‘Patients given combined therapy from the start of treatment responded better than those given monotherapy’

Prof Eoin O’Brien looks at the benefits of aliskiren in the treatment of hypertension but says it should not be prescribed with ACE inhibitors or ARBs in diabetic patients.

Aliskiren (available in Ireland as Rasilez and Rasilex HCT) is the first in a class of drugs called direct renin inhibitors. The earliest efficacy studies were conducted by my department in Beaumont Hospital in 2001 for Speedel Pharma.

When its efficacy in reducing blood pressure over 24 hours was established, Novartis marketed aliskiren as a new class of drug for the treatment of hypertension, which was approved by the US Food and Drug Administration (FDA) in 2007 either as monotherapy or in combination with other medications.

The efficacy and safety of aliskiren has been investigated in clinical studies in more than 57,000 patients.

Renin cleaves angiotensinogen to angiotensin I, which is converted by the angiotensin-converting enzyme to angiotensin II. Angiotensin II increases blood pressure by causing vasoconstriction and increased production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium and water, leading to an increase in plasma volume. Aliskiren prevents the conversion of angiotensinogen to angiotensin I, thereby lowering blood pressure.

ACCELERATE and ALTITUDE
The ACCELERATE study, reported in The Lancet last year, was a double-blind, randomised, parallel-group superiority trial performed in 10 countries, in which hypertensive patients were randomly assigned to treatment with aliskiren plus placebo, the calcium-channel blocker (CCB) amlodipine plus placebo, or aliskiren plus amlodipine.

Patients given combined two-drug therapy from the start of treatment responded better than patients initially given monotherapy, and those who later switched from monotherapy to combination therapy improved their response, but not to the same level as those who began with combination therapy.

In an accompanying comment in The Lancet, ACCELERATE was heralded as the first study to show that starting on combination therapy helps patients to achieve blood pressure goals faster than initial monotherapy.  So the stage was set for Novartis to combine aliskiren with other blood pressure-lowering drugs and approval for this was given by the FDA.

Despite this, aliskiren has been prescribed generally as a fourth-line hypertensive agent in patients with resistant hypertension. Nonetheless, total sales of aliskiren-based products for the first nine months of 2011 were US$449 million (€348.1 million, 1 per cent of Novartis Group sales).

So far, so good. But just before Christmas, Novartis announced termination of the multinational ALTITUDE study to evaluate the potential benefits of aliskiren with an angiotensin-converting-enzyme-inhibitor (ACEI) or an angiotensin-receptor-blocker (ARB) to reduce the risk of cardiovascular and renal events in 8,606 patients (recruited from 36 countries) with type II diabetes, reduced renal function and a previous cardiovascular event.

In December 2011, the data safety and monitoring board (DSMB) recommended termination of the study because the aliskiren-treatment group experienced an increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension. The DSMB concluded that patients were unlikely to benefit from aliskiren added to standard antihypertensive therapy. These findings represent a major setback for a drug that had once been considered to have significant potential as a new class of treatment for hypertension.

Prof Eoin O'Brien: 'The recent introduction of flexipills providing a range of doses for combinations of ARBs or ACEIs with other drug classes makes combination treatment very much easier for the patient'

Aliskiren with ACI or ARB
A press release from Novartis stated: “Novartis is in ongoing discussions with health authorities worldwide about the implications of the findings from ALTITUDE for patients.” But, “as a precautionary measure, Novartis will cease promotion of Rasilez-based products for use in combination with an ACE inhibitor or ARB”.

The Irish Medicines Board refers website queries to the European Medicines Agency (EMA) Press Release (22 December, 2011), which states that the EMA “is reviewing aliskiren-containing medicines, to assess the impact of data coming from the ALTITUDE study on the balance of benefits and risks of these medicines in their approved indication” and recommends in the meantime “as a precautionary measure, that doctors should not prescribe aliskiren-containing medicines to diabetic patients in combination with ACE inhibitors or ARBs”.

The message is therefore clear for diabetic patients. Patients with diabetes on aliskiren alone or in combination with HCTZ, who are not on an ACEI or ARB, need not modify treatment if blood pressure control is satisfactory. However, diabetic patients who are on aliskiren alone or in combination with HCTZ and are also on an ACEI or ARB, should stop the aliskiren-based drug.

