Diabetic Nephropathy

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1 Diabetic Nephropathy Dong-Ryeol Ryu Department of Internal Medicine, School of Medicine, Ewha Womans University

2 Brief History (1) 여자 1980년출생 1992년 : 제1형당뇨병진단 2000년 : 당뇨병성망막증으로레이저치료 2005년 : 당뇨병성신병증유무검사위해전원

3 제 1 형당뇨병에의한신병증을진단하는데있어서가장 예민한검사항목은? 1) 신장초음파 2) 신장조직검사 3) 혈청크레아티닌 4) 크레아티닌청소율 5) 소변알부민 / 크레아티닌비

7 성인당뇨병환자에서신병증동반유무를 선별검사하는데사용되는검사항목은? ( 두가지 ) 1) 신장초음파 2) 혈청크레아티닌 3) 경구당부하검사 4) 크레아티닌청소율 5) 소변알부민 / 크레아티닌비

8 당뇨병성신병증진단을위한미세알부민뇨검사에대한 설명으로맞는것은? 1) 미세알부민뇨가음성이면매 3년마다검사한다. 2) 미세알부민뇨가처음양성인경우 2차례더재검한다. 3) 미세알부민뇨가한번이라도양성이면진단가능하다. 4) 제1형당뇨병환자에서는당뇨병진단직후부터검사한다. 5) 제2형당뇨병환자에서는당뇨병진단 5년째부터검사한다.

9 Diagnosis of Diabetic Nephropathy (DN): Historical Definition A clinical syndrome characterized by Persistent albuminuria (> 300 mg/24 hr) A relentless decline in GFR Raised arterial BP Enhanced cardiovascular morbidity and mortality

10 Diabetic Kidney Disease (DKD): K/DOQI An elevated ACR should be confirmed in the absence of UTI with two additional 1 st void specimen collected during the next 3 to 6 months Persistent albuminuria 24HU > 300 mg/24hrs Timed urine > 200 μg/min Spot urine albumin-creatinine ratio > 300 mg/g Microalbuminuria with Presence of diabetic retinopathy Diabetes of at least 10 years duration in type I DM Absence of clinical and laboratory evidences of other kidney of renal tract diseases K/DOQI CPG and CPR for Diabetes in CKD, 2006

11 Natural History Designation Characteristics GFR (ml/min) Albumin Excretion Blood Pressure Stage 1 Hyperfunction and hypertrophy Glomerular hyperfiltration Increased in type 1 and type 2 May be increased Type 1 normal Type 2 normalhypertension Thickened BM Type 1 normal Type 1 normal Stage 2 Silent stage Expanded mesangium Normal Type 2 may be < mg/24hr Type 2 normalhypertension Stage 3 Incipient diabetes Microalbuminuria GFR begins to fall mg/24hr Type 1 increased Type 2 normalhypertension Stage 4 Overt diabetic nephropathy Macroalbuminuria GFR below normal > 300 mg/24hr Hypertension Stage 5 Uremia ESRD 0-10 Decreasing Hypertension

Prevalence / Incidence Prevalence of Microalbuminuria (%) Prevalence of Macroalbuminuria (%) Incidence of Macroalbuminuria (%/yr) Cumulative incidence of Macroalbuminuria (%/25yr) Clinic based

12 Prevalence / Incidence Prevalence of Microalbuminuria (%) Prevalence of Macroalbuminuria (%) Incidence of Macroalbuminuria (%/yr) Cumulative incidence of Macroalbuminuria (%/25yr) Clinic based Population based Type I Type II Type II 13 (9~20) 25 (13~27) 20 (17~21) 15 (8~22) 14 (5~48) 16 (9~46) 1.2 (0~3) 1.5 (1~2) - 31 (28~34) 28 (25~31) - The overall prevalence of microalbuminuria and macroalbuminuria is around 30% to 35% in both types of diabetes. The range in prevalence of DN is much wider in type 2 diabetic patients. Inability to define the onset of disease in type 2 diabetes Ethnic differences are also a major influence. Brenner and Rector s The Kidney, 9 th Edition

