Diabetic nephropathy management

Diabetic Nephropathy:“You can't cure it so you have to endure it”

BY DR.KARTHIK.RAO.N

Current Terminology

• Kidney, not Renal (or Reno)• CKD, not CRF• DKD (= diabetic nephropathy)• AKI, not ARF• Still ESRD (End Stage Renal Disease)• Still RRT (Renal Replacement Therapy)

Definition of CKD

Structural or functional abnormalities of the kidneys for >3 months, as manifested by either:

1. Kidney damage, with or without decreased GFR, as defined by

• pathologic abnormalities• markers of kidney damage, including

abnormalities in the composition of the blood or urine or abnormalities in imaging tests

2. GFR <60 ml/min/1.73 m2, with or without kidney damage

Definition and Problem

• Progressive in UAE a/w BP and GFR• 35-50% DN in Type 1 after 20 years of disease• 10- ? 20% DN Type 2 in patients on diagnosis ??• Renal risk is equal in both Type I and II DM • Progressive rise in ESRD: Up to 40% of patients

on RRT due to DN• Strong association with cardiovascular risk

(20-40 fold higher)

Stages of Chronic Kidney Disease

Stage DescriptionGFR (mL/min)

1Kidney damage ± normal or GFR ≥90

2Kidney damage ± mild GFR 60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney Failure <15

Use e-GFR and not S Creat in practice

Stages of Diabetic Nephropathy

• Hyperfilteration• Stage of Clinical Latency• Incipient Nephropathy• Overt Nephropathy• Renal Failure

(Mogensen Staging for T1DM)

Diagnosis

Hyperfiltration

Clinical Latency

Microalbuminuria

Macroalbuminuria

Renal failure

Diabetes

MicroalbuminuriaDipstick negative

MacroalbuminuriaDipstick positive

30 300 mg/d0

New Terminology

Micro-albuminuria = High Albuminuria

Macroabuminurai = Very high Albuminuria

Stage of hyperfiltration

Microalbumi- nuria

Macroalbumi- nuria

Azotemia (Renal failure)

End stage Renal disease

Normoalbumi-nuria

NATURAL HISTORY OF NEPHROPATHY

IN TYPE 1 DIABETES

15 - 20 yrs 1 yrs 4 - 5 yrs

Natural History

Type II

Microalbuminuria

Macroalbuminuria

Renal failure

Diagnosis

Perkins BA, Et al. N Engl J Med 2003;348:2285-93.

Diagnosis

Hyperfiltration

Clinical Latency

Microalbuminuria

Macroalbuminuria

Renal failure

Type 1

Definitions of abnormalities in albumin excretion

Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24h, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, pyuria, and hematuria may elevate urinary albumin excretion over baseline values.

Diabetes care 2004; 27(1): S79-S83

Type II

Macroalbuminuria

Renal failure

Diagnosis


Diagnosis

Hyperfiltration

Clinical Latency

Microalbuminuria

Macroalbuminuria

Renal failure

Type 1

Type II

Renal failure

Diagnosis


Diagnosis

Hyperfiltration

Clinical Latency

Microalbuminuria

Macroalbuminuria

Renal failure

Type 1

Microalbuminuria & Proteinuria

Normal Microalbuminuria

Overt proteinuria

F 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

•Diagnosis of microalbuminuria based on 2 out of 3 urine samples in absence of UTI

•After 5 years of Dx in T1DM & than annually.•At the time of diagnosis in T2DM.

U/A at Diagnosis(Type 2 patients)

Random spot collectionAlbumin:creatinineRepeat 3x in 3-6 months

2 of 3 ≥ 30mg/g creatinine

Microalbuminuria,begin treatment

NephropathyQuantify µalb:CrConsider referral

No microalbuminuriaRe-screen yearly

Negative

Positive

No Yes

16

What are Diabetics with Nephropathy Dying From?

Stroke MyocardialInfarction

HeartFailure

SuddenDeath

Risk Factors : Non Modifiable • Race: Indo-Asians, Africans, Hispanics, Native Americans.• Familial clustering:

In Type 1 DM if 1* relative > 80% chances of developing DN. In Type 2 DM (Pima Indians) 14%, 23% and 46% (0,1,2 parents DM)

• Genetic influenceACE gene polymorphism (DD in Type 2)Ag-II type 2 receptor gene (AT2) on X-chromosome. (AA haplotype risk than GT haplotype in type 1 DM)Inheritance of one allele of the aldose reductase gene,

• Low Birth weight• Age Type 1 onset < 5 risk of ESRD but risk in T2DM in Pima

indians <20 yrs. Type 1 no proteinuria till age 25 risk <1 %• Elevated pro-renin levels.

