Diabetic%20Nephropathy

1
Diabetic Nephropathy

• Lance Sloan, MD
• Stephen Fadem, MD

2
Objectives

• Educate physicians and nurses on practical
  management tips for diabetes control.
• Identify goals for diabetes therapy in patients
  with CKD with emphasis on prevention and
  medication side effects

3
At the end of this online presentation you should

• Understand the relationship between diabetes and
  kidney disease
• Know the difference between type 1 and Type 2
  diabetes
• Be familiar with some of the clinical trials that
  have shaped our progress
• List key management objectives for Diabetes as it
  relates to progressive CKD
• Be familiar with therapy for diabetes

4
Incidence ESRD due to Diabetes in Network 14 is
206/million
Each year in Texas 206/million patients start
dialysis because of diabetic nephropathy. Texas
has the highest incidence in the nation. Source
USRDS
5
Diabetes is the main cause of ESRD
6
Predicted and actual cost adjusted by diagnosis
Dialysis management of diabetic ESRD patients,
particularly with heart failure Source USRDS
7
Two Types of Diabetes

• Type 1 onset in youth, destruction of beta
  cells and a requirement for insulin
• Type 2 onset as adult or young adult, related
  to insulin resistance. May be treated with
  lifestyle modification, oral medications, and
  later may require insulin

8
Type 1 Diabetes

• Insulin-dependent/Juvenile onset
• 20 to 30 develop microalbuminuria after 15 years
• Amin, R, Widmer, B, Dalton, N Dunger, DB
  Unchanged incidence of Microalbuminuria in
  Children with Type 1 Diabetes since 1986 A UK
  based inception cohort. Arch Dis
  Childadc.2008.144337, 2009.
• Of the ones who develop this less than half
  progress to diabetic nephropathy
• Associated with microvascular disease retina
  and kidney. The increased sugar is neurotoxic
  hence neuropathy
• 2.2 percent will develop ESRD in 20 years and 7.8
  percent in 30 years
• Finne P, Reunanen A, Stenman S, et al. Incidence
  of end-stage renal disease in patients with type
  1 diabetes. JAMA 2005 294 1782-1787.

9
Type 1 Diabetes (Continued)

• The microalbuminuria can regress and it is not
  always related to the use of ACE or ARB therapy
• Perkins, BA, Ficociello, LH, Silva, KH,
  Finkelstein, DM, Warram, JH Krolewski, AS
  Regression of Microalbuminuria in Type 1
  Diabetes. N Engl J Med, 3482285-2293, 2003
• The risk of developing kidney failure after 20 to
  25 years in patients who have no proteinuria is
  low
• Labile swings in blood sugar because of autonomic
  insufficiency
• Always requires insulin
• If diabetic nephropathy develops, the patient
  will develop insulin resistance metabolic
  syndrome due to kidney disease. Atherosclerosis
  and hypertension are not primary but secondary
  events

10
Type 2 Diabetes

• Common in Hispanics, Native Americans and Pima
  Indians
• Incidence of ESRD is lower, but the disease is
  more frequent thus it is the most common cause
  of renal failure
• United Kingdom Prospective Diabetes Study
• UKPDS large British study, (predominantly
  Caucasians)
• Adler, AI, Stevens, RJ, Manley, SE, Bilous, RW,
  Cull, CA Holman, RR Development and
  progression of nephropathy in type 2 diabetes
  the United Kingdom Prospective Diabetes Study
  (UKPDS 64). Kidney Int, 63225-32, 2003.
• Incidence of microalbuminuria 25 but incidence
  of ESRD only 0.8
• Microlbuminuria patients spent an average of 11
  years before progressing to overt proteinuria
• Only 2.3 progress from macroalbuminuria to ESRD

11
Type 2 Diabetes (Continued)

• Disease progresses slowly over many years and is
  associated with proteinuria. The urine should
  show more than just red cells.
• In the elderly, it is impossible to clinically
  distinguish the hypertensive and atherosclerotic
  effects from the diabetic effects without a
  kidney biopsy.
• Not associated with labile blood sugar swings
• Insulin resistance

12
Incidence of Type 2 Diabetes

• Doubled in past 20 years
• Framingham Offspring Study
• Related to Lifestyle Change and Obesity
• BMI Increase confirmed by NHANES Dataset
• Source American Heart Association
• Prevalence of Diagnosed and Undiagnosed Diabetes
  in the United States, All Ages, 2007
• Total 23.6 million people
• 7.8 percent of the populationhave diabetes.
• Diagnosed 17.9 million people
• Undiagnosed 5.7 million people
• Source NIDDK

