Diabetic nephropathy

12/21 Nephro Fellow 1

Introduction

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.

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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 Dis. 2003;41(2):319.

Angiotensin inhibitionPrimary prevention for diabetic nephropathy

Preservation of renal function

Angiotensin inhibition Primary prevention for diabetic nephropathy * Diabetes induces renal vasodilation, intraglomerular hypertension and glomerular hypertrophy ACEI and ARB reduce intrarenal vascular resistance and inhibit TGF- reduce intraglomerular pressure, minimize glomerular injury, inhibit cellular hypertrophy and collagen synthesis

Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes.J Am Soc Nephrol. 2005;16(4):1135.

Captopril reduces (intra)renal vascular resistance in patients with type 2 diabetesKidney Int 1989;36:526.

Angiotensin inhibitionPreservation of renal function * T1DM: a. ACEI decreases albumin excretion, CKD progression rate, risk of overt nephropathy, ESRD or death.

NEJM 1993;329:1456.

Angiotensin inhibition b. ACEI + ARB produces a greater reduction in protein excretion (in 2 short-term studies, 8 wks) --- due to better BP control ???

Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.Kidney Int. 2003;63(5):1874.

* T2DM renal protection with ARBs a. Irbesartan Diabetic Nephropathy Trial (IDNT): @Irbesartan has lower risk (23%) in doubling of Scr, proteinuria, ESRD or death than amlodipine (and placebo) @Renal failure risk doubles with each doubling of baseline protein excretion @The renal outcomes are best at SBP

b. RENAAL study: @Losartan reduced the albuminuia, incidence of creatinine doubling and ESRD by 25% and 28% @ SBP every 10mmHg => ESRD or death risk 6.7% @ Albuminuria every 50% => CV risk 18%, ESRD risk @ Baseline retinopathy has poor renal outcome

Both of studies show ARB has clear benefits in T2DM patients with overt nephropathyARB had significant reductions in the development of heart faliure. However, CV mortality has no obvious reduction.

too short duration of the studies??

* T2DM renal protection with ACEIs a. ADVANCE trial : perindopril-indapamide combination vs placebo: @ significant reduction of new onset microalbuminuria or worsening of protienuria (19.6% vs 23.6% ) @ significant decrease in mean BP (5.6/2.2 mmHg) @ no significant defference in CKD progression => the renal benefits are due to the ACEI or BP control ??

b. DETAIL trial : enalapril vs. telmisartan vs. placebo @ at 5 yrs, enalapril has smaller GFR decline (NS) @ similar findings of BP, Scr, albuminuria, ESRD, CV events and mortality.

ACEIs are at least as effective as ARBs in diabetic patient with microalbuminuriaACEIs or ARBs has renoprotection in patient with diabetic nephropathy (progress slowly)1/3 of renoprotective effect with ACEI or ARB is due to proteinuria reduction in first 12 months of therapy

ACEI + ARB ??? * small studies decrease proteinuria in T1DM & T2DM * ONTARGET study proteinuria and GFR => ESRD and mortality rate => CKD progression => NS

ARB + aliskiren @ AVOID trial aliskiren + losartan vs. losartan * aliskiren + losartan has 20% greater reduction in proteinuria (no significant on BP) * role of aliskiren in preventing CKD progression ??

Aldosterone antagonism

small study 81 patient, f/u 48weeks lisinopril + sprionolactone or losartan or placebo * spironolactone + lisinopril urine ACR decre 34% (S) losartan + lisinopril urine ACR 17% (NS) * no long term data about CKD progression with ACEI/ARB + aldosterone blockade * Serum pottasium is significant high in both groupAntagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study.Am J Kidney Dis. 2005;46(1):45.

Another small studies 268 patient, f/u 40wks ACEI + eplerenone or placebo eplerenone has additive antiproteinuria effect, similar hyperkalemia rate

Aldosterone antagonists appear to reduce proteinuria when used alone or combination with ACEI/ARB in type 1 and type 2 diabetes. => suggestion : avoid NSAID, combine kaliuretic diuretic therapyBeneficial impact of spironolactone in diabetic nephropathy.Kidney Int. 2005;68(6):2829.

