원발성 신증후군과 당뇨병성 신증후군 사이의 고지혈증 양상의 비교

Abstract

[한글]

신증후군 환자에서 고지혈증(hyperlipidemia) 및 고지단백혈증(hyperlipoproteinemia)은 흔히 동반되는 소견이다. 신증후군과 동반되는 고지혈증은 특징적으로 혈청 total cholesterol이 증가하고, 심한 단백뇨를 가지는 환자에 있어서 혈청 triglyceride의 증가를 동반할 수 있다 또한 apo-B를 지닌 지단백인 very low density lipoprotein(VLDL), intermediate density lipoprotein(IDL), low density lipoprotein(LDL)이 증가하는 반면 high density lipoprotein(HDL)은 정상이거나 증가 혹은 감소될 수 있는 것으로 알려져 있다. 지단백의 구성 자체에도 변화가 있어 지단백내의 cholesterol ester나 triglyceride의 양이 정상에 비하여 증가되어 있으며 구성하는 apoprotein의 아형이나 양에도 변화가 있는 것으로 알려져 있다.

신증후군에서 발생하는 고지혈증 및 고지단백혈증의 발생 기전에 대하여 많은 연구가 있었음에도 불구하고 아직까지 정확한 기전이 규명되어 있지 않다. 초기 연구자들은 원발성 사구체 신염에 의한 신증후군에서 고지혈증 및 고지단백혈증이 발생하는 주요 원인으

로 간에서의 apo-B 지단백의 생성 증가를 제시하였으나 이후의 많은 임상 연구와 동물 실험 결과 지단백의 생성 증가 뿐 아니라 혈중 제거율의 감소 또한 중요한 기전인 것으로 제시되었다. 당뇨병성 신증후군에서도 원발성 사구체 신염과 같은 유형, 같은 기전의 고

지혈증 및 고지단백혈증이 동반되는지에 관한 연구는 국내외적으로 매우 드문 실정으로 이를 알아보기 위하여 본 연구를 진행하였다.

본 연구는 1990년 1월부터 1995년 2월까지 연세대학교 의과대학 부속 세브란스 병원에 내원하여 신증후군으로 진단된 원발성 사구체 신염 환자와 인슐린비의존형 당뇨병성 신증후군 환자를 대상으로 후향적 연구에 의해 혈청 total cholesterol과 triglyceride, HDL-cholesterol을 조사하여 지질 분포의 유형을 비교하고, 아울러 혈청 total cholesterol의 증가량과 24시간 단백뇨, 혈청 알부민 및 혈청 알부민 감소량과의 상관관계를 분석하였다.

1. 총 대상 환자는 89예로 미세 변화형(minimal change disease, MCD)군이 45예, 비미세 변화형(non-MCD)군이 25예였으며 당뇨병성 신증후군이 18예였다. 각 군의 남녀비는 각각 30:15, 14:12, 7:11이었으며 평균 연령은 당뇨병성 신증후군에서 가장 높았다. Non-MCD군은 국소성 분절성 사구체 경화증(focal segmental glomerulosclerosis)이 5예, 막성 신증(membranous g1merulonephropathy)이 14예, 막 증식성 사구체 신염 (membranoproliferative g1omerulonephritis)이 4예, IgA 신증(IgA nephropathy)이 3예였다.

2. MCD, non-MCD, 당뇨병성 신증후군 모두에서 혈청 total cholesterol과 trig1yceride치가 증가되고 HDL-cholesterol치는 정상으로 지질 분포의 유형은 각 군 사이에 차이가 없었다.

3. 혈청 total cholesterol치는 MCD군에서 489.7±128.2 mg/dl, non-MCD군에서 410.3±158.2 mg/dl, 당뇨병성 신증후군에서 308.7±55.1 mg/dl로 MCD, non-MCD 환자에서 당뇨병성 신증후군 환자에 비해 의의있게 높았다(p＜0.05).

4. MCD, non-MCO군에서는 혈청 total cholesterol 증가량이 뇨단백 소실량과 유의하게 정상관관계가 있었으나(p＜O.05), 당뇨병성 신증후군에서는 이와 같은 정상관관계를 관찰할 수 없었고, 뇨단백 소실량에 대한 total cholesterol의 증가량도 MCD, non-MCD군에 비

해 의의있게 낮았다(p＜0.05).

5. 혈청 trilglyceride의 증가량은 MCD, non-MCD, 당뇨병성 신중후군 사이에 의의있는 차이가 없었다.

