12/21 Nephro Fellow 1
Diabetic nephropathy occurs in type 1, type 2 diabetes mellitus and other secondary forms of diabetes mellitus A glomerulopathy defined by characteristic structural and functional changesmesangial expansion, glomerular basement membrane thickening, and glomerular sclerosisMajor clinical manifestation are albuminuria, progressive chronic kidney disease, and less often hematuria. ~ American Journal of Kidney disease vol 44, No 1, July 2004Introduction
PathogenesisGlomerulosclerosis result form : a. Intraglomerular hypertension due to renal vasodilatation b. Ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli
and why renal vasodilatation and glomeruli vessels hyaline narrowing ????
PathogenesisThere appear to be some different pathogenetic processes
1. Glomerular hyperfiltration 2. Hyperglycemia and AGEs 3. Prorenin 4. Cytokines 5. Nephrin expression 6. Impaired podocyte-specific insulin signaling
Glomerular hyperfiltrationIn an animal model of diabetic nephropathy : a. BP, intra-renal Ang II level, and type IV collagen expression are higher in prediabetic rats b. Renin-angiotensin system blockade reduced intrarenal Ang II, type IV collagen expression, risk of proteinuria and improved glomerular structure.Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol. 2005;16(3):703.
Glomerular hyperfiltration => glomerular hypertension and hyperfiltration have roles in diabetic nephropathy => Antagonizing the profibrotic effects of angiotensin II has benefit for diabetic nephropathyTemporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol. 2005;16(3):703.
Hyperglycemia and AGEs (advanced glycation end products)Hyperglycemia stimulates mesangial expansion and mesangial cell apoptosis via increased matrix production or glycation of matrix proteinExcess glucose combines with free amino acids on circulating or tissue protein circulating and tissue AGE accumulation crosslinking with collagen renal and microvascular complicationHyperglycemia activates protein kinase C upregulation of heparanase expression as a decrease in cell surface heparan sulfate glomerular basement membrane permeability to albumin
Increased expression of heparanase in overt diabetic nephropathy.Kidney Int. 2006;70(12):2100.
CytokinesActivation of cytokines, profibrotic elements, inflammation, and VEGF maybe involved in the matrix accumulation in diabetic nephropathy.1. Hyperglycemia stimulates VEGF expression VEGF blockde improves albuminuria in diabetic nephropathy
2. Hyperglycemia induced decrease in activated protein C --> structural lesion of diabetic nephropathy and worsens proteinuria in mice
Blockade of vascular endothelial growth factor ameliorates diabetic albuminuria in mice.J Am Soc Nephrol. 2006;17(11):3093.
Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.Nat Med. 2007;13(11):1349.
Cytokines3. TGF- contributes to cellular hypertrophy and enhances collagen synthesis hyperglycemia increases expression of TGF- in the glomeruli and matrix protein
4. Renal bone morphogenic protein-7 (BMP-7) counter the profibrogenic actions of TGF- diabetes is associated with decreased expression of BMP-7Molecular mechanisms of diabetic renal hypertrophy.Kidney Int. 1999;56(2):393.Renal bone morphogenetic protein-7 protects against diabetic nephropathy.J Am Soc Nephrol. 2006;17(9):2504.
ProreninProrenin binds to a specific tissue receptor that promotes activation of the mitogen-activated protein kinases(MAPK)p44/p42A Prolonged prorenin receptor blockade abolished MAPK activation prevent diabetic nephropathy despite an unaltered increase in angiotension II activity
Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol. 2006;17(7):1950.
Nephrin expressionImpaired in diabetic nephropathy and congenital mutations result in severe nephrotic syndrome
Diabetic nephropathy has markedly lower renal nephrin expression and fewer electron dense slit diaphram than minimal change and controls podocin and CD2AP expression are similar amont the three groups.
Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Kidney Int. 2004;65(6):2193.
