Role of Kidney Disease on CV Outcomes Underappreciated

London, United Kingdom — Nephrologists are calling for more recognition of the important role that chronic kidney disease (CKD) plays in morbidity and mortality from cardiovascular disease, and they are stressing the importance of properly treating hypertension, diabetes, and dyslipidemia in patients with impaired renal function.

This lack of awareness means that opportunities are being lost to prevent not only renal but cardiovascular diseases, says Dr Giusseppe Remuzzi (Mario Negri Institute for Pharmacological Research, Bergamo, Italy). Most important, kidney disease first needs to be identified, because of its silent nature, and the “simplest way to do this is to perform a dipstick test for proteinuria or to look at serum creatinine and see if there are any abnormalities,” he says. Remuzzi is involved in a worldwide effort to get some kind of screening for renal disease up and running in over 30 countries. A report discussing his efforts is featured in the April 10, 2010 issue of the Lancet, in an issue devoted to the kidney [1].

Remuzzi says he believes cardiologists are starting to recognize the importance of renal dysfunction in cardiovascular disease, particularly in the wake of the HOPE trial. But they, along with primary-care practitioners in the community, need to realize “that it is even more important to look at urine than to measure blood pressure. No one with urinary albumin excretion will have a normal blood pressure. If you see abnormalities in the urine, this is a sign of alarm, and you can send the patient for more sophisticated measures of renal function,” he says. “Checking for urinary abnormalities is a way to tell your patient their prognosis,” he notes.

Effective Control of BP With Agents That Reduce Proteinuria Is Key

“If you identify and treat renal disease, and in particular if you treat it early, you reduce the risk of cardiovascular events,” he adds. Of most importance is the effective control of blood pressure with antihypertensive agents that also reduce or prevent proteinuria, he told heartwire .

If you choose the right [antihypertensive] drug, you benefit the kidney and by doing that you are also avoiding cardiovascular events.

“What cardiologists need to know is that if you choose to treat hypertension with ACE inhibitors or [angiotensin-receptor blockers] ARBs, you will lower the BP but also protect the kidney at the same time. This is a profound effect, and it’s added value–if you choose the right drug, you benefit the kidney and by doing that you are also avoiding cardiovascular events.” This is true whether the nephropathy is of diabetic or nondiabetic origin, he notes, although he stresses that it is “fundamental” to start treatment to protect the kidney as early as possible in diabetics.

Others agree. In another paper [2] in the same issue of the LancetDr Matthew T James (University of Calgary, AB) and colleagues review all the recent literature with regard to CKD and conclude: “The treatment of hypertension is the mainstay of management to slow the progression of renal disease and reduce cardiovascular risk.”

James et al say the current recommended BP target for those with CKD is 125–135/75–85 mm Hg, and they agree with Remuzzi that the foundation of treatment should be ACE inhibitors or ARBs in patients with proteinuric kidney disease; the latter are particularly useful if patients are intolerant to ACE inhibitors. They note, however, that inhibitors of the angiotensin system should be avoided in pregnancy.

Use ACE Inhibitors and Arbs Together, If Necessary

Remuzzi also feels strongly that in a small minority of patients in whom there is still evidence of proteinuria despite maximally tolerated doses of ACE inhibitors, treatment with ARBs can be added on. James et al agree that this approach will provide renal protection: “Combination treatment reduces proteinuria by a greater amount than either agent alone and thus has the potential to provide additional renoprotection,” they observe.

But they also point out that the results of the ONTARGET study cast doubt on the role of dual blockade of the renin-angiotensin system, which was associated with a heightened risk of dialysis, doubling of creatinine concentration in the serum, or death.

Remuzzi says he believes the results of ONTARGET “have completely misled the community”–more than 80% of the participants did not have any evidence of kidney disease, he says. “This was not a renal trial, and it was not designed to demonstrate that combination therapy was better or not in patients with renal insufficiency.” In fact, the increase in dialysis seen in those taking the combination in the trial was actually the result of patients with heart failure having a transient need for dialysis, he said, adding that he and a colleague published a paper last year [3] discussing the shortcomings of this study.

In terms of other antihypertensives, there is some evidence that spironolactone may help prevent proteinuria, he says. But it is not yet known whether the new renin inhibitor aliskiren “will add anything to existing drugs,” he says.

