Early Detection and Therapeutic Intervention in Diabetic Kidney Disease. Milly Mathew, Georgi Abraham, Vivekanandan INTRODUCTION

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1 Early Detection and Therapeutic Intervention in Diabetic Kidney Disease Milly Mathew, Georgi Abraham, Vivekanandan INTRODUCTION Diabetes Mellitus is the most common cause of end stage renal disease worldwide with about 51 million Type 2 diabetics in India. Diabetic Kidney disease (DKD) is progressive and characterized by structural changes in the kidney that include predominantly hyalinosis of efferent arteriole glomerular hypertrophy, podocyte loss, thickening of glomerular basement membrane, expansion of mesangial matrix, glomerulo sclerosis and tubulointerstitial fibrosis. Less common changes include insudative lesions due to imbibed plasma proteins and lipids within the arterioles, glomerularcapillaries, Bowman s capsule or proximal convoluted tubules. Insudative lesion in Bowman s capsule are called capsular drop( located between parietal epithelium and Bowman s capsule) lesions and in the glomerular capillaries they are called fibrin cap lesions 1. These changes functionally lead to microalbuminuria progressing to macroalbuminuria and reduction in GFR. The pathogenesis of DKD is multifactorial. Hypertension, abnormal carbohydrate and lipid metabolism, accumulation of lipids, up regulation of profibrotic growth factors, vascular endothelial growth factor, up regulation of proinflammatory cytokines, interlukin 1β, increased oxidative stress and increased production of advanced glycartion end products all play an important role in the pathogenesis and progression of DKD. Nuclear hormone receptors have a role in pathogenesis of DKD including peroxisome proliferator associated receptors (PPARS) oestrogen receptors, Vitamin D receptors (VDR) heptocyte nuclear factor 4 and farnesoid x receptor 2. Human podocytes contain endothelin binding sites and express fully functional endothelin system. Angiotensin ll which is a strong inducer of endothelin synthesis in vivo promotes disruption of the podocyte actin cytoskeleton thereby increasing glomerular albumin permeability and podocyte apoptosis. PATHOLOGICAL CLASSIFICATION OF DKD 1 Glomerular Lesions of DN, Interstitial and Vascular lesions of Diabetic Nephropathy (DN) and Flow Chart for classifying DN are shown in Table I, II and Fig.1, 2 and 3 respectively. Current Management Strategies of Diabetic Kidney Disease Guidelines Screening and Diagnosis of Diabetic Kidney Disease Management of Diabetes and CKD Hyperglycemia and general Diabetes care. Hypertension. Dyslipidemia. Nutrition. Clinical Practice Recommendations Management of albuminuria in normotensive diabetic patients and albuminuria as a surrogate marker. Multi-faceted approach to intervention. Special populations. Behavioral self-management. SCREENING The onset and progression of nephropathy can be delayed by interventions, provided they are instituted early in the course of the disease. Screening is of paramount importance

mesangial expansion Biopsy does not meet criteria for class II or IV Mild mesangial expansion in >25% of the observed mesangium IIb Severe mesangial expansion Biopsy does not meet criteria for class

2 150 Medicine Update-2011 Class Description Inclusion Criteria I Mild or nonspecific LM changes and EM - proven GBM thickening Table I. Glomerular Lesions of DN Biopsy does not meet any of the criteria mentioned below for class II, III, or IV GBM> 395 nm in female and >430 nm in male individuals 9 years of age and older IIa Mild mesangial expansion Biopsy does not meet criteria for class II or IV Mild mesangial expansion in >25% of the observed mesangium IIb Severe mesangial expansion Biopsy does not meet criteria for class III or IV Severe mesangial expansion in >25% of the observed mesangium III IV Nodular sclerosis (Kimmelstiel Wilson lesion) Advanced diabetic glomerulosclerosis Biopsy does not meet criteria for class IV At least one convincing Kimmelstiel Wilson lesion Global glomerual sclerosis in > 50% of glomeruli Lesions from class I through III LM-Light microscopy On the basis of direct measurement of GBM width by EM, these individual cut of levels may be considered indicative when other GBM measurement are used Table II. Interstitial and Vascular lesions of Diabetic Nephropathy (DN) Lesion Criteria Score Interstitial lesions IFTA No IFTA 0 < 25% 1 25% to 50 % 2 >50% 3 Interstitial Inflammation Absent 0 Infiltration only in relaton to IFTA 1 Infiltration in areas without IFTA 2 Vascular lesions arteriolar hyalinosis Absent 0 At least one area of arteriolar hyalinosis 1 More than one area of arteriolar hyalinosis 2 Presence of large vessels Yes/No arteriosclerosis (score worst artery) No intimal thickening 0 Intimal thickening less than thickness of media 1 Intimal thickening greater than thickness of media 2 Mild ischemic changes Wide GBM Mild and moderate mesangial expansion Fig.1: Morphologic Lesions in DN

Medicine Update-2011 151 Kimmelstiel-Wilson lesion Glomerulosclerosis Fig.2: Morphologic Lesions in DN Fig.3: Flow Chart for classifying DN for this reason.

