Diabetic Nephropathy



DIABETIC NEPHROPATHY

Stephen J. Huot, M.D., Ph.D.

WEEK 4: 01/24 – 01/28/05

Learning Objectives:

1. Define microalbuminuria

2. Describe how to measure and follow albuminuria

3. Counsel a patient with diabetes about the importance of reducing albuminuria

4. Describe a therapeutic plan for treating micro and macro albuminuria in patients with diabetes

CASE ONE:

A 56-year-old woman is seen in the office for routine follow-up of hypertension and review of recent laboratory data. She was diagnosed with high blood pressure at the age of 44, was initially treated with HCTZ alone, and has been prescribed HCTZ and Atenolol for the past four years. Her BMI is 30, her seated blood pressure is 138/86 mmHg, heart rate is 66/minute and is regular. Remainder of the physical exam is notable for obesity. Fasting labs were obtained one week ago and include:

Na 140 mEq/L

K 4.0 mEq/L

Cl 105 mEq/L

HCO3 24 mEq/L

BUN 14 mg/dl

Cr 1.0 mg/dl

Glucose 135 mg/dl

Questions:

1. In addition to explaining to the patient that she has developed diabetes and starting to counsel her about management of this chronic disease and therapeutic options, what additional testing is indicated to assess her renal function? Why is this important?

What additional testing is indicated to assess her renal function? This patient has type 2 diabetes and should be screened for microalbuminuria at the time of diagnosis. As indicated in the article, patients with type 1 diabetes are usually diagnosed early in the course of their disease and proteinuria can take five or more years to develop, so screening for proteinuria can be delayed for this period of time. Patients with type 2 diabetes have usually had the disease for several years, and proteinuria is often present at time of diagnosis, so screening for proteinuria is indicated at time of diagnosis.

There is a nice description in this article about using spot urine protein: creatinine ratios vs. 24-hour urine collection to both screen for microalbuminuria or macroalbuminuria, as well as, to follow either of these, if present. The main teaching points are the following:

• Either method is appropriate for screening, and the spot urine is certainly more convenient.

• Proteinuria varies depending on several factors (exercise, fever, hyperglycemia, etc.) and unless the patient has nephrotic range proteinuria, microalbuminuria should be confirmed on a follow-up measurement over the next several months before establishing the diagnosis.

• There is a significant diurnal variation in daily protein excretion, so early morning samples are recommended as a standard when possible and if not, an individual patient should at least have their measurements performed at approximately the same time of day to be able to make comparisons from one measurement to the next.

• Most residents are uncertain about how one actually calculates the value for spot urine protein: creatinine ratios so this should be reviewed with the following points:

o The result is converted to units of measure that are mg of protein/gm of creatinine (this is the same as micrograms protein/mg creatinine)

o A value greater than 30 mg protein/gm creatinine is abnormal.

o Values of 30 – 299 = microalbuminuria

o Values > 300 = albuminuria (sometimes called macroalbuminuria)

Why is this important?

Microalbuminuria is the earliest clinical marker of nephropathy

• Proteinuria is an indication of increased cardiac risk

• Proteinuria is an indicator of increased risk of progressive renal failure

• There are specific interventions that can reduce the risk of progression of diabetic nephropathy in patients with proteinuria

2. What medication adjustments do you want to recommend if she has proteinuria in order to delay the progression of renal disease?

There are three main teaching points regarding treatment of proteinuria:

• Treating her diabetes is an important underpinning of therapy to delay progression of renal disease and, treating hyperlipidemia, if present, may also benefit her renal disease.

• Blood pressure goals are lower in patients with diabetes and are 130/80 mmHg as a maximum BP goal. Some would argue for a lower goal in the setting of proteinuria (125/75 mmHg). As a practical matter, in patients who monitor their BP at home, you are aiming for achieving target BP control 80 percent (or more) of the time.

• ACE inhibitors and ARB’s are superior to other therapies at any level of BP control for reducing the decline of renal function in this population.

As for the issue of ACE vs. ARB, current teaching is that ACE is preferred for patients with type 1 diabetes and ARB for patients with type 2 diabetes. This is by no means a hard recommendation or founded on a bed of impressive data. It is clear that both medications are superior to other BP meds and that they also have renal protective benefit, at least in patients with type 2 diabetes in the setting of proteinuria, whether or not the patient has high blood pressure. Which agent to choose, I think, should also be influenced by the patient’s cardiovascular risk profile, as there does seem to be reasonable data (HOPE and micro-HOPE trials) that ACE inhibitors are superior to ARB’s for reducing cardiovascular morbidity and mortality in patients with diabetes, possibly due to their effects on the bradykinin system which ARB’s do not affect.

I would also ask the group to debate the issue of combined ACE + ARB therapy as this always comes up. The data here of head to head combination vs. individual drug treatment is sparse. There are a couple of relevant conclusions that currently guide standard of care for this issue in the nephrology community:

• Maximize the dose of whichever agent is chosen regardless of BP if proteinuria is still present (you must monitor for hypotension, hyperkalemia, and dose-dependent increases in creatinine)

• If there is still proteinuria after you have achieved maximum dose of the ACE or ARB, it is reasonable to add the other agent and again increase to the maximum or highest tolerated dose. These are also the patients in whom stressing salt restriction may be most beneficial (decreasing salt intake can decrease proteinuria in patients taking ACE or ARB)

3. How will you follow effectiveness of your intervention and monitor side effects?

Both blood pressure and degree of proteinuria should be monitored with a goal of reaching target BP and of minimizing proteinuria. This is a good place to emphasize, again, the diurnal variation in protein excretion and the need to use sampling from the same time of the day for a given patient if spot urine protein: creatinine ratios are being used. Rechecking degree of proteinuria eight weeks after a change in medication dose is reasonable. Adjustments can be made at 3 – 4 week intervals if being done for BP control. Once you have reached the greatest possible reduction in proteinuria, it should be checked annually and at any time when the creatinine increases more than 10%.

The most important side effects to monitor are hypotension, hyperkalemia, and increases in serum creatinine of greater than 10%. Cough occurs with ACE, and patients should be specifically questioned about this as it often develops rather insidiously.

4. How, if at all, would your management plans change regarding treatment of proteinuria if the baseline creatinine = 1.8 mg/dl and potassium = 4.3 mEq/L?

No change in initial strategy is indicated, and these patients may benefit even more in terms of delaying progression of renal disease by taking ACE or ARB, compared to patients with normal serum creatinine. As creatinine increases, the risk of developing hyperkalemia and increasing creatinine in response to ACE and ARB also increases, so careful monitoring is warranted. Patients with elevated creatinine should have the creatinine clearance calculated using the MDRD formula to be certain that renal function has not deteriorated further than the serum creatinine would indicate. Patients with diabetes are more prone to the other metabolic complications of renal insufficiency and all patients with a calculated creatinine clearance of less than 60cc/min should be referred to a nephrologist for co-management of their metabolic issues (calcium, phosphate, PTH, vitamin D, anemia, etc.).

References:

1. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004; 27, Supplement 1: S79-S83.

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