A. Overview

1. Leading cause of and contributor to end stage renal disease (ESRD)
   1. Implicated as major etiologic factor in ~40% of ESRD cases (~17,000 per year)
   2. Overall risk for ESRD with DM is >12 fold higher than general population [3]
   3. DM usually causes albuminuria initially but can cause CRF early without albuminuria [4]
2. Development is related to duration of diabetes (DM) and degree of hyperglycemia
3. Major Risk Factors for Development in Type 2 DM (DM2)
   1. Plasma cholesterol levels
   2. Mean blood pressure
   3. Level of hyperglycemia
   4. Smoking
4. Progresses in stages from hyperfiltration to ESRD
5. ESRD itself exacerbates cardiovascular disease
6. Occurs with both Type 1 DM (DM1) and DM2

B. Stages
[Figure] "Stages of Diabetic Nephropathy"

1. Stage I
   1. Hyperglycemia leads to increased kidney filtration
   2. This is due to osmotic load and to toxic effects of high sugar levels on kidney cells
   3. Increased Glomerular Filtration Rate (GFR) with enlarged kidneys
2. Stage II: Clinically silent phase with continued hyperfiltration and hypertrophy
3. Stage III: Microalbuminuria (see also below)
   1. Definition: 30-300mg/day (20-200µg/min) urinary albumin
   2. Age specific urinary albumin to creatinine ratios are more accurate for detection of microalbuminuria than use of urinary albumin concentration alone [8]
   3. However, these urine samples were timed overnight, not spot urine levels [8]
   4. Basement membrane thickening due to AGEP
   5. GFR not markedly affected
   6. About 20% of patients with microalbuminuria develop nephropathy within 5 years on standard diabetic care
   7. This proportion increases with increasing duration of disease
   8. However, up to 50% of patients with DM microalbuminuria may not progress
   9. DM1 patients with microalbuminuria can have reduction in proteinuria [10]
   10. Control of nephropathy and vascular risk factors improves likelihood of reduction in proteinuria [10]
   11. Microproteinuria is a better predictor of of progression in DM1 than in DM2
4. Stage IV: Overt Nephropathy
   1. Historically, this was nearly always with hypertension (HTN)
   2. >300mg/day (>200µg/min) albumin in urine (>300µg/mg creatinine)
   3. About 10% of patients have nephrotic range proteinuria
   4. Glomerular Filtration Rate (GFR) is decreased
5. Stage V: ESRD
   [Figure] "Proteinuria and ESRD in Diabetes"
   1. Over 30 years, >25% of DM1 patients will develop severe renal failure
   2. Over 25 years, about 8% of DM2 patients develop ESRD
6. Progression
   1. Need for predictor of development of overt nephropathy in diabetics
   2. Study on spot urine collection was done on diabetic Pima Indians
   3. Albumin to creatinine ratio >30mg/g in an untimed urine specimen is a good predictor of the development of overt nephropathy during an 8 year followup period
   4. All patients with DM should be screened for nephropathy by puberty or within 5 years
7. Risk of Developing Microalbuminuria
   [Figure] "HbA1c and Microalbuminemia"
   1. In DM1, correlates with hemoglobin A1c (HbA1c) levels
   2. Risk of microalbuminuria increases abruptly above HbA1c levels above 8.1%
   3. This corresponds to an average serum glucose level >200mg/dL
8. Microalbuminuria Predicts [3]:
   1. Development of overt nephropathy and ultimately renal failure (especially in DM1)
   2. Development of macrovascular disease including cardiovascular disease [11]
   3. Development of macular edema
   4. Development of left ventricular diastolic dysfunction
   5. Dyslipidemias, elevation of atherogenic lipids
   6. Elevated blood pressure, other endothelial dysfunction
   7. Insulin resistance
9. Azotemia can occur in the absence of albuminuria in ~30% of patients with early DM [4]