Test for microalbuminuria should be conducted in the absence of overt proteinuria. This can be done by measuring albumin to creatinine ratio (ACR 30 mg/1gm) in a spot urine sample 3.

creatinine mg/dl and for woman X 0.85. Persistent microalbuminuria should be confirmed by two or more urine samples over the following 3 to 6 months.

3 Medicine Update Kimmelstiel-Wilson lesion Glomerulosclerosis Fig.2: Morphologic Lesions in DN Fig.3: Flow Chart for classifying DN for this reason. It is recommended that a urine analysis should be performed annually starting at 5 years after the onset of type 1 DM, at the time of diagnosis of type 2 DM then annually. Test for microalbuminuria should be conducted in the absence of overt proteinuria. This can be done by measuring albumin to creatinine ratio (ACR 30 mg/1gm) in a spot urine sample 3. Estimation of GFR (egfr) by using MDRD formula (not validated for India) or Cockroft and Gault formula for creatinine clearance ml/minute (140- age) X wt in Kg/ 72 X S. creatinine mg/dl and for woman X Persistent microalbuminuria should be confirmed by two or more urine samples over the following 3 to 6 months. Once a patient develops protenuria it is important to rule out causes other than diabetes. If the presence of glomerular disease other than diabetes is suspected a kidney biopsy may be required for confirmation. (Table III). Table III. Interpretation of Albuminuria Results. DKD is often present if: Macroalbuminuria (urine ACR> 300 mg/g) Microalbuminuria (urine ACR between mg/g) Presence of retinopathy In type 1 diabetes, duration at least 10 years DKD may not be present if: Absence of diabetic retinopathy Rapid decline in GFR (> 1 ml/min per month) Sudden onset of nephritic syndrome Refractory hypertension Active urinary sediment (hematuria) Signs or symptoms of systemic disease >30% reduction in GFR after starting an ACEi or an ARB

4 152 Medicine Update-2011 Treatment of DKD is based on the clinical stage of the disease process. Both renal and cardiovascular morbidity and mortality are increased in patients with type 2 DM. The level of albumin excretion is predictive of renal and cardiovascular outcome. Annual rates of nephropathy progression and death in type 2 diabetes in UKPDS study is shown in the flow chart 4. (Fig.4) Strategies for prevention and treatment of Proteinuria in diabetic kidney disease are shown in Table IV. Tight glucose control has been shown to reduce the degree of nephromegaly and hyper filtration in type 1 DM. The lowest possible HbA1c for the individual patient is the target which should between 6.5% to 7%. Blood pressure control is the most effective measure for delaying the progression of CKD in diabetic patient with overt proteinuria. Therefore it is important to treat hypertension to the recommended target of 140/80 in all diabetic patients. With optimal blood pressure control it is possible to slow down the progression of the natural course of CKD in diabetes from rate of approximately 12 ml/min/ year to 4 ml/min/year or lower. Hypertensive people with diabetes and CKD Stage 1-4 should be treated with an ACE inhibitor or an ARB, usually in combination with a diuretic. If blood pressure and proteinuria are not optimal, plasma rennin antagonist aliskiren 50mg once daily may be added and dose can be titrated up to 150mg/day. Aldosterone antagonist such as spirinolactone or eplirenone had been shown to be kidney protective. Hyporeninemic Hypo aldosteronism may coexist with diabetic nephropathy leading to severe hyperkalemia and hence caution should be exercised while using potassium retaining medications. The choice of ACEI/ ARB can be individualised. How ever in patients with hyperkalemia (K > 5 mmol/l) one should be careful in using ACEI, ARB, aliskiren. Fig.4: Flow Chart Annual Rates of Nephropathy Progression and Death in Type 2 Diabetes (UKPDS)

5 Medicine Update Table IV. Strategies for prevention and treatment of Proteinuria in diabetic kidney disease Stage No proteinuria Microalbuminuria Proteinuria Declining Kidney function Assessment Monitor blood pressure Monitor blood glucose, screen for microalbuminuria if type 1 diabetic for over 5 years, or type 2 diabetic Close monitoring of blood pressure, blood glucose and bold lipids. Monitor urinary protein and 24 hours cratinine clearance (measure of kidney function) Close monitoring of blood pressure, blood glucose and blood lipids. Monitor urinary protein and 24 hours creatinine clearance. Treatment Aim BP 140/80 mmhg. HbA1c under 7%. Dietary advice for sugar and fat. STOP SMOKING Add further blood pressure lowering drugs if needed. Aim total cholesterol under 200mg/dl. Add ACE inhibitor if possible. Low protein diet. Prepare for dialysis and / or transplantation Fig.5: Antidiabetic Therapy in Patients with Chronic Kidney Disease MANAGEMENT OF HYPERGLYCEMIA Reductions in hyperglycemia continued to be of therapeutic importance in Type 1 and Type 2 Diabetic patients with or without nephropathy. Intensive control of blood glucose reduces the incidence of microabuminuria by 59% and progression to macroalbuminuria by 84% 5. Target HbA1c for all people with diabetic should be < 7% irrespective of the presence or absence of CKD. Reduction in doses of insulin and oral hypoglycemic agents (OHA) is necessary to prevent hypoglycemia in patients with significant DKD because insulin is degraded by the kidney and also some sulfonylurea compounds are metabolised by the kidney. Insulin sensitising agent metformin is contraindicated in DKD if Serum cretinine > 1.5 mg/dl in males or > 1.4 mg/dl in females or creatinine clearance < 60 ml/min. metformin should be discontinued for 48 hours before any surgery or administration of contrast media. Newer OHA used in DKD 6 are given in the Fig.5.