Calcium channel blockerNon-dihydropyridine calcium channel blockers slow the rate of progression of diabetic nephropathy * diltiazem and verapamil is as effective as ACEI/ARB in lowering protein excretion in diabetic patients * the antiproteinuric effects of verapamil and ACEI may be addictive * However, diltiazem increases tubulointerstitial fibrosis andglobal glomerulosclerosis. The effect was prevented by combined an ACE inhibitor.

Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs.Kidney Int. 1994;46(1):161.

Antihypertensives and urinary protein excretion in diabetic nephropathyKidney Int. 1992;46(1):161.

Superior antiproteinuric effect with combination of antihypertensive therapyKidney Int. 1998;57(1):193.

Superior antiproteinuric effect with combination of antihypertensive therapyKidney Int. 1993;51(5):129.

The antiproteinuric mechanism of nondihydropyridine calcium channel blockers: 1. possible reduction in intraglomerular pressure 2. reduce the associated glomerular hypertrophy 3. diltiazem may improve glomerular size permselectivity.

Differential effects of calcium channel blockers on size selectivity of proteinuria indiabetic glomerulopathy.Kidney Int. 1998;54(3):889.

* Uncertain clinical relevance. * The efficacy in the preservation of renal fucntion in relation to ACEI has not yet been evaluated in humans

Dihydropyridine calcium channel blockers ( such as amlodipine, nifedipine, nitrendipine) have a variable effect ranging from increased protein excretion to no effect to a fall in protein excretion in different studies.

Beta-blockers have shown a variable response of protein excretion decrease

PPAR- agonistsPeroxisome proliferator-activated receptors (PPAR) which are ligand-activated transcritption factors, have a role in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, blood pressure, and development of T2DM nephropathy.

PPAR- agonists, such as the thiazolidinediones (eg, pioglitazone and rosiglitazone), induce reductions in fibrosis, mesangial cell proliferation, and inflammation in animal models of diabetic nephropathy .

Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.J Am Soc Nephrol. 2008;19(1):182.

PPAR- agonists

In small studies, PPAR-gamma agonists reduce urinary albumin excretion at various stages of nephropathy and to reduce blood pressure. Larger studies are required to detect a renoprotective effect

A post hoc analysis of the PROACTIVE trial failed to show a definitive benefit on cardiovascular risk reduction with pioglitazone in people with stage 3 or higher nephropathy

Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.J Am Soc Nephrol. 2008;19(1):182.

Other agents

Bardoxolone methylAn antioxidant inflammatory modulator that may also have prostaglandin-like effects. It has been beneficial in animal models of drug-induced or ischemic acute kidney injury.

In the Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) trial, Bardoxolone methyl therapy at all three doses significantly increased eGFR at 52 weeks of follow-up by 6 to 10 mL/min per 1.73 m2, while placebo therapy had no effect.

Bardoxolone methylThe disadvantages of Bardoxolone methyl therapy : a. significantly increased albuminuria The change in albuminuria was significantly correlated with the change in eGFR. Increase in eGFR may be mediated by increase in intraglomerular hydrostatic pressure b. significantly increased adverse events -- muscle spasms, nausea, and SBP 2~4 mmHg.Bardoxolone methyl and kidney function in CKD with type 2 diabetes.N Engl J Med. 2011;365(4):327.

Other agentslimited data, including a meta-analysis, suggest that pentoxifylline lowers proteinuria and may have similar antiproteinuric effects as ACE inhibitors.

Endothelin receptor antagonists, protein kinase C inhibitors,), sulodexide, and fish oil.There are insufficient data on any of these agents to advocate their use for the treatment or prevention of diabetic nephropathy.

The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis.Am J Kidney Dis. 2008;52(3):454.

Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the DiabetesAm J Kidney Dis. 2005;45(3):485.