Risk factors: Modifiable

• Hypertension• Dyslipidemia• Smoking• Poor glycemic control• Obesity• Oral Contraceptives• Increased protein intake

Natural History in Type 2 DM

• GFR decline once proteinuria present 12 ml/min/year untreated

• Patients often die of other causes (CVS disease) before ESRF

• CVS risk rises 2-3X with microalbuminuria, 9-10X with clinical proteinuria

• Higher rates of ESRF in T1DM

Hypertension

• Greater than 140/90 increases the risk of diabetes

• 50-60% of newly diagnosed patients also have HTN at diagnosis

• An interesting note: A family history of HTN in a child with Type 1 diabetes their risk of developing nephropathy

Undesirable lipid levels

• HDL less than 35 mg/dL

• Triglycerides greater than 150 mg/dL

• Think diabetes or hypothyroidism with the above lipid profile

• Draw a FBS and a TSH

Predictors of progression

• In normoalbuminuric person• Glycemic control

• In established DN• Hypertension• Degree of proteinuria

• In renal biopsy• Mesangial expansion• Tubulointerstitial lesions

• Hyperglycaemia Early histological lesions reversible

with normoglycaemia• Hypertension

Predicts microalbimunuria,

proteinuria paralleled by gradual rise in BP Correlation between BP and rate of of GFR

• Proteinuria Induces tubulointerstitial damage/ contributes to progression

Highly selective in early disease

Pathogenesis of DN

Oparil et al. Ann Intern Med 139:761-76, 2003.

ANG II ANG II

Cross-talk between the Insulin and Aangiotensin- II

Angiotensin II insulin sensitivity & insulin secretion, explaining the antidiabetogenic effect of RAS blockade

Hyperinsulinemia enhances Ang II-induced transcriptional activity in vascular smooth muscle cells

Treatment

1. Glycemic control

2. Blood pressure control

3. Angiotensin 2 control

4. Proteinuria control

5. Cholesterol control

DCCT

1400 T1DMIntensive

ConventionalHbA1C 7.3% 9.1%

Reduction in Retinopathy- 47%Microalbumnuria- 39%Clinical Nephropathy- 54%Neuropathy- 60%

Benefits of intensive control persisted even after study concluded and glycemic control worsened.

After 17 years 50% reduction in macrovascular complications.

Strict glycemic control prevents microalbuminuria in patients with

type 1: 2.2%/year DN in Intensive and 3.4% in conventional

Randomized prospective trial of treatment strategies in type II diabetes

ukpdsType 2 diabetic patients 5,102Person years follow-up 53,000

Intensive ConventionalHbA1c 7% 7.9%At 12 years 23 % 34 %

Each 1% decrease in HbA1C decreases microvascular complications by 35%.

Macrovascular advantage is seen after 10 years.

Strict BP control decreased microvascular complications.

Benefits of Glycemic Control•Delay the development of albumin excretion •Stabilize or protein excretion in pts with UAE•Slow the progressive renal injury in Macroalb.•May reverse early structural changes

UKPDS Study : Glycemic control is less than the

benefit from blood pressure control

ACEi are goodARB are good

What about both together?

33

Ang I

Ang II

Progressive Diabetic Nephropathy

ACE

Renal Injury and Proteinuria

ACEi

AT1 Receptor

Non-ACEPathways

Aldosterone

MRA

ARB

Can Dual Blockade of the RAAS Improve Renal Outcomes in Diabetic Nephropathy?

+

+

CALM Study

• N= 200• Type II DM with

microalbuminuria• Randomized to:

• Lisinopril 20 mg qd• Candesartan 16 mg qd• Combination of lisinopril

20 mg and candesartan 16 mg

Mogensen CE, Et al. BMJ 2000; 321: 1440-4.

Candesartan and Lisinopril Microalbuminuria (CALM)

24

39

50

0

10

20

30

40

50

Re

du

cti

on

in A

lbu

min

uri

a (

%)

Candesartan Lisinopril Combination

Calcium channel blockers

• Verapamil does not delay development of microalbuminuria

• Verapamil does reduce proteinuria in diabetics independent of changes in BP. Side effect: FGGS & TIF.

Aldosterone antagonists

• Spironolactone reduces proteinuria in diabetics• Change in proteinuria is

independent of blood pressure• All patients were treated with an

ACEi or ARB• 24-Hr ambulatory BP fell 6/2

Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.

ARBs: Evolution of protective benefits

↓BP

↓Stroke

↑Glycemic control

↓Heart failure

↓Renal dysfunction

↓CHD (?)

ONTARGET

• Telmisartan (16.7%) noninferior; combination (16.3%) not superior to ramipril (16.5%) for primary endpoint (CV death, MI, stroke, heart failure)

• Greater incidence of hypotension in combination (4.8%) and telmisartan (2.7%) groups, compared with ramipril group (1.7%) (p < 0.001)

Trial design: Patients at high risk for cardiovascular events, but without heart failure, were randomized to telmisartan, ramipril, or the combination. Patients were followed for a median of 56 months.

