Diabetic Kidney Disease
Hyunjin Noh, M.D., Ph.D.
Division of Nephrology, Department of Internal Medicine, Soon Chun Hyang University
대한내과학회 전공의 연수강좌 October 23, 2015 Seoul, Korea
• Diabetic nephropathy
• Diabetic kidney disease
• 당뇨병성 신병증
• 당뇨병성 신증
• 당뇨콩팥병
Causes of ESRD
(incident patients)1
2 3
대한신장학회 말기신부전 등록사업
Q. 1,2,3에 차례로 들어갈 진단은?
1. DKD - HTN - chronic GN 2. DKD - chronic GN - PCKD 3. HTN - DKD - PCKD
4. Chronic GN - DKD - HTN 5. Chronic GN - DKD - PCKD
Causes of ESRD
(incident patients)대한신장학회 말기신부전 등록사업
Percentage of incident ESRD patients with diabetes as the primary ESRD cause, by country, in 2012
USRDS ADR 2014
Complications of diabetes
Cardiovascular Disease
Diabetic
Nephropathy Leading cause of
end-stage renal disease
Diabetic Neuropathy Leading cause of non-traumatic lower extremity amputations
Stroke
2- to 4- fold increase in cardiovascular mortality
and stroke Diabetic
Retinopathy Leading cause
of blindness in working age adults
Periodontal Disease
Case
72 / F 73 / M
DM duration (yrs) 23 33
HbA1c (%) 7.8 7.2
BUN/Cr (mg/dl) 45.2/2.53 11/0.8 eGFR (ml/min/1.73m2) 18.4 95.7 Proteinuria 5033 mg/d (-)
Macrovascular Cx CVA, CAOD None Microvascular Cx DMR None
Genetic factors
• Given similar degrees of hyperglycemia only a third of patients with diabetes develop clinically important renal disease genetic determinant?
• Relatively increased DKD in African Americans, Native Americans, Mexican Americans,
Polynesians, etc.
• Familial clustering of DKD in both TI and T2DM.
• 55/F, general weakness, fatigue
• PHx: negative
• Fasting glucose: 132 mg/dl
• HbA1c: 6.8%
• RUA: protein negative to trace, RBC 1~4/HPF
Case
이 환자에서 DKD에 대한 선별검사를 시 행할 적절한 시점과 방법은?
1. 지금 Spot urine albumin과 eGFR 2. 5년 후 Spot urine albumin과 eGFR
3. 지금 24시간 urine total protein과 Ccr 4. 5년 후 24시간 urine total protein과 Ccr 5. 지금 Spot urine albumin/Cr 비와 eGFR
Q.
Screening for DKD
ADA guideline 2015
Comprehensive Clinical Nephrology, 5th ed.
Comprehensive Clinical Nephrology, 5th ed.
• 28/M, T1DM for 9 yrs
• 115/70 mmHg
• Mild background DMR
• BUN/Cr 14/1.1 mg/dl, HbA1c 7.1%
• RUA protein trace, Urine Alb/Cr 150 mg/g
Case
Which ONE of the following statements is correct regarding his prognosis?
Q.
1. He may revert to normal albumin excretion rates only if he receives an ACE inhibitor.
2. He should be considered to have overt proteinuria at this point and receive aggressive therapy including ACE
inhibition.
3. He has a >50% chance of having a spontaneous remission of his proteinuria.
4. His clinical presentation at this time does not influence the prognosis of his proteinuria.
5. None of the above
NEJM 348:2285, 2003
In which ONE of the following patients would you consider performing a renal biopsy to
determine the basis for the patient’s renal dysfunction?
Q.
1. 54/M, T2DM with proliferative DMR, urine protein 3.2 g/d, and eGFR 28 ml/min per 1.73 m2
2. 21/M, T1DM for 15 years, proliferative DMR, urinary albumin 2.3 g/d, eGFR 81 ml/min per 1.73 m2
3. 41/M, T2DM with a 6-month history of reduction of eGFR from 67 to 38 ml/min per 1.73 m2, proteinuria of 3.1 g/d (increased from 0.5 g/d 6 months ago)
4. 44/M, T2DM with a stable eGFR of 42 ml/min per 1.73 m2,
proteinuria of 2.1 g/d, and 2+ hematuria but no dysmorphic RBC 5. None of the above
Assessing criteria for DKD
KDOQI guideline
• 57/M
• Leg edema for 2 weeks
• DM for 8 yrs: metformin
• 130/80 mmHg
• 2주전 타병원 신장검사는 정상이었다고 진술
• 본원 내분비내과 RUA protein (-): 6년전
Case
CBC 4800-14.8-42.5-245k BUN/Cr (mg/dl) 20/0.74 (eGFR 102)
Alb (g/dl) 2.2
Total cholesterol (mg/dl) 335
HbA1c (%) 6.7
RUA Protein 3+, RBC 5-9/HPF
24h urine protein (mg) 4196.1 Ophthalmologic exam DMR
Assessing criteria for DKD
KDOQI guideline
• 66/M
• Nausea, vomiting, dizziness for 4 days
• DM for 5 yrs: metformin + lantus
• 2주전 중국 여행, 무릎통증으로 NSAID 복용
• 4개월 전 안과 망막검사: DMR (-)
• 4개월 전 BUN/Cr 15/0.6 mg/dl, ACR 22.4 mg/g
Case
CBC 7700-11.0-31.2-92k (eosinophil 3%) BUN/Cr (mg/dl) 70-7.93 (eGFR 6.4 ml/min/1.73m2)
ABG 7.403-30.8-121-18.8-98%
HbA1c (%) 7.5
Alb (g/dl) 2.5
Total cholesterol (mg/dl) 123, on statin
RUA Protein 3+, RBC 1-4/HPF, WBC 5-9/HPF 24h urine protein (mg) 16785
Assessing criteria for DKD
KDOQI guideline
Comprehensive Clinical Nephrology, 5th ed.