Schematic of the slit diaphragm and other important proteins involved in maintaining foot process assembly.Quaggin S E , Kreidberg J A Development 2008;135:609-620
Impaired podocyte-specific insulin signalingMouse models (podocyte-specific insulin receptor deficiency): In the absence of hyperglycemia, affected mice developed albuminuria, effacement of foot processes, apoptosis, glomerular basement membrane thickening, accumulation of mesengial matrix and glomerulosclerosis activation of the insulin receptor remodeling MAPK 42/44 and Phosphatidylinositol 3 (PI3) kinase signaling pathways proteinuria decrease
clinical implications of basic researchProteinuria, the Podocyte, and Insulin ResistanceN Engl J Med 2010; 363:2068-2069 November 18, 2010
Risk factorsFamily history of diabetes Black race, Mexican-American or Pima Indian ancestryHigher systemic blood pressuresPoor glycemic controlSmokingOral contraceptives Obesity Old age
TreatmentGlycemic controlBlood pressure controlLipid controlSalt and protein restrictionWeight reductionAngiotensin inhibitionCalcium channel blockerPPAR-gamma agonistsOther agents
Glycemic controlDelay the development of elevated albumin excretion, slow the rate of progressive renal injuryReverse the glomerular hypertrophy and hyperfiltration, improves glomerular structure : a. mesengial and mesengial matrix volume decrease b. glomerular and tubular basement membranes return to normal, nodular glomerular lesions disappear c. tubular atrophy improvesN Engl J Med 1993;329:977
Diabetic nephropathy reverses after pancreas transplantationN Engl J Med 1998; 339:69
- Blood pressure controlUnited Kingdom Prospective Diabetes Study (UKPDS) : a. SBP decrease 10 mmHg 12% risk reduction in diabetic complication (P
Blood pressure control
Irbesartan Diabetic Nephropathy Trial (IDNT) : a. progressively lower SBP to 120mmHg was associated with decreased cardiovascular death, heart failure, serum creatinine doubling and ESRD risk b. BP < 120/85 mmHg increased the risk of all-cause mortality, cardiovascular death and heart failureStrict BP control is important for preventing progression of diabetic nephropathy in type 2 DM, but the optimal lower limit for BP is unclear.
Lipid controlElevation in lipid levels lead to promote systemic atherosclerosis and glomerulosclerosis in CKD patient.
In type 1 diabetes mellitus patient, plasma cholesterol > 220mg/dL was an important risk factor for progressive renal disease, particularly if the diastolic pressure > 85 mmHg.
Hypercholesterolemia--a determinant of renal function loss and deaths in IDDM patients with nephropathy.Kidney Int Suppl. 1994;45:S125.
Lipid controlThe rate of progression from normal albumin excretion to microalbuminuria decreases with fenofibrate (a peroxisome proliferator activated receptor (PPAR)-alpha specific ligand) * Possible mechanisms of fenofibrate benefit : PPAR- activity --> inflammation and production of type 1 collagen in mesangial cells
PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice.Kidney Int. 2006;69(9):1511.
Salt restriction High salt intake blunt the antiproteinuric effects of angiotensin inhibitors Salt restriction and/or diuretics enhance the effect of renin-angiotensin blockade on proteinuria.Salt restriction to < 70 meq /day enhance the antiproteinuric effects of ARB in T2DM patient => If it is difficult to achieve: a. restrict sodium intake to 100 < 100meq/d b. give diuretic partially corrects the loss of antiproteinuric effect due to high sodium intake
Protein restrictionProtein reduction reduce the rate of progression in DM patient with overt nerphropathy. => Suggest: avoid a high protein diet (1g/kg/d) Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy.Kidney Int. 2002;62(1):220.
Weight reductionMarked decreases in proteinuria may be observed in obese diabetics who lose weight Proteinuria significantly decreased at five months among dieters versus the non-dieters control group ( mean weight loss of 4% in the diet group) No significant differences in renal function were reported in either group.the length of follow-up was probably too short to have observed renoprotection effect.Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am J Kidney