Diabetic nephropathy medical management

1. Diabetic Nephropathy and
Medical Management

2. Kidney Anatomy
Approximately 1,200 ml of blood or 25 % of Cardiac Output flows through
the kidney in one minute

3. Kidney Function
Urine
Extra
Water
Salts
Toxins
and
Wastes

4. Stages of Kidney Diseases
Persistent albuminuria categories
Description and range
Previous
NKF
CKD
stage
Guide to frequency of monitoring
(number of times per year) by GFR
and albuminuria category
A1 A2 A3
Normal to
mildly
increased
Moderately
increased
Severely
increased
<30 mg/g
<3 mg/mmol
30-300 mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
GFRcategories(mL/min/1.73
m2)
Descriptionandrange
1 G1 Normal or high ≥90 1 if CKD 1 2
2 G2 Mildly decreased 60-89 1 if CKD 1 2
3
G3a
Mild to moderately
decreased
45-59 1 2 3
G3b
Moderately to
severely decreased
30-44 2 3 3
4 G4 Severely decreased 15-29 3 3 4+
5 G5 Kidney failure <15 4+ 4+ 4+
CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation.
Levey AS, et al. Kidney Int. 2011;80:17-28.

5.  DIABETES:THE MOST COMMON CAUSE OF ESRD
 Comorbidities

6. Causes of Renal Disease in Diabetes
 Diabetic nephropathy
 Renal artery stenosis
 Myeloma, outflow obstruction, polycystic renal disease,
glomerulonephritis, etc.
 Drugs
 NSAIDS/Cox 2 inhibitors
 Fibrates
 ACEI, ARBs

7. Nephropathy
 Broad medical term used to donate disease or damage of the kidney
which eventually results in kidney failure.
 Is considered a progressive illness; in other words, as kidneys become
less and less effective over time (with the progression of the disease), the
condition of the patient gets worse if left untreated.
 It is pivotal to receive adequate diagnosis and treatment as early as
possible

8. Diabetic Nephropathy
 30% of all end-stage renal disease
 Is a chronic condition developing over many years, characterized by:
 Gradually increasing urinary albumin excretion (UAE)
 High blood pressure (BP)
 Declining glomerular filtration rate
 Absence of other renal/renal tract disease
 Presence of diabetic retinopathy
 May be prevented/delayed by early screening and treatment

9. Prevalence in South East Asian Counties

10. Stages of Diabetic Nephropathy
 Hyperfilteration
 Stage of Clinical Latency
 Incipient Nephropathy
 Overt Nephropathy
 Renal Failure

11. Diagnose
Hyperfilteration
Clinical Latency
Microalbuminura
Macroalbuminuria
Renal failure
Diabetes

12. Natural History of DN

13. Natural History of DN

14. Several estimated for patients o Dialysis

16. Pathophysiology
Usually Multifactorial
 Metabolic pathway
 Hemodynamic pathway
 Genetic

17. Pathophysiological Stages
Stage increased
GFR
Increased filtration pressure as result of increased
intraglolerular pressure
Increased UOP and low s.cra, urea
Pathological change but no clinically evident disease
Proteinuria
Mesangial expansion and increased matrix change in
pore
sizes leading to leakage of protein
Starling Foces: increased plasma flow, increased
glomerular capillary hydrostatic pressure
Microhematuria
Ischemic injury of tubules due to construction and
stenosis of efferent arteriole
Decreased GFR Atrophy and death of nephrons
CKD and ESKD Loss of compensation mechanisms of nephrons

18. Risk Factors
 Genetic factors
 Age
 Inadequate glucose control
 High Blood pressure
 Hyperlipidemia
 Smoking
 Long Standing Diabetes
 Obesity
 Increased protein intake

19. Factors Contributing to Progression

20. Minimum Screening for Renal Disease in
Diabetes
 Annual EMU for ACR. Repeat within a month if positive, in absence of
UTI/renal stones/other renal disease
 Annual serum creatinine
 Creatinine
 eGFR (preferred MDRD equation)

