2. Overview of diabetic nephropathy Dr. A. Emami

3. Diabetic nephropathy occurs in both type 1 and type 2 diabetes mellitus, including diabetes due to genetic defects of beta-cell function.

4. DN is the most important disorder leading to RF in adult. In the USA more than 44% of patients entering RSP are diabetic.

5. DX Clinical evidence

6. Staging of renal involvement in IDDM

7. Microalbuminuria: Persistent excretion of Alb in the urine at rates that are above the normal range but below values detected by conventional methods 20μg/min<UAE<200μg/min 20μg/min<UAE<200μg/min Persistent microalbuminuria Urine should be steril in nonketotic patients. Urine should be steril in nonketotic patients. Overt DN UAE 12-20μg/min UAE 12-20μg/min Microalbuminuria has apredictive value of approximately 75% to 80% for DN. Microalbuminuria has apredictive value of approximately 75% to 80% for DN.

8. Type 1 diabetes The epidemiology of diabetic nephropathy has been best studied in patients with type 1. Approximately 20 to 30 percent will have microalbuminuria after a mean duration of diabetes of 15 years. Less than half of these patients will progress to overt nephropathy. Microalbuminuria may regress or remain stable in a substantial proportion, probably related to glycemic and blood pressure control.

9. Prior to the current period of intensive monitoring and treatment, it was suggested that 25 to 45 percent of diabetic patients will develop clinically evident disease

10. The overall incidence of (ESRD) was also substantial, with reported rates of 4 to 17 percent at 20 years from time of initial diagnosis and approximately 16 percent at 30 years. In comparison to these findings, subsequent studies have found that the renal prognosis of type 1 diabetes, including the rate of progression to ESRD, has dramatically improved over the last several decades

11. The onset of overt nephropathy in type 1 diabetes is typically between 10 and 15 years after the onset of the disease. Those patients who have no proteinuria after 20 to 25 years have a risk of developing overt renal disease of only about 1 percent per year.

12. Type 2 diabetes In Caucasians, the prevalence of progressive renal disease has generally been lower in type 2 diabetes than in type 1 disease. however, the use of modern therapies lowers the incidence of ESRD, even in groups at extremely high risk such as the Pima Indians.

13. Data suggest that the renal risk is currently equivalent in the two types of diabetes.

14. With respect to the development and progression of nephropathy among over 5000 type 2 diabetics enrolled in UKPDS, the following results were reported; At ten years following diagnosis, the prevalence of microalbuminuria, macroalbuminuria, and either an elevated plasma creatinine concentration (defined as 2.0 mg/dL) or requirement for renal replacement therapy was 25, 5, and 0.8 percent, respectively.

15. An estimation of the median time spent in each stage without progression to another nephropathy stage was 19, 11, and 10 years for those with no nephropathy, microalbuminuria, and macroalbuminuria, respectively. Among those with an elevated plasma creatinine 2 mg/dL, renal replacement therapy was required after a median period of only 2.5 years.

16. RISK FACTORS Studies in patients who have or do not have clinically evident diabetic nephropathy have identified a number of factors as being associated with increased risk of renal involvement:

17. Genetic susceptibility — Genetic susceptibility may be an important determinant of both the incidence and severity of diabetic nephropathy. The likelihood of developing diabetic nephropathy is markedly increased in patients with a diabetic sibling or parent who has diabetic nephropathy; these observations have been made in both type 1 and type 2 diabetes.

18. Age — The impact of age at onset of diabetes on the risk of developing nephropathy and ESRD is unclear.

19. Blood pressure — Prospective studies have noted an association between the subsequent development of nephropathy and higher systemic pressures.