Summary of treatment Primary prevention for diabetic nephropathy Angiotensin inhibition Strict glycemic control PPAR gamma agonist ?

Preservation of renal function Antihypertensive therapy (particularly with an ACEI) ARB/ACEI (T2DM with overt nephropathy) Protein restriction (T1DM with overt nephropathy) ?

Combined therapy Steno type 2 diabetes study :

mean follow-up 7.8 yrs, intensive therapy reduced albumin excretion, microvascular and macrovascular disease GFR fall to the same degree in both groups.

120/75 mmHg vs 130/80mmHgAggressive blood pressure control has benefits in chronic kidney disease patientNEJM. 1994;68(6):2829.

RecommendationsType 1 DM: a. check urine ACR yearly after the first 5 yrs. If positive follow up 3-6 m x 2 (at least) confirm the diagnosis by at least 2 of 3 positive samples b. strict glycemic and lipid control c. give ACEI if BP > 130/80 mmHg or persistent microalbuminuria d. give loop diuretics to attain dry weight

Recommendations e. If BP > 130/80 mmHg or proteinuria >500 ~ 1000mg/d under ACEI treatment give nondihydropyridine calcium channel blocker (diltiazem/verapamil) or long-acting dihydropyridine calcium channel blocker if the patient already being treated with a beta- blocker f. If overt nephropathy take sodium < 90meq/d to achieve maximal antiproteinuric effects with ACEI g. Avoid high protein diet ( 1g/kg/d)

RecommendationsType 2 DM: a. give a ARB or ACEI ( not combine them !!) b. if BP > 130/80mmHg or proteinuria > 500 ~ 1000mg/d give diltiazem or verapamil c. if edema or renal insufficiency give loop diuretic to attain dry weight d. if overt nephropathy take sodium < 90meq/d to achieve maximal antiproteinuric effects with ACEI e. Avoid high protein diet ( 1g/kg/d)

Thanks for your attention !!

**Microalbuminuria = 30-300 mg/dMacroalbuminuria = >300mg/d*Olmesartan 0.01% in food 7 wksThe present study demonstrated that intrarenal AngII and type IV collagen expression are already augmented long before diabetes*(either by hyperglycemia or oververpression of glucose transporters)

Decrease in cell surface heparan sulfate( negative charged)*VEGF = a mediator of endothelial injury in human diabetes VEGF blockde improves albuminuria in an experimental model of diabetic nephropathyHypoxia-inflammation*ACEI administration decrease serum TGF-beta levels, increase GFRCombination of anti-TGF-beta antibody plus an ACEI proteinuria decrease in diabetic nephropathy rats, glomerulosclerosis and tubulointerstitial injury were also improved >> ACEI aloneAdministration of hepatocyte growth factor blocks the profibrotic actions of TGF beta, ameliorates diabetic nephropathy in miceHyperglycemia increased VEGF expression, decrease activated protein C, increase expression of TGF-beta and decrease expression of renal BMP-7 in the glomeruli worsens proteinuria