13
Metabolic Syndrome

• Characterized by insulin resistance 50 to 75
  million Americans
• High blood pressure
• High blood sugars
• High levels of triglycerides
• Low levels of HDL
• Increased waist line
• It is associated with
• Diabetes, Hypertension, stroke, cardiovascular
  disease
• Dominant Features
• Obesity, lack of exercise

14
Diet Plays a Major Role

• The Sugar Fix
• High fructose corn syrup
• Decreases the ATP in cells this decreases cell
  respiration and causes hypoxia in cells
• Releases cytokines that impair nitrous oxide
  synthesis
• Releases uric acid which increases blood pressure
• Causes leptin resistance (Leptin turns off the
  appetite) continue to be hungry
• Supersized HFCS is in many soft drinks and
  other products
• Americans eat more sugar, now have an epidemic of
  obesity, the metabolic syndrome, heart disease
  and diabetes

15
Management Objectives

• Lifestyle
• An aspirin a day
• Smoking and Exercise
• Weight/cholesterol
• Blood Pressure
• ACE and ARB
• Vitamin D
• Diabetes Control

16
Lifestyle - An aspirin a day - Smoking and
Exercise - Weight/cholesterol

• Can be a rewarding way to keep diabetes under
  control.
• Requires a lifelong strategy
• Diet Avoid fructose, excess salt, trans fats and
  excess carbohydrates
• Two alcoholic beverages at most/day
• 25 incident diabetics are smokers
• Potentiates kidney disease
• Increases inflammation
• Gentle aerobic exercise
• Aspirin a day to reduce cardiovascular risk

17
ACE and ARB
Blood Pressure Control
18
Blood pressure goal in CKDlt 130/80

• Any person with abnormal kidneys is at risk for
  heart disease
• Most patients will require two or more
  medications to control their blood pressure
• Lowering the systolic blood pressure to lt130 mm
  Hg is usually associated with a reduction in
  diastolic blood pressure to lt80 mm Hg

Adapted from American Journal of Kidney Diseases,
Vol 43, No 5, Suppl Suppl 1 (May), 2004 pp
S14-S15
19
Many blood pressures medications may be needed
to control severe blood pressure
20
Blood pressure is poorly controlled in patients
with kidney disease
21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
ACES ARBS are the two majorclasses of
medicationsused to treathigh blood pressure

25
Effect of ACE Inhibitorson Progression of CKD
Maschio. N Engl J Med. 1996334939.
26
Proteinuria is a powerful determinant of renal
deterioration.
Source The New England Journal of Medicine --
November 12, 1998 -- Vol. 339, No. 20 Mechanisms
of Disease Pathophysiology of Progressive
Nephropathies Giuseppe Remuzzi, Tullio Bertani
27
Collaborative Study Group Reduction of
proteinuria in Type 1 DM with ACE
Placebo Captopril
60
37
40
22
20
Percent
20
7
4
0
-20
-40
-40
-60
Changes in proteinuria
Incidence of ESRD
Incidence of mortality
Lewis EJ, et al. N Engl J Med. 19933291456-1462.
28
ARBS in Diabetes The RENAAL Trial

• (Reduction of Endpoints in NIDDM with the
  Angiotensin II Antagonist Losartan)
• Brenner. BM, Cooper ME, de Zeeuw D, Keane WF,
  Mitch WE, Parving HH, Remuzzi G,Snapinn SM, Zhang
  Z, Shahinfar S RENAAL Study InvestigatorsEffects
  of losartan on renal and cardiovascular outcomes
  in patients with type 2 diabetes and nephropathy.
  N Engl J Med. 2001 Sep 20345(12)861-9.
• Randomized, double-blind, multicenter,
  placebo-controlled
• Losartan Vs Placebo and conventional BP
  medications
• 1513 patients
• Outcome Composite of doubling creatinine, ESRD,
  Death
• Followup 3.4 years
• RESULT Reduced doubling of creatinine by 25 and
  ESRD by 28

