Diabetic nephropathy for presentation Ager.pptx

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1. Diabetic nephropathy Presenter-Dr. Agerye (IMR2) Moderator-Dr. Workagegnhu (consultant internist and nephrologist)

2. Outlines Definition Epidemiology Pathogenesis Clinical manifestations Pathology Diagnosis Management

3. Introduction Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in the developed world. It can develop in the course of both type 1 and type 2 diabetes and as a consequence of other forms of diabetes mellitus (DM).

4. DN vs DKD DN Presence of albuminuria usually accompanied by retinopathy in T1DM Albuminuria is considered to be an early sign of classical D. glomerulopathy (BM thickening, endothelial damage, mesangial expansion and nodules, and podocytes loss)---distinct pathologic entity DKD A clinical diagnosis (presence of albuminuria, decreased (eGFR), or both in diabetes) Doesn’t indicate a specific pathological phenotype Could be due to DN or other causes(HTN,GN…)

5. EPIDEMIOLOGY In most Western countries, DKD has become the leading cause of ESRD, currently stands between 40% and 60%. Classic features of DKD were observed in about 60% of diabetic patients (i.e., normal kidney size despite ESRD; proteinuria >1 g/24 h with or without retinopathy) 13% had an atypical presentation with ischemic nephropathy, 27% a known primary renal disease coexisted with diabetes. An important mode of presentation has become irreversible acute kidney injury (AKI).

6. The proportion of patients with type 1 and type 2 diabetes who develop proteinuria and elevated serum creatinine concentration is related to the duration of diabetes.

7. There is a more rapid increase in the prevalence of type 2 diabetes in the developing world compared with the developed world .

8. Pathogenesis Genetic and Environmental Factors 30% to 40% of patients with type 1 or type 2 diabetes will ultimately develop nephropathy. Race and ethnic factors- Relatively increased in African Americans, Native Americans, Mexican Americans, Polynesians, Australian aborigines than whites. Familial clustering- Type 1 dm 1 st degree relative with DN-83% risk Vs 17% with out DN. Maternal hyperglycemia during pregnancy causing ‘nephron underdosing’. Environmental factors- High sugar containing diet and smoking.

9. Hemodynamic Changes Hyperfiltration is common in early diabetes due to glucose-dependent effects causing afferent arteriolar dilation. Later it becomes maladaptive and causes glomerular hypertension. Disturbed glucose homeostasis. Tubular abnormalities- tubuloglomerular feedback.

10. Renal Hypertrophy and Mesangial Matrix Expansion Renal growth occurs early after the onset of diabetes. Glomerular enlargement is Associated with increased numbers of mesangial cells, mesangial cell hypertrophy, and increase of capillary loops, enhancing the filtration surface area. Hyperglycemia causes hypertrophy by stimulating growth factors in the kidney. Pathological hallmarks of DN mesangial expansion nodular diabetic glomerulosclerosis (the acellular Kimmelstiel -Wilson lesion) diffuse glomerulosclerosis Mesangiolysis and NO-deficiency

11. Inflammation and DKD Glomerular and interstitial infiltration by monocytes/macrophages and activated T lymphocytes. Chemokines and their receptors, and TNF receptors, as well as adhesion molecules, seem to contribute to this. TNF receptors appear to be a robust biomarker for progressive kidney disease in both type 1 and type 2 diabetes.

12. Tubular changes Tubulointerstitial injury ultimately determines the rate of attrition of renal function. Damage to the proximal tubular cell from AGE, angiotensin II, and albuminuria also results in increased TGF-beta with consequent conversion of pericytes into myofibroblasts (EMT), infiltration of macrophages, and an excess of collagen and fibronectin deposition. Polyol pathway to fructose, where it is degraded by local fructokinase to induce oxidative stress and local inflammation.

13. Even mild anemia (hemoglobin level <12.5 g/dl for men, 11.5 g/dl for women) increases the risk of progression of DN. Anemia presumably causes renal hypoxia. hypoxia is an important factor aggravating interstitial fibrosis, partly by the induction of TGF-β and VEGF. Change of tubular epithelial cells into fibroblasts is stimulated by cellular hypoxia Treatment of anemia early in renal failure with erythropoietin (EPO) may slow the decline of renal dysfunction in DN unproven.

