Diabetes Nepal 2013 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY ETIOLOGY OF ESRD IN NEPAL EPIDEMIOLOGY CAUSES OF CHRONIC KIDNEY DISEASE-5 (USRDS 2012)

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1 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in most Western societies. Prof.Dr. Pramod Chhetri Department of Nephrology, Nepal Medical College Teaching Hospital. Kathmandu It is also a common cause of ESRD in Nepal. 1 2 ETIOLOGY OF ESRD IN NEPAL Year 01/01/063-30/12/063 CAUSES OF CHRONIC KIDNEY DISEASE-5(NMCTH) Total HD patients HTN DM Idio CGN Obs. Reflux ADPKD RPGN Other /01/065-30/12/ (55%) 8 (24%) 5 (15%) 1( 3%) 1 (3%) 01/01/069-20/10/ (49%) 21 (38%) 7(13%) KhakurelS et al. Pattern of end stage renal disease in a tertiary care center JNMA; 2009 Apr-Jun;48(174): CAUSES OF CHRONIC KIDNEY DISEASE-5 (USRDS 2012) EPIDEMIOLOGY In most Western countries, DN is the leading cause of ESRD. According to the US Renal Data System (2012), DN was the most common cause of ESRD. 49% patients admitted for renal replacement therapy (RRT) were diabetics. More than >90% of patients suffering from Diabetes & ESRD were type 2 diabetes

2 PATHOGENESIS OF DIABETIC NEPHROPATHY PATHOGENESIS OF DIABETES NEPHROPATHY GENETIC FACTORS. HEMODYNAMIC CHANGES. RENAL HYPERTROPHY. MESANGIAL EXPANSION & NODULE FORMATION. INFLAMMATION & IMMUNE MECHANISM. MECHANISM OF PROTEINURIA. TUBULOINTERSTITIAL FIBROSIS & TUBULAR ATROPPHY. HYPERGLYCEMIA & DIABETIC NEPHROPATHY. ADVANCED GLYCATION END PRODUCTS, PROTEIN KINASE C. POLYOL PATHWAY. RENIN ANGIOTENSIN & ALDOSTERONE PATHWAY. 7 8 PATHOGENESIS OF DIABETIC NEPHROPATHY PATHOGENESIS OF DIABETES NEPHROPATHY GENETIC FACTORS : - The risk of nephropathy is strongly determined by polygenetic Factors. The prevalence of nephropathy varies according to race & ethnicity. Approximately 30% to 40% of patients with either type 1 or type 2 diabetes will ultimately develop nephropathy. Prevalence is relatively high in African Americans, Native Americans, Mexican Americans, Australian aborigines,and urbanized Indo- Asian immigrants in the United Kingdom compared with Caucasians. The risk for development of DN is equal in type 1 and type 2 diabetes PATHOGENESIS OF DIABETIC NEPHROPATHY MECHANISM OF PROTEINURIA Familial clustering of DN has been reported in both type 1 and type 2 diabetes among the both Caucasian and non-caucasian populations. Genome scans for susceptible chromosomal regions for DN has identified several susceptibility loci, for example, on chromosomes 3q, 7p, and 18q. Net reduction in negatively charged heparin sulfate. Podocytopathy. Biopsies in patients with DN has documented a correlation between the degree of proteinuria and podocytepathology, specifically the width of the foot processes. Low Nephrin ( permeability controlling protein ). The transcription of nephrin is suppressed by Ang II and restored by inhibitors of RAS

MECHANISM OF PROTEINURIA CONTD. Apoptosis of podocytes. ( triggered by AngiotensinII and TGF-β). Reduced activated protein C (APC). (APC formation inhibits podocyte apoptosis, in Diabetic mice ).

13 14 PROTEIN KINASE C (PKC ) PATHWAY ADVANCED GLYCATION ENDPRODUCTS (AGEs) PATHWAY Many of the adverse effects of hyperglycemia have been attributed to activation of PKC.

PKC-β selective inhibitor ameliorated glomerularhyperfiltration, albuminuria, and renal TGF-β overex-pression as well as extracellular matrix accumulation.