James and colleagues also point out that many patients with CKD will need several antihypertensives to control their BP, and they note that drugs from any class can be added after ACE inhibitors or ARBs, with decisions made according to the consideration of comorbidities in individual patients.

Few Data on Other Treatments to Reduce CV Risk in CKD Patients

The Canadian doctors explain in their article that few clinical trials have been undertaken specifically in populations with CKD. Assessment of usual cardiovascular treatments is needed in patients with CKD, and the risks and benefits of typical drug combinations also need further investigation in such populations, particularly in view of the high prevalence of polypharmacy and potential for toxic effects.

In the meantime, it is necessary “to either extrapolate data from randomized controlled trials done in the general population or rely on subgroup analyses of people with CKD enrolled in such trials,” they state.

Subgroup analyses that have been performed suggest that statins significantly reduce all-cause mortality and cardiovascular events in individuals with reduced glomerular filtration rates (GFRs), they say, and the recommendation is to treat patients with CKD to the same LDL-cholesterol targets as the general population.

However, the true renal benefits of statins “are uncertain,” they observe. And while statins are the preferred therapy for dyslipidemia, bile-acid sequestrants, niacin, and ezetimibe can be used and do not need dose adjustments in renal patients. Fibrates can also be used but do require dose adjustment.

There is also some evidence that vitamin D may be beneficial in CKD, says Remuzzi, with investigations ongoing.

The use of aspirin in renal patients is trickier, he says, noting that “it has to be given with some caution because of the risk of bleeding in patients with advanced chronic kidney disease.” However, it can be safely used in the earlier stages of kidney disease and should be employed in diabetics, he says, “where the benefits probably outweigh the risks.”

It is also important to ensure tight glycemic control in diabetics, say James et al, although they note too that the risk/benefit ratio of this approach must be carefully weighed, because in some patients, eg, those with a low GFR, risk of hypoglycemic events can be raised with tight glycemic control.

Nonpharmacologic treatments should also play an important role in the management of patients with CKD, say the nephrologists, with the usual lifestyle changes demonstrating benefit–stopping smoking, limiting sodium intake, losing weight, and exercising.

Complex Nature of CKD Leads to Low Use of Recommended Treatments

Despite the availability of effective strategies to slow the progression of kidney disease and reduce cardiovascular risk, studies suggest they are not being utilized, perhaps due to the “complex” nature of caring for CKD patients, say James et al.

For example, a UK study shows that only a fifth of patients with diabetes and CKD had a BP of 130/80 mm Hg or less, and fewer than half were receiving an ACE inhibitor or ARB. And only 50% of those with stage 3–5 CKD were prescribed an antiplatelet agent or lipid-lowering agent, “suggesting that the management of these patients could be enhanced considerably.”

And they observe, “Most cases of nonprogressive CKD can be managed without referral to a nephrologist . . . for all health systems, multi-intervention clinics and programs that enhance care of patients in the primary-practice setting are attractive alternatives to conventional models.”

Specialist intervention is required for those whose estimated GFR is less than 30 mL/min per 1.73 m2 and those with rapidly declining kidney function over a year, persistent proteinuria, or uncontrolled hypertension or diabetes, they note. And it might also be necessary to manage renal anemia and metabolic complications of CKD.

Remuzzi has no conflicts of interest. James and colleagues report no conflicts of interest.

References

  1. Kirby T. Screening for chronic kidney disease shows promise. Lancet 2010; 375:1240-1241.
  2. James MT, Hemmelgarn BR, and Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet 2010; 375:1296-1309.
  3. Ruggenenti P and Remuzzi G. Proteinuria: Is the ONTARGET renal substudy actually off-target? Nat Rev Nephrol2009; 5:436-437. Abstract

Authors and Disclosures

Journalist

Lisa Nainggolan

Lisa Nainggolan is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000. Previously, she was science editor of Scrip World Pharmaceutical News, covering news about research and development in the pharmaceutical industry, and a consultant editor of Scrip Magazine. Graduating in physiology from Sheffield University, UK, she began her career as a poisons information specialist at Guy’s Hospital before becoming a medical journalist in 1995. She can be reached at LNainggolan@webmd.net.