In The Name of GOD

1. In The Name of GOD

2. Diabet and Hypertension in CKD Patients Dr. SaharVahdat, Nephrologist

3. Diabetes • The prevalence of DM contibues to rise with an expected 370 million to be affected in 2030 • Leading cause of ESRD in Western countries

5. Diabetic Renal Disease • Can develop in the course of both Type I & Type II diabetes • The proportion of patients who develop proteinuria and elevated serum Cr is related to duration of diabetes • Overt diabetic nephropathy is characterized by persistent albuminuria 300mg/24h on at least 2 occasions separated by 3- 6 months

6. Prevalent counts & adjusted rates of ESRD, by primary diagnosisFigure 1.15 (Volume 2)

7. Pathogenesis of Diabetic Nephropathy • Haemodynamic changes- increased GFR- afferent arteriolar vasodilatation mediated by range of vasoactive mediators • Renal hypertrophy- plasma glucose stimulates several growth factors within the kidney • Mesangial expansion & nodule formation • Proteinuria • Tubulo-interstitial fibrosis

8. Normalglomerulus

9. Kimmelstiel-Wilson Nodule

10. Diagnosis • History of Diabetes Mellitus • Proteinuria • Presence of other diabetic complications eg retinopathy • Renal Impairment in later stages • Note no haematuria – if present may require renal biopsy

11. Albuminuria • Normoalbuminuria <30mg/g creatinine • Microalbuminuria 30-300 mg/g creatinine • Macroalbuminuria >300 mg/g creatinine

14. Proteinuria in Diabetics The greater the proteinuria, the higher the CV risk

18. Prevention & Treatment • Glycaemic control • Maintain tight glycaemic control • (HbA1c < 7) • Anti-hypertensive therapy • Tight BP control • ACE inhibitors and ARBs • Lipid control

19. Glycemic Targets

20. cardiovascuiarDisease(CVD) & Diabetes

22. 2015 American Diabetes Association (ADA) Diabetes Guidelines Summary Recommendations from NDEI • Microvascular Complications & Foot Care

23. 2015 American Diabetes Association (ADA) Diabetes Guidelines Summary Recommendations from NDEI • Immunizations

24. Factors favouring the diagnosis of classical diabetic nephropathy or alternative renal diagnoses

25. Conditions that can cause transient albuminuria

26. Screening for Albuminuria When screening for albuminuria, the test of choice is the random urine albumin-to-creatinine ratio (urinary ACR). The 24-hour urine collection for protein/albumin remains the gold standard; however, it is cumbersome to implement on a large scale and is often performed incorrectly. The random urine for albumin is insufficient, as the urinary albumin concentration can vary due to urine concentration. A random urine ACR predicts 24-hour urinary albumin excretion sufficiently well and is the test of choice for screening for albuminuria.

27. There is substantial day-to-day variability in albuminuria • . In addition, transient increases in albuminuria can be provoked by a number of factors. When such conditions are present, screening for kidney disease should be delayed to avoid false positives. • Furthermore, diagnosing a person as having albuminuria requires the elevated urinary albumin level to be persistent • . At least 2 of 3 urine samples over time exhibiting elevations in urinary albumin levels are required before it is considered to be abnormal.

28. Estimation of GFR The serum creatinine is the most common measurement of kidney function; however, it can inaccurately reflect renal function in many scenarios, particularly in extremes of patient age or size. Indeed, in people with diabetes, the GFR usually will be less than half of normal before the serum creatinine exceeds the lab normal range.

29. Relative risk of chronic kidney disease (CKD).

30. Treatment Algorithm for Diabetic Nephropathy

33. Despite the strong interplay between diabetes and CKD, the management of patients with diabetes and CKD stage 3b or higher (eGFR <45 mL/min) remains problematic. • Many guidance-providing documents have been produced on the management of patients with diabetes to prevent or delay the progression to CKD, mostly defined as the presence of micro and macro-albuminuria. • However, none of these documents specifically deal with the management of patients with CKD stage 3b or higher. • Key risk factors for diabetic nephropathy include long duration of diabetes, poor glycemic control, hypertension, male gender, obesity and cigarette smoking. Many of these factors are modifiable.

