Diabetic Nephropathy

Diabetic Nephropathy

Dong-Ryeol Ryu

Department of Internal Medicine,

School of Medicine, Ewha Womans University

Brief History (1)

• 여자

• 1980년 출생

• 1992년: 제1형 당뇨병 진단

• 2000년: 당뇨병성 망막증으로 레이저 치료

• 2005년: 당뇨병성 신병증 유무 검사 위해 전원

• 제1형 당뇨병에 의한 신병증을 진단하는데 있어서 가장 예민한 검사 항목은?

1) 신장 초음파 2) 신장조직검사 3) 혈청 크레아티닌 4) 크레아티닌 청소율

5) 소변 알부민/크레아티닌 비

• 성인 당뇨병 환자에서 신병증 동반 유무를

선별검사하는데 사용되는 검사 항목은? (두가지)

1) 신장 초음파

2) 혈청 크레아티닌 3) 경구 당부하검사 4) 크레아티닌 청소율

5) 소변 알부민/크레아티닌 비

• 당뇨병성 신병증 진단을 위한 미세알부민뇨 검사에 대한 설명으로 맞는 것은?

1) 미세알부민뇨가 음성이면 매 3년마다 검사한다.

2) 미세알부민뇨가 처음 양성인 경우 2차례 더 재검한다.

3) 미세알부민뇨가 한 번이라도 양성이면 진단 가능하다.

4) 제1형 당뇨병 환자에서는 당뇨병 진단 직후부터 검사한다.

5) 제2형 당뇨병 환자에서는 당뇨병 진단 5년째부터 검사한다.

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

Diabetic Kidney Disease (DKD): K/DOQI

 An elevated ACR should be confirmed in the absence of UTI with two additional 1

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

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 normal-

hypertension Stage 2 ‘Silent’ stage

Thickened BM Expanded mesangium

Normal

Type 1 normal Type 2 may be

<30-300 mg/24hr

Type 1 normal Type 2 normal-

hypertension

Stage 3 Incipient diabetes

Micro- albuminuria

GFR begins

to fall 30-300 mg/24hr

Type 1 increased Type 2 normal-

hypertension Stage 4 Overt diabetic

nephropathy

Macro- albuminuria

GFR

below normal > 300 mg/24hr Hypertension

Stage 5 Uremia ESRD 0-10 Decreasing Hypertension

Natural History

Prevalence / Incidence

Clinic based Population based

Type I Type II Type II

Prevalence of

Microalbuminuria (%) 13 (9~20) 25 (13~27) 20 (17~21) Prevalence of

Macroalbuminuria (%) 15 (8~22) 14 (5~48) 16 (9~46) Incidence of

Macroalbuminuria (%/yr) 1.2 (0~3) 1.5 (1~2) - Cumulative incidence of

Macroalbuminuria (%/25yr) 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

Edition

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.

- Studies have found decreased GFR in the absence of increased UAE in a substantial percentage of adults (13%) with diabetes.

Standards of Medical Care in Diabetes - 2012

Kramer HJ, et al. JAMA 2003

Screening for DN

U/A for protein

Test for microalbuminuria (spot or timed collection)

Exclude conditions that transiently increase albumin

excretion

Repeat microalbuminuria test within 3~6 month period

2/3 microalbuminuria tests (+) (Incipient nephropathy)

Exclude conditions that transiently increase albumin excretion

Quantitate 24-h urine protein

Overt nephropathy

Begin Treatment

- +

+

No Yes

-

Annually

Screening for DN

U/A for protein

Test for microalbuminuria (spot or timed collection)

Exclude conditions that transiently increase albumin

excretion

Repeat microalbuminuria test within 3~6 month period

2/3 microalbuminuria tests (+) (Incipient nephropathy)

Exclude conditions that transiently increase albumin excretion

Quantitate 24-h urine protein

Overt nephropathy

Begin Treatment

- +

+

No Yes

-

Annually

-3 0 3 5 10 15 20 25

Microalbuminuria

GFR, mL/min

Incipient nephropathy

Overt nephropathy

Time from onset of Diabetes, years

Gross proteinuria

Natural History of Type 1 DN

Natural History of Type 2 DN

Clinical type 2 diabetes

Cardiovascular death Functional changes

Proteinuria

ESRD Structural changes

Rising blood pressure

Rising serum creatinine levels Microalbuminuria

Onset of diabetes

2 5 10 20 30

Years

15년 전 제1형 당뇨병을 진단받은 환자의 검사 소견이 아래와 같다.