29
ARBS in Diabetes - IRMA

• IRMA (Irbesartan Microalbuminuria) study
• Parving HH, Lehnert H, Bröchner-Mortensen J,
  Gomis R, Andersen S, Arner PIrbesartan in
  Patients with Type 2 Diabetes and
  Microalbuminuria Study Group.The effect of
  irbesartan on the development of diabetic
  nephropathy in patients with type 2 diabetes. N
  Engl J Med. 2001 Sep 20345(12)870-8
• multicenter, randomized, double-blind,
  placebo-controlled trial, randomized
• 590 patients with type 2 diabetic nephropathy
  (albuminuria)
• Randomized to irbesartan, 150 mg, 300 mg (Avapro)
  or placebo
• Blood pressure medications allowed
• Endpoint was overt nephropathy a urine albumin
  at least 30 greater than baseline
• 10/194 (300 mg group) reached endpoint
• 19/195 (150 mg group) reached endpoint
• 30/201 (Placebo group) reached endpoint
• Blood pressure unchanged

30
ARBS in Diabetes IDNT

• IDNT (Irbesartan Diabetic Nephropathy Trial)
• Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl
  MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I
  Collaborative Study Group. Renoprotective effect
  of the angiotensin-receptor antagonist irbesartan
  in patients with nephropathy due to type 2
  diabetes. N Engl J Med 2001 345851-860.
• Randomized, double-blind, placebo-controlled
• 1715 patients to irbesartan,amlodipine or placebo
• 2.6 years
• BP therapy allowed (with exception on study
  drugs)
• Result
• Lowered risk of developing ESRD by 23

31
What slows progression?

• Proven interventions
• Control blood sugar in diabetics
• Strict blood pressure control
• Certain meds ACES (Angiotensin-converting enzyme
  inhibition) and ARBS (angiotensin-2-receptor
  blockade)
• Studied, but inconclusive
• Dietary protein restriction
• Lipid lowering therapy
• Partial correction of anemia
• Vitamin D administration

32
How are we doing?

• Elderly diabetic patients
• Medical insurance claims
• 65 years and older
• 30,750 patients studied (58.7 also had high
  blood pressure and/or protein in the urine)
• Of these only 50.7 (CI 50.0-51.4) received an
  ACE or ARB

Am J Kidney Dis. 2005 Dec46(6)1080-7.
33
ACCOMPLISH TRIAL

• Avoiding Cardiovascular Events Through
  Combination Therapy in Patients Living With
  Systolic Hypertension (ACCOMPLISH) trial
• Has been stopped early accomplished its goal
• benazepril plus amlodipine better than benazepril
  plus hydrochlorothiazide
• Study group Hypertensives at risk secondary to
  previous events or diabetes
• 11,464 patients
• 55 years old
• BP 160
• 60.4 with diabetes
• Obese
• Cardiovascular, renal disease or target damage
• 70 treated with two or more agents
• Only 37.5 had blood pressure les than 140/90
• Endpoints cardiovascular morbidity MI, (stroke,
  unstable angina, bypass) or death
• ACE/amlodipine Risk reduced by 20 compared with
  ACE/diuretic
• SOURCE Presented by KA Jamerson, American
  College of Cardiology, March 31, 2008

34
Vitamin D
35
Vitamin D

• Type 1 Diabetes in children might be prevented
  with vitamin D supplements and 5 10 minutes of
  noon sunlight
• Epidemiology study
• UCSD
• SOURCE University of California - San Diego.
  "Sun Exposure And Vitamin D Levels May Play
  Strong Role In Risk Of Type 1 Diabetes In
  Children." ScienceDaily 5 June 2008. 10 March
  2009 lthttp//www.sciencedaily.com
  /releases/2008/06/080605073804.htmgt.

36
Vitamin D Makes the News
37
Diabetes Control

• Sulfonylureas
• Biguanides
• Thiazolidinediones Glitazones
• Meglitinides
• DPP-4 Inhibitors
• Incretin Memetics
• Insulin

38
ADA Guidelines
39
Medications for Diabetes
TYPE NAME MECHANISM ROUTE, TIME
Sulfonylureas Glimepiride Glipizide Glyburide Increases insulin production through K channels of beta cells Po qd or bid
Biguanides Metformin (Glucophage) Reduce hepatic glucose output and increase its muscle uptake Po bid tid XR po qd
Thiazolidinediones Glitazones Rosiglitazone (Avandia) Pioglitazone (Actos) PPAR gamma ligand improves glucose utilization Po qd
Meglitinides Repaglinide (Prandin) Nateglinide (Starlix) Close K channel and open Ca channel in Beta cell increasing insulin Po 5 30 min AC
DPP-4 Inhibitors Sitagliptin (Januvia) Blocks, DPP-4 which catalyzes enzyme breaking down insulin 100 mg po qd
Incretin Memetics Exenatide (Byetta) Stimulates beta cells and slows digestion 10 mcg sc 60 min AC AM and PM meal
40
SULFONYUREAS