이상의 결과에서, 당뇨병성 신증후군에서는 원발성 사구체 신염에 의한 신증후군과 서로 다른 고지혈증 양상을 관찰할 수 있었다. 뇨단백 소실량에 대한 혈청 total cholesterol의 증가량이 당뇨병성 신증후군에서 원발성 사구체 신염보다 낮게 나타난 것은 간에서의 cholesterol의 생성 자체가 원발성 사구체 신염에 비하여 당뇨병성 신증후군에서 적을 가능성과 cholesterol의 생성 정도는 같으나 원발성 사구체 신염에서 apo-B 지단백의 혈중 제거율이 더욱 감소되어 있을 가능성, 그리고 이러한 두가지 기전의 복합적인 작용의 가능성을 생각할 수 있다. 향후 이러한 기전을 규명하기 위한 전향적 연구가 필요할 것으로 사료된다.

Comparison of the patterns of hyperlipidemia between athic nephrotic syndrome and

diabetic nephrotic syndrome

Hyun Jin Noh

Department of Medicine The Graduate School, Yonsei University

(Directed by Professor Ho Yung Lee)

Hyperlipidemia and hyperlipoproteinemia are major feature of the nerhrotic

syndrome. An increased risk for premature coronary atherosclerosis has been

nssociated strongly with elevated levels of total and low density

lipoprotein(LDL)-cholesterol, depressed high density lipoprotein(HDL) -cholesterol,

and high total to HDL-cholesterol ratio. These lipid and lipoprotein abnormalities

commonly occurin ratients with nephrotic syndrome. The most common finding is an

elevation of LDL-cholesterol levels. In more severe cases with heavy proteinuria,

hyperlriglyceridemia and elevated very low density lipoprotein (VLDL)-cholesterol

levels may become the dominant abnormalities. HDL-cholesterol levels have been

variously recorded as high, low or normal.

The mechanism for its occurrence is comp1ex and still controversial. For many

year it has been postulated that the primary mechanism for hyperlipidemia in the

nephrotic syndrome is a hepatic oveproduction and secretion of apo-B containing

lipoproteins. Also it has been proposed that hypoalbuminemia induces the

oversynthesis of lipoproteins. More recently, however, reduced catabolism of ape-B

containing lipoproteins was suggested as an important mechanism for hyperlipidemia

and hyperlipopoteinemia. Thus, two mechanisms might contribute to nephrotic

dyslipidemia: an overproduction of apo-B containing lipoproteins and an impaired

catabolism of these lipoproteins.

Few studies were performed to determine whether nephrotic syndrome due to

systemic disease such as DM(diabetes mellitus) and primary glomerulonehritis (GN)

have similar or dissimilar patterns of dyslipidemia. I retrospectively reviewed the

clinical records of patients with the nephrotic syndrome in Yonsei Medical Center

from January 1, 1991 to Feburary 28, 1995. Serum tota1 cholesterol, triglyceride

and HDL-cholesterol levels were assessed and the correlations among the increment

of serum total cholesterol, 24 hour proteinuria, serum albumin and the decrement of

serum albumin were analyzed.

1. Among 89 patients, 71 patients were primary GN and 18 patients were DM

nephropathy. Of primary GN, 45 patients were minimal change disease(MCD) and 26

patients were non-MCD. In nun-MCD group, there were 5 focal segmental

glomerulosclerosis (FSGS ), 14 membranous glomeu]onephropathy (MGN), 4

membranoproliferative glomerulonephritis (MPGN) and 3 IgA nephropathy patients.

Mean age was oldest in DM nephropathy group.

2. In MCO. non-MCD and DM nephropathy groups, serum total chulesterol and

triglyceride levels were increased and HDL-cholesterol levels were normal.

3. The serum total cholesterol levels were significantly higher in MCD and

non-MCD groups than DM nephropathy group(489.7± 128.2, 410.3±l58.2, 308.7±55.1

mg/dl in MCD, non-MCD and DM nephropathy, respectively) (p＜0.05).

4. There was a significant direct correlation between the increment of serum

total cholesterol and the decrement of serum albumin in MCD and non-MCD groups, but

not in DM nephropathy group. And the increment of serum total cholesterol to the

decrement of serum albumin ratio was significantly lower in DM nephropathy group

than that in MCD and non-MCD groups.

5. The serum triglyceride levels were increased in MCD, non-MCD and DM

nephropathy groups, and there were no significant differences among the groups.

6. In MCD, non-MCD and DM nephropathy groups, the amount of 24 hour urine protein

and serum triglyceride levels were not different, so it was postulated that the

amount of urinary losses of liporegulatory macrmolecules such as apo-C Ⅱ and

heparan sulfate, known as lipoprotein lipase cofactors, were similar in three

groups.