13 Screening of DN - Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of 5 years and in all type 2 diabetic patients starting at diagnosis. - Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of chronic kidney disease (CKD), if present. Standards of Medical Care in Diabetes Studies have found decreased GFR in the absence of increased UAE in a substantial percentage of adults (13%) with diabetes. Kramer HJ, et al. JAMA 2003

14 Screening for DN - Annually Test for microalbuminuria (spot or timed collection) + Exclude conditions that transiently increase albumin excretion - U/A for protein + Exclude conditions that transiently increase albumin excretion Quantitate 24-h urine protein Repeat microalbuminuria test within 3~6 month period Overt nephropathy No 2/3 microalbuminuria tests (+) (Incipient nephropathy) Yes Begin Treatment

15 Screening for DN - Annually Test for microalbuminuria (spot or timed collection) + Exclude conditions that transiently increase albumin excretion - U/A for protein + Exclude conditions that transiently increase albumin excretion Quantitate 24-h urine protein Repeat microalbuminuria test within 3~6 month period Overt nephropathy No 2/3 microalbuminuria tests (+) (Incipient nephropathy) Yes Begin Treatment

16 Natural History of Type 1 DN Time from onset of Diabetes, years Microalbuminuria Gross proteinuria GFR, ml/min <10 Serum creatinine >2.0 >5.0 mg/dl Incipient nephropathy Overt nephropathy

17 Natural History of Type 2 DN Clinical type 2 diabetes Functional changes Structural changes Rising blood pressure Microalbuminuria Proteinuria Rising serum creatinine levels ESRD Cardiovascular death Onset of diabetes Years

18 15 년전제 1 형당뇨병을진단받은환자의검사소견이아래와같다. ( 증례와무관 ) 소변검사 : 단백 (3+), 잠혈 (-) 24 시간소변단백 4.8 g/ 일, 신장초음파 : 신장크기감소안저소견 : 망막삼출, 신생혈관 당뇨병성신병증으로진단을내리고자할때, 가장도움이되지않는소견은무엇인가? 1) 소변검사 2) 안저소견 3) 당뇨병유병기간 4) 24시간소변단백 5) 신장초음파소견

21 Clues To Non-Diabetic Renal Disease The onset of proteinuria < 5 years from the onset of type 1 DM The acute onset of renal disease The presence of an active urine sediment containing RBCs (particularly acanthocytes) and cellular casts In type 1 DM, the absence of diabetic retinopathy or neuropathy Signs and/or symptoms of another systemic disease Significant reduction in the GFR (>30%) within two to three months of the administration of RAS blockades

22 The Diabetes Control and Complications Trial (DCCT) 을 통하여증명된만성고혈당에대한철저한조절의효과는? 1) 제1형당뇨병의미세혈관합병증 (microvascular complication) 을개선한다. 2) 제1형당뇨병의대혈관합병증 (macrovascular complication) 을개선한다. 3) 제2형당뇨병의미세혈관합병증을개선한다. 4) 제2형당뇨병의대혈관합병증을개선한다. 5) 제2형당뇨병의미세혈관및대혈관합병증을개선한다.

23 GFR (ml/min) Albuminuria (mg/day) Natural History & Prevention Strategy of DN Pre Incipient DN Overt DN Years

24 GFR (ml/min) Albuminuria (mg/day) Natural History & Prevention Strategy of DN Pre Incipient DN Overt DN Tight Glycemic Control Tight BP Control ACE inhibitors ARBs Protein Restriction ( g/kg/day) Years