Results

Conclusions

The ONTARGET investigators. N Engl J Med 2008;358:1547-59

Telmisartan(n = 8,542)

Combination(n = 8,502)

• Either telmisartan or ramipril, but not both, can be used in hypertensive patients at high risk for cardiovascular events

• Side effects greater with combination therapy

16.716.3

%

0

10

Primary endpoint

20

Ramipril(n = 8,576)

16.5

0

10

15

5

Mortality

11.612.5 11.8

%

(p < 0.004*)(p = ns)

* Telmisartan vs. ramipril for noninferiority

RENIN INHITORS PLUS ARBS/ACEI

Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE):

• To determine whether aliskiren 300 mg once daily, reduces CV and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB)

• Included high-risk type 2 diabetes patients

Treatment

Blood pressure control Glycemic control

3. Proteinuria control

4. Cholesterol control

Protein restriction slows progression of DN

Is Anemia Causing Cardiovascular

And Renal Disease In Diabetics,

Or is it Just A Marker?

Hypothesis: Anemia is an Important CV Risk Factor in Chronic Kidney Disease

Chronic Kidney Disease

Cardiovascular disease

Anemia

©2005. American College of Physicians. All Rights Reserved.

< 2 % pts of DRD require RRT because others often die of CVD before reaching ESRD.

DialysisGet an early vascular access for HDOffer PD to patients with adequate manual dexterityI P Insulin therapy in PD ptsOffer HD to diabetic with severe vascular disease

TransplantationRenal and renal-pancreas transplantationPreemptive transplantation (GFR<30 mL/min)Evaluation for CADPost-Tx UTI, Allograft Rejection, Glycemic Control

Management of ESRD in DN

How Should We Manage Patient With Diabetic Nephropathy Today?

Parameter• Lower BP……………• Block RAAS……• Improve glycemia ….• Lower LDL cholesterol..• Anemia management ...• Endothelial protection…• Smoking……………

Target

< 130/80 mmHg

ACEi or ARB to max

HbA1c < 6.5% (Insulin)

< 100 (70) mg/ statin + other

Hb 11-12 g/dl (Epo + iron)

Aspirin daily

Cessation

Conclusions

• Diabetic nephropathy is the most common cause of ESRD in the world

• ESRD is a rare out-come among diabetics

• Just over half of diabetics will develop nephropathy

• Blood pressure control• Glycemic control• Angiotensin 2 reduction• Proteinuria reduction

• ACEi + ARB• Statins• Aldosterone antagonists• Dihydropyridine calcium

channel blockers

Key messages• Screening for diabetic renal disease is easy and should be performed annually• Good glycaemic control is the main Pry prevention

therapy• Once microalbuminuria confirmed RAS blockade is

must• BP targets should be individualised• Treatment aims to stabilise e-GFR & maintain/ UAER• Attention to all vascular risk factors is vital• If RRT becomes necessary this needs to be carefully

planned well in advance

Diabetic NephropathyDiabetic Nephropathyh Over 40% of new cases of

end-stage renal disease (ESRD) are attributed to diabetes.

h In 2001, 41,312 people with diabetes began treatment for end-stage renal disease.

h In 2001, it cost $22.8 billion in public and private funds to treat patients with kidney failure.

h Minorities experience higher than average rates of nephropathy and kidney disease

Incidence of ESRD Resulting from Primary

Diseases (1998)

43%

23%

12%

3%

19%

Diabetes

Hypertension

Glomerulonephritis

Cystic Kidney

Other Causes

Five Stages of Kidney DiseaseFive Stages of Kidney DiseaseStage 1: Hyperfiltration, or an increase in glomerular filtration rate (GFR) occurs. Kidneys increase in size.

Stage 2: Glomeruli begin to show damage and microalbuminurea occurs.

Stage 3: Albumin excretion rate (AER) exceeds 200 micrograms/minute, and blood levels of creatinine and urea-nitrogen rise. Blood pressure may rise during this stage.

InvestigationsInvestigations

Urinary Protein assessment

Dipstick

24hour urinary protein estimation

Albumin: Creatinine ratio > 2.5 in males and > 3.5 in females is abnormal

Confirm with Albumin excretion rate (AER) of 20-200ug/min or 30-300mg/24hrs. This requires timed urine collection

Five Stages of Kidney Disease (con’t.)

Five Stages of Kidney Disease (con’t.)

Stage 4: GFR decreases to less than 75 ml/min, large amounts of protein pass into the urine, and high blood pressure almost always occurs. Levels of creatinine and urea-nitrogen in the blood rise further.

Stage 5: Kidney failure, or end stage renal disease (ESRD). GFR is less than 10 ml/min. The average length of time to progress from Stage 1 to Stage 4 kidney disease is 17 years for a person with type 1 diabetes. The average length of time to progress to Stage 5, kidney failure, is 23 years.

Screening for Diabetic Nephropathy

Screening for Diabetic Nephropathy

Test When Normal Range

BloodPressure1

Each office visit <130/80 mm/Hg

UrinaryAlbumin1

Type 2: Annuallybeginning at diagnosisType 1: Annually, 5-yearspost-diagnosis

<30 mg/day<20 g/min<30 g/mgcreatinine

1American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004

Treatment of Diabetic Nephropathy

Treatment of Diabetic Nephropathy

• 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

• Glycemic Control – 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

Treatment of Diabetic Nephropathy (cont.)

Treatment of Diabetic Nephropathy (cont.)

