이식신의 이식전후 사구체여과율의 변화에 관한 연구

정해혁(Hae Hyuk Jung),김경조(Kyung Jo Kim),장재원(Jae Won Jang),서장원(Jang Won Seo),김형호(Hyeong Ho Kim),양원석(Won Seok Yang),박정식(Jung Sik Park),한덕종(Duck Jong Han),문대혁(Dae Hyuk Moon) 대한내과학회 1996 대한내과학회지 Vol.50 No.4

N/A Objectives : The GFR of transplanted kidney has been studied in human, which has been reported to be around 50% to 70% of the donor total GFR before nephrectomy. The magnitude of hyperfiltration in the transplanted kidney is 0% to 40% on the assumption that each donor kidney functions 50% of the total GFR. These studies, however, did not take the relative function of the donated kidney into consideration. This study was performed to evaluate the magnitude of hyperfiltration in the transplanted kidney by measuring the GFR of the donated kidney before nephrectomy, and to determine factors that affect the GFR of the transplanted kidney. Methods The author measured GFR using 51Cr-EDTA clearance (CEDTA) and creatinine clearance (Ccr) in 70 donors of llving related renal transplantation performed in Asan Medical Center from December 1992 to January 1994. With relative kidney function measured by DMSA scan, the auther calculated the GFR of the donated kidney before nephrectomy(D'CEDTA and D'Ccr, respectively). When renal function was stable, usually 3 months after transplantation, the author repeated CEDTA and Ccr(R'CEDTA and R'Ccr, respectively) in 61 recipients. Nine patients were excluded because they did not maintain stable renal function within 2 months of transplantation. Results: The relative renal function of the donated kidney ranged 33 to 56% (mean 49%) The GFR of donated kidney before nephrectomy (D'CEDTA and DCcr) ranged 39 to 85m1/min(mean 59) and 26 to 80ml/min(mean 49), respectively. As expected, there was a close correlation between R'CEDTA and D'CEDTA with RCEDTA=0.72×D'CEDTA+26ml/min (r=0.59, p<0.01) and the geometric mean of R'CEDTA/DCEDTA was 115% (n=47). There was a significant correlation between R'Ccr and O'Ccr with R'Ccr=0.43×D'Ccr+48mVmin (r=0.44, p<0,01) and the mean of R'Ccr/D'Ccr was 140Fo(n=43). D'CEDTA (p<0.01) and the donor age(p=0.02) related independently with R'CEDTA on multiple regression analysis(n=47). Conclusion: With these results, we conclude that: 1) The relative function of the donated kidney was distributed in a wide range. 2) Transplanted kidney functions at 15 to 40N above the prenephrectomy level in about 3 months after transplantation. 3) The GFR of the donated kidney before nephrectomy and the donor age affect the GFR of the transplanted kidney.

신부전 환자에서 혈청 BNP 측정의 유용성

정해혁 ( Hae Hyuk Jung ),김상욱 ( Sang Wook Kim ) 대한내과학회 2005 대한내과학회지 Vol.69 No.2

Transforming Growth Factor-β1이 복막증피세포의 Vascular Cell Adhesion Molecule-1 발현에 미치는 영향

정해혁 ( Hae Hyuk Jung ),양원석 ( Won Seok Yang ),김순배 ( Soon Bae Kim ),김병식 ( Byung Sik Kim ),박수길 ( Su Kil Park ),박정식 ( Jung Sik Park ) 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.6