25 Glycemic Control (I) In type 1 DM, the level of glucose control seems to be the strongest modifiable risk factor. DCCT: Diabetes Control and Complications Trial (Kidney Int., 1995) Reduced incidence of microalbuminuria ( 40 mg/day) by 39% Reduced occurrence of albuminuria ( 300 mg/day) by 54% Beneficial effect of intensified treatment does not occur for at least 3 years 16% in the primary prevention cohort and 26% in the secondary prevention cohort developed microalbuminuria during the 9 years of intensive treatment EDIC: Epidemiology of Diabetes Interventions and Complications (JAMA, 2003) At 8 yrs of EDIC study, a long term study of DCCT, lesser new microalbuminuria (7 vs. 16%), lesser new proteinuria (1.4 vs. 9%), and lower hypertension (30 vs. 40%) in the intensive group. Metabolic memory

26 Glycemic Control (II) Type 2 DM UKPDS: UK Prospective Diabetes Study (Lancet, 1998) Type 2 diabetes Intensive glycemic control in a total of 3,867 patients HbA1c levels 7.0% vs. 7.9% Over 10 years follow-up Significant reduction in the development of microalbuminuria by 33%

27 Brief History (2) 2005 년 : 혈압 110/70 mmhg 이었고, 검사결과는다음과같았다. 혈청크레아티닌 : 0.5 mg/dl, HbA1C: 18.0% 소변검사 : 단백 3+, 24 시간소변단백 11.3 g 보다적극적으로혈당조절하도록하고, ACE 억제제투여를시작하였다 년 : 혈압 130/80 mmhg 이었고, 검사결과는다음과같았다. 혈청크레아티닌 : 1.0 mg/dl (egfr 71.2 ml/min/1.73 m 2 ), HbA1C: 8.2% 소변검사 : 단백 2+, 24 시간소변단백 3.3 g 적극적으로혈당 / 혈압조절이될수있도록교육및약물조정하였다. 몸이붓기시작하여이뇨제투여를시작하였다.

28 ( 증례와무관 ) 혈압 148/82 mmhg, 혈청크레아티닌 2.1 mg/dl인상태에서, ACE 억제제를투여한지 1주일후시행한혈청크레아티닌이 2.4 mg/dl로상승하였다. 혈압 128/74 mmhg, 혈청칼륨 4.9 meq/l이었고기타특이사항은없었다. 향후치료에대한설명중가장적절한것은? 1) ACE 억제제를감량한다. 2) 현재의치료를지속한다. 3) 안지오텐신수용체차단제로대치투여한다. 4) 신동맥협착치료를위한조영술을시행한다. 5) ACE 억제제를중단하고, 칼슘통로차단제로변경한다.

Components of the Normal Nephron Bowman s Capsule Proximal Convoluted Tubule Adventitial Mast Cell/Macrophage Glomerulus Mesangial Matrix

29 Components of the Normal Nephron Bowman s Capsule Proximal Convoluted Tubule Adventitial Mast Cell/Macrophage Glomerulus Mesangial Matrix Mesangial Cells Vascular Smooth Muscle Cells Renal Sympathetic Nerves Macula Densa Juxtaglomerular Distal Cells Convoluted Tubule Efferent Renal Arteriole

30 Potential Complications of RAS Blockade Initial fall in GFR Due to the associated reduction in glomerular capillary pressure Typically occurs early during dose titration Causes of late acute increases in serum creatinine: diuretics, some other renal insult (such as NSAIDs) An elevation in serum creatinine of as much as 30 to 35% above baseline that stabilizes within the first two to four months of therapy is considered acceptable and not a reason to discontinue therapy with these drugs (Bakris GL, et al. 2000; Chovanian AV, et al. 2003). Patients with a limited early acute increase in serum creatinine after initiation of ACE inhibitors were more likely to have long-term preservation of kidney function (Bakris GL, et al. 2000). Hyperkalemia Due to removal of the angiotensin II-mediated stimulus to the release of aldosterone Because of the decline in renal function and a rise in plasma potassium that typically occur soon after the onset of therapy, a plasma creatinine and potassium should be measured within three to five days.