Treatment of End-Stage Renal Disease (ESRD)

Treatment of End-Stage Renal Disease (ESRD)

There are three primary treatment options for individuals who experience ESRD:

1. Hemodialysis

2. Peritoneal Dialysis

3. Kidney Transplantation

HemodialysisHemodialysis• Procedure

– A fistula or graft is created to access the bloodstream

– Wastes, excess water, and salt are removed from blood using a dialyzer

– Hemodialysis required approx. 3 times per week, each treatment lasting 3-5 hrs

– Can be performed at a medical facility or at home with appropriate patient training

• Hemodialysis Diet– Monitor protein intake– Limit potassium intake– Limit fluid intake– Avoid salt– Limit phosphorus intake

• Complications– Infection at access site– Clotting, poor blood flow– Hypotension

Hemodialysis (cont.)Hemodialysis (cont.)

Peritoneal DialysisPeritoneal Dialysis• Procedure

– Dialysis solution is transported into the abdomen through a permanent catheter where it draws wastes and excess water from peritoneal blood vessels. The solution is then drained from the abdomen.

– Three Types of Peritoneal Dialysis• Continuous Ambulatory Peritoneal Dialysis

(CAPD)• Continuous Cycler-Assisted Peritoneal Dialysis

(CCPD)• Combination CAPD and CCPD

Peritoneal Dialysis (cont.)Peritoneal Dialysis (cont.)

• Peritoneal Dialysis Diet– Limit salt and fluid intake– Consume more protein– Some potassium restrictions– Reduce caloric intake

• Complications– Peritonitis

Kidney TransplantKidney Transplant

• Procedure– A cadaveric kidney or kidney from a related

or non-related living donor is surgically placed into the lower abdomen.

– Three factors must be taken into consideration to determine kidney/recipient match:• Blood type• Human leukocyte antigens (HLAs)• Cross-matching antigens

How Can You Prevent Diabetic Kidney Disease?

• Maintain blood pressure <130/80 mm/Hg• Maintain preprandial plasma glucose 90-

130 mg/dl• Maintain postprandial plasma glucose

<180 mg/dl• Maintain A1C <7.0%

63

Albuminuria then Proteinuria

• Microalbuminuria first (lower MW)– Raised by ↑GFR (i.e. ↑BSL, ↑protein diet,

fever, exercise)

• Spot urine ACR or PCR– more convenient than 24hr collection– more accurate than urinalysis– adjusts for fluid intake– underestimates the muscular patient

64

Diabetic Nephropathy

• From haemodynamic & metabolic stresses

• Metabolic stress – deposition of advanced glycosylation end

products in connective tissue & sml vessels.

• May take 10-20 yrs but many T2DM asymptomatic for several yrs, hence nephropathy may already be present at Dx

65

Nephropathy Risk Factors

• DM Type & Duration– 20% of Type I after 20 years– 40% of Type II any duration

• Poor diabetic control• Hypertension• Aboriginal > Indian > Caucasian• Smokers• Family history

66

• 1st clinical sign is microalbuminuria (ACR)• Kidney not able to catabolise albumin• This can also occur transiently with

– Fever– Exercise– Short term hyperglycaemia– High protein meal

• Hence, repeat at a later date/rule out reversible• DM + HPT, x 20 risk of progressive nephropathy• DM + HPT + poor diabetic & lipid control, x 40 risk

67


• DM Type & Duration– 20% of Type I after 20 years– 40% of Type II any duration

• Poor diabetic control• Hypertension• Aboriginal > Indian > Caucasian• Smokers• Family history

68


• Modifiable– HbA1c, BP & total cholesterol (Odds Ratio 43)

– Obesity, smoking

• Non-modifiable– Age, ethnicity, male sex

69

Delaying Complications

• Tight diabetic control– Prevention of microvascular Cmplx

• Risk of hypos

• Tight BP control– Prevention and management of micro &

macro Cmplx– Use ACEI, ARB’s or both combined

70

ACE Inhibitors can prevent progression of renal failure

120

160

200

240

280

320

350

400

800 1 2 3 4 5 6

Years

Ann Intern Med 118 577-581.1993

Placebo

Enalapril 85

90

95

100

105

110

800 1 2 3 4 5 6

Years

Placebo

Enalapril

Normotensive Type 2 Diabetics

Proteinuria

(mg/day)

% Initial GFR

71

ACEI/ARB Proteinuria Remission

H

L

H

L

30

40

50

60

70

80

90

2000Jan 2000

2001 2002

Creatinine - Plasma

umol

/L

H 0

500

1000

2000Jan 2000

2001 2002

Protein/Creat Ratio - Urine

mg/

mm

ol

72

Q. Which features are typical of diabetic CKD at presentation ?

• Haematuria NO• Small scarred kidneys NO• Progress to ESKD in <2yrs NO• Associated retinopathy YES• β-blockers better than ACE-I Rx NO

73

Diabetes and ESKD

• Reducing insulin requirements• Difficult vascular access• Accelerated macrovascular disease• Advanced microvascular disease• Frequent sepsis• Silent ischaemia• 2-3 x death rate vs non-DM patients

74

How can DM effect Dialysis?

