UPDATE ON DIABETIC KIDNEY DISEASE John Cijiang He, MD/PhD Division of Nephrology Department of Medicine Mount Sinai School of Medicine
np_q028
Question 1 A 22-year-old man comes for a routine evaluation. He has a history of type 1 diabetes mellitus and began taking insulin glargine and insulin lispro 8 years ago. Two days ago, he participated in a marathon race. On physical examination, temperature is 36.4 °C (97.5 °F), blood pressure is 112/70 mm Hg, pulse rate is 60/min, and respiration rate is 15/min. BMI is 24. Funduscopic examination is normal. There is normal sensation in the extremities. In addition to refraining from heavy exercise, which of the following is the most appropriate next step in this patient’s management? A. Begin losartan B. Perform kidney biopsy C. Repeat urine albumin-creatinine ratio in 1 year D. Repeat urine albumin-creatinine ratio in 2 weeks
Laboratory studies: Hemoglobin A1c 5.8% Urinalysis Normal Urine albumin100 mg/g creatinine ratio
np_q060
Question 2 An 18-year-old woman is evaluated for a 3-month history of foamy urine and swelling of the feet. Three years ago, she was diagnosed with type 1 diabetes mellitus. Medications are insulin glargine and insulin lispro. On physical examination, temperature is 36.6 °C (97.8 °F), blood pressure is 100/70 mm Hg, pulse rate is 80/min, and respiration rate is 15/min. BMI is 22. There is periorbital edema. Funduscopic examination is normal. There is no jugular venous distention, cardiac examination is normal without murmurs or extra sounds, and the lungs are clear. There is 1+ bilateral pitting edema of the lower extremities. In addition to initiating therapy with an angiotensin-converting enzyme inhibitor, which of the following is the most appropriate next step in this patient’s management? A. Cyclosporine B. Kidney biopsy Laboratory studies: C. Prednisone D. Repeat urinalysis in 3 months Hemoglobin A1c 7.7% Serum creatinine 0.6 mg/dL (53.0 µmol/L)
Total cholesterol
220 mg/dL (5.7 mmol/L)
Urinalysis
4+ protein; no blood; several oval fat bodies; no bacteria 4 mg/mg
Urine protein-creatinine ratio
Question 3 A 42-year-old woman with type 2 diabetes of 7 years duration, treated by diet and exercise alone, is noted to have an elevated blood pressure of 148/90 mmHg. A serum creatinine is 0.8 mg/dL and a urine albumin excretion is 12 mg/d. (Urine albumin to creatinine ratio is 14 mg/g). She is asymptomatic and her Hemoglobin A1c level is 6.5%. Based on currently available evidence what would be the BEST approach to preventing the development of incipient or overt diabetic nephropathy in this patient? A. Begin a program of dietary protein restriction. B. Begin a dihydropyridine calcium channel blocker. C. Begin a long-acting beta-blocker. D. Begin a non-dihydropyridine calcium channel blocker. E. Begin an angiotensin converting enzyme inhibitor.