The question to be answered in the ongoing analysis is what the implications are for non-diabetic patients who are on treatment with aliskiren in combination with an ACEI or ARB. The results of the ALTITUDE study must raise the question as to how suitable these combinations are in the overall treatment of hypertension.

Pending the results of further analyses, perhaps the wisest course would be to keep aliskiren in reserve only for hypertension that has proven resistant to combination treatment with diuretics, ACEIs and ARBs, CCBs and the newer beta-blockers in non-diabetic patients.

The recent introduction of flexipills providing a range of doses for combinations of ARBs or ACEIs with other drug classes makes combination treatment very much easier for the patient, with the likelihood of improved compliance and more efficient blood pressure control.

• Prof Eoin O’Brien, Professor of Molecular Pharmacology, Conway Institute, University College Dublin.

Analysis of a large Canadian database has confirmed a link between heart failure and osteoporotic fractures but showed for the first time it is independent of bone mineral density (BMD).

The conclusion was based on more than 45,000 men and women aged 50 or more who had BMD testing and were then followed for up to a decade. The main outcome was time to a major osteoporotic fracture — a clinical vertebral fracture or a fracture of the distal forearm, humerus or hip.

Ten per cent of the 1,841 subjects with recent-onset heart failure experienced a fracture compared with only 5 per cent of those without heart failure.
After accounting for age and other osteoporosis risk factors, as well as comorbidities and medications, fracture risk was increased 33 per cent by heart failure. Further adjustment for total hip BMD attenuated the risk only slightly to 28 per cent.

“For physicians, our findings suggest that a heart failure diagnosis portends a substantial increased risk of fracture and identifies an easily-recognised population that needs greater attention to their bone health,” the researchers said.

Factors contributing to the link might include shared risk factors (for example, smoking and diabetes), the use of some medications such as loop diuretics, hyperaldosteronism and secondary hyperparathyroidism resulting from heart failure that accelerated bone loss, and frailty associated with heart failure that increased the risk of falls.

Previous studies on the issue had been limited by short duration, small size, neglect of non-hip fractures, restriction to postmenopausal women, self-report of medications, or lack of data on the duration of heart failure.

“None of these previous reports had any data with respect to BMD, one of the strongest, most widely used and best-validated predictors of future fracture,” they said.

Journal of Endocrinology and Metabolism doi:10.1210/jc.2011-3055

'The atherosclerotic plaque is cholesterol and fatty-acid laden, and research efforts have been successful in unravelling some of the mechanisms involved in the formation and rupture of these plaques'

Prof Gerald H Tomkin provides an overview of the role played by LDL and the correlation between LDL cholesterol levels and atherosclerotic risk.

There has been a huge increase in our understanding of the atherosclerotic process, but there also has been a huge increase in both patients with the condition, and those who will potentially have the condition in the future. The rising tide of obesity, diabetes and hypertension, together with our reluctance to exercise and desire for fast, unhealthy food, has made atherosclerosis of major importance economically, politically, scientifically and medically.

Bypass operations
Treatment of the condition with procedures such as bypass operations, insertion of stents and pharmaceutical agents to treat hypertension, diabetes and dyslipidaemia pose an enormous burden on society. The atherosclerotic plaque is cholesterol and fatty-acid laden, and research efforts have been successful in unravelling some of the mechanisms involved in the formation and rupture of these plaques.

The lipoproteins are the major transporters of both cholesterol and fatty acids. Low-density lipoproteins (LDL) is the best known lipoprotein, not only because Brown and Goldstein discovered the receptor for LDL and demonstrated the importance of the receptor in maintaining cholesterol homeostasis, but also because the statin drugs that inhibit HMGCoA reductase (the rate-limiting enzyme for cholesterol synthesis) were shown to up-regulate the LDL receptor, lower cholesterol in the blood steam and reduce cardiovascular events by about 30 per cent. Indeed, the popularity of the statin drugs has been such that it has been proposed that they should be given to everyone in middle age.

Cholesterol
Cholesterol may be synthesised by almost every cell in the body, the majority in the liver and about 25 per cent in the intestine, or may be absorbed from the diet. Cholesterol from the intestine is delivered to the liver by the Apo B 48 containing lipoprotein in the chylomicron, a large, lipid-rich particle with a very short half life of circa 90 minutes. The cholesterol is then repackaged with de novo synthesised, hepatically-derived cholesterol, solubilised by apo B 100 and excreted as very low-density lipoprotein (VLDL).