배 경 :복막염이 발생하면 다형핵백혈구 외에도 대식세포와 같은 단핵구가 복강내로 급속히 유입되어 염종반응의 진행에 중요한 역할을 한다. 단핵구의 유입에는 복막중피세포의 vascular cell adhesion melecyle-1 (VCAM-1) 발현이 관여할 것으로알려져 있다. 본 연구에서는 tumor necrosis factor-α (TNF-α)와 interleukin-1β (IL-β1)의 작용을 알아보고자 하였다. 방 법 : 사람의 장간막에서 복막중피세포를 분리, 배양하였다. VCAM-1 mRNA 양은 northern blot assay로 측정하였다. 세포내 VCAM-1 단백질 양과 세포 표면의 VCAM-1 단백질 발현은 각각 western blot 과 cellular ELISA로 비교하였다. 결 과 : 복막중피세포를 TNF-α(10 ng/mL), IL-1β (1 ng/mL)로 자극하였을 때 VCAM-1 mRNA 양이 증가하였고, TGF-β1 (0.1, 1, 10 ng/mL)은 TNF-α, IL-1β 자극에 의한 VCAM-1 mRNA 양 증가를 억제하였다. TGF-β1 (10 ng/mL)은 자극을 하지 않은 상태의 복막중피세포에서도 VCAM-1 mRNA 양을 감소시켰다. Total cell lystate에서 western blot으로 측정한 VCAM-1 단백질 양이나, cellular ELISA로 측정한 세로 표면의 VCAM-1 단백질 발현도 TNF-α와 IL-1β에 의해 증가하였으나, TGF-1β은 그 증가를 억제하였다. 자극을 하지 않은 상태의 복막중피세포의 VCAM-1 단백질 양이나 발현도 TGF-β1에 의해 억제되었다. TNF-α나 IL-1β로 자극한 세포에서 actinomycin D 처리 후 mRNA aid을 시간별로 측정하여 비교한 VCAM-1 mRNA 분해 속도는 TGF-β1 투여에 의해 영향을 받지 않았다. 결 론 : TGF-β1은 복막중피세포에 작용하여 TNF-α와 IL-1β 자극에 의한 VCAM-1 mRNA 양 및 단백질 생성 및 발현 증가를 억제하였고, 이는 VCAM-1 mRNA 생성을 억제함으로써 작용할 것으로 생각된다. Background : In early phase of peritonitis, mononuclear cells as well as polymorphonuclear leukocytes migrate rapidly into peritoneal cavity. For the migration of mononuclear cells, the expression of VCAM-1 on peritoneal mesothelial cells is important. In this study, we investigated the effect of TGF-β1 on tumor necroses factor-α (TNF-α) or interleukin-1β(IL-1β) induced VCAM-1 expression in the cultured HPMCs, Methods :HPMCs were cultured in the presence of TNF-α, IL-1β and/or TGF-β1. VCAM-1 mRNA level was measured by Northern blot. VCAM-1 in total cell lysate and VCAM-1 expressed on cell surface were measured by Western blot and cellular FLISA, respectively. Results : Incubation of the cultured HPMCs with TNF-α (10 ng/mL) or IL-1β (1 ng/mL) caused an increased level of VCAM-1 mRNA, VCAM-l. protein in total cell lysate, and VCAM-1 expressed on cell surface. This stimulatory effects of TNF-α or IL-1β were inhibited by TGF-β1 (0.1, 1, 10 ng/mL), dose-dependently. The level of VCAM-1 mRNA, VCAM-1 protein in total cell lysate, and VCAM-1 expressed on cell surface in the unstimulated cells were also inhibited by TGF-βI (10 ng/mL). The rate of VCAM-1 mRNA degradation after an application of actinomycin D was not affected by TGF-β1 Conclusion : TGF-β1 inhibited inflammatory cytokine induced VCAM-1 production and expression in the cultured HPMCs. Treatment of the cells with TGF-β1 seems to suppress TNF-α or IL-1β induced VCAM-1 mRNA transcription rather than decrease stabilization of VCAM-1 mRNA.

이식신에서 발견된 IgA신병증의 임상적 중요성과 예후인자

김지훈(Ji Hoon Kim),정해혁(Hae Hyuk Jung),박정식(Jung Sik Park),유은실(Eun Sil Yu),김순배(Soon Bae Kim),박수길(Su Kil Park),박종하(Jong Ha Park),장상필(Sang Pil Chang),이미숙(Mee Sook Lee),정재걸(Jae Gul Chung) 대한신장학회 2000 Kidney Research and Clinical Practice Vol.19 No.2