21. Microalbumnuria and Proteinuria
 Diagnosis of microalbuminuria based on 2 out of 3 positive first passed
morning urine samples in absence of urinary tract infection
Normal Microalbuminuria Overt
proteinuriaF M F M
Albumin/creatinine
ratio (mg/mmol)
<3.5 <2.5 >3.5 >2.5 >30
Equivalent Albumen
excretion (mg/day)
<30 30-300 300

22. Initial Assessment of Patients with Diabetes
and Renal Impariment
 Is this likely to be diabetic nephropathy?
 Presence of retinopathy
 Microalbuminuria/proteinuria
 Is this likely to be renal artery stenosis?
 Family history, Drug history, GU history etc.
 AIP, myeloma screen, PSA
 Ultrasound

23. Screening and Diagnosis in Diabetic
Nephropathy
 Screening for diabetic nephropathy must be initiated at the time of
diagnosis in patients with type 2 diabetes, since 7% of them already have
microalbuminuria at that time
 For patients with type 1 diabetes, the first screening has been
recommended at 5 years after diagnosis
 Puberty, poor glycemic control and poor lipid control are independent risk
factors for micro albuminuria .Therefore, in type 1 diabetes, screening for
micro albuminuria might be performed 1 year after diabetes diagnosis in
these patients
 If micro albuminuria is absent, the screening must be repeated annually
for both type 1 and 2 diabetic patients

24. Screening for
microalbuminuria. in type
1 diabetes

25. Diagnosis
 Renal biopsy is the gold standard
 A renal biopsy may be deferred with the assumed diagnosis of diabetic
nephropathy in the context of
 Macro albuminuria (>300 mg/24 hours) that has developed
progressively,
 Microalbuminuria (30-300 mg/24 h) with retinopathy,
 Microalbuminuria in patients with diabetes for more than 10 years .

26. Management and Oral Drugs

27. Oral Hypoglycemics
METFORMIN
 Metformin has been used in low doses in patients with glomerular filtration
rate (GFR) as low as 30 to 60 ml/min. It
 Should not be used at a GFR below 30 ml/min -- risk for lactic acidosis.
 As renal function can deteriorate abruptly,
 Better to avoid metformin once serum creatinine concentration rises above
 1.5 mg/dl (132 μmo/l) in men
 1.3 mg/dl (117 μmol/l) in women

28. Oral Hypoglycemics
METFORMIN
 Metformin has been used in low doses in patients with glomerular filtration
rate (GFR) as low as 30 to 60 ml/min. It
 Should not be used at a GFR below 30 ml/min -- risk for lactic acidosis.
 As renal function can deteriorate abruptly,
 Better to avoid metformin once serum creatinine concentration rises above
 1.5 mg/dl (132 μmo/l) in men
 1.3 mg/dl (117 μmol/l) in women

29. INSULIN SECRETAGOGUES
(SULFONYLUREA AND MEGLITINIDES)
 Sulphonylureas (especially gliblenclamide) may accumulate as renal
function deteriorates
 Can be associated with hypoglycemia
Glycosidase inhibitors
 Contraindicated in renal failure

30. Thiazolidinediones
 Associated with weight gain, (fluid retention + nonfluid gains)
 Patients at risk for congestive heart failure -- should be avoided.
 Concern about increased bone fracture rates in patients using
thiazolidinediones,
 Could potentiate CKD - related bone disease.