3 MECHANISM OF PROTEINURIA CONTD. Apoptosis of podocytes. ( triggered by AngiotensinII and TGF-β). Reduced activated protein C (APC). (APC formation inhibits podocyte apoptosis, in Diabetic mice ). Lack of adiponectin (may further contribute to proteinuria ) PROTEIN KINASE C (PKC ) PATHWAY ADVANCED GLYCATION ENDPRODUCTS (AGEs) PATHWAY Many of the adverse effects of hyperglycemia have been attributed to activation of PKC. PKC activity is increasd in the retina, aorta, heart, and glomeruli of diabetic animals. PKC-β selective inhibitor ameliorated glomerularhyperfiltration, albuminuria, and renal TGF-β overex-pression as well as extracellular matrix accumulation.. Chronic hyperglycemia lead to nonenzymaticglycationof amino acids & proteins (Maillard or browning reaction). Over time, these products undergo rearrangement, including cross linking, to become irreversible AGEs. Ultimately, both circulating and tissue proteins as well as lipids and nucleic acids may thus become glycated. The concentration of AGEs is increased in the sera of DN patients. AGEs have also been localized to diabetic glomeruliby immunohistochemistry ADVANCED GLYCATION ENDPRODUCTS (AGEs) PATHWAY CONTD. AGEs bind to a variety of cell types, including macrophages and mesangial cells. They mediate a variety of cellular actions, including expression of adhesion molecules, cell hypertrophy, extracellular matrix synthesis, epithelial to mesenchymaltransition, and inhibition of NOS. AGEs injected in vivo induce albuminuriaand glomerulosclerosis. Administration of aminoguanidine, an inhibitor of AGE formation, to animals with diabetes reduces AGE deposition,mesangialmatrix expansion, and albuminuria

Activation of the intrarenal RAS plays a critical role in the development of DN. Proved in Animal experiments. RENIN ANGIOTENSIN & ALDOSTERONE SYSTEM CONTD.

4 RENIN ANGIOTENSIN & ALDOSTERONE SYSTEM ACEI & ARB Retard the progression of DN, Proved by Studies in patients with type 1 and type 2 diabetes. Plasma reninactivity is low in DN, it is inappropriate in relation to increased extracellular volume and exchangeable sodium,suggesting activation of the RAS. Activation of the intrarenal RAS plays a critical role in the development of DN. Proved in Animal experiments. RENIN ANGIOTENSIN & ALDOSTERONE SYSTEM CONTD. Local RAS is activated in glomeruli (podocytes, mesangialand endothelial cells), renal vessels, and tubular cells.(observed in experimental diabetes). High glucose concentration and AGEs stimulate angiotensinogenand reninexpression in various renal cells, mainly through reactive oxygen species. Proteinuria further activates the local RAS in tubular cells RENIN ANGIOTENSIN & ALDOSTERONE SYSTEM CONTD. AngII mediates cell proliferation, hypertrophy, matrix expansion, and cytokine (TGF-β, VEGF) synthesis through its nonhemodynamic effects. Aldosteroneaccelerates progression in renal damage models independent of Ang II. Aldosteronesynthesis is stimulated in DN, and it stimulates the synthesis of other proinflammatory and profibrogenic cytokines (MCP-1, TGF-β). Other vasoactiveagents may also be involved in the pathogenesis of DN,includingalteration of systemic or intrarenal production of endothelin, NO, the kallikrein-kinin system,and natriuretic peptides. 21 Mogensenproposed a scheme of the different stages of DN (Fig. 29.9) that is valid in type 1 diabetes but less reliable in type 2 diabetes, in which CKD may occur in the absence of microal-buminuria, possibly the result of microvasculardisease. 22 DIAGNOSIS OF DN The diagnosis of DN is based on the detection of proteinuria. In addition, most patients will also have hypertension and retinopathy. To establish the diagnosis of DN the following tests should be done, Measurement of urinary albumin or protein. Measurement of serum creatinine concentration and estimationof GFR. Measurement of BP. Ophthalmologic examination

The detection of urinary albumin is a specific indicator of DN.

General measures for prevention of DN include glycemic control and blood pressure control.

In type 1 diabetic patients, strict glycemiccontrol the risk for microalbuminuria.