N/A Recently IgA nephropathy(IgAN) in transplanted kidney have been reported a more grave prognosis of the disease, which account for progressive allograft loss as 12-16%. But, the studies for the clinical significance and the prognostic factors of IgAN developed in transplanted kidney were not sufficient. We analyzed the frequency and the prognostic factors of IgAN developed in patients who underwent Kidney transplantation(KT) between January 1990 and Octo-ber 1998. Total 231 renal biopsies was done. IgAN was diagnosed in 31 cases, and it was 13.4% of total cases and 24.4% of cases that acute rejection(AR) were excluded. After the 3 patients of IgAN was excluded due to combined AR, 28 patients were followed. The allograft dysfunction, which defined as serum creatinine at last follow-up was above 2.0 mg/dL, was observed in 10 patients(35.7%) and 4 patients(14.3%) of them had graft failure and restarted hemodialysis. The serum crcatinine and creatinine clearance at renal biopsy were significantly correlated with allograft dysfunction, also interstitial fibrosis, tubular atrophy and vascular fibrous intima1 thickening showed similar correlation with prognosis. In conclusion, when allograft dysfunction was developed, IgAN in transplanted kidney should be considered and if the evidences of elevated serurn creatinine and decresed creatinine clearence at biopsy, severe interstitial fibrosis and tubular atrophy, severe vascular fibrous intimal thickening were present, more closer follow-up and careful treatment should be taken.

혈액투석 중인 말기 신부전증 환자에서 관상동맥혈관 석회화와 혈청 Osteoprotegerin 및 Fetuin-A 농도의 상관관계

김상욱 ( Sang Wook Kim ),정해혁 ( Hae Hyuk Jung ),한헌 ( Heon Han ) 대한내과학회 2007 대한내과학회지 Vol.72 No.5

목적: 투석을 받고 있는 말기 신부전증 환자에서 관상동맥혈관 석회화 점수(coronary artery calcification score, CACs)와 혈청 OPG 농도 및 혈청 fetuin-A 농도의 상관관계를 알아보았다. 방법: 51명의 말기 신부전증 환자를 대상으로 MSCT를 촬영하여 CACs를 구하였으며, 혈청 OPG 농도와 fetuin-A 농도를 측정하였다. 모든 환자에서 체중, 신장, 혈압을 측정하였으며 심혈관 질환 병력과 투석기간을 조사하였다. 환자의 혈액을 채취하여 hs-CRP, 혈청 인, 혈청 CaxP, 혈청 지질 농도를 측정하였다. 결과: 대상 환자에서 혈청 OPG 농도의 평균값은 3,561±1,160 pg/mL, fetuin-A 농도의 평균값은 28.5±4.1 mg/dL이었다. 대상군의 연령, 성별, 체질량지수 (BMI), 흡연력, 당뇨병 유무를 보정하였을 때, 투석기간(p=0.0225), hs-CRP (p=0.0392), 혈청 인(p=0.0341), Ca x P(p=0.0434), 혈청 OPG 농도(p=0.0026), LDL 콜레스테롤(p=0.0438)이 관상동맥혈관 석회화 점수와 유의한 양의 상관관계를 나타내었다. 다변량 회귀분석에서는 혈청 OPG 농도(p<0.0001)와 혈청 인 농도(p=0.0003)가 CACs에 유의한 독립변수로 나타났다. CACs에 따라 3군으로 분류하여 비교한 결과, 혈청 OPG 농도는 CACs가 400 이상인 중증인 군에서 최소 또는 경미한 군 또는 중등도의 군과 비교하여 유의하게 높게 나타났으며 혈청 fetuin-A 농도는 CACs가 400 이상인 군에서 최소 또는 경미한 군과 비교하여 유의하게 낮게 나타났다. 결론: 유지 혈액투석을 받고 있는 말기 신부전증 환자에서 관상동맥혈관 석회화는 무기 인 대사의 장애, 혈청 OPG 농도의 증가와 밀접한 상관관계가 있었으며 혈청 fetuin-A 농도는 특히 관상동맥혈관 석회화가 심한 경우 저하되어 있음을 알 수 있었다. Background: Coronary artery calcification is frequently seen in hemodialysis patients. The development and progression of coronary artery calcification is similar to osteogenesis, and a naturally occurring serum inhibitor of calcification may be involved. The aim of this study was to evaluate the relationship between coronary artery calcification, bone remodeling related factor, serum osteoprotegerin (OPG), calcification inhibitor and the serum fetuin-A levels in hemodialysis patients. Methods: A total of 51 hemodialysis patient were assessed for their coronary artery calcium (CAC) scores with using multirow spiral computed tomography and measuring the serum OPG level, the serum fetuin-A level, the biochemical markers of inflammation, the lipid profile and the mineral metabolism. Results: The mean serum OPG level was 3,561±1,160 pg/mL and the mean serum fetuin-A level was 28.5±4.1 mg/dL. The CAC scores were significantly correlated with the duration of dialysis (p=0.0225), hs-CRP (p=0.0392), serum phosphate (p=0.0341), Ca x P (p=0.0434), the serum OPG level (p=0.0026) and LDL-cholesterol (p=0.0438), after adjusting for age, gender, BMI, smoking history and the presence of diabetes. Multiple regression analysis showed that the CAC scores were significantly associated with the serum OPG level (p<0.0001) and the serum phosphate level (p=0.0003). The subgroup of the patients with a CAC score greater than 400 (the severe CAC group) had significantly higher OPG levels and lower fetuin-A levels than the groups of the patients with lower CAC scores. Conclusions: Our data suggest that the CAC scores in the patients undergoing hemodialysis were related with higher serum OPG and higher serum phosphate levels. The serum fetuin-A level was significantly lower in the patients with severe coronary artery calcification. (Korean J Med 72:451-458, 2007)