• First category of oral agents for diabetes now
  in third generation
• Mainly for type 2 diabetes work on existing
  beta cells
• Increase secretion of insulin by binding to
  potassium channels and opening calcium channels
• Can cause hypoglycemia and weight gain

41
BIGUANIDES

• Metformin used in obese type 2 diabetics
• Maximum reduction in HgbA1c after 6 months
• Action lasts additional 9 months with
  thiazolidinedione
• With sulfonureas HgbA1C tends to increase
• Reduced cardiovascular risks
• Pharmacotherapy. 2007 Aug27(8)1102-10.Loss of
  glycemic control in patients with type 2 diabetes
  mellitus who werereceiving initial metformin,
  sulfonylurea, or thiazolidinedione
  monotherapy.Riedel AA, Heien H, Wogen J,
  Plauschinat CA.

42
ROSIGLITAZONE

• Controversy regarding risk of causing MI
• Odds ratio 1.43
• ADOPT increased fractures
• Associated with macular edema
• Stimulates the PPAR? receptor
• Not to be used in heart failure
• Nissen SE, Wolski K. Effect of Rosiglitazone on
  the Risk of Myocardial Infarction and Death from
  Cardiovascular Causes. N Engl J Med.
  2007356(24)2457-2471.

43
INCRETIN MIMETICS

• Exenatide (Byetta)
• From the saliva of the gila monster
• Incretin mimetic
• Enhances beta cell insulin
• Blocks glucagon
• Delays gastric emptying
• Injection sub cutaneously 30 to 60 minutes before
  first and last meal adjunctive therapy
• Side effects Gastrointestinal symptoms
• FDA warning pancreatitis may be fatal

44
WHEN TO START INSULIN

• Start with oral agents (metformin) and proceed to
  insulin if goal is not achieved
• May be able to manage for up to 6 years
• HgbA1C use a target
• In kidney patients and those who may be operating
  heavy machinery because of the risk of
  hypoglycemia may want to have a higher goal
• Mono-duo-triple therapy disease has advanced

45
HgbA1C

• American Diabetic Association 7.0
• American Society of Clinical Endocrinologist 6.5
• Many local endocrinologist 6.0
• CONTROVERSY The lower the HgbA1C the lower the
  risk of microvascular disease, but the higher the
  risk of hypoglycemia

46
INSULIN
47
INSULIN
PREPARATION ONSET PEAK DURATION MAX DURATION
RAPID ACTING Lispro (Humalog) 5 15 min .5-1.5 hr 5 hr 4-6 hr
RAPID ACTING Aspart (Novolog) 5 15 min .5-1.5 hr 5 hr 4-6 hr
RAPID ACTING Glulisine (Apidra) 5 15 min .5-1.5 hr 5 hr 4-6 hr
SHORT Regular .5 1 hr 2 3 hr 5 8 hr 6 10 hr
INTERMEDIATE NPH (isophane) 2 4 hr 4-10 hr 10-16 hr 14-18 hr
INTERMEDIATE Lente (zinc) 2 4 hr 4-12 hr 12-18 hr 16-20 hr
LONG Ultralente 6 10 hr 10-16 hr 18-24 hr 20-14 hr
LONG ANALOGUE Glargine (Lantus) 2 4 hr No Peak 20-24 hr 24 hr
COMBINATIONS 70/30 NPH/Reg .5 to 1 hr Dual 10 -16 hr 14-18 hr
COMBINATIONS 50/50 NPH/Reg .5 to 1 hr Dual 10 -16 hr 14-18 hr
CONBINATION ANALOGUES 75/25 NPL/lispro 5 15 min Dual 10 -16 hr 14-18 hr
CONBINATION ANALOGUES 70/30 NPL/aspart 5 15 min Dual 10 -16 hr 14-18 hr
Adapted from Hirsch IB, Edelman SV Practical
Management of Type 1 Diabetes, PCI Book,, West
Islip Ny (2005)
48
INSULIN