Overall Incidence and Prevalence of Diabetic Kidney Disease (DKD) in USA
USRDS data 2013
Epidemiology data of DKD 1. Nearly 29 million people in the US (9.3%) and 442 million people worldwide have diabetes in 2014 (8.5%). 2. Based on NHANES survey: 38.5% of diabetic patients had CKD with an eGFR of 15–59 or an ACR>30 mg/g and 13.8% diabetic patients had stage 3 or 4 CKD. 3. 44% of new ESRD cases in the United States are caused by DKD. 4. The 5-year adjusted survival for patients starting on dialysis was 31% (DKD), 38% (HTN), and 45% for GN
Patient demographics, socioeconomic status, and CKD etiology and severity in according to presentation in public or private hospitals Private
Public
Total
Number of cases Age (Years) Number of females
26,290 52.0 ± 14.7 8,068 (30.7)
25,983 48.2 ± 14.3 7,460 (28.8)
52,273 50.1 ± 14.6 15,528 (29.7)
Monthly family Income
25,302
24,948
50,250
< Rs 5,000 Rs 5,001-20,000 > Rs 20,000 Causes of CKD
9,190 (36.3) 12,305 (48.6) 3,807 (15)
12,279 (49.2) 9,996 (40) 2,673 (10.7)
21,469 (42.7) 22,301 (44.4) 6480 (12.9)
Diabetic nephropathy
8,378 (31.9)
7,993 (30.8)
16,371 (31.3)
Undetermined
3,692 (14.0)
4,693 (18.1)
8,385 (16.0)
Chronic glomerulonephritis
3,562 (13.5)
3,655 (14.1)
7,217 (13.8)
Hypertensive nephrosclerosis
3,799 (14.5)
2,942 (11.3)
6,741 (12.9)
Chronic interstitial nephritis
1,811 (6.9)
1,870 (7.2)
3,681 (7.0)
Obstructive uropathy
941 (3.6)
835 (3.2)
1,776 (3.4)
ADPKD Miscellaneous
747 (2.8) 3052 (11.6)
619 (2.4) 3087 (11.9)
1,366 (2.6) 6,139 (11.7)
Renovascular disease
222 (0.8)
209 (0.8)
431 (0.8)
Graft failure CKD stages (n = 49,004) I II III IV V
86 (0.3)
80 (0.3)
166 (0.3)
464 (1.9) 1,163 (4.8) 5,455 (22.4) 6,591 (27.1) 10,644 (43.8)
541 (2.2) 974 (3.9) 4,159 (16.8) 3,091 (24.7) 12,919 (52.3)
1,005 (2.1) 2,137 (4.4) 9,614 (19.6) 12,685 (25.9) 23,563 (48.1)
Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF, et al. What do we know about chronic kidney disease in India: First report of the Indian CKD registry. BMC Nephrol. 2012;13:10.
Case: You are asked to see a 72-year-old man with 5 years of type II diabetes for consideration of optimizing his treatment to prevent progression of kidney disease. The patient is a nonsmoker, takes two oral hypoglycemic drugs for diabetes control, and has hypertension treated with amilodipine 10 mg qd and lisinopril 20 mg qd. His physical examination reveals a BP of 140/76 mmHg. He has a BMI of 32 kg/m2. The rest of the examination is unremarkable. His laboratory results show HbA1c of 7.2%, a serum creatinine level of 1.8 mg/dl and a urinary albumin/creatinine ratio of 0.08. Questions: 1) Does he have diabetic kidney disease? 2) Does he need kidney biopsy? 3) What is the target of optimal BP control? 4) What is the target for optimal hyperglycemic control? 5) What is his risk of progression to ESRD? 6) If he develops ESRD, what is the best option of renal replacement therapy for him?
Question 4
Does this patient need a kidney biopsy? Which statement below is correct? 1. Diagnosis of DKD is purely based on clinical presentations and does not need a kidney biopsy 2. Kidney biopsy is required to confirm the diagnosis of DKD in most patients. 3. Kidney biopsy is required only for type 2 diabetic patients with DKD. 4. Kidney biopsy is required for diabetic patients with atypical presentations of DKD. 5. Kidney biopsy is contraindicated in diabetic patients.
Diagnosis • Type I DM: based on clinical evidence: – – – –
History of DM more than 10 years. Microalbuminuria or proteinuria. Big kidney and slow progression. Presence of diabetic retinopathy in 90% (Klein et al Diabetes 2005).
• Less clear in type 2 Dm: – Duration? – Incidence of non-diabetic nephropathy: 25-50%.
• Atypical Presentation: need kidney biopsy. – Rapid progressive renal failure. – Active urine sediments: Hematuria. • 65% patients may have hematuria but only 4% has dysmorphic RBC.
– History of DM is short in type 1. – Absence of diabetic retinopathy • Patients with early DKD and type 2 DM (30%) may not have diabetic retinopathy
– Sudden onset of nephrotic syndrome or nephrotic range of proteinuria with normal renal function – Signs or symptoms of systemic disease
Pathology of Diabetic Kidney Disease • Accumulation of ECM is the central pathology of DKD: – Early stage: • Thickening of GBM, the earliest structural finding (1.5-2.5 years after the onset of type 1 DM). • Mesangial expansion with matrix deposition (5-7 years after the onset of type 1 DM).