14. Mechanisms Underlying Proteinuria The expression of one permeability-controlling protein, nephrin , is abnormally low in DN and its transcription is suppressed by Ang II. Apoptosis of podocytes is triggered by various factors including Ang II, TGF-β and hyperglycemia-induced ROS generation. Adhesion of podocytes to the GBM is reduced by advanced glycation end products (AGEs)-induced suppression of neuropilin-1. Thrombomodulin-dependent APC formation inhibits podocyte apoptosis.

15. Hyperglycemia and DKD Role of glucose control Lower HbA1c levels are associated with: Reversal of hyperfiltration Albuminuria regression Reductions in worsening albuminuria and rapid eGFR decline Delay in the development of stage 3 CKD Such improvements can be observed, even in later stages of diabetic kidney disease, including severely increased albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) and eGFR <60 mL/min/1.73 m2

16. Evidence for the role of tight glycemic control in retarding the development of DKD includes: DCCT trial UKPDS ADVANCE study EMPA-REG Euglycemia after pancreatic transplant leading regression of DN

17. ADVANCE study

18. UKPDS group Compares Intensive (A1C-7%)control vs conventional (7.9%) control over a 10 year period.

19. Mechanism of hyperglycemia in DKD Damage resulting from hyperglycemia can occur; Alteration of tissues(glycation) By products of glucose metabolism

20. Advanced glycation end products pathway. Chronic hyperglycaemia can lead to non-enzymatic glycation of amino acids and proteins. Over time, these products undergo rearrangement, including cross-linking, to become irreversible AGEs The concentration of AGEs is increased in the serum, glomeruli, and tubules of DN patients AGEs bind to macrophages, mesangial cells, tubular cells and mediate cellular actions, including expression of adhesion molecules, cell hypertrophy, ECM synthesis, epithelial-mesenchymal transition (EMT), and inhibition of NOS. RAGE is expressed in renal tubles and podocytes (induced by AT2R )

21. Protein kinase C pathway A family of serine-threonine kinases that regulate diverse vascular functions Its activity is increased in the retina, aorta, heart, and glomeruli of diabetic animals PKC-β inhibitor reduced albuminuria and renal TGF-β overexpression, as well as ECM accumulation in animal studies

22. Polyol pathway. Activation of the enzyme aldose reductase within cells when intracellular concentrations of glucose rise to hyperglycemic levels. It involves the conversion of glucose to sorbitol and eventually fructose. This depletes the cellular NADPH concentration and alters the redox ratio, which can reduce NO bioavailability and alter enzyme function.

23. Hexosamine pathway. The rate-limiting enzyme of the hexosamine pathway is glutamine:fructose-6-phosphate-amidotransferase (GFAT), which catalyzes fructose-6-phosphate and produce glucosamine-6-phosphate. Overexpression of GFAT increases TGF-β1 production.

24. Renin-Angiotensin-Aldosterone System and Kidney Disease Sites of local RAS activation have been identified in glomeruli, renal vessels, and tubular cells Hyperglycemia and AGEs stimulate angiotensinogen and renin expression in various renal cells, mainly through ROS. Proteinuria and adipocytes in obese patients further activates the local RAAS of tubular cells prorenin levels are elevated –changed to renin and induce proinflammatory and profibrogenic cytokines.

25. 1,25-dihydroxyvitamin D3 (calcitriol) suppresses RAAS. Thus, in DKD, decreasing calcitriol production further activates the RAAS Ang II has many nonhemodynamic effects and mediates cell proliferation, hypertrophy, ECM expansion, and cytokine (TGF- β, VEGF) synthesis. Aldosterone accelerates progression in renal damage models independently of Ang II Aldosterone synthesis is stimulated in DKD, and stimulates the synthesis of proinflammatory and profibrogenic cytokines (MCP-1, TGF- β)

26. Uric acid and fructose in DKD Uric acid is generated during the metabolism of fructose and induces oxidative stress in mitochondria. Besides from diet, in diabetes, fructose is generated in the kidney, where it is metabolized to generate uric acid and oxidative stress. Elevated uric acid level can predict the development of DKD and pilot studies have reported early benefit of allopurinol therapy on diabetic albuminuria.