• Autonomic neuropathy – may suffer hypotension increased by large fluid shift in HD

• Uncontrolled blood sugars – may absorb some glucose in PD fluid

• Severe PVD – difficult to get vascular access for HD• PVD may also affect peritoneum and reduce PD

success • Increased risk of infections – problem in both• Transplants – new kidneys develop nephropathy, hence

good glycaemic control important

75

Strict BSL Control in early Type I

• Target HbA1c < 7%• For every 1%↓ HbA1c:

– 10% ↓CVD – 40% ↓Microvascular Cmplx

• BUT:• Doubles risk of hypoglycaemia• Loss of control with DM duration:

– 50% at 3yr– 30% at 6yr– 15-25% at 9yr (= % patients with HbA1c < 7% on Met or OHA

alone)

76

Strict BSL Control in DM CKD

• AND:• Minimal benefit if overt proteinuria• Diabetes “cured” by advancing CKD

– reduced appetite and CHO intake– prolonged insulin half-life

– false elevation of HbA1c by 0.5-1%

77

Metformin in CKD

• No hypos or weight gain• Inexpensive• BUT:

– Renally-excreted– Excess doses → anorexia, diarrhoea– Dose adjust to GFR: 2g to 250mg/day– Protocol says

• eGFR 30 – 59 max 1gm/day

• cease when eGFR <30 but…

– Risk of fatal lactic acidosis if unwell

78

Glitazones in DM

• Av.1% fall in HbA1c as monoRx or add-on• Preserves beta-cell fn - use early • Durable effect >3yrs• BUT:

– 1-2/12 delayed onset – Average 4kg SC fat gain, visceral fat loss

– Oedema (Na+/H20, ↑vasc. permeability)

– Expensive

79

Strict BP Control at any stage

• ½’s (or even stops) rate of fall in GFR• Greater benefit than tight BSL control • Falling BP Target = 120/70 currently• Preferential use of ACEi/ARBs • Complete regression of proteinuria

possible• Helps all micro- & macrovascular disease• (Parving, UKPDS, Captopril Trial, MicroHOPE, IRMA/IDNT, JNC

VI)

80

Use of ACEi/ARBs: actions

• Antihypertensive– ↓ by salt excess, ↑by thiazides– need mean of 3 agents in mild CKD

• Antiproteinuric– 30-50%↓ alone, 40-70%↓ together

• Renoprotective– corrects ↑GFR, expected 30% ↑creatinine

Creatinine- it’s the best we have!

Rough GFR

Equations should be used only in the steady state

Not useful in ARFReasonable criteria

◦ CrCl> 50ml/min◦ CrCl 10 – 50 ml/min◦ Crcl< 10 ml/min◦ Oliguric and non

oliguric

Creatinine GFR

1 100

2 50

3 25

4 12.5

5 6.125

6 3.06125

Natural history of DN

Diabetes

1,2 3 4 5

Time

GFRCreat

Problems Precautions Blood pressure control Dietary protein restriction Management of MBD Management of anemia Vaccination Volume control Cardiovascular disease screening Options of renal replacement

PrecautionsNo nephrotoxics

◦Impair glomerular function: NSAIDS◦Impair tubular function:

Aminoglycosides◦NO contrast agent exposure

Drug dose adjustmentTreat intercurrent infections

properlyEducate about native drugsEarly referral to nephrologist

Blood pressure management

Systemic BP reduction Intra-glomerular BP reduction

Anti-proteinuric effect

Blood pressure control

Beta blockersAlpha -blockersVasodilators

ARBACEi

Preservation of other target organs Preservation of kidneys

Protein restrictionPreservation of organ repairDaily dietary requirement (FAO)

◦0.6 g/Kg/d plus 2 SD= 0.8 g/Kg/dMDRD study

◦Dietary protein restriction may offer a benefit

Remember to preserve adequate calories

Secondary hyperparathyroidism

89

90

Decreased GFR

Hyperphosphatemia

Hypocalcemia

Low vitamin D+

decreased activation+

Resistance


Binders

Phosphate binder+/-Calcium supplement

Vitamin D/ analoguesCalcimimetics

91

Decreased GFR

Hyperphosphatemia

Hypocalcemia

Low vitamin D+

decreased activation+

Resistance


Binders

Phosphate binder+/-Calcium supplement

Vitamin D/ analoguesCalcimimetics


DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15-20% of patients with type II diabetes (NIDDM).

Definition or Criteria for diagnosis of DNPresence of persistent proteinuria in sterile urine

of diabetic patients with concomitant diabetic retinopathy and hypertension.