5 The detection of urinary albumin is a specific indicator of DN PREVENTION OF DIABETIC NEPHROPATHY PREVENTION IS BETTER THAN CURE Prevention and early detection of nephropathy improve patient outcome. General measures for prevention of DN include glycemic control and blood pressure control. Treatment of dyslipidemia,modification of diet and lifestyle, including physical activity and weight reduction as appropriate and smoking cessation, can significantly lower the CV risks. In type 1 diabetic patients, strict glycemiccontrol the risk for microalbuminuria. DCCT, compared the effects of intensive glucose control with conventional treatment on the development and progression of the long-term complications of type 1 diabetes. During a 9-year period, patients receiving intensive therapy (mean HbA1c 7%) had a 35% to 45% lower risk for development of microalbuminuria compared with the control group (mean HbA1c 9%). Renoprotection can persist even after a return to less intensive therapy Several major studies have demonstrated a lower risk of nephropathy with stricter glycemiccontrol in type 2 diabetse. Kumamoto study found a 60% reduction in the rate of microalbuminuria in relatively young nonobese type 2 diabetic patients receiving intensive glycemic treatment (HbA1c 7.1%) compared with conventional treatment (HbA1c 9.4 % ). In the U.K. Prospective Diabetes Study (UKPDS) trial, newly diagnosed patients with type 2 diabetes were randomly assigned to intensive management (HbA1c 7.0%) with a sulfonylurea or insulin or to conventional management (HbA1c 7.9%) with diet alone. After 9 years of intensive therapy, relative risk reduction for the development of microalbuminuria was 24%. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23(Suppl 2):B21-B29.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:

Insulin secretagogues(sulfonylurea and meglitinides) can be associated with hypoglycemia, with occurrence rates reported from 10% to 35%.

6 Metformin has been used in low doses in patients with GFR as low as 30 to 60 ml/min. It should not be used at a GFR below 30 ml/min. As renal function can deteriorate abruptly, it is better to avoid metforminonce serum creatinineconcentration rises above 1.5 mg/dl (132 µmo/l) in men and above 1.3 mg/dl (117 µmol/l) in women. Insulin secretagogues(sulfonylurea and meglitinides) can be associated with hypoglycemia, with occurrence rates reported from 10% to 35%. These can be severe and long lasting in those receiving sulfonylureas, requiring hospitalization for treatment. Glycosidase inhibitors are short acting(because they interfere with the absorption of sucrose or starch) so the patients taking these agents need to use dextrose tablets or glucose powder to treat hypoglycemia. Glycosidase inhibitors are contraindicated in renal failure. Thiazolidinedionesare associated with weight gain( partly due to fluid retention & also due to nonfluidgains. In patients at risk for congestive heart failure, these should be avoided. There is also concern about increased bone fracture rates in patients using thiazolidinediones,whichcould potentiate CKD-related bone disease Insulin regimens are the most commonly used to control glycemia in CKD. However the half-life of insulin increases as CKD progresses, so, there is risk for hypoglycemia. Consequently, multiple daily injections, by which insulin doses can be more closely regulated, would be appropriate choice. However, ideal insulin therapies remain undefined in CKD. It is also unclear whether intermediate or longer acting insulins should be avoided and rapid-acting analogues used instead The rapidly acting insulin analogues lispro and aspartexhibit similar pharmacokinetics in CKD patients as in patients with normal GFR. The same is true for detemir, but so far no clinical data on its use in CKD patients are available. Glargine has been shown to reduce hypoglycemia in hemodialysis (HD) patients

increased risk of kidney failure. The NKF, JNC7 & ADA recommend a target blood pressure value of below 130/80 mm Hg in diabetic patients. Tarnow L, Rossing P, Gall MA, et al.

7 37 38 TREATMENT OF HYPERTENSION Hypertension is present in about 40% of type 1 and 70% of type 2 diabetic patients with normoalbuminuria. Higher blood pressure level is associated with an increased risk for the development of nephropathy; and in patients with established nephropathy, it is associated with more rapid progression and increased risk of kidney failure. The NKF, JNC7 & ADA recommend a target blood pressure value of below 130/80 mm Hg in diabetic patients. Tarnow L, Rossing P, Gall MA, et al. Prevalence of arterial hypertension in diabetic patients before and after the JNC V.DiabetesCare 1994;17: Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36: American Diabetes Association Clinical Practice Recommendations Diabetes Care. 2001;24(Suppl1):S1-S133 RENIN ANGIOTENSIN ALDOSTERONE BLOCADE IN DN In diabetic patients with established DN, RAS blockade with ACEI or ARBs confers renoprotectionthat is independent of blood pressure reduction. Many studies have demonstrated a beneficial effect of ACE inhibitors and ARBs in retarding progressive renal disease. Plasma aldosteronelevels are elevated in a subset of patients despite ACE inhibitor and ARB therapy (also known as aldosteroneescape or aldosterone breakthrough). Aldosteronecause retention sodium and excretion of potassium and magnesium as well as promotes tissue inflammation and fibrosis. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int. 2004;66: RAS BLOCADE IN TYPE 1 DIABETES In type 1 diabetics with microalbuminuria, ACE inhibitors reduce the risk of progression to overt nephropathy. In a meta-analysis of 12 placebo-controlled trials in 698 normotensivepatients with type 1 diabetes and microalbuminuria treated with ACE inhibitors, the majority for more than 2 years, treatment was associated with a 60% reduction in progression to macroalbuminuria and a threefold increase in regression to normoalbuminuria. RAS BLOCADE IN TYPE 1 DIABETES In patients with macroalbuminuriaor overt nephropathy, the Collaborative Study Group trial demonstrated that captopril reduced albuminuria, slowed the decrement in GFR, and delayed the onset of kidney failure compared with placebo. There are insufficient data and no large long-term clinical trials to demonstrate the efficacy of ARBs in type 1 DN. The Microalbuminuria Captopril Study Group. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabeto-logia. 1996;39: Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The Collaborative Study Group: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329: Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A metaanalysis of individual patient data. Ann Intern Med. 2001;134:

8 RAS BLOCADE IN TYPE 2 DIABETICS In type 2 diabetics, there are more data available on the renoprotectiveeffect of ARBs compared with ACE inhibitors. In the stage of microalbuminuria, the IRMA 2 study showed that the ARB irbesartan reduces progression to overt nephropathy by 70% in hypertensive type 2 diabetic patients during a 2-year. In the MARVAL trial, the ARB valsartan (80 mg/day) produced a greater reduction in UAE than did amlodipine (44% versus 8%) with the same degree of blood pressure reduction, suggesting that the antiproteinuric effect of ARBs is blood pressure independent. ACEI & ARB COMBINATION ACE inhibitors and ARBs have been used simultaneously for therapeutic synergy in patients with nondiabetic renal disease (COOPERATE trial). In both type 1 and type 2 diabetics with nephropathy, results of several earlier small trials suggested that the combination of an ACEI & an ARB is more effective in reducing BP and proteinuriathan is either drug alone. However, there were no data from these trials on the effect of combined therapy on kidney disease progression. Parving HH, Lehnert H, Brochner-Mortensen J,et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345: Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: A blood pressure independent effect. Circulation. 2002;106: Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-ii receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet. 2003;361: Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hyperten-sion, microalbuminuria, and non insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000; 321: ACEI & ARB COMBINATION The recent ONTARGET study, which included diabetic and nondiabetic patients with CV risk, failed to show improved CV outcomes from a combination of an ACEI & an ARB. Instead, it showed increased renal functional decline, a trend toward an increase in the development of ESRD. ACEI & ARBs have also been studied in combination with aldosterone receptor antagonists (e.g., spironolactone, eplerenone) and a direct renin inhibitor (aliskiren); further reductions in proteinuriahave been reported with these combinations compared with the ACEI or ARB alone. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1: Parving HH, Persson F, Lewis JB, et al; the AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N EnglJ Med. 2008;358: OTHER ANTIHYPERTENSIVE AGENTS USED IN DN DIURETICS The antiproteinuriceffects of RAS blockade are enhanced by sodium restriction. Thus, patients receiving ACE inhibitors or ARBs should be instructed to take a low-sodium diet (e.g., less than 2 g of sodium/d). The combination of a loop diuretic or a thiazidediuretic with agents that block the RAS may be more effective than either type of treatment alone for lowering blood pressure OTHER ANTIHYPERTENSIVE AGENTS USED IN DN Nondihydropyridinecalcium channel blockers (e.g., diltiazem, verapamil) have been shown in some studies to have antiproteinuriceffects. In type 2 diabetic patients with normoalbuminuria, however, nondihydropyridinecalcium channel blockers did not reduce the incidence of microalbuminuriarelative to placebo, nor do they enhance the effect of ACE inhibitors in preventing microalbuminuria. Dihydropyridinecalcium channel blockers (e.g., nisoldipine, nifedipine, amlodipine) may be used as additional antihypertensive agents,butthey have not been shown to reduce albuminuriaor to slow the progression of renal disease. OTHER ANTIHYPERTENSIVE AGENTS USED IN DN B-BLOCKER Classic β-blockers have adverse metabolic effects and are therefore not recommended in diabetics,but this is no longer true for the modern β- blockers carvedilol and nebivolol. Despite insufficient controlled evidence, β-blockade with these novel blockers appears to be useful because of the extremely high CV risk in diabetic patients with nephropathy. Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist sub classes on markers of nephropathy progression. Kidney Int. 2004;65:

9 OTHER ANTIHYPERTENSIVE AGENTS USED IN DN DIRECT RENIN INHIBITION Aliskiren is the first orally active direct renin inhibitor approved for treatment of hypertension. In the AVOIDtrial, the addition of aliskirenproduced greater reduction in UAE compared with placebo in type 2 diabetic patients with hypertension & nephropathy receiving the maximum recommended dose of losartan (100 mg daily). TREATMENT OF DYSLIPIDEMIA Patients with DN have dyslipidemia, characterized by low levels of HDL cholesterol, high TG levels, & a shift from larger toward smaller LDL cholesterol. Dyslipidemia in diabetic patients may contribute to the development of glomerulosclerosis and progressive renal disease. The major side effects of aliskirenare, hyperkalemia, hypotension, & reduced GFR. Parving HH, Persson F, Lewis JB, et al; the AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358: Jenkins AJ, Lyons TJ, Zheng D, et al. Lipoproteins in the DCCT/EDIC cohort: Associations with diabetic nephropathy. Kidney Int. 2003;64: Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia a determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int Suppl. 1994;45:S125-S TREATMENT OF DYSLIPIDEMIA In type 2 diabetic patients with nondialysisdependent DN, treatment with statinsprovides substantial CV benefit. TREATMENT OF DYSLIPIDEMIA Major statintrials have failed to demonstrate that lowering of LDL cholesterol prevents the majority of adverse CV events. Current guidelines recommend a goal for LDL cholesterol below 100 mg/dl for diabetic patients in general and below 70 mg/dl for diabetic patients with CVD. However, LDL cholesterol is not the sole lipid that defines CV risk. Elevated TG, low HDL cholesterol, elevated apolipoprotein β, & C-III, are more atherogenic & thought play a key role diabetic patients. Elevated TG was independently associated with albuminuria in type 2 diabetic patients ( UKPDS ). Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110: Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: A call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102:1K-34K. HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial. Lancet. 2004;364: NON PHARMACOLOGIC INTERVENTATION Dietary protein restriction may alleviate uremic symptoms in patients at or approaching ESRD. Small trials have shown low-protein diet (0.8 g/kg /d) to significantly reduce proteinuriawith an increase in plasma albumin in macroalbuminuric type 2 diabetic patients. NON PHARMACOLOGIC INTERVENTATION Nutritionist counseling is advised for all patients with advanced CKD to avoid protein-calorie malnutrition before renal replacement therapy. All patients with DN should be given counseling on salt, potassium, and phosphate restriction as well as choice of carbohydrates and fats. Giordano M, Lucidi P, Ciarambino T, et al. Effects of dietary protein restriction on albumin and fibrinogen synthesis in macroalbuminuric type 2 diabetic patients. Diabetologia. 2008;51:

NON PHARMACOLOGIC INTERVENTATION LIFE STYL MODIFICATION Lifestyle modifications such as smoking cessation and weight reduction can provide additive renal benefits and lower the

There is evidence that smoking cessation ameliorates progression of microalbuminuria to macroalbuminuria and improves renal prognosis.

Pioglitazonein combination with the ARB losartanseems to offer greater renoprotection than does losartan alone in short-term studies. Redon J.

Continued smoking exacerbates but cessation ameliorates progression of early type 2 diabeti nephropathy. Am J Med Sci. 2008;335:284-291.

10 NON PHARMACOLOGIC INTERVENTATION LIFE STYL MODIFICATION Lifestyle modifications such as smoking cessation and weight reduction can provide additive renal benefits and lower the risk of CV events in patients with established DN. There is evidence that smoking cessation ameliorates progression of microalbuminuria to macroalbuminuria and improves renal prognosis. NEWER TREATMENT DN Peroxisome proliferator-activated receptors (PPAR). Thiazolidinediones (e.g., pioglitazone, rosiglitazone) are PPARγ agonists with insulin-sensitizing actions. Pioglitazonein combination with the ARB losartanseems to offer greater renoprotection than does losartan alone in short-term studies. Redon J. Measurement of microalbuminuria what the nephrologist should know. Nephrol Dial Transplant. 2006;21: Phisitkul K, Hegazy K, Chuahirun T, et al. Continued smoking exacerbates but cessation ameliorates progression of early type 2 diabeti nephropathy. Am J Med Sci. 2008;335: NEWER TREATMENT DN The glycosaminoglycan sulodexide has recently been shown to have no benefit for micro albuminuricor overtly proteinuric DN. Several other agents, including avosentan (an endothelina receptor blocker), protein kinasec inhibitors, fenofibrate, pirfenidone, monoclonal anti connective tissue growth factor antibody, mycophenolate mofetil (MMF), and fish oil, have been evaluated for proteinuric renal disease including DN

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