Which ONE of the following is not a pathologic feature of DKD?
Q.
1. GBM thickening
2. Mesangial expansion
3. Hyalinosis of afferent and efferent arterioles 4. Kimmelstiel Wilson nodule
5. Podocyte hyperplasia
Pathologic classification
JASN 2010
Class I
Class I EM
Class IIA
Class IIB
Class III
Albumin
Modified from Nature Rev Nephrol 7:327, 2011 and Nat Rev Drug Discov 8:417, 2009
Glucotoxicity leading to diabetic complications
Nat Rev Drug Discov 8:417, 2009
AGE ROS Angiotensin II NF-κB activity Inflammatory cytokines
Leukocyte adhesion PKC activity
Insulin VEGF
APC PDGF Antioxidant
enzymes Anti-inflammatory
factors
Modified from Nature Med 16:40, 2010
Mechanisms of injury
NEJM 329:977,1993, NEJM 365:2366, 2011
Hyperglycemia
DCCT (Diabetes Control and Complications Trial)
EDIC (Epidemiology of Diabetes Interventions and Complications): metabolic memory
NephSAP, 2012
Recommendations for glycemic control
Glycemic goals should be individualized based on
• Duration of DM
• Age / life expectancy
• Comorbid conditions
• Known CVD or advanced microvascular complications
• Hypoglycemia unawareness
• Individual patient considerations
• Based on the results from ADVANCE, VADT, ACCORD studies
Diabetes Care 33, S1, 2010
Average course of MABP, GFR, and albuminuria before and during long-term antihypertensive tx in 9 T1DM patients
MABP(mm Hg)
55 65 75 85 95 105
0 500 1000
GRF:0.94 (ml/min/month)
GRF:0.29 (ml/min/month)
GRF:0.10 (ml/min/month)
ALBUMINURIA(㎍/min) GFR (ml/min/1.73㎡)
95 105 115 125
START OF ANTIHYPERTENSIVE TREATMENT
-2 -1 0 1 2 3 4 5 6
Parving et al, BMJ 294:1443, 1987
Years
ACE inhibitor slows progression of nephropathy in T1DM: captopril study
0 5 10 15 20 25 30 35 40 45 50
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Captopril Placebo
P=0.007
Years of Follow-up
Percentage with Doubling of Base-Line Creatinine
0 5 10 15 20 25 30 35 40 45 50
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Captopril Placebo P=0.006
Years of Follow-up
Percentage Who Died or Needed Dialysis or Transplantation
Lewis EJ et al. NEJM 329:1456,1993
ARB slows progression of nephropathy in T2DM: IDNT, RENAAL
Lewis EJ et al. NEJM 345:851-860, 2001 Brenner BM et al. NEJM 345:861-869, 2001 Irbesartan
Amlodipine
Placebo Risk reduction, 30~37%
Placebo
Losartan Risk reduction, 25%
BP control
ADA guideline 2015
• 61/M, T2DM for 8 yrs
• 150/85 mmHg
• Urine Alb/Cr 150 mg/g
• eGFR 90 ml/min/1.73m2
• Referred to you for management of his HTN and proteinuria
Case
Which ONE of the following outcomes would be expected if you decide to begin an ACE
inhibitor rather than an ARB in this patient?
Q.
1. A fall in eGFR of 1 ml/min per year if an ACEi is used
compared with a 5 ml/min per year decrease if you begin an ARB
2. A 0.5 mg/dl rise in serum creatinine over 3 years if an ACEi is used compared with a 0.1 mg/dl increase if an ARB is begun 3. A fall in eGFR of 15 ml/min over 5 years with either agent 4. A 50% fall in albumin excretion with the ACEi compared with
the ARB
5. None of the above
NEJM 351:1952, 2004
• 50/M, T2DM, consulted for evaluation of AKI
• Treated with pioglitazone for 1 yr
• 120/60 mmHg
• Recently telmisartan added to his regimen of metoprolol, ramipril, hydrochlorothiazide for BP control
• Cr 1.0 1.8 mg/dl
• HbA1c 7.1%, urine protein negative
• P/E: BMI 26, others non-specific
Case
Which ONE of the following is the most likely cause of his AKI?
Q.
1. Extracellular fluid volume depletion 2. Progression of his DKD
3. Antihypertensive medication 4. Pioglitazone toxicity
5. His BMI
Renal outcomes of ONTARGET study
Primary renal outcome
(dialysis, doubling of sCr, and death)
Secondary renal outcome (dialysis and doubling of sCr)
Lancet 372: 547, 2008
• Direct renin inhibitor
• Aldosterone receptor blocker
• Endothelin receptor blocker
• SGLT2 inhibitor
• RAGE blocker
• AMPK activator
• MCP-1, CCR2 blockade