C. Pathogenesis

1. Likely genetic predisposition specifically for renal damage with DM
   1. No confirmed strong associations, but many contributing polymorphisms
   2. Erythrocyte sodium/lithium counter-transporter levels implicated
   3. ACE gene polymorphisms may play some role
   4. Hypercholesterolemia, elevated HbA1c, HTN all contribute to renal decline
2. Interplay of metabolic and hemodynamic effects of hyperglycemia and abnormal insulin
   1. Advanced glycation end products (AGEP)
   2. Activation of Protein Kinase CßII - stimulation of TGFß and VEGF
   3. Extracellular matrix (ECM) crosslinking leading to accumulation
   4. Cytokine and other humoral imbalances
   5. Proliferative vasculopathies
   6. Increased vascular permeability (of new and old vessels)
   7. Stimulation of angiotensin II and endothelin production
   8. Glomerular Hyperfiltration - osmotic load
   9. Activation of glucose metabolizing enzymes
   10. Oxidant Stress - related to glomerular hypertrophy and abnormal metabolism
3. Nonenzymatic Glycosylation
   1. AGEP formation stimulates TGFß AND VEGF production
   2. Collagen and other ECM proteins are abnormally crosslinked
   3. This leads to reduced ECM degradation and abnormal remodelling
   4. Basement membrane (BM) components (mainly Type IV collagen) affected
   5. Decreased degradation of Type IV collagen inhibits normal BM remodelling and repair
   6. Altered charge on, and structure of, BM may explain albuminuria
   7. ECM accumulates in patients with DM
4. Toxic Oxygen Species
   1. AGEP formation also leads to increased toxic oxygen species
   2. This leads to cell and tissue damage
   3. Repair mechanisms impaired due to abnormal ECM structures
   4. Macrophage receptor activation leads to IL1, TNF production which stimulates matrix
5. Glomerular Hyperfiltration
   1. Glucose provides an osmotic diuretic effect, as well as vasodilation
   2. Result is increased renal filtration, leading to glomerular hypertrophy
   3. Glomerular pressure increases
   4. Kidney responds with hypertrophy of epithelium and endothelium
   5. Accelerates glomerular cell failure
   6. Result is premature glomerulosclerosis
6. Humoral Imbalances in DM Nephropathy
   1. Insulin Deficiency
   2. Elevated Glucagon Concentrations
   3. Increased Transforming Growth Factor (TGF)-ß
   4. Increased angiotensin II [9] and endothelin
   5. Abnormally regulated thromboxanes
   6. Abnormal insulin like growth factor (IGF)-1
   7. Elevated platelet derived growth factor (PDGF)
7. Role of TGF-ß
   1. Stimulates extracellular matrix synthesis
   2. Inhibits extracelluular matrix degradation
   3. Upregulates protease inhibitors; downregulates matrix degrading enzymes
   4. Stimulates synthesis of integrins (matrix receptors)
   5. Key role in glomerular and tubuloepithelial hypertrophy, basement membrane thickening, and mesangial matrix expansion
   6. TGF-ß has been implicated in a number of chronic, scarring diseases

D. Diagnosis [2]

1. High suspicion in ALL patients with DM
2. Careful monitoring of urinary protein and blood pressure
3. Specific test for urinary albumin must be done
   1. Critical to detect microalbuminuria to aggressively prevent progression
   2. If urinary dipstick is negative, additional more sensitive tests should be done
   3. Micral test or radioimmunoassay for albumin recommended
4. Ratio of urinary albumin to creatinine is most useful
   1. Normal: <30µg urinary albumin per mg creatinine (<30mg/gm creatinine)
   2. Microalbuminuria: 30-300µg/mg creatinine
   3. Macroalbuminuria: >300µg/mg creatinine
5. A 24-hour urine collection for creatinine clearance and protein at least annually