20. Glomerular filtration rate — Approximately one-half of patients with type 1 diabetes of less than five years duration have an elevated (GFR) that is 25 to 50 percent above normal. Approximately one-half of patients with type 1 diabetes of less than five years duration have an elevated (GFR) that is 25 to 50 percent above normal. Those patients with glomerular hyperfiltration appear to be at increased risk for DN.This is particularly true for overt nephropathy if the initial GFR is above 150 mL/minThose patients with glomerular hyperfiltration appear to be at increased risk for DN.This is particularly true for overt nephropathy if the initial GFR is above 150 mL/min

21. The findings in type 2 diabetes are somewhat different. Up to 45 percent of affected patients initially have a GFR that is more than 2 standard deviations above age-matched nondiabetic and obese controls. However, the degree of hyperfiltration (averaging 117 to 133 mL/min) is less than that seen in type 1 diabetics. Type 2 diabetics are also older and more likely to have arteriosclerotic vascular disease which will limit increases in both glomerular filtration and glomerular size

22. Glycemic control — Diabetic nephropathy is more likely to develop in patients with worse glycemic control (higher HbA1c levels) Diabetic nephropathy is more likely to develop in patients with worse glycemic control (higher HbA1c levels)

23. Race — The incidence and severity of diabetic nephropathy are increased in blacks (3- to 6-fold compared to Caucasians), Mexican-Americans, and Pima Indians with type 2 diabetes. This observation in such genetically disparate populations suggests a primary role for socioeconomic factors, such as diet, poor control of hyperglycemia, hypertension, and obesity.This observation in such genetically disparate populations suggests a primary role for socioeconomic factors, such as diet, poor control of hyperglycemia, hypertension, and obesity.

24. Obesity — A high (BMI) has been associated with an increased risk of CKD among patients with diabetes.In addition, weight loss may reduce proteinuria and improve kidney function among patients with diabetes. Oral contraceptives — An initial report suggested a link between oral contraceptive use and the risk of diabetic nephropathy.

25. RELATION BETWEEN DIABETIC NEPHROPATHY AND RETINOPATHY RELATION BETWEEN DIABETIC NEPHROPATHY AND RETINOPATHY

26. Based upon the correlation between retinopathy and nephropathy, the 2007 K/DOQI Guidelines for diabetes and chronic kidney disease suggest that; chronic kidney disease should be attributed to diabetes in most patients with diabetes if microalbuminuria and diabetic retinopathy are both present. By comparison, other causes of CKD should be entertained if diabetic retinopathy is absent chronic kidney disease should be attributed to diabetes in most patients with diabetes if microalbuminuria and diabetic retinopathy are both present. By comparison, other causes of CKD should be entertained if diabetic retinopathy is absent

27. OTHER RENAL DISEASES — Proteinuria in diabetes mellitus is occasionally due to a glomerular disease other than DN. As examples, membranous nephropathy, minimal change disease, IgAN,HSP,TBM, and a proliferative GN have all been described. The major clinical clues suggesting nondiabetic glomerular disease are :

28. Onset of proteinuria less than five years from the documented onset of diabetes (since the latent period for overt diabetic nephropathy is usually at least 10 to 15 years); this is more difficult to ascertain in type 2 diabetics in whom the true onset of disease is not known. The acute onset of renal disease: Diabetic nephropathy is a slowly progressive disorder characterized by increases in protein excretion and the serum creatinine concentration over a period of years.

29. Presence of an active urine sediment containing red cells (particularly acanthocytes) and cellular casts. Patients with only microscopic hematuria may have TBM disease, which may affect up to nine percent of the general population, with or without underlying diabetic nephropathy In type 1 diabetes, the absence of diabetic retinopathy or neuropathy. In type 1 diabetes, the absence of diabetic retinopathy or neuropathy.

30. In contrast, lack of retinopathy in type 2 diabetes does not preclude diabetic nephropathy, which remains the most likely diagnosis In contrast, lack of retinopathy in type 2 diabetes does not preclude diabetic nephropathy, which remains the most likely diagnosis

31. Signs and/or symptoms of other systemic disease. Significant reduction in the glomerular filtration rate (>30 percent) within two to three months of the administration of ACE inhibitors or angiotensin II receptor blockers. Significant reduction in the glomerular filtration rate (>30 percent) within two to three months of the administration of ACE inhibitors or angiotensin II receptor blockers.