31 Brief History (3) 2009년 : 이뇨제증량에도불구하고소변량이감소하고전신부종이점점심해졌으며, 호흡곤란이발생하였다. 혈압 170/100 mmhg이었고, 검사결과는다음과같았다. 헤모글로빈 6.8 g/dl 혈청크레아티닌 : 8.5 mg/dl 혈청전해질 : 나트륨 140, 칼륨 5.3, 염소 115, 총이산화탄소 : 5 meq/l 동맥혈검사 : ph 7.244, 이산화탄소분압 30.3 mmhg, 산소분압 50.4 mmhg 소변검사 : 단백 3+

33 현재상태에서치료계획으로가장좋은것은? 1) 신장이식 2) 복막투석 3) 혈액투석 4) 이뇨제증량 5) 혈압강하제투여

35 현재상태에서치료계획으로가장좋은것은? 1) 신장이식 2) 복막투석 3) 혈액투석 4) 이뇨제증량 5) 혈압강하제투여

36 Benefits of Transplantation in DN Kidney transplantation is the preferred RRT for diabetic patients with ESRD, since it generally results in better survival and quality of life than dialysis. Preemptive kidney transplantation rather than initiation of dialysis followed by transplantation is preferred, and if possible, a living donor kidney is preferred to a deceased donor kidney. Combined pancreas-kidney transplantation offers the promise of normoglycemia and freedom from dialysis. Nephrology consultation should be considered when the estimated GFR < 60 ml/min/1.73 m 2. Once macroalbuminuria ensues, the likelihood of ESRD is very high.

37 Survival Benefit of KT At 18 months post-transplantation, the subset of 7,200 diabetic transplant recipients had a 73% reduced risk of death compared with the approximately 15,000 diabetic wait-listed patients (relative risk 0.27, 95% CI, ). The projected increase in life was 11 years among diabetic patients who undergo transplantation compared with diabetics who remain on the waiting list. Wolfe RA, et al. NEJM 1999

38 47 세인환자의오빠가신장기증의사를밝혔다. 혈압 116/74 mmhg, 체질량지수 28 kg/m 2 이었다. 외래에서검사한결과는다음과같았다. 공복혈당 : 108 mg/dl (1 차 ), 105 mg/dl (2 차 ) 추정사구체여과율 (egfr) 88 ml/min/1.73 m 2 소변검사 : 단백 (-), 잠혈 (-); 소변알부민 / 크레아티닌비 3 mg/g 저밀도콜레스테롤 118 mg/dl, 중성지방 80 mg/dl 상기잠재공여자는어떠한상태인가? 1) 당뇨병이다. 2) 당뇨전단계이다. 3) 경구당부하검사가필요하다. 4) 이식을위한검사결과는정상이다. 5) 당뇨병유무를확인하기위하여 HbA1C 검사가필요하다.

39 The Revised Guideline 2012 (1) Standards of Medical Care in Diabetes

40 The Revised Guideline 2012 (2) Standards of Medical Care in Diabetes

41 잠재공여자에게설명할사항으로맞는것은? 1) 공복혈당이 mg/dl 사이인경우공복혈당장애 (impaired fasting glucose) 로진단가능하다. 2) 공복혈당장애가있으므로, 향후당뇨병발생위험성이있다. 3) 현재정상이므로향후 3년마다당뇨병에대한추적검사가필요하다. 4) 공복혈당장애여부를확인하기위하여 HbA1C 추가검사가필요하다. 5) 공복혈당장애는심혈관질환발병에영향을미치지않으나, 과체중은 영향을미칠수있다.

