1. Nephrology Core Curriculum Diabetic Nephropathy

2. Diabetic Nephropathy 35% of all the patients enrolled in the Medicare ESRD program –63% are type II $2 billion per year (1990) Impact on morbidity and mortality –DM with proteinuria-- 100 fold increased risk of dying vs. 2x increase without proteinuria

3. Diabetic Nephropathy Epidemiology Rarely develops before 10 years of diabetes Cumulative incidence of proteinuria is 40% at 40 years in type I patients Annual incidence peaks at <20 years and thereafter declines –if survives >35 years of DM without nephropathy, extremely low risk of progressing in the future African Americans, Mexican Americans, American Indians, Maoria, and Polynesians have higher risk of DM Nephropathy

4. Diabetic Nephropathy Pathogenesis Insight from transplant population –kidneys from non-DM transplanted into DM develop DM lesions –kidneys with DM and pre-existing lesions transplanted into non-DM patients have resolution of DM lesions –strongly suggests it is the diabetic milieu not an intrinsic defect in the kidneys which predisposes to DM nephropathy

5. Diabetic Nephropathy Pathogenesis- Systemic BP Studies with diabetic rats and humans with DM- –unilateral renal artery stenosis has been reported to protect the kidney distal to the blocked renal artery from development of DM kidney disease –suggests exposure to elevated systemic BP is an important factor in the development of diabetic kidney disease

6. Diabetic Nephropathy Pathogenesis- Intraglomerular BP Studies with diabetic rats, decreasing intraglomular pressures by decreasing angiotensin II-mediated efferent arteriolar vasoconstriction preserves the structure and function of the glomerulus

7. Diabetic Nephropathy Natural History- Type I Onset Structural Changes Onset of proteinuria Incr Cr ESRD of Diabetes 0 2 5 11-23 13-25 15-27 Early Nephropathy -Microalbuminuria -Rising Blood Pressure Functional Changes -Inc GFR -Inc kidney size -Reversible Albuminuria -Increased GBM thickness -Mesangial expansion

8. Diabetic Nephropathy Natural History-- Type I Once proteinuria established, renal function INEXORABLY declines with 50% of patients reaching ESRD 7-10 years after the onset of proteinuria Type II –harder to date-- but in Pima Indians (whom you can date), they follow a very similar natural history

9. Diabetic Nephropathy Natural History-- Functional Changed Increased kidney size, and albuminuria reverses with blood sugar control, and glomerular hyperfiltration Increased GFR-- predictive of future development of clinically overt DM nephropathy at 20 years –increased renal plasma flow, increased transcapillary hydraulic pressure gradient which leads to glomerulosclerosis

10. Diabetic Nephropathy Natural History-- Pathology Within 1.5 to 2.5 years, renal biopsy –glomerular basement membrane thickening ? Response to pressure (reactive hypertrophy) vs. 2nd AGEs/deposits (similar to membranous) 2-3 fold increased GBM thickness, associated with mesangial matrix expansion

11. Diabetic Nephropathy Natural History-- Pathology Within 1.5 to 2.5 years, renal biopsy –glomerular basement membrane thickening ? Response to pressure (reactive hypertrophy) vs. 2nd AGEs/deposits (similar to membranous) Other lesions nodular intracapillary glomerulosclerosis (Kimmelstiel- Wilson) capsular drop lesion fibrin cap mesangial matrix expansion Biopsies with type II are indistinguishable from type I Kimmelstiel-Wilson lesions - collar of cells surrounding the nodular sclerosis distinguishes from Fibrillary GN/amyloidosis

12. Diabetic Nephropathy Natural History-- Microalbuminuria Normal urinary albumin excretion <30mg/24hrs Overt proteinuria not detected unless urinary albumin >300mg/24hrs Microalbuminuria therefore defined as 30- 300mg/24hrs –simple easy way is spot urine microalbumin to creatinine ratio (mg/grams)-- >30mg/g c/w microalbuminuria best on mid-morning specimens

13. Diabetic Nephropathy Natural History-- Microalbuminuria Microalbuminuria is highly predictive of progression to overt proteinuria and renal insufficiency over the next 10-15 years in TYPE I DM Type II DM-- correlation not as strong –because of XS CV mortality with microalbuminuria (they die of an MI before onset of renal failure) –microalbuminuria also caused by other etios-- hypertension, CHF, hyperglycemia

14. Diabetic Nephropathy Proteinuria and decreasing GFR GFR begins to decline with onset of proteinuria Average time to ESRD 10 years

15. Diabetic Nephropathy Insulin requirements Decline with ESRD –kidney catabolizes 30-40% of insulin –decreased po intake assoc with uremia

16. Diabetic Nephropathy Other renal manifestations Other comps of DM can exacerbate renal dysfunction –neurogenic bladder –papillary necrosis –UTI –type IV RTA

17. Diabetic Nephropathy Screening Who –IDDM-start at 5 years, then qyear –NIDDM- at dx, then qyear False positives –hyperglycemia, UTI, PE, essential HTN, CHF, water loading If albumin excretion rate increased, repeat THREE times over 3-6 months (this is to r/o transient causes)

18. Diabetic Nephropathy Screening Factors which rule against DM nephropathy as etiology of proteinuria –lack of DM retinopathy (95% of patients with nephropathy have retinopathy (63% of type 2)) retinopathy correlates with nodular sclerosis (7 of eight patients with DM nephropathy and retinopathy). DM nephropathy associated with mesangial sclerosis-- usually no retinopathy –Macroscopic hematuria (90% of patients with DM nephropathy have no macrohematuria, but more than 50% will have micro) –RBC casts found in only 4% of biopsies –onset of proteinuria earlier than 5 years or greater than 30 years after onset of DM –acute onset of disease (NIDDM nephropathy takes years)

19. Diabetic Nephropathy Treatment of Progressive Disease Impact of Glucose control Diabetes Control and Complications Trial (DCCT) –risk reduction for development of microalbuminuria by: 34% in those with no evidence of pre-existing disease 43% in those with baseline mild retinopathy –risk of developing proteinuria was reduced by 56%

20. Diabetic Nephropathy Treatment of Progressive Disease Impact of Glucose control UKPDS (NIDDM) at 15 years –risk for development of microalbuminuria: 27% vs. 37% in non-intense group –risk of developing overt proteinuria 7% vs. 13% in non-intense group

21. Diabetic Nephropathy Treatment of Progressive Disease Impact of Glucose control Pancreas transplant -- ultimate in glucose control –Renal parameters stabilized at 5 years, but no improvement –by 10 years, decreased mesangial volume and tubular and glomerular basement membrane thickness within normal limits

22. Diabetic Nephropathy Treatment of Progressive Disease Impact of Blood Pressure Control Goal of <125/75 –no J point ACE-I preferred agents –48% risk reduction for doubling of serum creatinine –50% risk reduction for the secondary outcome of time to death, dialysis, or transplantation –effect independent of its effect on systemic blood pressure-- equally effective in normotensive and hypertensive patients