Dr Grace SL Lee and Prof Woo Keng Thye, Department of Renal Medicine, Singapore General Hospital

Diabetic nephropathy is the most common cause of end-stage renal failure in Singapore and accounted for 47.2% of the new cases starting on dialysis in 2000 [1]. About 90% of patients with diabetes have type 2 diabetes (non-insulin dependent diabetes) and approximately 40% of all patients with diabetes are at risk of developing diabetic nephropathy and end-stage renal disease (ESRD). It is therefore imperative that patients at risk are identified early and provided optimal therapy.

There are many strategies to reduce the risk of diabetic nephropathy [2] and these include (i) excellent blood glucose control with a target HbA1c <7.0%. (ii) excellent blood pressure control with a target blood pressure < 130/80 mmHg, (iii) the use of angiotensin II receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACE inhibitors), (iv) excellent lipid control and (v) a moderate restriction of dietary protein intake when chronic renal failure is present. This paper focuses on optimizing the use of ARB% in type 2 diabetes with special attention to (1) identifying patients who will benefit from ARBs, (2) the significance of proteinuria and its impact on prognosis, (3) optimal doses of ARBs, (4) dual therapy with ARBs and ACE inhibitors and (5) initialing and monitoring when starting an ARB in diabetic patients (especially those with renal impairment).
 


ARBs in Diabetic Nephropathy
 

Blockade of the renin-angiotensin-aldosterone system (RAAS) with an angiotensin-receptor blocker (ARB) has emerged as a key strategy for reno-protection. This followed the results from three large clinical trials published in 2001 - IRMA (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria) [3]. IDNT (Irbesartan Diabetic Nephropathy Trial) [4] and RENAAL (Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan) [5]. IRMA enrolled patients with hypertension and microalbuminuria while both IDNT and RENAAL enrolled patients with advanced diabetic nephropathy (proteinuria and renal impairment). While IRMA showed that treatment with the ARB irbesartan reduced urinary albumin excretion and risk of progression to overt diabetic nephropathy, both the IDNT (using irbesartan) and RENAAL (using losartsan) demonstrated the ARBs were able to reduce the risk of reaching a combined renal end-point of doubling of serum creatinine, ESRD or death. In all three trials, the higher doses (losartsan 100mmg and irbesartan 300mg) were more effective than the lower doses (losartan 50mg and irbesartan 150mg).

Apart from their antihypertensive and anti-proteinuric properties, some ARBs have other metabolic and anti-inflammatory effects including anti platelet activity (losartsan, irbesartan, valsartan and telmisartan) and a uricosuric effect (losartan) which are beneficial in renal disease
 

 

Patients at Risk of Developing Diabetic Nephropathy
 

Various studies in patients with type 2 diabetes have shown that the following groups demonstrate a reduced risk of progressive renal disease when treated with an ARB and therefore should be initiated on therapy. They are those with:
 

1. hypertension.
2. microalbuminuria regardless of blood pressure and
3. overt nephropathy (proteinuria with or without renal impairment).

It is recommended that patients with type 2 diabetes be screened annually for microalbuminuria/proteinuria in order to allow early identification and treatment. Renal impairment should NOT be a contraindication for starting a patient on an ARB as shown by the IDNT and RENAAL studies but the patient should be monitored closely for hyperkalemia and an acute rise in serum creatinine (see below).
 


Proteinuria - Clinical Impact and Targets


While excellent control of blood pressure remains one of the cornerstones of therapy aimed at reducing the risk of progressive diabetic nephropathy, there has recently been more focus on proteinuria and its impact on prognosis. Proteinuria has traditionally been viewed as the consequence, rather than the cause, of renal injury. However, there is evidence to suggest that the proteinuria itself is deleterious to the kidney and that tubulointerstitial fibrosis occurs as the result of the inability to handle the excess protein filtering through the glomeruli and tubules. While, again, we are aware that the degree of proteinuria at presentation is a prognostic indicator of progression of renal disease, it is perhaps more important to realize that studies have also shown that the anti-proteinuric response to intervention is a strong predictor of renoprotective efficacy. Hence, more attention should be focused on reducing proteinuria. Although the recommended target is a ≥ 50% reduction in proteinuria from baseline values, an effort must be made to reduce the proteinuria to as low a level as possible.
 


Optimal doses of ARBs in diabetic nephropathy


There is a growing consensus that the current recommended doses for ARBs may not be adequate to provide a maximal anti-proteinuric effect (ie reno-protective effect). This is because the current recommended doses for ARBs are based on hypertension trials and the dose-response for the anti-proteinuric effect is probably not the same as the blood pressure lowering effect. Evidence that higher doses of ARBS (and better RAAS blockade) provide additional renoprotection comes from animal studies and also the three trials mentioned above (IRMA, IDNT and RENAAL), where the higher doses were more effective than the lower doses. Further indirect evidence that "adequate" RAAS blockade increases renoprotection comes from studies using dual therapy of both ARBs and ACE inhibitors in both diabetic [6,7] and non-diabetic renal disease. Most recently, a trial using irbesartan at a dose of 900mq (three times the normal recommended dose) in hypertensive type 2 diabetic patients with microalbuminuria [8] reported better reduction in urinary albumin excretion compared to patients on the lower dose of 300mg, There was essentially no difference in the blood pressured between those on the 300mg and 900mg doses.

