7. Nephropathy
Broad medical term used to donate disease or damage of the kidney
which eventually results in kidney failure.
Is considered a progressive illness; in other words, as kidneys become
less and less effective over time (with the progression of the disease), the
condition of the patient gets worse if left untreated.
It is pivotal to receive adequate diagnosis and treatment as early as
possible
8. Diabetic Nephropathy
30% of all end-stage renal disease
Is a chronic condition developing over many years, characterized by:
Gradually increasing urinary albumin excretion (UAE)
High blood pressure (BP)
Declining glomerular filtration rate
Absence of other renal/renal tract disease
Presence of diabetic retinopathy
May be prevented/delayed by early screening and treatment
17. Pathophysiological Stages
Stage increased
GFR
Increased filtration pressure as result of increased
intraglolerular pressure
Increased UOP and low s.cra, urea
Pathological change but no clinically evident disease
Proteinuria
Mesangial expansion and increased matrix change in
pore
sizes leading to leakage of protein
Starling Foces: increased plasma flow, increased
glomerular capillary hydrostatic pressure
Microhematuria
Ischemic injury of tubules due to construction and
stenosis of efferent arteriole
Decreased GFR Atrophy and death of nephrons
CKD and ESKD Loss of compensation mechanisms of nephrons
18. Risk Factors
Genetic factors
Age
Inadequate glucose control
High Blood pressure
Hyperlipidemia
Smoking
Long Standing Diabetes
Obesity
Increased protein intake
20. Minimum Screening for Renal Disease in
Diabetes
Annual EMU for ACR. Repeat within a month if positive, in absence of
UTI/renal stones/other renal disease
Annual serum creatinine
Creatinine
eGFR (preferred MDRD equation)
21. Microalbumnuria and Proteinuria
Diagnosis of microalbuminuria based on 2 out of 3 positive first passed
morning urine samples in absence of urinary tract infection
Normal Microalbuminuria Overt
proteinuriaF M F M
Albumin/creatinine
ratio (mg/mmol)
<3.5 <2.5 >3.5 >2.5 >30
Equivalent Albumen
excretion (mg/day)
<30 30-300 300
22. Initial Assessment of Patients with Diabetes
and Renal Impariment
Is this likely to be diabetic nephropathy?
Presence of retinopathy
Microalbuminuria/proteinuria
Is this likely to be renal artery stenosis?
Family history, Drug history, GU history etc.
AIP, myeloma screen, PSA
Ultrasound
23. Screening and Diagnosis in Diabetic
Nephropathy
Screening for diabetic nephropathy must be initiated at the time of
diagnosis in patients with type 2 diabetes, since 7% of them already have
microalbuminuria at that time
For patients with type 1 diabetes, the first screening has been
recommended at 5 years after diagnosis
Puberty, poor glycemic control and poor lipid control are independent risk
factors for micro albuminuria .Therefore, in type 1 diabetes, screening for
micro albuminuria might be performed 1 year after diabetes diagnosis in
these patients
If micro albuminuria is absent, the screening must be repeated annually
for both type 1 and 2 diabetic patients
25. Diagnosis
Renal biopsy is the gold standard
A renal biopsy may be deferred with the assumed diagnosis of diabetic
nephropathy in the context of
Macro albuminuria (>300 mg/24 hours) that has developed
progressively,
Microalbuminuria (30-300 mg/24 h) with retinopathy,
Microalbuminuria in patients with diabetes for more than 10 years .
27. Oral Hypoglycemics
METFORMIN
Metformin has been used in low doses in patients with glomerular filtration
rate (GFR) as low as 30 to 60 ml/min. It
Should not be used at a GFR below 30 ml/min -- risk for lactic acidosis.
As renal function can deteriorate abruptly,
Better to avoid metformin once serum creatinine concentration rises above
1.5 mg/dl (132 μmo/l) in men
1.3 mg/dl (117 μmol/l) in women
28. Oral Hypoglycemics
METFORMIN
Metformin has been used in low doses in patients with glomerular filtration
rate (GFR) as low as 30 to 60 ml/min. It
Should not be used at a GFR below 30 ml/min -- risk for lactic acidosis.