(증례와 무관)

• 당뇨병성 신병증으로 진단을 내리고자 할 때, 가장 도움이 되지 않는 소견은 무엇인가?

1) 소변검사 2) 안저 소견

3) 당뇨병 유병기간 4) 24시간 소변단백 5) 신장초음파 소견

소변검사: 단백 (3+), 잠혈 (-) 24시간 소변단백 4.8 g/일, 신장 초음파: 신장 크기 감소 안저 소견: 망막 삼출, 신생혈관

2005.06

2010.02

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

• The Diabetes Control and Complications Trial (DCCT)을 통하여 증명된 만성 고혈당에 대한 철저한 조절의 효과는?

1) 제1형 당뇨병의 미세혈관 합병증 (microvascular complication)을 개선한다.

2) 제1형 당뇨병의 대혈관 합병증 (macrovascular complication)을 개선한다.

3) 제2형 당뇨병의 미세혈관 합병증을 개선한다.

4) 제2형 당뇨병의 대혈관 합병증을 개선한다.

5) 제2형 당뇨병의 미세혈관 및 대혈관 합병증을 개선한다.

Natural History & Prevention Strategy of DN

GF R (mL/min ) A lb umin uria (mg/d ay )

50 100 150

20 200 1000 5000

5 10 15 20 25

Years

Pre Incipient DN Overt DN

Natural History & Prevention Strategy of DN

GF R (mL/min ) A lb umin uria (mg/d ay )

50 100 150

20 200 1000 5000

5 10 15 20 25

Years

Pre Incipient DN Overt DN

Tight Glycemic Control Tight BP Control

ACE inhibitors ARBs

Protein Restriction (1.0 → 0.8 g/kg/day)

Glycemic Control (I)

 In type 1 DM, the level of glucose control seems to be the strongest modifiable risk factor.

• DCCT

– 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”

Glycemic Control (II)

 Type 2 DM

• UKPDS: UK Prospective Diabetes Study (Lancet, 1998)

– 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%

Brief History (2)

혈청 크레아티닌: 0.5 mg/dL, HbA1C: 18.0%

소변검사: 단백 3+, 24시간 소변 단백 11.3 g

혈청 크레아티닌: 1.0 mg/dL (eGFR 71.2 mL/min/1.73 m²), HbA1C: 8.2%

소변검사: 단백 2+, 24시간 소변 단백 3.3 g

→보다 적극적으로 혈당 조절하도록 하고, ACE 억제제 투여를 시작하였다.

• 2006년: 혈압 130/80 mmHg이었고, 검사 결과는 다음과 같았다.

• 2005년: 혈압 110/70 mmHg이었고, 검사 결과는 다음과 같았다.

→ 적극적으로 혈당/혈압 조절이 될 수 있도록 교육 및 약물 조정하였다.

몸이 붓기 시작하여 이뇨제 투여를 시작하였다.

•

향후 치료에 대한 설명 중 가장 적절한 것은?

1) ACE 억제제를 감량한다.

2) 현재의 치료를 지속한다.

3) 안지오텐신 수용체 차단제로 대치 투여한다.

4) 신동맥 협착 치료를 위한 조영술을 시행한다.

5) ACE 억제제를 중단하고, 칼슘통로차단제로 변경한다.

• 혈압 148/82 mmHg, 혈청 크레아티닌 2.1 mg/dL인 상태에서, ACE 억제제를 투여한 지 1주일 후 시행한 혈청 크레아티닌이 2.4 mg/dL로 상승하였다. 혈압 128/74 mmHg, 혈청 칼륨 4.9 mEq/L이었고 기타 특이 사항은 없었다.

(증례와 무관)

Glomerulus

Mesangial Matrix

Efferent Renal Arteriole Mesangial Cells

Renal Sympathetic Nerves

Bowman’s Capsule

Distal

Convoluted Tubule Proximal Convoluted

Tubule Adventitial Mast Cell/Macrophage

Components of the Normal Nephron

Vascular Smooth Muscle Cells

Juxtaglomerular Cells

Macula Densa

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.

