advantage of avoiding hypervolemia because it exchanges calcium for potassium. SPS was first introduced in the 1950s and used for a long time in western countries, and CPS is currently prescribed in Asia including South Korea. In contrast with the paucity of clinical studies using SPS or CPS, the recent ran- domized, controlled trials reported that two newer potassium binders, patiromer and sodium zirconium cyclosilicate(ZS-9), effectively and safely reduce serum potassium levels in CKD patients taking RAAS blockades. Our experiences showed that the long-term administration of a small dose of CPS was also effec- tive and safe in treatment of chronic hyperkalemia. Further comparative trials among patiromer, ZS-9, and CPS are required to provide guides to cost-effective management of hyperkalemia in CKD patients.