As renal function can deteriorate abruptly,
Better to avoid metformin once serum creatinine concentration rises above
1.5 mg/dl (132 μmo/l) in men
1.3 mg/dl (117 μmol/l) in women
29. INSULIN SECRETAGOGUES
(SULFONYLUREA AND MEGLITINIDES)
Sulphonylureas (especially gliblenclamide) may accumulate as renal
function deteriorates
Can be associated with hypoglycemia
Glycosidase inhibitors
Contraindicated in renal failure
30. Thiazolidinediones
Associated with weight gain, (fluid retention + nonfluid gains)
Patients at risk for congestive heart failure -- should be avoided.
Concern about increased bone fracture rates in patients using
thiazolidinediones,
Could potentiate CKD - related bone disease.
31. Recommendations for Non-Insulin Hyperglycemia Drug Therapy for
Patients With Moderate to Severe CKD
Volume 25, Number 3, 2007 • Clinical Diabetes
32. INSULIN
Insulin regimens are the most commonly used to control glycemia in CKD
Increasing half-life of insulin as CKD progresses, the risk for hypoglycemia
increases.
Insulin requirements decrease further in HD patients, particularly in those
with residual diuresis (<500 ml/day),
Insulin requirement often decreases by 30%
In peritoneal dialysis (PD) patients,
Intraperitoneal insulin is more physiologic than subcutaneous, as portal
absorption of insulin may better mimic the endogenous insulin effect.
Insulin requirements typically increase by 200% to 300% in this situation
33. INSULIN IN PT. ON HEMODIALYSIS
Insulin inhibitors – dialyzable
Insulin resistance diminishes after the start of dialysis.
Half-life of insulin is prolonged.
The potential for hypoglycemia with both oral agents and insulin increases
in the presence of CKD (with the exception of gliquidone and glimepiride).
Self-monitoring of blood glucose concentration is imperative.
Insulin requirement often decreases by ~30%
Glargine has been shown to reduce hypoglycemia in hemodialysis
patients
34.
35. Management of Diabetic Nephropathy
Optimal control of blood pressure, glucose, and lipids
Smoking cessation
RAAS blockade
ACE inhibitor, ARB, or renin inhibitor
Do not combine RAAS blocking agents
Monitor serum potassium
Nephrologist referral
Atypical presentation
Rapid decline in eGFR or albuminuria progression
Stage 4 CKD
ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blocker; CKD = chronic kidney disease; eGFR = estimated
glomerular filtration rate; RAAS = renin angiotensin aldosterone system.
37. Preprandial plasma glucose 90-130 mg/dl
A1C <7.0%
Peak postprandial plasma glucose <180 mg/dl
Self-monitoring of blood glucose (SMBG)
Medical Nutrition Therapy
Restrict dietary protein to RDA of 0.8 g/kg body weight per day
Glycemic Control
38. Blood Pressure Management
Preferred drugs:
Angiotensin receptor blocker
ACE inhibitor
Non DHP calcium channel blocker: Diltiazem
Diuretic
Beta blocker
Target blood pressure : 125/75 mm Hg
BP reduction in type 1 & type 2 DM patients reduces rate of CKD
progression
At any given level of GFR, blood pressure tends to be higher in diabetic
than in non-diabetic patients with CKD
39. Drugs to Control Blood Sugars
Drugs contraindicated: Metformin
Preferably not used: Glibenclamide, Chlorpropamide
Can be used: Glimiperide, Repaglinide, Pioglitazone
Insulin: prefer
40.
41. Impacts of Diabetes on Blood Pressure
Management
Autonomic Insufficiency
BP drops and very labile
Medial Calcificaton
Wide pulse pressure
Hypertensive Cardiomyopathy
Preload
Cardiac function
After load
46. ACEI/ARB
begin at a low dose;
increase dose at 4-week intervals to reduce microalbuminuria
antiproteinuric effects not necessarily attained at antihypertensive doses
increase dose until proteinuria reduced by 30 to 50%
Titrate to maximal suppression of urinary albumin excretion for DM patients
with persistent microalbuminuria despite intensive insulin therapy even
without HTN
titration limited by adverse effects:
an acute increase in serum creatinine of 50% or more;
renal artery stenosis;
hypovolemia; congestive heart failure
hyperkalemia resistant to corrective maneuvers
ARB : consider for subjects with documented aldosterone escape
47. ACE Inhibitors can prevent progression
of renal failure
Risk reduction is 51%
Reduce microalbuminuria
All causes of mortality
Ann Intern Med 118 577-581.1993
J Am Soc Nephrol 2006
48. Lipid Control
Heart Protection Study
Patients with DM and CKD who received statins had a 23% decrease in
cardiovascular risk with an absolute event reduction of 80%
In HD patients with type 2 DM, the addition of 20 mg of atorvastatin
40% decrease in lowdensity lipoprotein cholesterol levels & significant decrease in
cardiac events
49. Lipid Lowering agents
Increased risk of cardiovascular diseases
FIELD STUDY showed improved regression microalbuminaria to
normoalbuminuria in pts with type 2 diabetes
(Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular
events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled
trial. Lancet. 2005;366(9500):1849-1861.)