특발성 원섬유성 사구체신염 (Fibrillary Glomerulonephritis)

김지훈(Ji Hoon Kim),정해혁(Hae Hyuk Jung),박정식(Jung Sik Park),이상구(Sang Koo Lee),유은실(Eun Sil Yu),장상필(Sang Pil Chang),이준승(Joon Seung Lee),정재걸(Jae Gul Chung) 대한신장학회 2000 Kidney Research and Clinical Practice Vol.19 No.3

A 17-year-old girl was admitted to our hospital due to mild generalized edema. Laboratory tests revealed a serum creatinine was 0.7mg/dL, protein/ albumin 6.7/3.5g/dL, cholesterol 190mg/dL, hemoglobin 10.0g/dL, and 24 hour urinary protein 4,40mg/day. Chest X-ray and renal ultrasound were normal. There were no clinical or serologic evidences of para-proteinemia, cryoglobulinemia, light chain disease or systemic lupus erythematosus. Renal biopsy showed membranoproliferative glomerulonephritis-like pattern with lobular accentuation, hypercellularity and diffuse GBM thickening by light microscope. Congo red stain-ing was negative. Granular IgG and C3 deposits were found along the glomerular capillary wall and mesangium by immunofluorescence microscope. Ultrastruc-turally, abundant subendothelial and mesangial fibril- lary deposits were found associated with thickening and wrinkling of GBM. These fibrils, measured about 20-30nm in diameter, were nonbranching and ran- domly arranged without either periodicity or an organized structure. These findings were compatible with those of fibrillary glomerulonephritis. Thus we report a case of idiopathic fibrillary glomerulonephritis, which is a rare cause of nephrotic syndrome.

중환자에서 발견되는 저혈압을 동반한 원인 불명의 다뇨와 나트륨뇨

천광진 ( Kwang Jin Chun ),이동규 ( Dong Kyu Lee ),백현정 ( Hyun Jung Baek ),김상욱 ( Sang Wook Kim ),정해혁 ( Hae Hyuk Jung ) 대한신장학회 2009 Kidney Research and Clinical Practice Vol.28 No.6

Purpose: We observed excessive renal excretion of salt and water, without underlying renal diseases or definite causes, accompanied with severe hypotension in critically ill patients. This study investigates the clinical courses and characteristics of these patients. Methods: We retrospectively analyzed 13 patients with polyuria of unknown origin, which persited equal to or longer than 3 days, among hypotensive patients, who were admitted to intensive care unit. Results: The causes of hypotension included sepsis in 11 patients and adrenal insufficiceny in one patient. The cause of hyptension was unknown in one patient. Vassopressors were used in all patients, and hypotension persisted for 13.2±8.6 days. Polyuria persisted for 10.6±8.2 days, and the duration of polyuria was strongly correlated with that of hypotension (R=0.919, p<0.001). Low dose steroid was used in 8 patients for the treatment of hypotension, and hypotension improved in 3 patients within 2 days after steroid administration. Four patients died during the hosptialization, and the duration of hypotension in non-survivors was greater than that in survivors (21.2±9.7 days and 9.6±5.2 days respectively, p=0.020). Conclusion: In critically ill patients with severe hypotension, we observed 13 cases of inappropriate natriuresis and polyuria. These results suggest that the persistence of poyluria and hypotension might affect the prognosis of these patients, and adrenal insufficicieny might be associated with this appearance in some patients. Further studies are needed to establish causes and treatments for this appearance.

