Diabetic Nephropathy

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DIABETIC NEPHROPATHY

Kidneys are the physiological filter of the body playing an important role in maintaining a

normal internal environment. Each kidney consists of about one million nephrons, which are the

functional units of the kidneys. A large amount of circulating blood flows through the kidneys.

Approximately 25% of the cardiac output or 1200 mL of blood per minute is received by the

kidneys, where waste chemicals and metabolic waste products (urea, uric acid) are filtered out

and eliminated from the body in the form of urine. Thus, kidneys are not only a site of

elimination but also the seat of metabolism for xenobiotics. Kidneys maintain the acid-base

balance of the body and maintain a normal plasma osmolality. The kidneys also help in

maintaining normal blood pressure by secreting renin, which is sensitive to changes in the blood

pressure.

Q. How is kidney function assessed?

The kidney function is assessed by performing renal function test, the normal reference values of

which are listed below;

1. Creatinine: 0.6-1.2 mg/dL

2. Creatinine clearance: 90-140 mL/min/1.73 m2 body surface area

3. Blood urea nitrogen: 8-20 mg/dL

4. Urinalysis

o Specific gravity: 1.006-1.030

o pH: 4.6-8.0

o Normally urine does not contain glucose, ketone bodies, protein or red cells

o Urine output: 800 to 2000 mL/day

Case: A 45-year-old patient came to the clinic for a regular follow-up and complained of

occipital headache and dizziness on and off. He is a known diabetic since 12 years under

treatment with combination oral hypoglycaemic agents. Physical examination revealed the

following;

Patient was obese

Blood pressure: 150/94 mmHg

Fasting blood glucose: 168 mg/dL

Post prandial blood glucose: 224 mg/dL

BUN: 30 mg/dL

Serum creatinine: 1.5 mg/dL

Urinalysis showed 2+ proteins without sugar

Q. Is this patient’s kidney function abnormal?

Diabetic nephropathy occurs in 20-40% of patients with diabetes and is the single leading cause

of end-stage renal disease (ESRD).

The patient’s history and results of the urine report favour an index of suspicion towards diabetic

kidney disease. This is so because urine normally should not reveal proteins but in the above

case the presence of 2+ proteins is highly suggestive of abnormal glomerular function. Also, the

serum creatinine and BUN levels are mildly elevated. Creatinine and urea nitrogen are waste

products that kidneys normally excrete from the blood. Hence, when kidneys are dysfunctional,

these substances may build up in the blood and levels will rise which is seen in this patient.

The criteria for diagnosing diabetic nephropathy are as follows;

Q. What is diabetic nephropathy?

Diabetic nephropathy is a microvascular complication of long standing Type 1 and Type 2

diabetes whereby the raised blood glucose causes the kidney function to fall progressively. It is

defined by either macroalbuminuria (urinary albumin excretion of >300 mg in a 24-hour

collection) or by abnormal renal function as represented by an abnormality in serum creatinine,

calculated creatinine clearance, or glomerular filtration rate (GFR).

Q. How does diabetic kidney disease develop and progress?

The pathogenesis of diabetic nephropathy is multifactorial and genetic susceptibility has been

proposed to be an important factor in the development and progression of diabetic nephropathy.

Three major histologic changes occur in the glomeruli in diabetic nephropathy;

1. Mesangial expansion is directly induced by hyperglycaemia, perhaps via increased matrix

production or glycosylation of matrix proteins;

2. Glomerular basement membrane thickening occurs; and

3. Glomerular sclerosis is caused by intraglomerular hypertension.

The stages of progression of diabetic nephropathy to end stage renal disease (ESRD) are as

shown in the figure;

Q. What are the clinical features of diabetic nephropathy?

During the early stages of diabetic nephropathy, patients are usually asymptomatic. They are

normally diagnosed at a routine check up as clinical features appear quite late in the course of the

disease. As the condition progresses, the clinical presentation is characterised by pedal oedema,

hypertension, massive proteinuria and elevated levels of serum cholesterol and triglycerides.

Once the kidneys are more severely damaged, blood glucose levels may drop because the

kidneys retain insulin in the body and a stage of "burnt out diabetes" may occur. In the late

stages, patients may develop renal failure characterised by severe anaemia, breathlessness and

rise in serum potassium levels necessitating urgent dialysis.

Q. Who is at risk of developing nephropathy?

Following factors increase the risk of developing diabetic nephropathy;

Elevated blood glucose levels

Duration of diabetes

Hypertension

Smoking

Glomerular hyperfiltration

Proteinuria levels

Dyslipidemia

Family history

Genetic susceptibility

Dietary factors, such as the amount and source of protein and fat

Q. What are the chances for diabetic patients to develop nephropathy?

The estimated number of diabetics in India is more than 40 million. 21% of Type 1 and 20-

35% of Type 2 diabetics develop nephropathy after 20 to 25 years. Progression from

microalbuminuria to overt nephropathy occurs in 20-40% within a 10-year period with

approximately 20% of these patients progressing to end-stage renal disease. End-stage renal

disease develops in 50% of Type 1 diabetes patients with overt nephropathy within 10 years and

in more than 75% by 20 years in the absence of treatment. In Type 2 diabetes, a greater

proportion of patients have microalbuminuria and overt nephropathy at or shortly after diagnosis

of diabetes.