33. Treatment and prevention of diabetic nephropathy

34. IMPORTANCE OF GLYCEMIC CONTROL — The efficacy of strict glycemic control depends in part upon the stage at which it is begun and the degree of normalization of glucose metabolism; intensive insulin therapy has the following benefits with respect to the kidney;

35. It can partially reverse the glomerular hypertrophy and hyperfiltration It can delay the development of microalbuminuria.

36. It can stabilize or decrease protein excretion in patients with microalbuminuria, although this effect may not be apparent until relative normoglycemia has been maintained for two years.

37. Blood pressure control — Strict blood pressure control is clearly important for preventing progression of diabetic nephropathy and other complications, however the optimal lower limit for systolic blood pressure is unclear. In the United Kingdom Prospective Diabetes Study (UKPDS), each 10 mmHg reduction in systolic pressure was associated with a 12 percent risk reduction in diabetic complications (P<0.001); the lowest risk occurred at a systolic pressure below 120 mmHg In the United Kingdom Prospective Diabetes Study (UKPDS), each 10 mmHg reduction in systolic pressure was associated with a 12 percent risk reduction in diabetic complications (P<0.001); the lowest risk occurred at a systolic pressure below 120 mmHg

38. There is now clear evidence that antihypertensive therapy (particularly with an ACE inhibitor) can reduce the rate of progression in patients with type 1 diabetes and overt nephropathy. In patients with type 2 diabetes, more data are currently available on the preferential renoprotective efficacy of angiotensin receptor blockers (ARBs). However, ACE inhibitors appear to have a similar benefit.

39. Other antihypertensives — Most sympathetic blockers and dihydropyridine CCB do not have significant antiproteinuric action despite effective blood pressure reduction, unlike nondihydropyridine CCB.

40. Although the dihydropyridine CCB (such as nifedipine, nitrendipine, and amlodipine) may be effective in lowering BP, they have a variable effect ranging from increased protein excretion to no effect to a fall in protein excretion in different studies.

41. Only diltiazem and verapamil appear to be as consistently effective as an ACE inhibitor or ARB in lowering protein excretion in diabetic patients; furthermore, the antiproteinuric effects of verapamil and an ACE inhibitor may be additive.

42. patients on ACE inhibitors or ARBs who do not have sufficient reduction in proteinuria despite appropriate blood pressure goals should be instructed to take a low sodium diet. An assessment of baseline sodium intake can be undertaken by obtaining a 24-hour urine for sodium and creatinine.

43. Aldosterone antagonism — Diuretics have generally not been considered to have an antiproteinuric effect despite reductions in blood pressure. However, aldosterone antagonists appear to reduce proteinuria when used alone, and to have an additive effect on proteinuria when used in combination with an ACE inhibitor or an ARB in both type 1 and type 2 diabetes. Further blood pressure reduction may partially explain the beneficial effect, although an anti-inflammatory mechanism has also been proposed Further blood pressure reduction may partially explain the beneficial effect, although an anti-inflammatory mechanism has also been proposed

44. There are no long term data regarding benefit with the combination of ACE inhibitor or ARB and aldosterone blockade in terms of slowing the rate of loss of GFR. The risk of inducing or aggravating hyperkalemia in patients with long-standing diabetic nephropathy may limit the use of aldosterone antagonists. However, aldosterone blockade in combination with an ACE inhibitor or ARB is indicated in the therapy of heart failure. Close monitoring for the development of hyperkalemia is required in patients with diabetic nephropathy.