These results suggest that relatively milder hypercholesterolemia in DM

nephropathy group might be due to different mechanisms for dyslipidemia in DM

nephropathy group from primary GN group. First, hepatic overproduction of

cholesterol might be relatively mild in DM nephropathy group. Second, despite of

similar degree of hepatic overproduction in two gruops, the removal of apo-B

containing lipoproteins might be more impaired in primary GN group. And the

combination of these two mechanisms might be another mechanism. Further studies

will be necessary to clarify the different mechanisms by measuring the amount of

urinary loss of macromolecules, the activities of 3-hydroxy -3- methylglutaryl-

CoA-reductase(HMG-CoA-reductase), tumover rates of LDL-apo B, fractional catabolic

rates of LDL-apo B and LDL input rates.

[영문]

Hyperlipidemia and hyperlipoproteinemia are major feature of the nerhrotic syndrome. An increased risk for premature coronary atherosclerosis has been nssociated strongly with elevated levels of total and low density lipoprotein(LDL)-cholesterol, depressed high density lipoprotein(HDL) -cholesterol, and high total to HDL-cholesterol ratio. These lipid and lipoprotein abnormalities

commonly occurin ratients with nephrotic syndrome. The most common finding is an elevation of LDL-cholesterol levels. In more severe cases with heavy proteinuria, hyperlriglyceridemia and elevated very low density lipoprotein (VLDL)-cholesterol

levels may become the dominant abnormalities. HDL-cholesterol levels have been variously recorded as high, low or normal.

The mechanism for its occurrence is comp1ex and still controversial. For many year it has been postulated that the primary mechanism for hyperlipidemia in the nephrotic syndrome is a hepatic oveproduction and secretion of apo-B containing

lipoproteins. Also it has been proposed that hypoalbuminemia induces the oversynthesis of lipoproteins. More recently, however, reduced catabolism of ape-B containing lipoproteins was suggested as an important mechanism for hyperlipidemia and hyperlipopoteinemia. Thus, two mechanisms might contribute to nephrotic dyslipidemia: an overproduction of apo-B containing lipoproteins and an impaired catabolism of these lipoproteins.

Few studies were performed to determine whether nephrotic syndrome due to systemic disease such as DM(diabetes mellitus) and primary glomerulonehritis (GN) have similar or dissimilar patterns of dyslipidemia. I retrospectively reviewed the

clinical records of patients with the nephrotic syndrome in Yonsei Medical Center from January 1, 1991 to Feburary 28, 1995. Serum tota1 cholesterol, triglyceride and HDL-cholesterol levels were assessed and the correlations among the increment of serum total cholesterol, 24 hour proteinuria, serum albumin and the decrement of serum albumin were analyzed.

1. Among 89 patients, 71 patients were primary GN and 18 patients were DM nephropathy. Of primary GN, 45 patients were minimal change disease(MCD) and 26 patients were non-MCD. In nun-MCD group, there were 5 focal segmental glomerulosclerosis (FSGS ), 14 membranous glomeu]onephropathy (MGN), 4 membranoproliferative glomerulonephritis (MPGN) and 3 IgA nephropathy patients. Mean age was oldest in DM nephropathy group.

2. In MCO. non-MCD and DM nephropathy groups, serum total chulesterol and triglyceride levels were increased and HDL-cholesterol levels were normal.

3. The serum total cholesterol levels were significantly higher in MCD and non-MCD groups than DM nephropathy group(489.7± 128.2, 410.3±l58.2, 308.7±55.1 mg/dl in MCD, non-MCD and DM nephropathy, respectively) (p＜0.05).

4. There was a significant direct correlation between the increment of serum total cholesterol and the decrement of serum albumin in MCD and non-MCD groups, but not in DM nephropathy group. And the increment of serum total cholesterol to the

decrement of serum albumin ratio was significantly lower in DM nephropathy group than that in MCD and non-MCD groups.

5. The serum triglyceride levels were increased in MCD, non-MCD and DM nephropathy groups, and there were no significant differences among the groups.

6. In MCD, non-MCD and DM nephropathy groups, the amount of 24 hour urine protein and serum triglyceride levels were not different, so it was postulated that the amount of urinary losses of liporegulatory macrmolecules such as apo-C Ⅱ and heparan sulfate, known as lipoprotein lipase cofactors, were similar in three groups.

These results suggest that relatively milder hypercholesterolemia in DM nephropathy group might be due to different mechanisms for dyslipidemia in DM nephropathy group from primary GN group. First, hepatic overproduction of cholesterol might be relatively mild in DM nephropathy group. Second, despite of similar degree of hepatic overproduction in two gruops, the removal of apo-B containing lipoproteins might be more impaired in primary GN group. And the combination of these two mechanisms might be another mechanism. Further studies

will be necessary to clarify the different mechanisms by measuring the amount of urinary loss of macromolecules, the activities of 3-hydroxy -3- methylglutaryl- CoA-reductase(HMG-CoA-reductase), tumover rates of LDL-apo B, fractional catabolic

rates of LDL-apo B and LDL input rates.