Q. What is the relation between elevated blood glucose levels (hyperglycaemia) and

kidney function?

The exact cause of diabetic nephropathy is unknown, but various mechanisms postulated are

elevated blood glucose levels, advanced glycosylation end products (AGE) and activation of

cytokines. Hyperglycaemia produces qualitative and quantitative changes in the composition of

the small blood vessels of the kidney. At consistently higher blood glucose levels, glucose binds

irreversibly to proteins in the kidney and circulation to form AGEs. These end products stimulate

protein synthesis; increase permeability of the kidney glomerulus and cause endothelial

dysfunction.

Case contd…: The patient was diagnosed as a case of diabetic nephropathy with hypertension.

He was now shifted to insulin therapy and was prescribed tablet enalapril 5 mg OD for his high

blood pressure. He was advised dietary restrictions, exercise and regular glucose monitoring, and

was asked to follow-up after 1 month.

At the one month follow-up, the patient did not have any complaints and laboratory

investigations were as follows;

FBG 130 mg/dL

PPBG 170 mg/dL

Urinalysis showed 1+ protein without sugar

Serum creatinine 1.2 mg/dL

BUN 23 mg/dL

The patient was asked to continue the same regimen as well as regular glucose monitoring and

was asked to return for a follow-up after 3 months.

Q. What are the criteria for screening and diagnosis of diabetic nephropathy?

Microalbuminuria in the range of 30-299 mg/24 h has been shown to be the earliest stage of

diabetic nephropathy in Type 1 diabetes and a marker for development of nephropathy in Type 2

diabetes. The first step in the screening and diagnosis of diabetic nephropathy is to measure

albumin in a spot urine sample, collected either as the first urine in the morning or at random as

recommended by the American Diabetes Association guidelines. Screening should be initiated at

the time of diagnosis in patients with Type 2 diabetes and 5 years after diagnosis in patients with

Type 1 diabetes. Alternative tests include measurement of total protein and glomerular filtration

rate. Ultrasonography of kidneys and renal biopsies are usually performed to rule out the other

causes of nephropathy.

Q. When should screening not be performed?

Screening should not be performed in the presence of conditions that increase urinary albumin

excretion, such as urinary tract infection, haematuria, acute febrile illness, vigorous exercise,

short-term pronounced hyperglycaemia, uncontrolled hypertension, and heart failure.

Q. How is hypertension associated with diabetic nephropathy?

In patients with Type 1 diabetes, hypertension is usually caused by underlying diabetic

nephropathy. In Type 1 diabetics, it typically becomes manifest about the time that patients

develop microalbuminuria whereas in patients with Type 2 diabetes, it is present at the time of

diagnosis of diabetes in about one-third of patients. However, hypertension in Type 2 diabetic

patients may also be related to underlying diabetic nephropathy due to coexisting "essential"

hypertension, or due to a myriad of other secondary causes, such as renal vascular disease. Both

systolic and diastolic hypertension markedly accelerate the progression of diabetic nephropathy

by reducing GFR.

Q. Can diabetic nephropathy be prevented?

The following strategies when adopted properly help in preventing the progression of diabetic

nephropathy;

Glycaemic control: Tight glycaemic control is the keystone in the treatment and

prevention of diabetic nephropathy. In the Diabetes Control and Complications Trial

(DCCT), intensive therapy with insulin in patients with Type 1 diabetes reduced the

incidence of microalbuminuria by 39%. In the UKPDS, patients with Type 2 diabetes

treated with OHAs showed a 30% risk reduction for the development of

microalbuminuria.

Blood pressure control: Treatment of hypertension dramatically reduces the risk of

cardiovascular and microvascular events in patients with diabetes. The ADA

recommends the use of either ACE inhibitors or ARBs as a first-line therapy for Type 1

and Type 2 diabetic patients with microalbuminuria, even if they are normotensive. The

ADA recommends a blood pressure lowering to <130/80 mmHg in diabetic

hypertensives.

Dietary protein intake: The ADA recommends a dietary allowance of protein intake of

0.6 - 0.8g/kg body weight/day in patients with diabetic nephropathy.

Glucose monitoring: Glucose monitoring is an innovation poised to improve the lives of

millions of diabetic patients. Landmark studies have demonstrated that tightly managing

blood glucose levels to stay within a near-normal range can dramatically decrease the risk

of serious complications and death. As a result, tight glucose management has become

today’s standard of care. Glucose monitoring is an integral tool for tight glycemic control

as it keeps the patient and the health care professionals informed about the blood glucose

levels throughout the day and thus assess the effectivity of the ongoing treatment

regimen. It also helps the doctors to adjust the drug dosages so as to maintain a near

normoglycaemic state and achieve the desired target goals of blood sugar and HbA1C

levels.

