Diagnosis and Treatment of

Diabetic Nephropathy

SFM DidacticsJanuary 14, 2003Carol Cordy, MD

1. Why should you screen for diabetic nephropathy?

2. How should you screen for diabetic nephropathy?

3. What should you do with the results of your screening tests?

Why screen? Why treat?Prevention and treatment of

diabetic nephropathy can reduce the incidence of end

stage renal disease and death

Diabetic Nephropathy and ESRD

• Diabetic nephropathy is the leading cause of end stage renal disease in the United States accounting for over 40% of dialysis patients

• The 5-year mortality rate for a dialysis patient is 93%

• Dialysis for one patient costs over $50,000 annually

EpidemiologyType 1 Diabetic

– 25 - 45% will develop diabetic nephropathy

– 80 - 90% with microalbuminuria will progress to overt diabetic nephropathy in 5 - 10 years

– nearly 100% with gross proteinuria will progress to ESRD in 7 - 10 yrs

EpidemiologyType 2 Diabetic

– 50% will have microalbuminuria at the time of presentation probably secondary to HTN

– 10-20% with microalbuminuria will progress to overt nephropathy– minority populations have a 2 to 20-fold higher incidence of diabetic nephropathy

Risk Factors for Diabetic

Nephropathy• Age, Race, Ethnicity• History of microalbuminuria• Hypertension• Poor glycemic control• Smoking• Family history of nephropathy

– genetic abnormalities of ACE gene

• Stage I – Hyperfiltration - increased blood flow through the kidney, early renal hypertrophy

• Stage II - Glomerular lesions without clinically evident disease

• Stage III - Incipient nephropathy with microalbuminuria - alb/cr ratio .03 - .3 or albumin 20-200 mcg/min on timed specimen

Stages of Diabetic Nephropathy

Stages of Diabetic Nephropathy

020406080

100120140160180

0 5 10 15 20 25 30

Duration of Diabetes

GF

R

III III

IV

V

Stages of Diabetic Nephropathy

• Stage IV - Overt diabetic nephropathy with proteinuria >500 mg/24 hr- creatinine clearance <70 ml/min

• Stage V – End stage renal disease (ESRD) - creatinine clearance <15 ml/min - creatinine = 6mg/dl

Stages of Diabetic Nephropathy

020406080

100120140160180

0 5 10 15 20 25 30

Duration of Diabetes

GF

R

III III

IV

V

Primary care physicians have the most frequent contact with diabetic patients and therefore have the greatest potential to favorably affect their health

How are we doing?

Studies show that primary care physicians screen only 20% of their

diabetic patients for diabetic nephropathy

How are we doing?

Once screened many physicians are not sure

what to do with the results

Diabetic Nephropathy Algorithm

• Evidence-based approach• Goal –

The use of the algorithm will improve renal function screening in the diabetic population and encourage the initiation of appropriate therapy in patients with all stages of renal disease

Using the Algorithm

U r in a ly s is f o r p ro te inU A m a y b e f a ls e l y p o s i t i ve o r e l e v a te d i n th e

s e t t i n g o f p o o r g lu co s e c o n t r o l,U T I , h e a v y e xe rc is e , fe v e r o r s e p s is - -t re a t a s

a p p r o p ri a te b e fo re r e -te s t i n g .

P o s it i v e fo r p ro te i n1 + o r g r e a te r

R e f e r to N e p h r o lo g yf or di ag n os is, t re atm en t

o pt i on s & p a ti e ntp re pa ra t io n & e d uc at i on

C o n s id e r C o n s u l tw i th N e p h r o lo g y

f or di ag n os is a ndt re atm en t op t io n s

In i t ia l o r a n n u a lT e st fo r A l b u m i n u ri a

Is K + > 5 .5o r

C r > 2 .0 ?