BMDDietary

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

Anemia management

EPO deficiency

Defect in iron absorption

B12 and folate deficiency

Diseases like myeloma

Hyperparathyroidism

Drugs like ARB

Aluminum toxicity

Blood loss

Hemolysis

Pure Red Cell Aplasia

Correction of anemiaIdentify iron

deficiencyOral iron vs

parenteral ironIron sucroseDon’t overload

ironAvoid

transfusions

EPO therapy if iron replete

Target 11 to 12 g/dl

Start at small dose and titrate upwards

Twice weekly to thrice weekly

Newer analogues may be used less frequently

VaccinationsHepatitis B

◦20 mcg each deltoid IM 0, 1, 2, 6 months

◦Check Anti HBS titre post vaccination after 3rd dose

◦Only 60 % seroconvert in ESRDPneumococcal vaccineInfluenza vaccine

Volume controlProblems with salt and water

excretion in CKD is relatively laterProteinuric conditions may

develop this problem earlyDiabetic remain proteinuric even

while fibrosis continues to proceed

Fluid restriction and salt restriction is important

Diabetes Asymptomatic bacteriuria is more common

(20%) UTIs are likely to be more severe in diabetic

than nondiabetic women Asymptomatic bacteriuria often precedes

symptomatic UTI in type 2 diabetes [RR] 1.65 Risk factors for UTI in diabetics includes those

who take insulin (relative risk 3.7) longer diabetes duration (>10 years, relative risk 2.6)

○ but not glucose control

Emphysematous pyelonephritis, xanthogranulomatous UTI and fungal UTI are common

Diabetic Nephropathy A clinical syndrome

DM +

Persistent albuminuria, Worsening proteinuria, Hypertension &

progressive renal failure

Diabetic nephropathy (DN) is a major

cause of ESRD, and the incidence of diabetes

mellitus is rising rapidly.

Diabetic Nephropathy DN occurs in 35-40% of patients with type I

diabetes (IDDM) whereas it occurs only in 15-20% of patients with type II diabetes (NIDDM).

Definition or Criteria for diagnosis of DN Presence of persistent proteinuria in sterile urine of

diabetic patients with concomitant diabetic retinopathy and hypertension.

Effect of Angiotensin Blockade

Afferent arteriole

Efferent arteriole

¯Glomerular pressure¯(¯ GFR)

Glomerulus

Bowman’s Capsule

Angiotensin IIAngiotensin II

ProteinuriaProteinuria

A II blockade:A II blockade:

Irbesartan in patients with type 2 diabetes & microalbuminuria study590 NIDDM patients with HTN and

microalbuminuria with nearly normal GFR.Randomly assigned to placebo, 150 mg or

300 mg of irbesartan for 2 years.Primary outcome was time to the onset of

diabetic nephropathy (urinary albumin excretion rate >200 mcg/min and at least 30% greater albuminuria)

14.9% patients on placebo group, 9.7% of irbesartan 150mg group and 5.2% of irbesartan 300 mg group reached the primary point.

(Parving et al, NEJM, 2001)

ARBs in NIDDM,HTN & microalbuminuria-Parving 2001

D.N.-Management ACEI or AII RB- in both expt & human

Reduce glomerular hypertension Reduce proteinuria independent of

hemodynamic effects Reduce glomerular hypertrophy well tolerated apart from hyperkalemia &

worsening of anemia in severe CRF Cautious use in presence of severe renovascular

disease

DN: ADA Position Statement

Screening:

Perform an annual test for the presence of microalbuminuria in1) type 1 diabetic patients who have had diabetes > 5 years and2) all type 2 diabetics patients starting at diagnosis.

Treatment:

• In the treatment of albuminuria/nephropathy both ACE inhibitors and ARBs can be used:

• In hypertensive and nonhypertensive type 1 diabetic patients with microalbuminuria or clinical albuminuria, ACE inhibitors are the initial agents of choice

• In hypertensive type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARBs are the initial agents of choice.

• If one class is not tolerated, the other should be substituted

American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002

UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions

Better blood pressure control reduces… Strokes by > one third Serious deterioration of vision by > one third Death related to diabetes by one third

Better glucose control reduces… Early kidney damage by one third Major diabetic eye disease by one fourth

Turner RC, et al. BMJ. 1998;317:703-

713.

National Kidney Foundation Recommendations on Treatment of HTN and Diabetes

Blood pressure goal: 130/80 mmHgTarget blood pressure: 125/75 for

patients with >1 gram/day proteinuriaBlood pressure lowering medications

should reduce both blood pressure + proteinuria

Therapies that reduce both blood pressure and proteinuria have been known to reduce renal disease progression and incidence of ischemic heart disease

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients

Hypertension◦ BP < 130/80 mmHg

Hypercholesterolemia◦ LDL < 100 mg/dL

Hyperglycemia

◦ Hgb A1C < 7.0 %

American Diabetes Association Clinical Practice Recommendations. Diabetes Care. 2001;24(suppl1):S1-S133.

Management of HTN and Chronic Renal Disease (CRD) in Diabetics

Reduce BP to <130/80 mmHgUse multiple antihypertensive drugs

(ACEI, ARB, diuretic, CCB, beta-blocker)

Maximal reduction of proteinuriaTreat hyperlipidemia (LDL <100

mg/dL)Control Hgb A1C to <7%Low salt diet (<2 gm NaCl/day)Stop cigarette smoking


Clinical syndrome characterised by persistent albuminuria

(>300mg/24hrs)on at least 2 occasions separated

by 3 months.