34. The earliest stage of diabetic nephropathy is hyperfiltration, where the glomerular filtration rate (GFR) is significantly higher than normal. • Identification of hyperfiltration is not clinically useful, as it is difficult to determine from routine testing. • Persistent albuminuria is considered the earliest clinical sign of diabetic nephropathy. Initially, small amounts of albumin are leaked, below the detection threshold of a urine dipstick. This stage is referred to as “microalbuminuria.”

35. This can worsen so that the urinary albumin excretion is sufficiently high to be detectable by a urine dipstick, a stage known as “overt nephropathy.” • The rate of progression from normoalbuminuria to microalbuminuria then to overt nephropathy usually is slow, typically taking 5 years or longer to progress through each stage. During the early stages of diabetic nephropathy, the rate of loss of renal function is relatively slow (1 to 2 mL/min/1.73 m2 per year) and not impressively higher than what is seen in the general population (0.5 to 1 mL/min/1.73 m2 per year) However, late in the overt nephropathy phase, the rate of decline of renal function can accelerate (5 to 10 mL/min/1.73 m2 per year). • Thus, significant renal dysfunction is not usually seen until late in the course of diabetic nephropathy.

36. It is important to note that the rate of progression can vary between individuals, and that the clinical markers of the disease (i.e. estimated glomerular filtration rate [eGFR], urinary albumin levels) do not always correlate well with the severity of renal disease seen on biopsy. • Additionally, aggressive control of blood pressure (BP) and glycemia, and the use of renal protective drugs can slow or stop progression of diabetic nephropathy.

37. Key Messages • Identification of chronic kidney disease (CKD) in diabetes requires screening for proteinuria, as well as an assessment of renal function. • All individuals with CKD should be considered at high risk for cardiovascular events and should be treated to reduce these risks. • The progression of renal damage in diabetes can be slowed through intensive glycemic control and optimization of blood pressure. Progression of diabetic nephropathy can be slowed through the use of medications that disrupt the renin-angiotensin-aldosterone system.

38. Renin-Angiotensin System Blockade in Prevention • The role of blockade of the renin-angiotensin system (RAS) in normotensive, normoalbuminuric diabetic patients for the primary prevention of DN is unproved and cannot be recommended at this time. • Most patients with diabetes do not develop DN, even after long periods of uncontrolled hyperglycemia, and there are hazards with the use of RAS-blocking drugs, including their potential teratogenicity in pregnancy. • In hypertensive diabetic patients, an angiotensin-converting enzyme (ACEinhibitor) or an angiotensin receptor blocker ARB is effective as a first-line antihypertensive agent.

39. Nonpharmacologic Interventions • For all diabetic patients, emphasis should be placed on lifestyle modification to lower the risk of diabetic kidney disease and CV events, including dietary restriction of salt and saturated fat, weight reduction and exercise as appropriate, and smoking cessation. • Smoking in particular is an independent risk factor for the development of nephropathy in type 2 diabetes and is associated with an accelerated loss of renal function.

40. Treatment of Diabetic Patients with Microalbuminuria • Overt nephropathy for diabetic patients with incipient or established DN, the optimal therapeutic approach to reduce the rate of progression of nephropathy and to minimize the risk for CV events involves aggressive management of hypertension with emphasis on a RAS blocker, combined with management of dyslipidemia, hyperglycemia, and albuminuria, as well as diet modification, exercise, and smoking cessation

41. In general, patients with DN require multiple antihypertensive agents (including RAS-blocking agents) to achieve BP goal, intensive insulin therapy in type 1 diabetes, two or more drugs for glucose control in type 2 diabetes, at least one lipid-lowering agent, and an aspirin or other antiplatelet agent for CV protection. • One obstacle to achieving adherence is the number of medicines and the complexity of these regimens. • Therefore, treatment of patients with DN needs to be individualized and requires considerations of the cost,side effects, and convenience of the drug regimen. Regular monitoring of UAE and serum creatinine concentration to assess response to therapy and progression of disease is required