– later stage: • Afferent and efferent arteriolar hyalinosis (a quite specific finding for DN) • Kimmelstiel-Wilson nodules (a specific finding for DN) • Tubular basement thickening (parallel to GBM thickening). Mauer et al Diabetes 2002
< IIb
Pathology of DKD in Type 2 Diabetes • Classification in type 2 DM: – Class 1: classic diabetic GS – Class 2: predominant vascular changes, relatively normal glomerular structure with some GBM thickening and mild mesangial expansion. Clinically, patients have early decline of GFR without significant proteinuria. – Class 3a: Another glomerular disease superimposed on diabetic GS (19%) 3b: only non-DKD glomerular disease (with no changes of GBM and mesangial expansion) (18%).
Fioretto & Mauer: Semin Nephrol 2007
Question 5
What is the stage of DKD for this patient and what is his risk of progression? 1. This patient has early stage of DKD and microalbuminuria is a sensitive early biomarker for prediction of DKD progression? 2. We need to perform a kidney biopsy to determine the risk of progression. 3. All patient with DKD progress from microalbuminuria to overt proteinuria and then to ESRD. 4. Glomerular hyperfiltration is a predictive marker for DKD progression. 5. Circulating TNFR1 and TNFR2 instead of HbA1c are predictive markers for DKD progression.
Clinical presentations and progression Pre-clinical
• Stage I: – Glomerular hyperfiltration and hypertension with increased GFR, with no microalbuminuria, normal BP. Normal structure.
• Stage II: – Mild increased GFR with normal or intermittent microalbuminuria, normal BP. Increasing GBM thickness and mesangial area.
Clinical
• Stage III: – Persistent microalbuminuria, GFR starts to decline toward the late stage, elevated BP, more GBM thickening and mesangial expansion with some glomerular closure.
• Stage IV: – Overt proteinuria, marked HTN, decreased GFR, more glomerular closure.
• Stage V: – ESRD, uremia, GFR 0-10 ml/min. Generalized glomerular closure.
Progression of DKD in Type 1 DM
Epidemiology data of DKD Type 1 Diabetes with normoalbuminuria 1/3 (15-20 y)
Microalbuminuria 1/3 (10y)
Macroalbuminuria 1/3 (10y)
ESRD 1/3 (5y) Survival
Early GFR Changes-Hyperfiltration 1. The initial increase in GFR (hyperfiltration) can be reduced with improved control of hyperglycemia and is affected by use of ACEI and SGLT2 inhibitors 2. Larger cohorts from the Joslin Clinic (426 patients) and the FinnDiane cohort (2168 patients) with long-term follow-up of patients did not show that hyperfiltration is associated with progression of DKD. 3. No clinical benefit to measure an eGFR in diabetic patients with normoalbuminuria to determine the risk of progression.
Microalbuminuria (moderately increased albuminuria) • MA is a dynamic marker at the early stage of DKD – 1/3 of type 1 diabetic patients with MA progress to overt proteinuria over 10 years, while 1/3 of those become normoalbuminuric, and the remainder have sustained MA (Perkins & Krolewski NEJM 2003). – Decline of Renal function (DRF) prior to the development of MA predicts the progression of DKD (Zerbini & Chiumello. Diabetes, 2006).
Patterns of changes in microalbuminuria is associated with progression of DKD
Perkins et al JASN 2007
Macroalbuminuria-Overt proteinuria (severely increased albuminuria) • The amount of proteinuria predicts the rate of progression to ESRD in patients with overt diabetic nephropathy. – In vitro studies suggest that albumin causes tubular interstitial fibrosis by stimulation of TGFβ and cytokines.
• Progression of DKD to ESRD may occur without a transition from MA to overt proteinuria. • Some diabetic patients progress to ESRD with minimal albuminuria, suggesting a non-albuminuric pathway for progression of DKD (Kramer HJ, JAMA 2003, Perkins JASN 2007).