31. Recommendations for Non-Insulin Hyperglycemia Drug Therapy for
Patients With Moderate to Severe CKD
Volume 25, Number 3, 2007 • Clinical Diabetes

32. INSULIN
 Insulin regimens are the most commonly used to control glycemia in CKD
 Increasing half-life of insulin as CKD progresses, the risk for hypoglycemia
increases.
 Insulin requirements decrease further in HD patients, particularly in those
with residual diuresis (<500 ml/day),
 Insulin requirement often decreases by 30%
 In peritoneal dialysis (PD) patients,
 Intraperitoneal insulin is more physiologic than subcutaneous, as portal
absorption of insulin may better mimic the endogenous insulin effect.
 Insulin requirements typically increase by 200% to 300% in this situation

33. INSULIN IN PT. ON HEMODIALYSIS
 Insulin inhibitors – dialyzable
 Insulin resistance diminishes after the start of dialysis.
 Half-life of insulin is prolonged.
 The potential for hypoglycemia with both oral agents and insulin increases
in the presence of CKD (with the exception of gliquidone and glimepiride).
 Self-monitoring of blood glucose concentration is imperative.
 Insulin requirement often decreases by ~30%
 Glargine has been shown to reduce hypoglycemia in hemodialysis
patients

35. Management of Diabetic Nephropathy
 Optimal control of blood pressure, glucose, and lipids
 Smoking cessation
 RAAS blockade
 ACE inhibitor, ARB, or renin inhibitor
 Do not combine RAAS blocking agents
 Monitor serum potassium
 Nephrologist referral
 Atypical presentation
 Rapid decline in eGFR or albuminuria progression
 Stage 4 CKD
ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blocker; CKD = chronic kidney disease; eGFR = estimated
glomerular filtration rate; RAAS = renin angiotensin aldosterone system.

36. Recommendations for the Comprehensive
Management of T2DM Patients with CKD

37.  Preprandial plasma glucose 90-130 mg/dl
 A1C <7.0%
 Peak postprandial plasma glucose <180 mg/dl
 Self-monitoring of blood glucose (SMBG)
 Medical Nutrition Therapy
 Restrict dietary protein to RDA of 0.8 g/kg body weight per day
Glycemic Control

38. Blood Pressure Management
 Preferred drugs:
 Angiotensin receptor blocker
 ACE inhibitor
 Non DHP calcium channel blocker: Diltiazem
 Diuretic
 Beta blocker
 Target blood pressure : 125/75 mm Hg
 BP reduction in type 1 & type 2 DM patients reduces rate of CKD
progression
 At any given level of GFR, blood pressure tends to be higher in diabetic
than in non-diabetic patients with CKD

39. Drugs to Control Blood Sugars
 Drugs contraindicated: Metformin
 Preferably not used: Glibenclamide, Chlorpropamide
 Can be used: Glimiperide, Repaglinide, Pioglitazone
 Insulin: prefer

41. Impacts of Diabetes on Blood Pressure
Management
 Autonomic Insufficiency
 BP drops and very labile
 Medial Calcificaton
 Wide pulse pressure
 Hypertensive Cardiomyopathy
 Preload
 Cardiac function
 After load

42. Hypertension Control - Goal: lower blood pressure to <130/80 mmHg
 Antihypertensive agents
 Angiotensin-converting enzyme (ACE) inhibitors
 captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril,
perindopril, trandolapril, moexipril
 Angiotensin receptor blocker (ARB) therapy
 candesartan cilexetil, irbesartan, losartan potassium, telmisartan,
valsartan, esprosartan
 Beta-blockers

46. ACEI/ARB
 begin at a low dose;
 increase dose at 4-week intervals to reduce microalbuminuria
 antiproteinuric effects not necessarily attained at antihypertensive doses
 increase dose until proteinuria reduced by 30 to 50%
 Titrate to maximal suppression of urinary albumin excretion for DM patients
with persistent microalbuminuria despite intensive insulin therapy even
without HTN
 titration limited by adverse effects:
 an acute increase in serum creatinine of 50% or more;
 renal artery stenosis;
 hypovolemia; congestive heart failure
 hyperkalemia resistant to corrective maneuvers
 ARB : consider for subjects with documented aldosterone escape

47. ACE Inhibitors can prevent progression
of renal failure
Risk reduction is 51%
Reduce microalbuminuria
All causes of mortality
Ann Intern Med 118 577-581.1993
J Am Soc Nephrol 2006