42 Significances of Prediabetes Individuals with IFG and/or IGT have been referred to as having prediabetes, indicating the relatively high risk for the future development of diabetes. IFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease (CVD). IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. Standards of Medical Care in Diabetes

43 외래에서추가검사한결과는다음과같았다. 공복혈당 : 105 ( 재검 ) mg/dl, HbA1C 5.8% 경구당부하검사 2 시간혈당 128 mg/dl 신장공여는가능한가? 1) 예 2) 아니오

44 Are Donors with IFG or Diabetes More Susceptible to DN? Kidney damage may be accelerated in patients with IFG or diabetes who have single kidneys. Renal disease progresses after nephrectomy in animal studies (Lopes GS, et al. 2004; O Donnell MP, et al. 1986) Higher rates of the development of CKD in patients with IFG and IGT in the Framingham Heart Study (Fox CS, et al. 2005) Nephrectomy might increase the risk for albuminuria and accelerate DN in patients with type 2 DM (Silveiro SP, et al. 1998) However, there have been some data against this theory. No difference in the development of kidney damage between one kidney in transplanted patients and two kidneys in matched patients with type 1 DM (Chang S, et al. 2008). None of donors with well-controlled DM and IGT (N=71) developed ESRD during the 88 months of follow-up (Okamoto M, et al. 2010). The other study showed a greater frequency of hypertension and proteinuria in donors (predominantly white) who developed type 2 diabetes compared with those who did not, but egfr was similar in both groups (Ibrahim HN, et al. 2010).

45 Are Donors with IFG or Diabetes More Susceptible to CVD? Patients with diabetes and prediabetes are at an increased risk for CVD. Furthermore, there is a widely known relationship between a decline in egfr and increasing risk for CVD in patients with CKD. However, It is not known whether donors with a reduced GFR as a result of donor nephrectomy carry the same risk. Only one study from Canada has addressed this question directly, and no increase in mortality or CVD in donors with diabetes was observed. In that study, however, mean follow-up was only 6 years, and 92% of donors among a total of 1,278 living donors were white. Garg AX, et al. 2008

46 Contraindications To Donation Absolute Contraindications Age < 18 yr Mentally incapable of making informed decision Uncontrolled HT or HT with end organ damage DM BMI > 35 Active malignancy or incompletely treated malignancy Untreated psychiatric conditions Nephrolithiasis with high likelihood of recurrence Evidence of donor coercion Persistent infection Relative Contraindications Age yr CCr < 2 SD below mean for age HT in non-caucasian race HT in young donor Prediabetes in young donor BMI > 30 Microalbuminuria or proteinuria Bleeding disorder History of thrombosis or embolism Nephrolithiasis History of malignancy, especially if metastatic Significant CVD Kher A, et al. CJASN 2012

47 Making Patients with IFG into More Suitable Donors Lifestyle modifications can have a significant effect on altering the predicted risks for CVD and diabetes. Horton ES, et al Knowler WC, et al Wing RR, et al For our candidate, with light exercise, smoking cessation for 1 year, and diet to achieve a weight reduction as well as an alteration in his lipid profile, his risk for diabetes and MI could be reduced. As part of the informed consent process, we presented these data to him. Acknowledging these risks and uncertainties, he elected to proceed with the donation.

48 Brief History (4) 2010 년 : 오빠로부터공여받은신장으로이식수술을시행하였다. 퇴원후외래에서측정한혈압 110/80 mmhg 이었고, 검사결과는다음과 같았다. 헤모글로빈 9.6 g/dl 혈청크레아티닌 : 0.9 mg/dl, HbA1C 8.6% 소변검사 : 단백 (±)

49 Brief History (5) 2010 년 : 이식 4 개월후심한탈모발생하여 Tacrolimus 를 CsA 로교체하였다 년 : 외래에서측정한혈압 104/60 mmhg 이었고, 검사결과는다음과 같았다. 헤모글로빈 12.0 g/dl 혈청크레아티닌 : 1.1 mg/dl, HbA1C 12.1% 소변검사 : 단백 (-) 2012 년 : 현재복용중인약제는다음과같다. Cyclosporine 100 mg q 12 h MMF 750 mg q 12 h Deflazacort 6 mg D

한국성인에서초기황반변성질환과 연관된위험요인연구

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