45. ACE inhibitors, ARBs, diltiazem, and verapamil have relatively unique beneficial effects on proteinuria diltiazemverapamildiltiazemverapamil The reduction in protein excretion may reflect both a fall in intraglomerular pressure and, at least with the ACE inhibitors, an apparent direct improvement in the size-selective properties of the GBM.(via an uncertain mechanism) The reduction in protein excretion may reflect both a fall in intraglomerular pressure and, at least with the ACE inhibitors, an apparent direct improvement in the size-selective properties of the GBM.(via an uncertain mechanism) The observation that protein excretion progressively declines over time is consistent with an effect on permselectivity, since the hemodynamic effects of ACE inhibition occur very rapidly and are then stable

46. PRESERVATION OF RENAL FUNCTION

47. Protein restriction — It remains uncertain whether dietary protein restriction slows the long-term decline in GFR in DN. Two small controlled trials (35 and 19 patients, respectively) demonstrated that protein (and phosphate) restriction (0.6 g/kg per day) slowed the rate of decline in GFR by 60 to 75 percent from, for example, approximately 12 mL/min per year to 3 mL/min per year Protein restriction — It remains uncertain whether dietary protein restriction slows the long-term decline in GFR in DN. Two small controlled trials (35 and 19 patients, respectively) demonstrated that protein (and phosphate) restriction (0.6 g/kg per day) slowed the rate of decline in GFR by 60 to 75 percent from, for example, approximately 12 mL/min per year to 3 mL/min per year

48. WEIGHT REDUCTION — Marked decreases in proteinuria may be observed in obese diabetics who lose weight.

49. HYPERLIPIDEMIA — Hyperlipidemia is common in diabetic patients, a tendency that is increased by the development of renal insufficiency. Aggressive lipid lowering is an important part of the medical management of all diabetic patients, since diabetes is considered a coronary heart disease equivalent.

50. In addition to promoting systemic atherosclerosis, an elevation in lipid levels also may contribute to the development of glomerulosclerosis in chronic kidney disease.

51. Other agents — A variety of other agents have been tried with the goal of reduction of proteinuria in diabetes and other proteinuric nephropathies. As an example, pentoxifylline appears to block tubulointerstitial fibrosis in experimental models. pentoxifylline

52. Thus, an aggressive combined approach may offer optimal protection against disease progression for patients with either type 1 and type 2 disease Thus, an aggressive combined approach may offer optimal protection against disease progression for patients with either type 1 and type 2 disease

53. RECOMMENDATIONS RECOMMENDATIONS It now seems clear in type 1 diabetes that ACEI, as part of a therapeutic regimen to achieve BP goals, both lower protein excretion and slow the rate of disease progression in patients with microalbuminuria and in those with overt nephropathy. a similar effect is seen in type 2 diabetes with ARBs or ACE inhibitors. It is important to appreciate, however, that these agents slow the rate of progression, but do not stop progression andThus, other modalities are also required

54. ACE inhibitors and ARBs appear to provide equivalent renal protection in patients with type 2 diabetes and microalbuminuria. This equivalence is less clear among those with overt proteinuria, as renal protection is better studied with ARBs in this setting. Despite this theoretical limitation, we suggest either an ARB or an ACE inhibitor (if tolerated) for the prevention of progression of nephropathy in patients with type 2 diabetes.

55. Compared to monotherapy with an ACE inhibitor or ARB alone, combined therapy produced a greater reduction in protein excretion in most studies, and as demonstrated in nondiabetic chronic renal failure, a greater degree of slowing of progression

56. Type 1 diabetes — Patients with type 1 diabetes should probably be screened yearly (after the first five years) for the presence of microalbuminuria. Use of the albumin-to-creatinine ratio in an untimed urinary sample is recommended as the preferred screening strategy for all diabetic patients Measurement of the serum creatinine concentration and estimation of the GFR should also be performed. An elevated albumin-to-creatinine ratio should be confirmed with at least two additional tests performed over the subsequent 3 to 6 months, with confirmation of the diagnosis requiring at least 2 of 3 positive samples An elevated albumin-to-creatinine ratio should be confirmed with at least two additional tests performed over the subsequent 3 to 6 months, with confirmation of the diagnosis requiring at least 2 of 3 positive samples

57. Type 2 diabetes — Screening for microalbuminuria is not as useful in type 2 diabetes because it is not as predictive of progression to overt nephropathy as in type 1 diabetes.