42. Renin-Angiotensin System Blockade in Treatment • In diabetic patients with established DN, RAS blockade with ACE inhibitors or ARBs confers preferential renoprotection that is independent of BP reduction. Intraglomerular hemodynamic and nonhemodynamic renal effects of angiotensin II (Ang II) best explain the observed renoprotection

43. Dosing and Adverse Effects Associated with ACE Inhibitors and ARBs • The antiproteinuric effect of ACE inhibitors and ARBs is at least in part independent of blood pressure reduction, and in individual patients, proteinuria may continue to respond to dose escalations beyond those recommended for BP control • Unfortunately, maximal dosing of ACE inhibitors or ARBs may be limited by side effect reproductive age, counseling about pregnancy prevention and contraceptive use should begin before ACE inhibitor or ARB is started.

44. Serum creatinine concentration may increase up to 30% in proteinuric patients with renal impairment and therefore the ACE inhibitor should not necessarily stopped in these patients. • Increases in serum creatinine concentration above 30% after initiation of an ACE inhibitor should raise the suspicion of renal artery stenosis. Aggressive dose increments of ACE inhibitors or ARBs, especially in conjunction with diuresis, can precipitate acute kidney injury (AKI). • In advanced CKD and aggressive sodium restriction, although ACE inhibitors and ARBs are not contraindicated, the de novo introduction of these agents or injudicious dose increments may precipitate the need for dialysis prematurely, so some caution is appropriate.

45. Combination Therapy with Renin-Angiotensin System Antagonists • In both type 1 and type 2 diabetic patients with nephropathy, results of several earlier small trials suggested that the combination of an ACE inhibitor and an ARB is more effective in reducing BP and proteinuria than is either drug alone • In summary, evidence from clinical trials suggest caution in the use of RAS antagonists in combination, which is presumably not superior to maximum tolerated dose of the monotherapies.

47. Diuretics and Low Sodium Intake • The antiproteinuric effects of RAS blockade are enhancedby sodium restriction and diuretic use. Patients receiving ACE inhibitors or ARBs should be instructed to take a low-sodium diet (e.g., <2 g sodium/day). • The combination of a loop diuretic or a thiazide diuretic with agents that block the RAS may be more effective than either type of treatment alone for lowering blood pressure and proteinuria. • Selective aldosterone receptor antagonists (e.g., spironolactone,eplerenone) have been shown to reduce proteinuria when used alone and have an additive effect on proteinuria when used with ACE inhibitor or ARB..

48. Calcium Channel Blockers • Dihydropyridinecalcium channel blockers (dCCBs; e.g., nisoldipine, nifedipine, amlodipine) may be used as additional antihypertensive agents, but they have not been shown to reduce albuminuria or to slow the progression of renal disease. • Nondihydropyridine calcium channel blockers (ndCCBs; e.g., diltiazem, verapamil) have been shown in some studies to have beneficial antiproteinuric effects. Taken together, these findings suggest ndCCBs are reasonable agents for BP control and can be used in combination with a RAS antagonist in patients with DN.

49. β-Blockers • Classic β-adrenergic blockers have adverse metabolic effects and are therefore undesirable in diabetic patients, but this is no longer true for the novel β-blockers (e.g., carvedilol,nebivolol). • Despite insufficient controlled evidence, β-blockade appears to be useful because of the extremely high CV risk in diabetic patients with nephropathy and can be used in combination with ACE inhibitors or ARBs but not ndCCBs to achieve optimal BP control

50. Glycemic Control • Most of the evidence favoring strict glycemic control comes from studies of patients with normoalbuminuria or early stages of DN. • For type 2 diabetic patients with established DN, large trials (e.g., Kumamoto study, ADVANCE, ACCORD trial) suggest that strict glycemic control may provide some renoprotection but does not protect against macrovascular complications.