New Biomarkers of DKD Progression •
Candidate hypothesis approaches • • • •
•
•
Cytokines: there is convincing evidence that soluble TNF-a receptors are linked to DKD and may perform better than albuminuria for long-term predictability (Niewczas MA et al JASN 2012). Urine and plasma levels of TGF-β and CTGF levels Urinary podocyte number and mRNA levels of podocyte specific genes Urine NGAL and KIM1 may be good indicators in the early phase of DKD. Urinary type IV collagen level
Unbiased approaches using proteomics. •
•
Urinary proteomics studies identified that a group of urinary peptides could correctly predict 75% of patients with normoalbuminuria, 87.5% of those with microalbuminuria, and 87.5% of those with DKD (Merchant ML et al JASN 2009). However, the excitement with proteomic methods have unfortunately not been met our need because many of the proteins that drive the progression of DKD are in low abundance compared to urine albumin.
Cumulative risk for CKD≥3 in patients with T1D during 12 years of followup according to quartile (Q1–Q4) of circulating TNFR2 at baseline.
Question 6
What do we know about the pathogenesis of DKD? 1. There is a clear genetic factor for the development of DKD and the major genes responsible for DKD have been identified. 2. AGE inhibitors have failed to shown renal protective effects. However, a new study is ongoing with a new AGE inhibitor. 3. Recent clinical trial proves the beneficial effect of anti-TGFbeta therapy in DKD patients with renal fibrosis. 4. Bardoxolone is an anti-oxidative stress drug which failed in clinical trial because it did not improve renal function. 5. SGLT2 inhibitor is a promising new therapy for DKD through improving diabetes and weight control.
Pathogenesis of DKD Hemodynamic factors
Intraglomerular HyerfiltrationHypertension Growth factors
Metabolic factors (Hyperglycemia)
Polyol pathway AGE
PKC Lipid Genetic risk factors
Signaling pathways
Renin/Ag II,
MAPK
TGFb/BMP7 VEGF, CTGF GH/IGF1
Smad
Notch
ROS:
B-catenine Mitochondria NAPDH oxidase Stat3
Inflammation NFkB IL-6, TNFa, Akt/mTOR MCP-1, ICAM1
Environmental factor Epigenetic factor
Cellular changes Podocyte: apoptosis detachment Mesan cell: ECM proliferation
Endoth cell: fenestration eNOs
DKD
Genetic factor Incidence Rate of Diabetic retinopathy and nephropathy
Data from the USRDS in 2010 showed that the rates of diabetes-related ESRD in the USA were different among ethnic populations: -117.8 per million in Caucasians -310 per million in Hispanics -333 per million in Native Americans -425 per million in African American
NEJM 1987
Genetic Factors 1. The Family Investigation of Nephropathy and Diabetes (FIND) Research Group recently reported on the largest genome-wide linkage scan in patients with DKD from different ethnic populations including 2616 participants in 1235 pedigrees. No region showed linkage across all ethnic groups. However, evidence for linkage to DN was detected in the individual ethnic patient populations. 2. The GoKinD study collected a large cohort of type I diabetic patients (1700) with and without nephropathy. None of the SNPs achieved significance based on the number of tests conducted. 3. APOL1 gene region, which is highly implicated in AfricanAmerican nondiabetic kidney disease with odd ratio of >10. However, APOL1 is not or weakly associated with DKD in AA.
Metabolic factor: Hyperglycemic control •
•
•
DCCT trial: Intensive therapy (HgbAic < 7%) effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with type 1 diabetes (NEJM 1993). ADVANCE trial: Intensive glucose control to achieve a HbA1c of 6.5% or less in patients with type 2 DM yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy (NEJM 2008). DCCT/EDIC trial: Over a mean follow-up period of 22 years, the relative risk of developing reduced renal function (estimated GFR [eGFR] ,60 ml/min per 1.73 m2) was reduced by 50% in the group of patients who received intensive treatment versus conventional treatment (NEJM 2011).
Intensive insulin treatment improves microalbuminuria in type I DM patients
Primary prevention
Secondary intervention
Cumulative Incidence of an Impaired Glomerular Filtration Rate, According to Treatment Group.