27. CLINICAL MANIFESTATIONS AND NATURAL HISTORY DKD is part of a generalized microvascular syndrome that is accompanied by macrovascular disease. Most common clinical abnormalities are: persistently elevated urine albumin excretion and/or persistently decreased (eGFR) Microscopic hematuria(less often) Are usually asymptomatic and detected through routine, periodic testing.

28. Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) may occur in type 1 or 2 DM. These individuals develop a propensity to hyperkalemia and acidemia, which may be exacerbated by medications like ACEIs, ARBs and MRA. Radiocontrast induced nephropathy.

29. Nonalbuminuric DKD Among patients with T1DM and reduced eGFR (<60 mL/min/1.73 m2), 7 to 24% are nonalbuminuric Among patients with T2DM and reduced eGFR, 39 to 52% are nonalbuminuric. Result of macrovascular disease Slow progression Whether the initial lesion of progressive renal decline is in the glomerulus, tubule, interstitium , or vasculature remains unclear.

30. Evolution of Diabetic Kidney Disease Earliest change of renal function is an increase in GFR, or hyperfiltration, which is accompanied by an increase in renal size. The next change is the development of albuminuria(moderate/severely increased) . Diabetic patients with persistent microalbuminuria have increased risk of overt DN, heralded by the development of: proteinuria ( albuminuria >300 mg/day)- Average 15 years after disease onset Progressive increase in BP Development of progressive CKD

31. Hypertension and DKD Hypertension in a patient with type 1 diabetes is almost always caused by renal parenchymal disease. In type 2 diabetes Hypertension often precedes the onset of diabetes by many years as a feature of metabolic syndrome. At diagnosis an abnormal BP and an abnormal circadian BP profile are found in 80% of patients. Isolated systolic HTN is common Nondipping. Ambulatory pulse pressure and impaired nocturnal BP decline are independent predictors of nephropathy progression.

32. Associated Extrarenal Microvascular and Macrovascular Complications Diabetic retinopathy is present in virtually all patients with type 1 diabetes and albuminuria from DN. In contrast, only 50% to 60% of proteinuric patients with type 2 diabetes have retinopathy. Many patients with DN also have polyneuropathy. The major macrovascular complications associated with DKD are stroke, coronary heart disease, and peripheral vascular disease, occurs 5 times more frequent in patients without DKD .

33. Survival in Patients With Diabetic Kidney Disease The presence of DKD greatly increases mortality. Mortality in patients with type 1 diabetes and no proteinuria is elevated only 2-fold to 3-fold; in contrast, it is increased 20-fold to 200-fold in patients with proteinuria. The major increase in risk starts when abnormal levels of albuminuria have developed. Urinary albumin excretion is a good predictor of cardiovascular events the first 5 years after measurement . causes endothelial cell dysfunction, thus increasing the risk for atherosclerosis It is associated with many CV risk factors like HTN, Platelet aggregation, dyslipoprotenemia and Other association is with autonomic polyneuropathy, which predicts death from MI and arrythmia.

34. Diagnosis and differential diagnosis The diagnosis of DKD is based on the detection of proteinuria. Most patients also have hypertension and retinopathy. The main evaluation procedures: Measurement of urinary albumin or protein Measurement of serum creatinine concentration and estimation of GFR Measurement of BP Ophthalmologic examination

35. Measurement of proteinuria Confounding factors such as fever, physical exercise, urinary tract infection, nondiabetic renal disease, hematuria from other causes, heart failure, uncontrolled hypertension, uncontrolled hyperglycemia have been excluded

36. The main advantage of searching for microalbuminuria early in the course of diabetes is that it predicts a high renal and cardiovascular risk and thus allows targeted intervention. The ADA and other societies recommend annual testing of all diabetic patients. KDIGO recommends using the albumin-to-creatinine ratio or protein to-creatinine ratio annually to determine if there is disease progression.