These particles are delipidated by lipoprotein lipase and become LDL when they shed their apo E. Apo E is another lipoprotein, which is involved in clearance of VLDL via the B/E receptor in the liver before being transferred to HDL, where it plays a part in reverse cholesterol transport. Thus, the LDL particle is a cholesterol-rich, lipid-poor particle.

Esterified and free cholesterol
The cholesterol is both esterified and free. The particle has a phospholipid surface and accepts cholesterol from HDL via cholesterol ester transfer protein. The particle has a half-life of about four days and the levels in the blood are remarkably stable throughout life, rising with age but only to a very limited extent.

Homeostasis is achieved through a regulated uptake by the LDL receptor, too little cholesterol increasing the LDL receptor activity to increase cholesterol uptake by the cell and inhibiting de novo cholesterol synthesis in the cell by HMGCoA reductase.

Confirmation of this comes from the finding that inhibition of HMGCoA reductase by the statins — and thus decrease of cholesterol synthesis in the cell — results in an increase in receptor activity and uptake of cholesterol by the cell, the net result being a decrease in serum cholesterol.

LDL that has been taken up by the liver is broken down in the lysosomes and the cholesterol removed from the circulation in the bile. This pathway includes Niemann Pick C1-like 1, an enzyme that has been popularised by the discovery of ezetimibe. In the intestine, ezetimibe inhibits NPC1-L1 and thus reduces cholesterol absorption and, in the liver, it reduces cholesterol excretion in the bile.

The discovery of PCSK9 has added another level of information on the control of LDL cholesterol and raised the possibility of yet more effective ways of reducing LDL cholesterol. PCSK9 is fascinating in that it regulates LDL receptor activity, thus an increase in PCSK9 will increase the LDL receptor uptake and degradation in the lysosome, therefore reducing the number of LDL receptors on the surface of the cell.

Early studies have suggested that inhibition of PCSK9 can increase the cholesterol reduction by statins by up to 50 per cent. This is particularly exciting, since there is general consensus that the greater reduction in cholesterol, the greater reduction in risk, with no suggestion of a J-shaped curve, such as is found when blood pressure is reduced beyond a certain point.

Mechanism goes wrong
So how does this wonderfully-tuned mechanism go wrong in atherosclerosis? This short article attempts to dissect the role of LDL cholesterol, while recognising that LDL cholesterol is only a small part of the whole jigsaw. Historically, a breakthrough came with the demonstration that the LDL particle could be modified by oxidation. This modification led to the unregulated uptake of cholesterol through the scavenger and other receptors. This deregulated pathway did not have the ability to down-regulate de novo cholesterol synthesis in the cell, hence accumulation of cholesterol in the cell.

The scenario now would be that a damaged endothelial surface attracts the monocyte-derived macrophage through the expression of various chemoattractant proteins, such as VCAM and ICAMs.

The macrophage has the ability to scavenge, among other things, modified LDL. The cholesterol-laden macrophage becomes entrapped beneath the endothelium in the sub-endothelial space to form the lipid-laden plaque. Increase in free radicals and the formation of oxidised LDL contributes to the tissue damage and also occurs in hyperglycaemia.

Prof Gerald H Tomkin: 'Historically, a breakthrough came with the demonstration that the LDL particle could be modified by oxidation. This modification led to the unregulated uptake of cholesterol through the scavenger and other receptors'

Oxidation is not the only modification of LDL. Another important modification is glycation. Even in pre-diabetes, the increase in glycation of LDL will alter the particle sufficiently to be taken up by the macrophage. Modified LDL is recognised by the immune system as being abnormal and antibodies against modified LDL have been demonstrated and also play a role in uptake by the macrophage and the development of the atherosclerotic plaque.

It is interesting that measures of oxidised LDL in the blood and LDL antibodies have been used as surrogate markers of atherosclerotic burden with some limited success. The oxidation of LDL may occur at many sites. The apo B100 protein may be oxidised, but the fatty acids may be a major source of LDL oxidation.

The major fatty acid in the LDL particle is linoleic acid, which has two double bonds and is very susceptible to oxidation, whereas oleic acid, with one double bond, is resistant to oxidation — one reason, perhaps, why the Mediterranean diet is to be preferred to a high polyunsaturated fat diet, such as may be obtained by the use of sunflower oil instead of olive oil.