Brief History (3)

• 2009년: 이뇨제 증량에도 불구하고 소변량이 감소하고 전신부종이 점점 심해졌으며, 호흡곤란이 발생하였다. 혈압 170/100 mmHg이었고,

검사결과는 다음과 같았다.

헤모글로빈 6.8 g/dL

혈청 크레아티닌: 8.5 mg/dL

혈청 전해질: 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+

2009.01

2008.05

•

현재상태에서 치료계획으로 가장 좋은 것은?

1) 신장이식 2) 복막투석 3) 혈액투석 4) 이뇨제 증량

5) 혈압강하제 투여

2008.05

•

현재상태에서 치료계획으로 가장 좋은 것은?

1) 신장이식 2) 복막투석 3) 혈액투석 4) 이뇨제 증량

5) 혈압강하제 투여

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 m². Once macroalbuminuria ensues, the likelihood of ESRD is very high.

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, 0.24-0.30).

• The projected increase in life was 11 years among diabetic patients who

Wolfe RA, et al. NEJM 1999

47세인 환자의 오빠가 신장 기증 의사를 밝혔다. 혈압 116/74 mmHg, 체질량지수 28 kg/m²이었다. 외래에서 검사한 결과는 다음과 같았다.

• 상기 잠재 공여자는 어떠한 상태인가?

1) 당뇨병이다.

2) 당뇨전단계이다.

3) 경구 당부하검사가 필요하다.

4) 이식을 위한 검사 결과는 정상이다.

5) 당뇨병 유무를 확인하기 위하여 HbA1C 검사가 필요하다.

공복 혈당: 108 mg/dL (1차), 105 mg/dL (2차) 추정 사구체여과율 (eGFR) 88 mL/min/1.73 m²

소변검사: 단백 (-), 잠혈 (-); 소변 알부민/크레아티닌 비 3 mg/g 저밀도 콜레스테롤 118 mg/dL, 중성지방 80 mg/dL

The Revised Guideline – 2012 (1)

Standards of Medical Care in Diabetes - 2012

The Revised Guideline – 2012 (2)

Standards of Medical Care in Diabetes - 2012

• 잠재 공여자에게 설명할 사항으로 맞는 것은?

1) 공복 혈당이 110 – 125 mg/dL 사이인 경우 공복혈당장애 (impaired fasting glucose)로 진단 가능하다.

2) 공복혈당장애가 있으므로, 향후 당뇨병 발생 위험성이 있다.

3) 현재 정상이므로 향후 3년마다 당뇨병에 대한 추적 검사가 필요하다.

4) 공복혈당장애 여부를 확인하기 위하여 HbA1C 추가검사가 필요하다.

5) 공복혈당장애는 심혈관질환 발병에 영향을 미치지 않으나, 과체중은 영향을 미칠 수 있다.

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 - 2012

•

• 신장 공여는 가능한가?

1) 예

2) 아니오

공복 혈당: 105 (재검) mg/dL, HbA1C 5.8%

경구 당부하검사 2시간 혈당 128 mg/dL

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).

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,

Garg AX, et al. 2008

Contraindications To Donation

Absolute Contraindications Relative 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

Age 18-21 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

Making Patients with IFG into More Suitable Donors

• Lifestyle modifications can have a significant effect on altering the predicted risks for CVD and diabetes.

• 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.

Horton ES, et al. 2009

Knowler WC, et al. 2002

Wing RR, et al. 2010

Brief History (4)

• 2010년: 오빠로부터 공여 받은 신장으로 이식수술을 시행하였다.

• 퇴원 후 외래에서 측정한 혈압 110/80 mmHg이었고, 검사결과는 다음과 같았다.

헤모글로빈 9.6 g/dL

혈청 크레아티닌: 0.9 mg/dL, HbA1C 8.6%

소변검사: 단백 (±)

Brief History (5)

• 2010년: 이식 4개월 후 심한 탈모 발생하여 Tacrolimus를 CsA로 교체하였다.

• 2012년: 외래에서 측정한 혈압 104/60 mmHg이었고, 검사결과는 다음과 같았다.

헤모글로빈 12.0 g/dL

혈청 크레아티닌: 1.1 mg/dL, HbA1C 12.1%

소변검사: 단백 (-)

Cyclosporine 100 mg q 12 h MMF 750 mg q 12 h

Deflazacort 6 mg D

• 2012년: 현재 복용 중인 약제는 다음과 같다.