M a c ro a lb u m in u r ia ?1 + o r g r e a te r

B e g in T re a tm e n t :1 . A CE Inh ib ito r o r al tern a t ive the ra py

2 . A nn u al cre at i ni ne , po ta ssi um an d U A3 . C o nt i nu e P ro tect i ve Re co m m e nd a ti on s a s

li s te d b e lo w.

R e p e a t m i cr o a l b u m in u ri ate s t

2 o f 3 T e s tsp o s i t iv e ?

A n n u a l te s t fo rm i cr o a l b u m i n u ri a

B

Y es Y es

N oN o

Y es

N o

Y es

N o

B A n n u al lyA

A

O n A C E -I n h ib i to r ?

N o

Y es

C

I s m ic r o a lb u m in u r ia p re s e n t ?m i cr o a l b u m i n u ri a :

0 .0 3 - 0 .3 0 m g a lb u m in /m g cr e a t i n in e ;3 0 - 3 0 0 µ g m a lb u m in /m g cr e a t i n in e (s p o t c o ll e c t i o n );

2 0 - 2 0 0 µ g m a lb u m in /m in ( t im e d co ll e c t io n ); o r3 0 - 3 0 0 m g a l b u m i n /2 4 h r (2 4 h r c o l le c t i o n )

Y es

Q u a n t i ta te to ta l p r o te in w i th a 2 4 - h o u ru r in e s p e c i m e n o r a sp o t A M p ro te in /

c re a t i n i n e ra t io ( m g p r o te i n /m gc re a t i n i n e )

I s u ri n e p r o te i n > 1 g /d a y o r 1 0 0 0 m g /gc re a t i n i n e o r ra t i o > 1 .0 ?

Y es

N o

C

Type 1 and Type 2; age 12 years and older with no overt renal disease

R e n a l P r o t e c ti v e R e c o m m e n d a t io n s fo r p e r s o n s w i t h d ia b e t e s :1 . S t ri c t g lu c o s e c o n t ro l m e a s u r e d b y g ly c a t e d h e m o g lo b in < 7 .02 . B lo o d p r e s s u r e c o n t r o l< 1 3 0 /8 53 . L ip id e v a lu a tio n a n d tr e a tm e n t p e r e s ta l is h e d g u id e l in e s

UA (Urine Dipstick)• Use as an initial screen for all patients• Negative to trace proteinuria requires

further testing for microalbuminuria• 1+ or greater proteinuria requires

further testing to quantitate proteinuria• Once a patient has microalbuminuria,

UA (urine dipstick) testing for gross proteinuria may be adequate although yearly testing for albuminuria may have become standard of care

Microalbuminuria

• Spot AM urine: Alb/Cr ratio .03-.3*• Timed urine collection: 20-200µg

albumin/min• 24 hour urine collection: 30-300

mg albumin in 24 hours

*This is the most practical test

Microalbumin TestingFactors that Cause False Positive Test

– poorly controlled diabetes– morbid obesity– acute illness, fever, UTI– pregnancy, menstruation– high protein diet– CHF– hematuria, major stress: surgery or

anesthesia

Incipient Nephropathy

Type 1 Diabetes– 2 out of 3 urine tests + for

microalbuminuria (start screening 5 years after the initial diagnosis)

– presence of proliferative diabetic retinopathy

– 80-90% of type 1 patients with microalbuminuria will progress to DN

Incipient Nephropathy

Type 2 Diabetes– 2 out of 3 urine tests + for

microalbuminuria (start screening at the time of diagnosis of diabetes)