The fatty acid content of LDL is largely dependent on its precursor VLDL. VLDL, together with the chylomicron, are the triglyceride-rich particles and their levels are largely influenced by excess dietary calories, whether they be from fat or carbohydrate. Hypertriglyceridaemia is associated with both an increase in the number and size of the triglyceride-rich particles and has been shown to influence LDL oxidisability.

It has been a little disturbing to find that antioxidants do not appear to work in reducing atherosclerosis and indeed may be harmful. The explanation may be the rapidity of free radical production and the oxidation process in damaged tissue and the inability of the antioxidant activity to influence these processes through insufficient concentrations at the damaged site.

Another concern is that the antioxidants may actually be working as pro-oxidants in damaged tissue. Reduction in glycation of the LDL particle through meticulous control of blood sugar in diabetic and perhaps pre-diabetic patients is one method to reduce atherosclerosis.

Although there is no doubt about the association between blood glucose and atherosclerosis, there is still some confusion about the merits of lowering blood glucose in the prevention of atherosclerotic events.

A consensus has arisen that early on in the diabetic disease, meticulous control of blood sugar does pay dividends and one mechanism may be through reduction in glycated LDL.

LDL’s role in atherosclerosis
In conclusion, LDL plays a major part in the atherosclerotic process, with excellent correlation between LDL cholesterol levels and atherosclerotic risk.

Reduction in LDL is beneficial and has made an important impact on reduction in coronary heart disease. The level of LDL is a good index of its atherogenicity in the absence of screening tests that can easily identify LDL modifications.

There appears to be no lower limit beyond which LDL reduction becomes unsafe and guidelines now suggest that ideal levels of LDL should be below 1.8, particularly in high-risk groups such as those who have already had a heart attack or who have diabetes. Diet, exercise and weight reduction in those who are overweight are mandatory.

The statins are the first line of drug treatment to lower LDL cholesterol, with further benefit from ezetimibe, which inhibits cholesterol absorption.

Ezetimibe may prove to be particularly useful in those patients who are high absorbers of cholesterol, but definitive endpoint studies have not yet been completed.

Fibrates are effective in lowering triglycerides — and to a lesser extent cholesterol — and are probably useful, particularly in patients who have hypertriglyceridaemia together with raised LDL.

In 2012, the tools to prevent atherosclerosis have never been better and access to information and the reduction of ignorance in the community about cholesterol has never been greater. The task ahead is to persuade the public to utilise the knowledge available to protect against heart disease.

• Prof Gerald H Tomkin, Diabetes Institute of Ireland, Beacon Clinic, Dublin 18.

Researchers are closing in on a rare genetic disorder causing a heart condition in infants. Histiocytoid cardiomyopathy (HC) often causes sudden death before a child reaches two years of age. Gene analysis is helping to narrow the many theories surrounding the genetic basis of HC.

A study reported in Pediatric and Developmental Pathology compares cardiac tissue from 12 patients with HC and 12 age-matched controls.

Researchers found differences in gene expression that could indicate a predisposition for HC.

HC typically occurs in the first two years of life. It affects females three times more often than males, leading to the theory that it is an X chromosome-linked disorder with prenatal death is occurring in males. Eighty per cent of the cases occur in whites; 15 per cent in blacks; and 3 per cent in Latin Americans. It is very rare in those of Asian heritage.

A worldwide registry of HC was started in 1999, attempting to identify the gene responsible for this fatal disorder. These data have shown a family tendency for the disease.

The gene analysis undertaken in the current study found decreased protein expression, or downregulation, in two sets of genes aligned sequentially along the genome. This offers several genes as candidates for the mutation, possibly predisposing individuals to HC.

The downregulation of a particular gene could result in reduced survival of cardiac myocytes, leading to cardiac failure during a baby’s development.

These candidate genes now will offer a starting point for further research for inherited patterns of mutation. Utilising the HC registry, researchers will seek to confirm the findings of this study and to collect and analyse blood from parents and siblings of HC patients in an effort to further expose the inheritance pattern.

Pediatric and Developmental Pathology 14, 370–377, 2011.

Cardiovascular disease (CVD) patients might be particularly vulnerable to the effects of complementary and alternative medicine (CAM), cardiologists say.

Writing in a perspective in the MJA, cardiologists Hosen Kiat and Dennis Hsu-Tung Chang and colleagues said the adverse effects were due primarily to drug interaction or reduced adherence to conventional therapies.

