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 hyper- filtration
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
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
Diagnosis
Hyperfiltration
Clinical Latency
Microalbuminuria
Macroalbuminuria
Renal failure
Type 1
Type II
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
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
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
68
Nephropathy Risk Factors
• 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
Secondary hyperparathyroidism
Binders
Phosphate binder+/-Calcium supplement
Vitamin D/ analoguesCalcimimetics
91
Decreased GFR
Hyperphosphatemia
Hypocalcemia
Low vitamin D+
decreased activation+
Resistance
Secondary hyperparathyroidism
Binders
Phosphate binder+/-Calcium supplement
Vitamin D/ analoguesCalcimimetics
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 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
Diabetic Nephropathy
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
Mechanisms for the Renoprotective Effect of ACE Inhibitors
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
Mechanisms for the Renoprotective Effect of ACE Inhibitors
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
Renal preglomerular vasodilation
Systemic hypertension
Glomerular hypertension
Glomerular sclerosis
HyperglycemiaGenetic factorsD metabolism of glom. cells
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
Renal preglomerular vasodilation
Systemic hypertension
Glomerular hypertension
Glomerular sclerosis
HyperglycemiaGenetic factorsD metabolism of glom. cells
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
Renal preglomerular vasodilation
Systemic hypertension
Glomerular hypertension
Glomerular sclerosis
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….
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