Epidemiology

Incidence of Diabetic Nephropathy in

Type 1 Diabetes 4-17% 20 years 16-30% 30 years 30-40% 40 years

Epidemiology

Incidence of Diabetic Nephropathy in

Type 2 Diabetes 5% at diagnosis 20% after 20 years

Screening for Microalbuminuria

Albumin excretion increased due to

Strenuous exerciseOral Protein intakeUrinary infectionFluid loadingPregnancy

Urinary Albumin Excretion RatesNormoalbuminuria < 30mg/day

Microalbuminuria 30-300mg/day

Overt Nephropathy > 300mg/day

Screening for Microalbuminuria

Type 1: Yearly after 5 years of diagnosis

Type 2: Annually from diagnosis

Protein Kinase CRenal injury due to hyperglycaemia

increase reactive oxygen species.

Activation of PK C and TGF b results in increased:

Vascular Contractility Blood Flow Cellular Proliferation Vascular Permeability

Inhibition of PKC by Ruboxistaurin in Rats

Reduces Glomerular Hyperfiltration

AlbuminuriaExtra cellular Matrix

accumulation

Mechanisms for the Renoprotective Effect of ACE Inhibitors

Lower Systemic Blood PressureLower Intra glomerular Pressure

and filtration rates Reduce Proteinuria


Inhibit non Heamodynamic effects of Angiotensin on various cell types

Reduction in Cytokine and Growth factor synthesis e.g. TGF β

Mesangium: Reduced Cell proliferation

Hypertrophy Matrix Expansion


Reduction in Oxidative Stress

Inhibit macrophage activation, proliferation and migration

Renal preglomerular vasodilation

Systemic hypertension

Glomerular hypertension

Glomerular sclerosis

HyperglycemiaGenetic factorsD metabolism of glom. cells

Treatment of DM nephropathy:Glucose control

from T. Hostetter






Treatment of DM nephropathy:Hypertension control

from T. Hostetter

Blood pressure management

Systemic BP reduction Intra-glomerular BP reduction

Anti-proteinuric effect

Blood pressure control

Beta blockersAlpha -blockers

Vasodilators

ARBACEi

Preservation of other target organs Preservation of kidneys

Treatment

• Hypertension control:– Lower the BP, slower the decline in GFR in patients with diabetic

nephropathy

– JNC VI recommended BP < 130/85 mmHg in patients with renal insufficiency

– Patients with CKD and > 1g proteinuria, BP goal should be < 125-130/75-80 mmHg

Role of Aldosterone in the Pathogenesis of Diabetic Nephropathy

Treatment

• ACE inhibitors:– Type I diabetes with nephropathy: captopril vs. placebo

– 50% RR of combined end points of death, dialysis and transplantation in ACEI group independent of BP

Lewis et al. NEJM, 1993

Treatment

• Angiotensin-receptor blockers:– RENAAL study(2001)

• 1513 pts with type II DM and nephropathy. Losartan vs. placebo. Losartan reduced the rate of doubling of cr by 16% but no effect on the rate of death.

– IDNT(2001)• 1715 type II DM pts with nephropathy. Irbesartan vs. amlodipine

vs. placebo. Irbesartan has 20% lower risk of reaching endpoints compared to placebo and 23% lower incidence than that in the amlodipine group






Treatment of DM nephropathy:Effect of ACEIs and ARBs

from T. Hostetter

Diabetic Nephropathy: Important Message

• Lower blood pressure < 130 / 80 mmHg

• Reducing Proteinuria

• Inhibition of Renin-Angiotensin System

• Multiple risk factor intervention– Glycemia

– Dyslipidemia

– Physical activity

– Aspirin

– Smoking cessation

ACEi- or ARB-Based Regimens for Diabetic Nephropathy Do Not Go Far Enough!

Diabetic Nephropathy: Important Message

• Small short-term studies suggest combinations of ACEi and ARB reduce proteinuria synergistically

– Greater reductions in proteinuria with or without additional lowering in blood pressure

– Hyperkalemia and Increased creatinine not well documented

• Safety and Efficacy of combination ACEi and ARB in diabetic with nephropathy not well established

Secondary hyperparathyroidismAbnormalities in metabolism of calcium and phosphorus in patients with chronic kidney disease

Targets

Stage Calcium* Phosphorous PTH

Stage 3 8.4 to 9.5 2.7 to 4.6 35-70

Stage 4 8.4 to 9.5 2.7 to 4.6 70-110

Stage 5 8.4 to 9.5 3.5 to 5.5 150 to 300

*Corrected calcium

BMD

• Replenishment of vitamin D stores

• Activated vitamin D 1, 25 (OH)2D3

• Vitamin D analogues

– Paricalcitrol

– Doxercalcitriol

• Dietary phosphate restriction

• Phosphate binders– Aluminium– Calcium– Magnesium– Non aluminium, calcium, magensium binders