A meta analysis shows a small positive effect on urinary albumin excretion
and renal function
(Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic
kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ.
2008;336(7645):645-651.)
50. Dosing of Statins in CKD
IN PT.S ON HEMODIALYSIS AND PERITONEAL DIALYSIS
Atorvastatin - up to 80 mg/day
Fluvastatin – up to 80 mg/day.
Pravastatin - limited to 10 mg, as active metabolites can accumulate,
Pravastatin Pooling Project - of up to 40 mg were safely (GFR of 30 ml/min per
1.73 m2)
Simvastatin – upto 20 mg/day (40-mg/day in stage 3 CKD (Heart Protection
Study))
Rosuvastatin - not more than 10 mg/day when GFR falls below 30 ml/min per
1.73 m2.
Ezetimibe - safely used (effects absorption mainly bile acid sequestrants)
Fenofibrate –
reduced by one third in CKD stage 2,
reduced by two thirds in CKD stages 3 and 4
avoided in CKD stage 5.
Gemfibrozil - safely used, although in PD, elevated CPK levels have been
reported
51. Diet
Dietary phosphate restriction
Phosphate binders
Aluminium
Calcium
Magnesium
Non aluminium, calcium,
magensium binders
Replenishment of vitamin D
stores
Activated vitamin D 1, 25
(OH)2D3
Vitamin D analogues
Paricalcitrol
Doxercalcitriol
52. Protein Restriction
Preservation of organ repair
Daily dietary requirement (FAO)
0.6 g/Kg/d plus 2 SD= 0.8 g/Kg/d
MDRD study
Dietary protein restriction may offer a benefit
Remember to preserve adequate calories
53. Fluid Management
Many diabetics have nephrotic state and severe edema and need rigorous
salt & fluid restriction
Severe edema - 600 - 800 ml / day
Mild to moderate - equal to UOP
No edema - UOP + insensible losses
54. Diabetic Management in CD
Parameter
Lower BP………………………
Block RAAS……………………
Improve glycemia …………….
Lower LDL cholesterol………..
Anemia management ………...
Endothelial protection…………
Smoking………………………..
Target
< 125/75 mmHg
ACEi or ARB to max tolerated
A1c < 6.5% (Insulin/TZD)
< 100 (70) mg/dl statin + other
Hb 11-12 g/dl (Epo + iron)
Aspirin daily
Cessation
55. Renal Replacement Therapy in CKD with DM
Start dialysis at eGFR - 15 ml/min per 1.73 m2 (normally - eGFR <7-8)
they tend to tolerate uremia poorly and frequently have sodium retention
and fluid overload.
Peritoneal dialysis–associated glucose loading
Replace glucose solutions in part by amino acid solutions and
polyglucose.
Loss of solute and water transport often limits long-term use of
peritoneal dialysis to 3 to 5 years.
Switching to hemodialysis should be considered before volume
overload or uremic symptoms occur
Pt.s on PD, Glucose meters based on GLUCOSE OXIDASE TEST should
be used
maltose and polyglucose present in PD solution, affect glucose
dehydrogenase–based glucose meters
57. Transplants
Type 1 DM - pancreas transplant
Can induce regression of moderate Diabetic Nephropathy lesions in
native kidneys
but only during a period of 10 years after transplantation.
Pancreas transplantation at the time of renal transplantation
Prevents / slows the development of Diabetic Nephropathy in the
transplanted kidney.