The optimal reno-protective dose of ARBs has yet to be determined but is likely to be higher than the current recommended doses. In clinical practice, most nephrologists are comfortable with using double to triple the recommended dose of ARBs with close monitoring of do serum creatinine and potassium.
 


Dual therapy – ARBs and ACE inhibitors


Prior to the studies using higher doses of ARBs, there have been many trials in both diabetic and non-diabetic renal disease demonstrating the anti-proteinuric efficacy of dual therapy with ARBs and ACE inhibitor versus monotherapy with either drug. Although, it can be argued that a sufficiently high dose of a single agent may be as effective as both drugs combined at "suboptimal" doses, there are advantages to dual therapy. In monotherapy with ACE inhibitors, Angiotensin II can still be generated via non-ACE pathways resulting in inadequate RAN blockade despite maximal doses. On the other hand, blockade of the angiotensin type 1 receptor with an ARB results in a rise in renin and consequently angiotensin II. Hence dual therapy may provide more complete RAAS blockade.

In dual therapy, both drugs are prescribed at the highest recommender dose for each drug, Hence, close monitoring of the serum potassium is required to reduce the risk of potentially fatal hyperkalemia. In addition a reduction in the haemoglobin level may be observed and this is likely the result of blockade of angiotensin II which is known to stimulate erythropoietin synthesis.
 


Starting a Patient on an ARB – Practical Points


ARBs have two potential side effects and they are (1) the development of acute, reversible (if detected early), renal failure in patients with bilateral renal artery stenosis, dehydration or cardiac failure and (2) severe hyperkalemia. Figure I provides an approach to safely initiate an optimize the use of an ARB in a diabetic patient.

An acute rise in serum creatinine is more likely to occur in patient with renal impairment and the change in creatinine occurs within the first two weeks of initiating or increasing the dose and is stable after four weeks. A rise of up to 30% of the baseline serum creatinine is acceptable in patients with renal impairment [9] as the ARB reduces intraglomerular pressure and thus the glomerular filtration rate. A sudden increase of the serum creatinine in a previously stable patient may occur as a result of dehydration or the use of diuretics or NSAIDs (non-steroidal anti-inflammatory drugs).

The dose of the ARB should be increased to the highest recommended dose (or higher, as discussed above). Addition of an ACE inhibitor may be considered if the target blood pressure or anti-proteinuric effect is not achieved. Adding a diuretic to the therapeutic regimen (thiazide in normal renal function and loop diuretic in renal impairment) has advantages in reducing the risk of hyperkalemia; aside from assisting with blood pressure control and reducing proteinuria.
 


When to discontinue the ARB


Where possible, the ARB should NOT be discontinued unless the patient shows an acute rise in serum creatinine of >30% from baseline value on initiation of the ARB or if there is persistent hyperkalemia. In fact, the patient can still remain on the ARB even after the onset of end-stage renal disease and dialysis for its cardio-protective effects.
 


References

1. Lee G. End-stage renal disease in the Asian-Pacific region. Semin Nephrol 2003:23:107-14.


2. Lee G. Woo KT. Diabetic nephropathy in A Clinical Approach to Medicine (2nd ed.). Editors: Ong YY, Woo KT. Ng HS, Tan P, Tang OT,  World Scientific Publishing Co Pte Ltd, Singapore. 2005.


3. Parving H-H, Lenten H, Brochner-Mortensen J, Comes R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Ergl J Med 2001:345:870-8.


4. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes, N Engl J Med 2001:345:851-60.


5. Brenner BM, Cooper ME, de Z.eet w D, Keane WE Mitch WE. Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, N Engl J Med 2001:345:861-9.


6. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, at al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. Br Med J 2000:321:1440-4.


7. Rossing K, Christensen PK, Jensen BR, Parving HH. Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study. Diabetes Care 2002:2595-100.


8. Rossing K, Schioedt KJ, Jensen BR, Boomsma F, Parving HH. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney kit 2005: 68:1190-8.


9. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000: 160685-93.

 

 

 

 

Cr: creatinine, K+ potassium


* doses to optimally reduce proteinuria may be higher than recommended, see text


Figure 1, Initiating a diabetic patient on an ARB


 

Teaching Points

  • ARBs should be initiated in patients with type 2 diabetes and (1) hypertension, (2)microalbuminuria (with or without hypertension) and (3) overt nephropathy (proteinuria with or without renal impairment)

  • The target blood pressure for diabetic patients is >130/90mmHg

  • Proteinuria is an independent and modifiable prognostic factor and the treatment target is ≥50%reduction from the baseline value

  • ARBs should be used at the highest recommended doses for optimal anti-proteinuric effects. Dual therapy with an ARB and ACE inhibitor can be considered to achieve the blood pressure and proteinuria reduction targets

  • Serum creatinine, potassium and haemoglobin should be monitored at regular intervals

  • A diuretic is useful in reducing the risk of hyperkalemia. in addition to its anti-hypetensive and synergistic antiproteinuric effects