Anaemia

• May occur when GFR < 50 % & almost always present when GFR < 30 %

• Correct deficiencies– Iron, Folic acid, Vit B12, Pyridoxine

• Erythropoietin 75 - 150 iu/kg SC– With Iron supplements

– Expensive therapy Rs. 8 - 10, 000 / month

– Hb % maintained at 11 - 12• > 13 in pts with CAD

Vaccinations

• Hepatitis B

– 20 mcg each deltoid IM 0, 1, 2, 6 months

– Check Anti HBS titre post vaccination after 3rd dose

– Only 60 % seroconvert in ESRD

• Pneumococcal vaccine

• Influenza vaccine

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

Cardiovascular disease screen

• Renal disease is a cardiovascular risk factor

• CKD promotes vascular calcification

• Non invasive evaluation important

• Contrast agents carries risk of RCIN- benefits to risk

Options of renal replacement

• Hemodialysis

• Peritoneal dialysis

• Renal transplantation

Peritoneal dialysis

Advantages • Slow, gentle

• Round the clock clearance

• Greater salt, fluid and dietary freedom

• Mobility

• No need for vascular access

Disadvantages • Visual acuity important

• Metabolic problems and some mechanical problems

• Peritonitis

Others

• Lipid lowering - diet, statins

• Low dose aspirin

• Avoid nephrotoxic drugs & contrast procedures

• Prevent & treat infections energetically

• Hepatitis B immunization– Early immunization ideal

– if Cr. > 3 double & more frequent dosing

Diabetic Nephropathy: Some Novel Therapies Under Investigation

• Pirfenidone –antifibrotic agent

• Aliskerin anti-renin agent

• Robuxistaurin- Protein Kinase C Beta-1 antagonist

• Advanced Glycation Endproduct antagonists

Recommendations:Nephropathy treatment (1)

• Nonpregnant patient with micro- or macroalbuminuria

– Either ACE inhibitors or ARBs should be used (A)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S33.

Control blood sugars: which drug to use ?

• Drugs contraindicated: Metformin

• Preferably not used: Glibenclamide,

Chlorpropamide

• Can be used: Glimiperide, Repaglinide,

Pioglitazone

• Insulin: prefer

Target : HbA1c <7 %, FPG: <100 mg/dl, PPBG<140 mg/dl

Blood pressure managementPreferred drugs: Angiotensin receptor blocker

ACE inhibitor Non DHP calcium channel blocker:

Diltiazem Diuretic Beta blocker

Target blood pressure : 125/75 mm Hg

Recommendations:Nephropathy treatment (2)

• In patients with type 1 diabetes, hypertension, and any degree of albuminuria– ACE inhibitors have been shown to delay progression of nephropathy

(A)

• In patients with type 2 diabetes, hypertension, and microalbuminuria– Both ACE inhibitors and ARBs have been shown to delay progression

to macroalbuminuria (A)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S33.

Recommendations:Nephropathy Treatment (4)

• Reduction of protein intake may improve measures of renal function (urine albumin excretion rate, GFR) (B)– To 0.8 –1.0 g x kg body wt–1 x day–1 in those with diabetes, earlier

stages of CKD

– To 0.8 g x kg body wt–1 x day–1 in later stages of CKD

• When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine, potassium levels for development of acute kidney disease, hyperkalemia (E)

Adverse effects of ACEI and ARB

• Cough : 0-39%, F>M, class effect

• Angioedema: 0.1-0.2 %: 1hr to <1 wk

• Metallic taste: captopril

• Hyperkalemia

• Worsening renal failure

Treatment of DM nephropathy:Effect of statins

from T. Hostetter





HyperglycemiaROSGenetic factorsD metabolism of glom. cells

• Normalize BP. Target <130/80.

• Treat with ACE inhibitors or ARBs.

• Treat hyperlipidemia and hyperglycemia aggressively.

• Moderate protein restriction (0.8- 1.0 gm/kg/day).

• Treat cardiovascular disease aggressively.

• Refer to nephrologist early in course of azotemia.

Management of Diabetic Nephropathy-Rx

Diabetic Nephropathy: Introduction (2)

Do you know… • At diagnosis 30% of people with T2DM have

nephropathy

Tobe SW et al. CMAJ; 2002; 167 (5):499-503

Category 24-h Timed Spot

collection collection collection

mg/24 h µg/min µg/mg creat

Normal <30 <20 <30

Microalbuminuria 30-300 20-199 30-299

Overt Nephropathy >300 ≥200 ≥ 300

(Macroalbuminuria)

(Alb./Cr.ratio)

Definitions of abnormality in albumin excretion

Diabetic Nephropathy : Introduction (3)

Obese, sedentary, “wrong diet”, genetic predisposition,…….

IGT

DMIncipient Nephropathy

Overt or Clinical Nephropathy

ESRD

Progression of Nephropathy (2)

• Glycemic Control means– FPG= 90-130 mg/dl

– PPPG <180 mg/dl

– HbA1c <7.0%

– Self-monitoring of blood glucose (SMBG)

– Medical Nutrition Therapy• Restrict dietary protein to RDA of 0.8 g/kg body weight / day

• BP control – Maintain BP <130/80 mm/Hg

Glycemic control is a must….Glycemic control is a must….

Education

Diabetic nephropathy management