48. Lipid Control
 Heart Protection Study
 Patients with DM and CKD who received statins had a 23% decrease in
cardiovascular risk with an absolute event reduction of 80%
 In HD patients with type 2 DM, the addition of 20 mg of atorvastatin
 40% decrease in lowdensity lipoprotein cholesterol levels & significant decrease in
cardiac events

49. Lipid Lowering agents
 Increased risk of cardiovascular diseases
 FIELD STUDY showed improved regression microalbuminaria to
normoalbuminuria in pts with type 2 diabetes
(Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular
events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled
trial. Lancet. 2005;366(9500):1849-1861.)
 A meta analysis shows a small positive effect on urinary albumin excretion
and renal function
(Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic
kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ.
2008;336(7645):645-651.)

50. Dosing of Statins in CKD
 IN PT.S ON HEMODIALYSIS AND PERITONEAL DIALYSIS
 Atorvastatin - up to 80 mg/day
 Fluvastatin – up to 80 mg/day.
 Pravastatin - limited to 10 mg, as active metabolites can accumulate,
 Pravastatin Pooling Project - of up to 40 mg were safely (GFR of 30 ml/min per
1.73 m2)
 Simvastatin – upto 20 mg/day (40-mg/day in stage 3 CKD (Heart Protection
Study))
 Rosuvastatin - not more than 10 mg/day when GFR falls below 30 ml/min per
1.73 m2.
 Ezetimibe - safely used (effects absorption mainly bile acid sequestrants)
 Fenofibrate –
 reduced by one third in CKD stage 2,
 reduced by two thirds in CKD stages 3 and 4
 avoided in CKD stage 5.
 Gemfibrozil - safely used, although in PD, elevated CPK levels have been
reported

51. Diet
 Dietary phosphate restriction
 Phosphate binders
 Aluminium
 Calcium
 Magnesium
 Non aluminium, calcium,
magensium binders
 Replenishment of vitamin D
stores
 Activated vitamin D 1, 25
(OH)2D3
 Vitamin D analogues
 Paricalcitrol
 Doxercalcitriol

52. Protein Restriction
 Preservation of organ repair
 Daily dietary requirement (FAO)
 0.6 g/Kg/d plus 2 SD= 0.8 g/Kg/d
 MDRD study
 Dietary protein restriction may offer a benefit
 Remember to preserve adequate calories

53. Fluid Management
Many diabetics have nephrotic state and severe edema and need rigorous
salt & fluid restriction
 Severe edema - 600 - 800 ml / day
 Mild to moderate - equal to UOP
 No edema - UOP + insensible losses

54. Diabetic Management in CD
Parameter
 Lower BP………………………
 Block RAAS……………………
 Improve glycemia …………….
 Lower LDL cholesterol………..
 Anemia management ………...
 Endothelial protection…………
 Smoking………………………..
Target
< 125/75 mmHg
ACEi or ARB to max tolerated
A1c < 6.5% (Insulin/TZD)
< 100 (70) mg/dl statin + other
Hb 11-12 g/dl (Epo + iron)
Aspirin daily
Cessation

55. Renal Replacement Therapy in CKD with DM
 Start dialysis at eGFR - 15 ml/min per 1.73 m2 (normally - eGFR <7-8)
 they tend to tolerate uremia poorly and frequently have sodium retention
and fluid overload.
 Peritoneal dialysis–associated glucose loading
 Replace glucose solutions in part by amino acid solutions and
polyglucose.
 Loss of solute and water transport often limits long-term use of
peritoneal dialysis to 3 to 5 years.
 Switching to hemodialysis should be considered before volume
overload or uremic symptoms occur
 Pt.s on PD, Glucose meters based on GLUCOSE OXIDASE TEST should
be used
 maltose and polyglucose present in PD solution, affect glucose
dehydrogenase–based glucose meters

56. Option for Dialysis / Renal Replacement
 Hemodialysis
 Peritoneal dialysis
 Renal transplantation

57. Transplants
 Type 1 DM - pancreas transplant
 Can induce regression of moderate Diabetic Nephropathy lesions in
native kidneys
 but only during a period of 10 years after transplantation.
 Pancreas transplantation at the time of renal transplantation
 Prevents / slows the development of Diabetic Nephropathy in the
transplanted kidney.