– presence of diabetic retinopathy– 20-30% may have diabetic nephropathy

but not diabetic retinopathy– 25% may have a diagnosis of

nephropathy other than diabetic nephropathy

Macroalbuminuria• Spot AM urine: Alb/Cr ratio greater

than .3• Timed urine collection: greater than

200µg albumin/min• 24 hour urine collection: greater

than 300 mg albumin in 24 hours• If macroalbuminuria is present then

test for gross proteinuria

Gross Proteinuria• Defined as urine protein >500mg/24 hr.• Gold standard test is

– 24 hour urine collection for total protein and creatinine clearance

• Can also test protein/creatinine ratio– measures total mg protein/mg

creatinine– correlates 1:1 with a 24 hr urine in

grams/24 hr – less accurate in ARF, intersitial

nephritis, high degrees of proteinuria

Overt Diabetic Nephropathy

• Gold Standard is biopsy• Diagnosis can be made by clinical history

and exclusion of other renal disease• Workup includes

– Renal ultrasound for size, shape, abnormalities

– 24 hour urine for total protein and creatinine clearance

Treatment• Lifestyle changes

– Lose weight– Stop smoking– Low salt diet for BP control– Low protein diet?

• Glycemic Control – Benefit in both Type 1 and Type 2

patients– Recommended: HbA1C <7.0%

(some say <6.5%)

Blood Pressure Control• Current ADA recommendations are

for blood pressure <130/80-85 (if nephropathy <125/75)

• Several randomized controlled trials indicate that improved blood pressure control decreases the rate of progression of renal disease in both type 1 and type 2 patients

ACE’s and ARB’s

• Angiotensin converting enzyme inhibitors and angiotensin receptor blocking agents have been shown in animal models and in randomized controlled trials to improve diabetic nephropathy

• Mechanism of action - ACE-inhibitors limit angiotensin II production by blocking angiotensin converting enzyme, ARB-agents block angiotensin II receptors

Questions for future studies

• Will higher doses of ACE’s and ARB’s improve outcome and decrease microalbuminuria?

• Will patients without microalbuminuria benefit from the use of ACE’s and ARB’s?

• What about other BP medications for patients who cannot tolerate ACE’s and ARB’s?

• Which of the newer oral agents for glucose control are also renal protective?

• Is there a place for low protein diets for diabetics before renal disease develops?

Case #1

Your first patient is a 25 year old young man with a 5 year history of type 1 diabetes. His urine dipstick is negative for protein. You check a spot AM urine alb/cr ratio which is .019. His blood pressure is 112/66. His HbA1C is 6.9.

Which is (are) true?1. The patient has early or incipient diabetic

nephropathy.

2. The patient should maintain a HbA1C of less than 7 to help protect his kidneys.

3. You should start the patient on an ACE inhibitor to protect his kidneys.

4. All of the above are true.

Patient #2

Your next patient is a 43 year old woman with a six year history of type 2 diabetes. A urine dip shows trace protein and a spot AM urine alb/cr ratio is .039. Her blood pressure is 135/80 and her HbA1C is 6.7.

Which is (are) not true?1. You should check the patient’s serum

creatinine and potassium.2. You should start the patient on an ACE

inhibitor if her K+ and Cr are okay. 3. You should check a 24 hour urine for total

protein and creatinine clearance.4. The patient has overt diabetic

nephropathy and should be referred to a nephrologist.

Case #3Your last patient is a 60 year old with HTN, dyslipidemia and newly diagnosed type 2 diabetes. A urine dip shows 2+ protein. He has a fever and his HbA1C is 10.3. His blood pressure is 140/88. He is taking HCTZ and glipizide.

Which is (are) true?1. You should get the patient’s diabetes

under better control before rechecking his urine.

2. A fever will not cause proteinuria.3. The patient’s blood pressure is under

good control.4. You should check the patient’s

potassium and creatinine.

Case #3

Three months later with exercise, metformin and enalapril your patient’s HbA1C is now 7.5 and his blood pressure is 135/85. A urine dip now shows 1+ protein.

Which is (are) true?1. You should check a 24 hour urine for

total protein and cr. cl.2. A spot AM urine albumin/creatinine

ratio correlates well with a 24 hour urine for total protein

3. The patient likely already has diabetic nephropathy and should be referred to a nephrologist.

Use the Algorithm!• Check all your diabetic patients

annually for renal disease .• Help your diabetic patients’ protect

their kidneys by helping them keep their diabetes under control.

• Help your diabetic patients protect their kidneys by helping them keep their blood pressure under control.