37. Measurement of BP Appropriate cuff size Patients with severe autonomic neuropathy-check orthostatic hypotension. Nocturnal and ambulatory BP measurement Pseudo hypertension.

38. Typical DKD is Persistent albuminuria and/or persistent decreased eGFR (at least 3mon) Long duration of diabetes or established diabetic retinopathy Consider other ddx if: Young patients with recent dx of DM Proteinuria without retinopathy in T1DM RBC casts, dysmorphic RBCs, or WBC casts in the urine sediment, gross hematuria Presence of another systemic disease that is commonly associated with kidney disease ( eg , SLE) A sudden increase in albuminuria or a rapid decline in eGFR

39. Renal pathology In patients with diabetes of more than 10 years duration, regardless of whether nephropathy is present, GBM thickening up to three times the normal range is an almost universal feature. Nodular glomerular lesions are reported in only 10% to 50% of biopsy specimens in both type 1 and type 2 diabetes. The diffuse glomerular lesion occurs more than 90% in patients with type 1 diabetes longer than 10 years and in 25% to 50% in patients with type 2 diabetes. Immunohistology examination is usually negative Tubulointerstitial fibrosis and tubular atrophy

40. Pathologic classification Class I: Isolated glomerular basement membrane thickening . Class II: Mild (class IIa ) or severe (class IIb) mesangial expansion Class III: At least one Kimmelstiel -Wilson lesion (nodular intercapillary glomerulosclerosis) and <50 percent global glomerulosclerosis . Class IV: Advanced diabetic sclerosis ( >50 percent global glomerulosclerosis).

41. General measures Glycemic control BP control Treatment of dyslipidemia Diet and lifestyle modifications, including physical activity and weight reduction Smoking cessation

42. Glycemic control

43. In T1DM with DKD, glycemic control may also improve renal histology For T2DM with established DN, strict glycemic control provides Reno- protection FIGURE 405-4 Diabetic glomerular changes in a patient with type 1 diabetes are reversed by 10 years of normoglycemia as a result of pancreas transplantation. Left panel shows diabetic glomerulosclerosis ( arrow ) and arteriolar hyalinosis ( arrowhead ) on kidney biopsy. Right panel shows a near-normal glomerulus in the same patient after 10 years of normoglycemia from pancreas transplantation. (Reproduced with permission from P Fioretto et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69, 1998.)

44. Glycemic target must be individualized and take into account The patient’s age Duration of diabetes Presence of CVD Presence of CKD Microvascular risks and complications Previous glycemic control Susceptibility to and awareness of hypoglycemia.

45. Antihyperglycemic Therapeutic Options in Type 2Diabetic Kidney Disease

46. Metformin First line management in type 2 DM patients. Is an insulin sensitizer The dose of metformin should be reduced according to renal function. It reduces all-cause and CV mortality

47. SGLT2 Inhibitors Widely approved antihyperglycemic therapies with a glycosuric mechanism. They decrease systolic and diastolic BP by 4 to 6/1 to 2 mm Hg, respectively. They also decrease weight. Associated with an acute, dose-dependent reduction in eGFR by approximately 5 ml/min/1.73 m2 and approximately 30% to 40% reduction in albuminuria. For patients with established ASCVD or indicators of high ASCVD risk, HF, or CKD, an SGLT2 inhibitor demonstrated CVD benefit and recommended as part of 1 st line therapy.

48. For initiation eGFR should be above 20 ml/min/1.73m2. Once an SGLT2i is initiated, it is reasonable to continue an SGLT2i even if the eGFR falls below 20 ml/min per 1.73 m2, unless it is not tolerated or kidney replacement therapy is initiated. Major concern is an increase incidence of AKI, reported in up to 6% of cases, especially with canagliflozin. Others are DKA, genital mycotic infections and amputation.