58. Management of Diabetes in Peritoneal
Dialysis
 The evidence for improving glycemic control in patients on dialysis having
an impact on mortality or morbidity is sparse
 Improving glycaemic control in patients on dialysis is very challenging
 difficulties with hypoglycemic drugs
 monitoring difficulties
 dialysis strategies that exacerbate hyperglycemia or hypoglycemia
 Therapeutic nihilism or inertia.

59. Diabetologist must keep up to date with the dialysis practices….to be able to
adjust the insulin regimens appropriately

60. Diabetes Management in Peritoneal Dialysis I
 The evidence for improving glycemic control in patients on dialysis having
an impact on mortality or morbidity is sparse
 Improving glycaemic control in patients on dialysis is very challenging
 difficulties with hypoglycemic drugs
 monitoring difficulties
 dialysis strategies that exacerbate hyperglycemia or hypoglycemia
 Therapeutic nihilism or inertia

61. Diabetes Management in Peritoneal Dialysis II
 Standard drug therapy for hyperglycemia is clearly not possible in patients
on dialysis
 Sulphonylureas and insulin are the mainstay of treatment.
 Newer therapies for hyperglycaemia have become available, but until
recently, renal failure has precluded their use
 Newer gliptins, however, are now licensed for use in ‘severe renal failure’.
They have yet to be trialed in dialysis patients
 Diabetic patients on dialysis have special needs, as they have a much
greater burden of complications (cardiac, retinal and foot)

62. Diabetes Management in Peritoneal Dialysis III
 They may be best managed in a multidisciplinary diabetic–renal clinic
setting, using the skills of:
 Diabetologists
 Nephrologists
 Clinical nurse specialists in nephrology and diabetes
 Dietitians
 Podiatrists

63. Intra-peritoneal Insulin in PD Patients
PROS
• More physiologic absorption
(less fluctuation of BG).
• Continuous insulin infusion.
• Avoids injections
• Less hyper-insulinemia
• Avoids antibody formation.
• Improved HbA1c
CONS
• High insulin doses
• Higher cost
• Insulin losses in effluent
• Lipid effects
• Specific dialysis complications:
e.g. excess glucose
absorption.

64. Precautions
 No nephrotoxics
 Impair glomerular function: NSAIDS
 Impair tubular function: Aminoglycosides
 NO contrast agent exposure
 Drug dose adjustment
 Treat intercurrent infections properly
 Educate about native drugs
 Early referral to nephrologist

65. Management of Diabetes in Patients with
Impaired Kidney Function: Agenda
 The role of the kidneys in carbohydrate metabolism and insulin handling
and The changes in carbohydrate metabolism in CKD
 Management of Diabetes in CKD:
• Management diabetes in CKD 
• Effective and safe use of anti-diabetic agents 
• Special Issues : Dialysis, Monitoring, Targets 
 Summary and Conclusions 

66. Summary of Recommendations for Care of
Patients With Diabetes and CKD

67. Summary of Diabetic Nephropathy
 Diabetic nephropathy is a disease that develops slowly and if treated early, progression
can be delayed.
 40% of dialysis cases of ESRD are DN
 45% of patients will have microalbuminuria after 5 to 10 yrs of onset of type 1 DM
 50% of the cases of macroalbuminuria end up in ESRD will need renal replacement
therapy for survival
 There are no signs and symptoms of early disease so screening is important.
 Aggressive treatment of Blood glucose, BP, Lipids helps in prevention of renal function
and can improve the outcome.
 In CKD, some people progress to Dialysis and few to Kidney Transplantation.