신질환 환자에서 Anti - Neutrophil Cytoplasmic Autoantibody 의 의의

김태원(Tae Won Kim),강재영(Jae Yeoung Kang),정해혁(Hae Hyuk Jung),양원석(Won Seok Yang),김순배(Soon Bae Kim),박수길(Su Kil Park),박정식(Jung Sik Park) 대한내과학회 1995 대한내과학회지 Vol.48 No.2

N/A Objectives: To clarify the spectrum of renal disease in patients with positive anti-neutrophil cytoplasmic autoantibody (ANCA); to compare the occurrence of crescent according to the type of ANCA; to assess the association between change of renal function and serial ANCA titers. Methods: Forty-five patients with biopsy proven renal disease underwent determination of ANCA by indirect immunofluorescent technique. Titers were repeated in 6 patients with median duration of 12 months (range, 3 to 28 months). Results: ANCA was detected in 17 of 45 patients. Six contained cytoplasmic and eleven had perinuclear pattern. One patient with pauci-immune crescenteric glomerulonephritis had both cytoplasmic and perinuclear pattern and showed perinuclear pattern only on the follow-up test. All four patients with pauci-immune crescenteric glomerulonephritis and all three patients with polyarteritis nodosa revealed positive results. The titers of ANCA were significantly higher in the group with pauci-immune crescenteric glomerulonephritis, polyarteritis nodosa, and lupus nephritis (type 4) than in the other group of patients. Twelve of 45 patients exhibited crescent formation. Crescent was more frequently detected in patients with ANCA positive group (53%) than in negative group (11%), but there was no difference between cytoplasmic and perinuclear pattern. All two patients with ANCA positive IgA nephropathy revealed crescent formation, but only one out of four patients of IgA nephropathy with negative ANCA did. All four patients with reduction in titer levels showed improved renal function. Out of 2 patients without change in titers, one revealed no change and the other showed aggravated renal function. Conclusions: ANCA is a useful diagnostic marker in pauci-immune crescenteric glomerulonephritis and polyarteritis nodosa and can be found in lupus nephritis, IgA nephropathy, tubulointerstitial nephritis, and focal segmental glomerulosclerosis.

말기신부전 환자에서 혈중 Adiponectin과 심혈관 질환

이희영 ( Hui Young Lee ),허애영 ( Ae Young Her ),최동욱 ( Dong Wook Choi ),박명옥 ( Myoung Ok Park ),백현정 ( Hyun Jeong Baek ),정해혁 ( Hae Hyuk Jung ) 대한내과학회 2006 대한내과학회지 Vol.71 No.6