In both Type 1 and Type 2 diabetics glycosylated haemoglobin (HbA1C) should be

maintained at or <7% for primary prevention of diabetic nephropathy, and for prevention of

progression from microalbuminuria to overt nephropathy. The longer the patients can

maintain a target HbA1c level of 7.0%, the greater their protection from nephropathy. Long-

term studies, not only in Type 1, but also in Type 2 diabetic patients, indicate that good

glycaemic control results in clinically significant preservation of renal function.

Thus, the value of glucose monitoring in the prevention of diabetic nephropathy in both Type

1 & 2 patients cannot be under rated, as the above mentioned target levels cannot be achieved

without proper glucose monitoring. For most patients with Type 1 diabetes and pregnant

women taking insulin, glucose monitoring is recommended three or more times daily. The

optimal frequency and timing of glucose monitoring for patients with Type 2 diabetes on oral

agent therapy is not known but should be sufficient to facilitate reaching glucose goals.

Case contd…: On second follow-up, the patient came back with no presenting complaints.

On history, he was strictly following his insulin regimen and monitoring his blood glucose as

advised regularly. He was also taking his anti-hypertensive medications as advised. His

examination revealed the kidney functions and blood pressure to be normal. He was advised

to continue the same treatment regimen and monitor his blood glucose regularly.

Suggested reading

1. Diabetic Kidney Disease. Diabetes UK. Updated June 2006. Article on the net. Available

from: http://www.patient.co.uk/showdoc/27001107/

2. Webner D. Urinalysis. VeriMed Healthcare Network 2003. Article on the net. Available

from: http://health.allrefer.com/health/urinalysis-values.html

3. Nephropathy in Diabetes. American Diabetes Association Position Statement. Diabetes

Care 2004; 27:S79-83.

4. Vishwanathan V. Prevention of diabetic nephropathy: A diabetologist’s perspective.

Indian J Nephrol 2004; 14: 157-162.

5. Augustine J, Vidt DJ. Diabetic Nephropathy. The Cleveland Clinic Foundation August 4

2003. Article on the net. Available from:

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/diab

eticnephropathy/diabeticnephropathy.htm

6. Nand N, Aggarwal HK, Sharma M. Recent Advances in the Management of Diabetic

Nephropathy. Journal, Indian Academy of Clinical Medicine 2001; 2(1): 78-84.

7. Gross JL, Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic

Nephropathy: Diagnosis, Prevention, and Treatment. Diabetes Care 2005; 28:164-176.

8. Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy-A review of the natural

history, burden, risk factors and treatment. J Natl Med Assoc. 2004; 96(11):1445-54.

9. Nicholls K. Glucose control and progression of diabetic nephropathy. The CARI

Guidelines – Caring for Australasians with Renal Impairment. April 2006.Available

from:

http://www.cari.org.au/Glucose%20control%20and%20progression%20of%20diabetic%

20nephropathy.pdf

10. Spurgeon S.A, Nocon R.S, Zhang B, and Fleishman V. Continuous Glucose Monitoring:

Innovation in the Management of Diabetes. New England Healthcare Institute. March

2005:1-70.

11. Standards of Medical Care in Diabetes-2007. American Diabetes Association Position

Statement. Diabetes Care 2007; 30:S4-S41.

DIABETIC NEPHROPATHY

POST TEST

1. Overt nephropathy is characterised by;

a. Microalbuminuria

b. Macroalbuminuria

c. Both A and B

d. None of the above

2. Renal failure in diabetic nephropathy is characterised by;

a. Hypokalemia

b. Severe anaemia

c. Chronic cough

d. All of the above

3. When should screening for nephropathy be initiated in a Type 1 diabetic?

a. At the time of diagnosis

b. 2 years after diagnosis

c. 5 years after diagnosis

d. 10 years after diagnosis

4. Prevention of diabetic nephropathy includes all of the following except;

a. Regular glucose monitoring

b. Blood pressure control

c. Protein intake of 1-2 g/kg/day

d. Tight glycaemic control

5. The target HbA1C level for Type 1 and Type 2 diabetes to prevent development of

nephropathy is

a. _6%

b. _7%

c. _8%

d. _7.5%

For answers refer to next page

DIABETIC NEPHROPATHY

ANSWER KEY

1. Overt nephropathy is characterised by;

a. Microalbuminuria

b. Macroalbuminuria

c. Both A and B

d. None of the above

2. Renal failure in diabetic nephropathy is characterised by;

a. Hypokalemia

b. Severe anaemia

c. Chronic cough

d. All of the above

3. When should screening for nephropathy be initiated in a Type 1 diabetic?

a. At the time of diagnosis

b. 2 years after diagnosis

c. 5 years after diagnosis

d. 10 years after diagnosis

4. Prevention of diabetic nephropathy includes all of the following except;

a. Regular glucose monitoring

b. Blood pressure control

c. Protein intake of 1-2 g/kg/day

d. Tight glycaemic control

5. The target HbA1C level for Type 1 and Type 2 diabetes to prevent development of

nephropathy is

a. _6%

b. _7%

c. _8%

d. _7.5%