*Schematic of the slit diaphragm and other important proteins involved in maintaining foot process assembly. Many proteins are omitted to emphasize the two major complexes of proteins discussed in the text. For clarity, one complex is shown within the left foot process, the other in the right foot process. Two adjacent foot processes are shown. In the left foot process is the nephrin-FYN-NCK complex, associated with an actin filament. In the right foot process, the nephrin-podocin-CD2AP complex and the integrin-linked kinase (ILK)-parvin-pinch complex associated with both 31 integrin and nephrin are shown. Synaptopodin and -actinin 4 are also shown associated with the cytoskeleton, the latter also with integrins. Nephrin and FAT are shown as two major proteins that bridge the space between adjacent foot processes, although, as noted in the text, nephrin also associates with Neph proteins. The integrin and dystroglycan complexes are shown in each foot process. P, phosphorylation (see key for other abbreviations used in the figure).Figure 1. The Insulin-Sensing Podocyte.A recent study by Welsh and colleagues1 indicates that, in podocytes of wild-type mice, insulin activation of the insulin receptor results in the phosphorylation of Akt (the v-akt murine thymoma viral oncogene homologue 1 protein) and Mapk42 or Mapk44 (mitogen-acti-vated protein kinase 42 or 44), resulting in physiologic remodeling of the actin cytoskeleton and preservation of cell function and survival. In podocytes of mice lacking the insulin receptor, insulin signaling through Akt and Mapk42 or Mapk44 is abrogated and results in the effacement of foot processes, thickening of the glomerular basement membrane, and cell malfunction or death, leading to proteinuria.*No one factor is predictive in the individual patient*T1DM with pancreas transplantationBoth of the basal state and after a protein loadEven after overt dipstick-positive proteinuria developedNEJM 1993 1441 *12 patient*In T2DM pt, ARB > ACEIUKPDS --- prospective study, 23 hospital, 4801 patient newly diagnosed type 2 DM (25-65 y/o) follow up 8.4yrs. IDNT --- 1715 patient, type 2DM with diabetic nephropathy, mean cr:1.7 => Irbesartan, amlodipine, placebo** Too small to determine whether the effect of low blood pressure was independent of the prior history of cardiovascular disease. *Fewer studies have also demonstrated this in diabtic kidney disease patient*35, 40-60 yrs, type 2 DM. Olmesartan, 12wksRenin, L-arginine, ADMA, NODoppler-sonography using an Ultramark 9 HDI ultrasound machine (ATL, Bothell, WA) as described in detail elsewhere (12). In brief, intrarenal Doppler signals were obtained from two to three representative proximal segmental arteries. The peak systolic velocity (Vmax) and the minimal diastolic velocity (Vmin) were determined, and the renal segmental arterial resistance index was calculated as 100 x [1 (Vmin/Vmax)]. The results from two or three measurements were averaged. All measurements were performed by the same investigator. *70 wks*225 patient T1DM, normal BP, microalbuminuriaReducing blood pressure alone, especially to lower than 120/75 mmHg, may be sufficient to slow the rate of progression of nephropathy, regardless of agent used.ACEI: Albuminuria < 600 mg/24hrs > 1yrACEI*The most significant risk factor for progressive kidney disease was the degree of proteinuria, both initially and after 6 months of therapyIndependent of BP ( ARB more proteinuria reduction )CV mortality reduction => duration *1513 t2DM with diabetic nephropathy, with or without HTN*@ even SBP < 120 mmhg also has benefit@ serum creatinine doubling rate and progression to ESRD risk@ 11140 pt T2DM f/u 5-6yrs*Detail trial : 250 patient, T2DM with early nephropathy, 82% microalbuminuria, mean GFR 93 follow up 5 yrs*25620 patient with vascular disease or diabetes, ACEI + ARB compare to ramipril*2007Absence of a large fall in GFREffect on renal excretion -- proteinuria is associated with intraglomerular pressure => reduction in protein excretion has better renal outcome ACEI, ARB, protein restriction

*Small studies 81 patient, 48 wksAnother small studies 268 patient ACEI + eplerenone / pacebo additive antiproteinuria effect, similar hyperkalemia rate*Large studies of long duration**227 patients with type 2 diabetes and an estimated GFR (eGFR) between 20 and 45 mL/min per 1.73 m2 were randomly assigned to either placebo or one of three doses of bardoxolone methyl (25, 75, or 150 mg/day) [66].** Reducion of proteinuria*Blood pressure control and proteinuria reduction*Blood pressure control and proteinuria reduction*Normotensive ABCD trialAccord BP trialSADS trial

* ACEI 3-5 d f/u cr and K, increase 30-35% of baseline 2~4 month is reasonable** Proteinuria decrease, but adverse side effect and mortality rate increase, no obvious renal function improve!!If no aggresive intervention, progression from overt proteinuria to ESRD = 6-7 yrs

Diltiazem or verapamil reduction in protein excretion and renal protection*