E. Treatment [2,5,6]

1. Aggressively treat hyperglycemia [5], proteinuria and blood pressure [7]
   1. Proteinuria can be monitored with spot urine albumin:creatinine ratios (see above)
   2. Goal reduction of proteinuria to <0.3gm/d with pharmacologic agents
   3. Dietary protein intake should be <0.8gm/kg/day, probably <0.6gm/kg/day [12]
   4. Weight loss and smoking cessation are critical to long-term success
   5. Blood pressure reduction to <130/80 mm Hg
   6. LDL cholesterol reduction to <100mg/dL (<2.6 mmol/L)
   7. Aggressive treatment of hypercholesterolemia with atorvastatin (Lipitor®) reduces renal decline (proteinuria) and should be added to ACE-I or ARB [14]
   8. Goal reduce HbA1c to <7.5%
   9. Preventing development and progression of microalbuminuria is critical
   10. Once macroproteinuria develops, difficult to prevent progression to ESRD
   11. Aggressive combination therapy can cause remissions even in patients with nephrotic range proteinuria [2]
2. Diabetic Control [5,6]
   1. Improved glucose control reduces incidence of microalbuminuria [15]
   2. Improved glucose control also reduces indicence of HTN
   3. Improved glucose control does not appear to affect progression from microabulinuria to macroproteinuria and renal failure
   4. Over time, intensive insulin therapy may have less impact on glycemic control compared with standard therapy, but still reduced progression of retinopathy and nephropathy
   5. Eight years after intensive insulin therapy of DM1, reduced nephropathy observed [6]
3. Angiotensin Blockade [2,6,7,18]
   1. Angiotensin converting enzyme inhibitors (ACE-I) are best studied
   2. Angiotensin II receptor blockers (ARB) are also well studied
   3. ACE-I and ARB clearly slow progression from microalbuminuria to macroalbuminuria
   4. Both reduce progression of renal failure in DM1 and DM2
   5. ACE-I remain the agents of choice for normotensive and hypertensive diabetics with ANY proteinuria [18,20,21]
   6. Irbesartan, telmisartan, or losartan (ARB) should be used in ACE-I intolerant patients and are probably as effective as ACE-I [17,23,24,25]
   7. ARB may be used alone or added to ACE-I to further reduce proteinuria
   8. Renin inhibitor alikiren (Tekturna®) added to losartan (Cozaar®, an ARB), reduces urinary albumin-to-creatinine ratio in type 2 DM with nephropathy [29]
   9. Irbesartan reduced diabetic nephropathy progression but had no effect on cardiovascular endpoints when added to standard antihypertensive therapy [26]
   10. Telmisartan reduced the risk of developing microabulinuria in DM2 patients [25]
   11. Increase doses of ACE-I and/or add ARB to reduce proteinuria to <0.3gm/d
   12. Intensive therapy with various ACE-I + Vitamin E + Vitamin C in patients with DM2 and microalbuminuria reduced progression to macroalbuminuria >70% [27]
4. Calcium Channel Blockers (CCB)
   1. Non-dihydropyridine CCB may be used 2nd/3rd line
   2. Combination therapy with ACE-I and CCB as [21] or more [3] effective than either alone for proteinuria in patients with DM2 and HTN [3]
   3. Nitrendipine (a dihydropyridine CCB) was safe and effective in DM2 in small study [13]
   4. Amlodipine (a dihydropyridine CCB) alone does not provide renal protection and may slightly exacerbate renal decline in DM2 [23]
   5. Verapamil alone had no benefit in preventing microalbuminuria in DM2 with HTN [21]
5. ß-Adrenergic Blockers
   1. Typical ß-blockers should be avoided as they increase hypoglycemic risk 3-fold
   2. Mixed function ß-blockers such as carvidilol may be safe and effective in diabetic nephropathy
   3. Overall, ß-blockers may reduce albuminuria similar to ACE-I [2]
6. Hypertension (HTN)
   1. HTN is strong contributor to worening renal function
   2. However, DM also causes or is associated with HTN
   3. Improved glucose control reduces risk of HTN [16]
   4. ACE-I or ARB are the drugs of choice for diabetics with HTN
   5. ACE-I and ARB improve diabetic nephropathy independent of blood pressure control
   6. ARB are alternative first line treatment for DM with HTN
   7. Nitrendipine (a dihydropyridine) reduced blood pressure and improved GFR in DM2 [13]
   8. Target BP <130/80 mm recommended, particularly with proteinuria >1gm/d [3]
   9. Combination ACE-I and CCB are very effective and reduce proteinuria
7. Aggressive combination therapy with high-dose statin, intensive glucose control, ACE-I and ARB can reduce or reverse severe diabetic nephropathy [2]
8. Newer Therapies for Nephropathy with Type I DM
   1. Prophylactic Insulin therapy in patients at risk for DM development may prevent disease
   2. Immunosuppressive therapy may be effective in patients with new onset DM1
   3. Aminoguanidine inhibition of AGEP formation
   4. Pancreas transplantation with kidney transplant
   5. Pure allogeneic islet cell transplants (into the liver via portal vein) are being tested
9. Pancreas Transplantation [28]
   1. Most currently used immunosuppressives worsen glycemic control
   2. Mesangial proliferation is major component with resultant albuminuria
   3. Reversal of diabetic renal pathology requires 5-10 years

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