58. Management of Diabetes in Peritoneal
Dialysis
The evidence for improving glycemic control in patients on dialysis having
an impact on mortality or morbidity is sparse
Improving glycaemic control in patients on dialysis is very challenging
difficulties with hypoglycemic drugs
monitoring difficulties
dialysis strategies that exacerbate hyperglycemia or hypoglycemia
Therapeutic nihilism or inertia.
59. Diabetologist must keep up to date with the dialysis practices….to be able to
adjust the insulin regimens appropriately
60. Diabetes Management in Peritoneal Dialysis I
The evidence for improving glycemic control in patients on dialysis having
an impact on mortality or morbidity is sparse
Improving glycaemic control in patients on dialysis is very challenging
difficulties with hypoglycemic drugs
monitoring difficulties
dialysis strategies that exacerbate hyperglycemia or hypoglycemia
Therapeutic nihilism or inertia
61. Diabetes Management in Peritoneal Dialysis II
Standard drug therapy for hyperglycemia is clearly not possible in patients
on dialysis
Sulphonylureas and insulin are the mainstay of treatment.
Newer therapies for hyperglycaemia have become available, but until
recently, renal failure has precluded their use
Newer gliptins, however, are now licensed for use in ‘severe renal failure’.
They have yet to be trialed in dialysis patients
Diabetic patients on dialysis have special needs, as they have a much
greater burden of complications (cardiac, retinal and foot)
62. Diabetes Management in Peritoneal Dialysis III
They may be best managed in a multidisciplinary diabetic–renal clinic
setting, using the skills of:
Diabetologists
Nephrologists
Clinical nurse specialists in nephrology and diabetes
Dietitians
Podiatrists
63. Intra-peritoneal Insulin in PD Patients
PROS
• More physiologic absorption
(less fluctuation of BG).
• Continuous insulin infusion.
• Avoids injections
• Less hyper-insulinemia
• Avoids antibody formation.
• Improved HbA1c
CONS
• High insulin doses
• Higher cost
• Insulin losses in effluent
• Lipid effects
• Specific dialysis complications:
e.g. excess glucose
absorption.
64. Precautions
No nephrotoxics
Impair glomerular function: NSAIDS
Impair tubular function: Aminoglycosides
NO contrast agent exposure
Drug dose adjustment
Treat intercurrent infections properly
Educate about native drugs
Early referral to nephrologist
65. Management of Diabetes in Patients with
Impaired Kidney Function: Agenda
The role of the kidneys in carbohydrate metabolism and insulin handling
and The changes in carbohydrate metabolism in CKD
Management of Diabetes in CKD:
• Management diabetes in CKD
• Effective and safe use of anti-diabetic agents
• Special Issues : Dialysis, Monitoring, Targets
Summary and Conclusions
67. Summary of Diabetic Nephropathy
Diabetic nephropathy is a disease that develops slowly and if treated early, progression
can be delayed.
40% of dialysis cases of ESRD are DN
45% of patients will have microalbuminuria after 5 to 10 yrs of onset of type 1 DM
50% of the cases of macroalbuminuria end up in ESRD will need renal replacement
therapy for survival
There are no signs and symptoms of early disease so screening is important.
Aggressive treatment of Blood glucose, BP, Lipids helps in prevention of renal function
and can improve the outcome.
In CKD, some people progress to Dialysis and few to Kidney Transplantation.
Editor's Notes
Insulin in peritoneal dialysis
The fluctuations of blood glucose, hyperinsulinemia and the rare formation of insulin antibodies under subcutaneous insulin (sc) injection can be prevented by peritoneal dialysis PD). Investigations of insulin in patients treated with PD indicate that the intraperitoneal (ip) administration on of insulin leads to more even glucose levels, but that when dialysis fluids with glucose concentrations higher than 13.6 g/L are used, the absorption of glucose from the abdominal cavity is greater in PD with ip insulin treatment than it is with sc administration (Quellhorst, 2002) The raised glucose absorption from the abdominal cavity in ip insulin administration must be regarded as a disadvantage. Investigations of insulin in PD showed, that after a dwell time of 30 min, the absorption of insulin from the abdominal cavity in the patients with diabetes was much higher than in the patients without diabetes. In several studies the authors compared both routes of insulin administration. they observed a better fall of HbA1c after switching from sc to ip administration (Grodstein et al, 1981)