58. Recommendations : The following recommendations for therapeutic goals are consistent with the K/DOQI Clinical Practice Guidelines for diabetes and chronic kidney disease; A reduction in protein excretion to less than 500 to 1000 mg/day; recognizing the difficulty of achieving such a goal in many patients, we recommend a minimum reduction of at least 60 percent of baseline values

59. A reduction in blood pressure to less than 130/80 mmHg. Caution: The diastolic blood pressure should not be lowered below 75 mmHg in patients with active coronary disease, and the systolic blood pressure should not be lowered to below 110 mmHg in any patient. Caution: The diastolic blood pressure should not be lowered below 75 mmHg in patients with active coronary disease, and the systolic blood pressure should not be lowered to below 110 mmHg in any patient.

60. Monitoring in patients with DM Smoking cessation every visit BP control every visit Dilated eye exam annually Foot examination annually Serum lipid profile annually HbA1c every 3 to 6 month Microalbuminuria annually Serum Cr As indicated. ECG annually Pneumovax vaccination one time Influanza vaccination annually

62. Dialysis in diabetic nephropathy Diabetes is the most common cause of new patients requiring renal replacement therapy, accounting for approximately 46 percent of cases in the United States. Although less frequent in other countries, 34 and 30 percent of incident dialysis patients have diabetes in Germany and Australia, respectively.

63. PATIENT SURVIVAL — Patient survival in diabetics on maintenance dialysis is lower than that seen in nondiabetics with ESRD due to chronic glomerular disease or hypertension. only approximately 25 percent of patients with diabetes survived five years after initiation of dialysis.Survival also varies inversely with age, being best in young patients with good blood pressure control and no clinically evident cardiac disease

64. Cardiovascular disease is the most common cause of death, accounting for more than one-half of cases. the tissue deposition of advanced glycosylation end products (AGEs) may also enhance cardiovascular mortality once dialysis is begun. the tissue deposition of advanced glycosylation end products (AGEs) may also enhance cardiovascular mortality once dialysis is begun.

65. DIALYSIS VERSUS RENAL TRANSPLANTATION : In one USRDS report relating to diabetics with end-stage renal disease, patient survival at five years after renal transplantation in diabetics ranged from 75 to 83 percent at five years

66. HEMODIALYSIS VERSUS PERITONEAL DIALYSIS — Choice of a dialysis modality in diabetics is dependent in part upon the following factors which apply to nondiabetics as well. Comorbid conditions Home situation Ability to tolerate volume shifts — Diabetic patients with autonomic neuropathy are often more likely to have hypotensive episodes during hemodialysis. Fluid removal is more gradual with CAPD and therefore hypotension is not a problem unless the patient becomes volume depleted.

67. Status of the vasculature and/or abdomen — Older patients with type 2 diabetes are more likely to have severe peripheral vascular disease that limits the ability to create and sustain adequate vascular access for hemodialysis. Unfortunately, these are often the same patients who are unable to perform CAPD due to concomitant illnesses. Risk and history of infection

68. RECOMMENDATIONS RECOMMENDATIONS The following are our recommendations concerning renal replacement therapy in dialysis patients: Renal and renal-pancreas transplantation should be offered to any suitable diabetic patient with end- stage renal disease For those requiring dialysis, we continue to recommend peritoneal dialysis to diabetics who have adequate manual dexterity and visual acuity to perform this technique, although there is no consensus to support this recommendation; very few such patients opt for home hemodialysis which is associated with the highest survival rates

69. Given the problems with hemodialysis access due to vascular disease, early and close attention must be paid to the development of the vascular access in diabetic patients with chronic renal disease. As with nondiabetics, the preferred type is a native arteriovenous fistulaThe optimal dose of peritoneal dialysis or hemodialysis in diabetic patients is uncertain. We aim for the same goals in diabetics as in nondiabetics

70. Most studies, after adjustment for comorbid factors, have not found a statistically significant survival difference between hemodialysis and CAPD in diabetic patients.