6 154 Medicine Update-2011 Clinical study DCCT/ EDIC GREACE MRC/BHF Heart Protection study (HPS) FIELD Perkins et al. Table V. Clinical Studies of lipids in diabetic nephropathy 7 Relevance to lipids and diabetic nephropathy Renal dysfunction as measured by albumin excretion rate correlated positively with elevated levels of TGRL subclasses; renal dysfunction was also associated with a shift towards smaller LDL and HDL particles and elevated apob and apoa1 levels. Atorvastatin significantly increased GFR in dyslipidemic patients Renal function as measured by estimated GFR in dyslipidemic patients Rate of progression to albuminuria was significantly reduced by therapy with fenofibrate Low levels of both cholesterol and triglyceride were independently associated with regression of microalbuminuria in patients with type 1 diabetics Abbreviations: apo-apolipoprotein, GFR- glomerular filtration rate; TGRL-Triglyceride rich lipoprotein Table VI AGE inhibitors and cross link breakers Protein Kinase C beta inhibitors Oxidative stress inhibitors Enhancers of ACEi / ARB action Selective Estrogen Receptor Modulator Vitamin D analogues Alagebrium, pyridoxamine ( intermediate of B6 ) Ruboxistaurin Thiamine and benfothiamine Osiglitazone, pioglitazone Sulodexide, glycosaminoglycan Raloxifene Paricalcitol 2 mcg/day lowers albuminuria in patients with Type 2 diabetic nephropathy along with ACEI or ARB 9 Lipid Management The treatment of hyperlipidemia is known to be important in the prevention of artherosclerosis. Use of statins may protect against the development of glomerulosclerosis. The current treatment goals said by the ADA are a low density lipoprotein cholesterol level of less than 100 mg/dl, triglycerides less than 150mg/dl and high density lipoprotein greater than 40mg/dl 7. (Table V) Novel Therapeutic Strategies Various therapies that reduce or inhibit the progression of renal fibrosis are being investigated as a strategy to treat DKD 8. (Table VI) Avoidance of Nephrotoxic agents and Relieving Obstruction Nephrotoxic agents are detrimental to the residual renal function 10 NSAIDS Aminoglycosides radio-contrast media certain herbs (aristolochic acid) Lower urinary tract obstruction BPH, neurogenic bladder Treatment of End Stage Renal Disease (ESRD) in Diabetes Once a diabetic patient reaches ESRD options for renal replacement therapy should be offered. Haemo Dialysis, Peritoneal dialysis or kidney and pancreas - kidney transplantation. Diabetic kidney disease is a complex issue and requires multidisciplinary approach involving Diabetologist, cardiologist, renal physician, ophthalmologist, neurologist, nutritionist and podiatrist.

7 Medicine Update REFERENCES 1. Thijs W. Cohen Tervaert, Antien L. Mooyaart, Kerstin Amann et al. Pathologic classification of diabetic nephropathy. JASN 2010;21: Xiaoxin X. Wang, Tao Jiang, Moshe Levi. Nuclear hormone receptors in diabetic nephropathy. Nature Reviews Nephrology 2010;6: Fuad N. Ziyadeh. Management of diabetic nephropathy. Primer on kidney diseases 2009: Alder Al et al. Kidney Int. 2003;61: UKPDS Lancet 1998;352: , Diabets Rs Clin Pract 1995;28: G Schernthaner - State of the Art Lecture EDTA-ERA Congress in Stockholm John C. Rutledge, Kit F. Ng, Hnin H. Aung and Dennis W. Wilson. Nature Reviews Nephrology 2010;6: Abaterusso C. Treat Endocinol 2006, Tuttle K R Diabetes Care Nephrology Times 2010;3: 1, ISN Workshop on Prevention of Progression of CKD, Hong Kong 2004

Diabetic Nephropathy

Diabetic Nephropathy Objectives: Know what Diabetic Nephropathy means. Know how common is Diabetic nephropathy in Saudi Arabia and to appreciate how bad are this complications. Know the risk factors of