49. Analogues of Human Glucagon-Like Peptide-1(semaglutide, liraglutide) They effectively lower glucose levels and slightly reduce weight and BP. LEADER trial showed - Fewer patients experienced a nephropathy end-point (−23%), which consisted mainly in a reduction of severely increased albuminuria. Dipeptidyl Peptidase-4 Inhibitors (gliptins) Can be used even in patients with advanced CKD. Reduce albuminuria no additional CV outcome benefit

50. Blood Pressure Control Effective treatment of systemic hypertension is the single most important strategy in the treatment of established DKD . 2012 KDIGO guideline for BP control in diabetic patients, aiming for a target BP of less than 140/90 mm Hg for all diabetic patients less than 130/80 mm Hg for patients with CKD and/or UAE of greater than 30 mg/24 h. ADA 2022 recommends- higher cardiovascular risk a blood pressure target of <130/80 mmHg lower risk for cardiovascular disease less than 140/90 mmHg.

51. Renin-Angiotensin System Blockade Not recommend the use of RAS blockade in normotensive, normoalbuminuric diabetic patients for the primary prevention of DKD (DIRECT trial). In hypertensive, normoalbuminuric diabetic patients, are effective as a first-line antihypertensive agent.(BENEDICT). With established DKD, RAS blockade confers renoprotection that is independent of BP reduction. Serum creatinine concentration may increase up to 30% in proteinuria patients with renal impairment after starting a RAS blocker, is associated with long-term renoprotection.

52. Aldosterone Blockade Plasma aldosterone levels are elevated in a subset of patients despite ACE inhibitor and ARB therapy -also known as aldosterone breakthrough . Small studies have demonstrated considerably faster decline in GFR in patients who experienced aldosterone breakthrough than in those who does not. MRA has been shown to reduce proteinuria when used alone and has an additive effect on proteinuria when combined with ACE inhibitor or ARB. Risk of hyperkalemia is high, especially in patients with reduced GFR .

53. Other Antihypertensive and Antiproteinuric Agents Diuretics and Low Sodium Intake low sodium diet (e.g., <2 g sodium/day) loop or a thiazide diuretic Calcium Channel Blockers Nondihydropyridine CCBs- antiproteinuric effect Dihydropyridine CCBs- antihypertensive effect β- Blockers(carvedilol, nebivolol)

54. Treatment of Dyslipidemia Most patients with DKD have dyslipidaemia characterized by low levels of high-density lipoprotein (HDL) cholesterol, high triglyceride (TG) levels, and a Shift from larger toward smaller LDL cholesterol Statin is recommended for: secondary prevention among those with established CVD for primary prevention for individuals over age 40 with diabetes and for primary prevention for persons over age 40 with CKD stages 1–4 and kidney transplant No benefit in persons on chronic dialysis

55. Nonpharmacologic Interventions Dietary restriction of salt, protein and saturated fat. weight reduction and exercise smoking cessation.

56. Management of the Diabetic Patient With Chronic Kidney Disease CKD stage 3b to 5 need nephrologist referral. The mainstay of treating DM with CKD and monitoring its progression is based on successfully controlling the product of two assays; HbA1c and albuminuria. Hypoglycemia becomes increasingly frequent with advancing CKD.

57. Oral agents

58. Insulin Thirty to eighty percent of insulin is removed by the kidney, 40% via proximal tubular reabsorption and intracellular degradation and 60% via glomerular filtration With a falling GFR the risk for hypoglycemia is high and insulin dosing should be continuously reviewed with advancing CKD. For T1DM, the basal bolus regimen of 3 daily injections of short acting insulin with meals combined with 1 or 2 injections of long-acting insulin. In T2DM, patients requiring insulin, the regimen usually starts on once-daily or twice-daily, long-acting, or intermediate-acting insulin .

59. Monitoring during therapy DKD should be monitored every three to six months with; assessments of blood pressure volume status estimated glomerular filtration rate (eGFR) based on serum creatinine serum potassium glycated hemoglobin (A1C) evaluation of urine protein/albumin

60. References KDIGO_2022_Diabetes_Management In CKD ADA 2022 Comprehensive Clinical Nephrology Harrison 21 st edition Journals

61. Thank you