Furthermore, these adverse effects could be amplified by the variable quality and lack of standard dosing of complementary medicines and the number of CAM products consumed.

Examples of CAM that were commonly used in the treatment of CVD — and their adverse effects — included aloe vera (diarrhoea and potassium depletion); fenugreek (diarrhoea and hypoglycaemia); ginseng (insomnia); ephedra (stroke and myocardial infarction); gingko biloba (bleeding); and red yeast rice (myopathy and rhabdomyolysis).

The relatively wide use of complementary medicines in people with CVD meant it was “vital” that doctors were aware of CAM use, particularly as use was not disclosed by cardiac patients up to 65 per cent of the time, the authors said.

“The main reasons were fear of clinician disapproval and because clinicians had not asked about CAM use,” they wrote.

“This strongly suggests that clinicians need to take a less judgmental and more pro-active approach to encourage patient discussion of CAM use, regardless of adherence to conventional treatment,” they concluded.

MJA 2011; doi:10.5694/mja10.10976

People who are obese in childhood but are of normal weight as adults have similar cardiovascular risks to an individual who has a normal weight both as a child and an adult, new research has shown.

The findings were based on four long-term cohort studies with a mean follow-up of 23 years. Participant numbers were 6,328 in total and were from an Australian study, a Finnish study and two American studies.

Compared to people who were consistently of normal weight, those who were obese both as children and adults had a significantly higher risk of type II diabetes (relative risk 5.4), hypertension (2.7), high LDL cholesterol (1.8), low HDL cholesterol (2.1), high triglycerides (3.0) and increased carotid intima-media thickness (1.7).

However, there were no significant increases in these risk factors among the minority of obese children who were of normal weight as adults.

“Primary care physicians should not take the pessimistic view that once childhood obesity is established, cardiovascular risk is also determined, but should recognise that cardiovascular risk may be substantially reduced if childhood obesity is also treated,” the researchers said.

An editorial emphasised that only 15 per cent of normal-weight children in the study became obese as adults during the follow-up period, but 82 per cent of those who were obese as children remained obese as adults.

“If we want to reduce the incidence of adult heart disease and thereby start to control the continuing escalation in healthcare expenditures, now is the time to do whatever it takes to develop more effective methods for both the prevention and the treatment of childhood obesity,” it said.

Targeting interventions for prevention and treatment specifically to children at high risk might be more valuable and more cost-effective than targeting whole populations of children, it added.

NEJM 2011; 365: 1876-1885

Methotrexate (MTX) appears to reduce the risk of cardiovascular disease (CVD) in patients with conditions such as rheumatoid arthritis (RA), a systematic review finds, supporting the inflammatory hypothesis of atherothrombosis.

The review, published in the American Journal of Cardiology, identified 10 observational studies: eight in patients with RA, one in patients with RA or polyarthritis, and one in patients with psoriasis.

“Methotrexate was associated with a 21 per cent lower risk for total cardiovascular disease and an 18 per cent lower risk for myocardial infarction,” it concluded. In studies that specifically addressed the issue, there was also a reduced incidence of stroke.

There was no evidence of heterogeneity between the 10 studies. Associations between MTX use and lower cardiovascular risk were stronger after accounting for underlying disease severity and other medications, adding weight to the hypothesis that MTX was beneficial.

“Systemic inflammation is strongly linked to increased risk for CVD,” the Harvard Medical School researchers wrote.

“However, whether this relation is causal or simply an association is not established. No randomised trials have directly addressed whether targeted anti-inflammatory agents that do not have concomitant lipid-lowering or antiplatelet effects also reduce CVD event rates.”

MTX was well known to reduce inflammatory biomarkers such as C-reactive protein, interleukin-6 and tumour necrosis factor in patients with RA and psoriasis, explaining its efficacy in these conditions. It had no adverse effects on platelet function and was not known to have any detrimental effects on lipid metabolism or insulin resistance, the authors noted.

“Our findings provide support for the inflammatory hypothesis of atherothrombosis,” they concluded.

American Journal of Cardiology 2011; 108: 1362-1370.

The notion that being over 70 years puts patients undergoing coronary artery bypass graft (CABG) at increased risk of stroke has been challenged by a large study, which suggests the burden of atherosclerosis plays a more important role.