목적: 지방조직에서 유래하는 adiponectin은 인슐린 감수성 및 항염증의 특성이 있고. 심혈관 질환의 발생억제와 연관되어 있는 것으로 알려지고 있다. 그러나 심부전이나 신장질환과 같은 만성소모성 질환이 있는 환자들에서는 그 연관이 뚜렷하지 않고 논란이 있다. 본 연구는 유지 혈액투석 중인 말기신부전 환자에서 adiponectin의 혈청 농도와 심혈관 질환 위험/예측인자들과의 관련성을 알아보고자 하였다. 방법: 유지 혈액투석 중인 48명의 성인 환자를 대상으로 adiponectin과 leptin의 혈청 농도를 측정하였다. 또한 심혈관생화학지표인 B-type natriuretic peptde (BNP), cardiac troponin T (cTnT) 등을 측정하고 심혈관 질환의 병력을 조사하여 지방세포 호르몬과의 관계를 알아보았다. 결과: Adiponectin의 혈청 농도는 HDL-cholesterol (r=0.456, p=0.001), triglyceride (r=-0.528, p<0.001) 및 leptin (r=-0.427, p=0.002)의 혈청 농도와 유의한 상관관계를 보였고, 체질량지수(r=-0.326, p=0.024)와 음의 상관관계를 보였다. 심혈관지표 중 BNP는 adiponectin (r=0372. p=0.009)과 양의 상관관계가 있었고, 체질량지수(r=-0.310, p=0.032)와 음의 상관관계가 있었으며, cTnT는 adiponectin (r=0.276, p=0.058)과 유의하지는 않으나 양의 상관성을 보였다. 과거 심혈관 질환의 병력이 있는 군(n=20)이 없는 군에 비해 체칠량지수 (p=0.026)는 더 낮고 BNP (p=0.017)와 cTnT (p=0.012)가 더 높았으나, adiponectin은 두 군 간에 유의한 차이를 보이지 않았다. 결론: 말기신부전 환자에서 고 adiponectin 혈증은 양호한 혈증 지질 농도와 관련이 있었으나, 심혈관 질환병력과 직접적인 관계가 없었고, 오히려 심혈관 질환의 위험인자였던 BNP의 증가 및 체질량지수의 감소와 연관이 있었다. 따라서 말기신부전 환자에서 adiponectin은 일반인과는 다르게 심혈관 질환 발생에 복잡한 역할을 할 것으로 생각되며 이에 대한 추가 연구가 필요할 것이다. Background: Adiponectin is a fat-based protein that alters the insulin sensitivity, has anti-inflammatory properties, and reduces the incidence of cardiovascular disease (CVD). However, this connection is unclear in patients with chronic wasting disease, such as heart failure or end-stage renal disease (ESRD). Therefore, this study examined the relationship between adiponectin and the cardiovascular risk/predictive factors in ESRD patients. Methods: The serum concentrations of adiponectin and leptin were measured in 48 adult patients on maintenance hemodialysis. In addition, the blood levels of B-type natriuretic peptide (BNP) and cardiac troponin T (cTnT) as cardiovascular biomarkers were measured, and the CVD history was reviewed in order to determine if there was any correlation with adiponectin. Results: There was a significant correlation between the adiponectin levels and the serum concentrations of HDL-cholesterol (r=0.456, p=0.001), triglyceride (r=-0.528, p<0.001), and leptin (r=-0.427, p=0.002) and an inverse correlation with the body mass index (BMI) (r=-0.326, p=0.024). The BNP levels were positively correlated with the adiponectin concentrations (r=-0.372, p=0.009) and negatively correlated with the BMI (r=-0.310, p=0.032), and there was a slight positive correlation between cTnT and adiponectin (r=0.276, p=0.058). Patients with a history of CVD had higher levels of cTnT (p=0.012) and BNP (p=0.017), and a lower BMI (p=0.026) than patients without such a history. There was no significant difference in the adiponectin levels between the two patient groups. Conclusions: A higher adiponectin level is related to a favorable lipid profile. However, adiponectin is not directly associated with a history of CVD, and there was a correlation between a higher adiponectin level and a higher BNP and lower BMI, which are cardiovascular predictive factors, in ESRD patients. However, further research with more patients will be needed to properly determine the complicated relationship between adiponectin and the development of CVD. (Korean J Med 71:646-653, 2006)

혈액투석을 받는 만성신부전 환자의 수면장애의 특성 및 임상변인과의 상관관계

김성재,정해혁,이정희 大韓神經精神醫學會 2005 신경정신의학 Vol.44 No.4

Objectives : Sleep disturbances are very common in hemodialysis (HD) patients with chronic renal failure (CRF). This study aimed to examine the characteristics of sleep disturbances, and to illustrate the relationship of sleep parameters with clinical Parameters reflecting metabolic dysfunction in HD patients with CRF. Methods : The Epworth Sleepiness Scale (ESS) and Sleep Disorders Questionnaire (SDQ) were administered in 26 HD Patients with CRF. For fifteen patients with the risk of sleep disorder, nocturnal polysomnographic study (NPSG) and blood Sampling were done. Results : Among 15 patients, 14 patients (93%) were diagnosed as sleep disorders, sleep breathing disorder or periodic limb movements in sleep. Uric acid (UA) was positively correlated with sleep efficiency (r=0.571), and negatively correlated with waking after sleep onset, the amount of stage 1 sleep, and respiratory disturbance index (r= -0.515, -0.564, -0.646). Interleukin-6 was positively correlated with obstructive apnea index (r=0.661). Conclusion : In our study, the difficulty in maintaining sleep was found in HD patients with CRF. It also showed that increased UA was associated with improved sleep maintenance and decreased breathing disturbance during sleep. This might be related with antioxidant effect of UA in CRF. Further studies on total CRF patients including those without the risk of sleep disorder are necessary.