• Glucose homeostasis declines
• Loss of post prandial glycemic control
• Decline in control around breakfast
• Nocturnal Hyperglycemia
• Consider prandial insulin before starting basal
  insulin
• Basal insulin typically started in type 2

49
Diabetes and the eye

• Type 1
• Almost always have retinopathy and neuropathy by
  the time they develop nephropathy, but many
  patients with retinopathy do not have nephropathy
• Detected clinically by the doctor or
  opthalmologist
• Type 2
• Retinopathy will likely be accompanied by
  nephropathy
• If no retinopathy is present, they may have
  something other than diabetic nephropathy

50
Background Diabetic Retinopathy
NORMAL
BDR
51
ADOPT A Diabetes Outcome Progression Trial

• 4360 Patients with type 2 diabetes
• Rosiglitazone, metformin, glyburide
• Double blind randomized
• Treated 4 years
• Outcome time to medial failure
• Results
• Monotherapy at five years when compared with
  metformin
• 32 risk reduction with rosiglitazone
• 63 risk reduction with glyburide
• Better blood sugar control with glitazone
• N Engl J Med. 2006 Dec 7355(23)2427-43. Epub
  2006 Dec 4..Glycemic durability of rosiglitazone,
  metformin, or glyburide monotherapy.Kahn SE,
  Haffner SM, Heise MA, Herman WH, Holman RR, Jones
  NP, Kravitz BG, LachinJM, O'Neill MC, Zinman B,
  Viberti G ADOPT Study Group.

52
DREAM

• Lancet. 2006 Sep 23368(9541)1096-105.
• Effect of rosiglitazone on the frequency of
  diabetes in patients with impaired glucose
  tolerance or impaired fasting glucose a
  randomised controlled trial.
• DREAM (Diabetes REduction Assessment with
  ramipril and rosiglitazone Medication) Trial
  Investigators, Gerstein HC, Yusuf S, Bosch J,
  Pogue J, Sheridan P, Dinccag N, Hanefeld M,
  Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B,
  Holman RR.
• Multicenter RCT Rosiglitazone v placebo
  follow up median of 3 years
• Primary Outcome Composite incident diabetes
  or death
• Type Intent to treat
• GOAL prevent type 2 diabetes in high risk
  patients
• 5269 adults 30 years old with abnormal glucose
  tolerance, no prior CV diease
• Composite reached
• Rosiglitazone 11.6
• Placebo 26
• Euglycemic
• Rosiglitazone 50.5
• Placebo 30.3
• Cardiovascular
• Heart Failure
• Rosiglitazone 0.5
• Placebo 0.1

53
Common Medications to avoid in CKD

• NSIADS
• Ibuprofen (Motrin)
• Indomethacin (Indocin)
• Naproxen (Aleve, Anaprox, Naprosyn)
• (Celecoxib) Celebrex
• (Rofecoxib) Vioxx
• METFORMIN
• Glucophage, Diaformin

54
DRUGS THAT RAISE POTASSIUM

• Beta blockers like propanolol
• ACES
• ARBS
• Renin inhibitors
• NSAIDS
• Potassium sparing diuretics

55
Lowering Potasium

• Glucose and insulin
• Albuterol
• Kayexalate
• Loop diuretics
• Thiazide diuretics

56
Hardening of the Arteries

• Vascular Calcification
• Potentiated by metabolic syndrome and kidney
  disease
• Accumulation of phosphorus with decreased bone
  turnover in CKD associated with the metabolic
  syndrome potentiates changes in cells inside
  blood vessel walls
• These vessels accumulate phosphorus and calcium
  leading to vascular calcification
• Common in diabetes and in CKD

57
Diabetes Complications

• Vascular Disease
• Peripheral vascular disease
• Amputations
• Autonomic insufficiency
• Gastroparesis
• Postural hypotension
• Bladder dysfunction
• Neuropathy
• Charcot Joints
• Burning Neuropathy

58
Impact of diabetes on dialysis blood pressure
management

• Autonomic insufficiency
• BP drops and very labile
• Medial Calcification
• Wide Pulse Pressure
• Hypertensive cardiomyopathy
• Preload
• Cardiac function
• Afterload

59
Summary of prevention

• Lifestyle Modification
• ACE inhibitor therapy
• ARB therapy
• Control Blood sugar
• Control Blood pressure
• Vitamin D
• Titrate proteinuria

60
The End