Improved glycemic control in the early phases of type I diabetes results in reduced incidence of DKD in long-term follow-up, suggesting a form of “metabolic memory.”----Epigenetic changes? The DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-2376.
Metabolic factor: Hyperglycemic control •
•
VADT trial (NEJM 2008): Intensive glucose control with 1.5% reduction of HbA1c (8.4 to 6.9%) in poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications. The Action to Control Cardiovascular Risk in Diabetes Study Group (NEJM 2008): As compared with standard therapy, the use of intensive therapy to target normal HbA1c (6.4 versus 7.5%) for 3.5 years increased mortality and did not significantly reduce major cardiovascular events.
Take home messages: Tight glucose control is important for slowing the progression of DKD. However, it may cause harmful effects in high-risk patient population with type 2 diabetes.
Glycation (AGE) and oxidation (ROS) Pyridoxamine (Effective in subpopulation, JASN 2012, phase 3: PIONEER)
Glucose
HbA1c Amadori Schiff base products
AGE/ALE
Aminoguanidine (failed)
Benfothiamine (failed, Diabetes Care 2010)
RCOs: GO, MGO, 3-DG Carbonyl stress AGE precursors
Myeloperoxidase (Mitochondria)
ROS
Alagebrium (AT711) Terminated
Pentosidine Pyraline CML MOLD
Imidazole (RAGE) AGE receptors Inhibitors (no progress)
Inflammation
Bardoxolone: (Failed, NEJM 2013)
Apoptosis
N Engl J Med. 2011 Jul 28;365(4):327-36. Epub 2011 Jun 24. Bardoxolone methyl and kidney function in CKD with type 2 diabetes By BEAM Study Group
CONCLUSIONS: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD.
N Engl J Med. 2013 Dec 26;369(26):2492-503. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. de Zeeuw D1, et al CONCLUSIONS:
Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial.
Hemodynamic Factor Glomerular hyperfiltration and hypertension
Central role of RAS
Brenner, BM et al: JCI 110:1753, 2002
EFFECTS OF LOSARTAN ON RENAL AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES
Renin-Angiotensin System 3 Renin
1
2 4
Aldosterone
Combination of ACEI and ARBs • Many clinical studies with small to moderate patient populations suggest that combination therapy results in greater antihypertensive and antiproteinuric effects than monotherapy in DKD. • ONTARGET Study : – 25,620 participants with vascular disease or diabetic with vascular complications – ramipril 10 mg daily (n = 8,576), telmisartan 80 mg daily (n = 8,542) or both agents (ramipril 10 mg daily plus telmisartan 80 mg daily, n = 8,502 followed for 56 months – composite primary outcome (dialysis, doubling of serum creatinine level or death) was higher in combination group than monotherapy group. – The eGFR declined significantly more with combination therapy. Much of the renal function decline was possibly due to reduction of BP and episodes of AKI. – Urinary albumin:creatinine ratio decreased more compared with baseline in the combination therapy group then in the monotherapy groups.
Combination of ACEI and ARBs 1. VA NEPHRON-D: J Am Soc Nephrol. 2009, 20:655-64. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death.
N Engl J Med. 2013 Nov 14;369(20):1892-903. Combined angiotensin inhibition for the treatment of diabetic nephropathy. Fried LF1, et al VA NEPHRON-D Investigators.
Conclusions: Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy.
Renin inhibitor and ARBs •
Aliskiren combined with losartan in type 2 diabetes and nephropathy(AVOID) (Parving et al NEJM 2008) – The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months – Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P45 years with diabetes. • In a recent analysis, six large-scale registry studies and three prospective cohort studies conducted in the United States, Canada, Denmark, and the Netherlands were reviewed. When comparing mortality between hemodialysis and PD hemodialysis was associated with better survival for diabetic individuals aged >45 years in the United States. The advantage of hemodialysis over PD was most apparent among those older patients with coincident cardiovascular disease. • Conversely, PD confers survival advantage over hemodialysis for diabetic individuals aged