While patients aged 60-65 were 70 per cent more likely to have a stroke within 30 days of surgery than those under 60 — and those aged 65-70 were 140 per cent more likely — the increasing risk levelled off at age 70.

The database study of more than 25,000 Danish patients who underwent CABG between 1997 and 2007 found a previous stroke increased a patient’s risk of stroke within 30 days of surgery four-fold. Stroke risk was also raised by diabetes 1.3-fold and hypertension 1.4-fold. Statin use lowered the risk of stroke by 20 per cent.

The results contrasted with those of earlier studies suggesting the risk of stroke increased exponentially with age over 60 years, the authors wrote in Stroke.

The difference between theirs and earlier studies was the use of the EuroSCORE to select candidates for surgery, they said. “This study shows that by applying EuroSCORE criteria in selecting suitable candidates for CABG, the risk of stroke among patients age >70 years has been reduced to a constant rate…

“Our data suggest that the risk of stroke after CABG in patients age >70 years is not caused by age per se, but rather is a consequence of the burden of atherosclerosis.”

Stroke 2011;  doi: strokeaha.111.620880.

'A study by Liam Glynn et al in the west of Ireland (IMJ 2002) found that most CKD was unrecognised in general practice'

Consultant nephrologist Prof George Mellotte informed a recent Dublin meeting that appropriate primary-care management of patients with chronic kidney disease may reduce overall cardiovascular risk and delay progression to renal failure, reports Gary Culliton.

Chronic kidney disease (CKD) is common and often unrecognised in many patients due to the asymptomatic nature of the condition. CKD is strongly associated with adverse cardiovascular outcomes. The vast majority of patients with mild-to-moderate CKD will not require dialysis and can be managed in primary care. Appropriate management of patients with CKD by general practitioners may reduce overall cardiovascular risk and delay progression to renal failure.

There is a very close correlation between CKD and other conditions. All patients with known risk factors over the age of 55 should be screened for kidney disease, Prof George Mellotte, Consultant Nephrologist at St James’s Hospital and Tallaght Hospital, told the recent BMJ Masterclass in Dublin. Dr Mellotte talked about assessing the cardiovascular risks and clinical goals in the context of declining renal function.

Serum creatinine levels are only part of the story, he said. The problem with serum creatinine is that it depends on age and gender. Weight and height are factors, as is race. It is a metabolic by-product of muscle and is based on muscle mass.

The more muscle one has, the more creatinine is produced. Estimated glomerular filtration rate (GFR) is a better measure of renal function: eGFR is a useful measure of renal function and can be calculated easily in clinical practice using serum creatinine, age, gender and race. Reduced eGFR is a potent marker for cardiovascular morbidity and mortality and should be regarded as a risk factor for cardiovascular disease, just like hypertension, cholesterol level and diabetic status.

eGFR can be interpreted as the percentage of normal kidney function such that an eGFR of 50 mL/minute/1.73 m2 approximates to 50 per cent of normal kidney clearance. The big advantage is that a technique has now been developed to measure it automatically and very accurately in most cases.

“It’s easier to notice decline in renal function,” Dr Mellotte said. The level of eGFR correlates to severity of complications.

There are two formulae for calculating eGFR. A ‘best fit’ formula was derived from the Modification of Diet in Renal Disease (MDRD) study. Serum creatinine was correlated to GFR. This applies in standard practice. It will not be accurate for patients whose bodies are very small or very large and adjustments must be made.

Age, diabetes, hypertension and family history put people at risk. The kidney, which has 0.5 per cent of body mass, takes 20 per cent of cardiac output. If there is any damage to the blood supply, the kidney malfunctions. GFR and creatinine are ways of assessing which patients have kidney damage and heart damage. They serve as markers of vascular damage. Proteinuria is associated with damage to the heart and kidneys and coronary artery disease.

CKD stages
Staging CKD is a way of quantifying its severity. CKD has been classified into five stages. Stage 1 is characterised by normal GFR (≥ 90 mL/min/1.73m2) plus either persistent albuminuria or known structural or hereditary renal disease. Stage 2 involves a GFR of 60 to 89mL/min/1.73m2 plus either persistent albuminuria or known structural or hereditary renal disease. Patients with GFR above 60mls/min/1.73m2, without either persistent albuminuria or known structural or hereditary renal disease, do not have kidney disease and do not require investigation.

Stage 3 involves GFR of 30 to 59mL/min/1.73m2. Stage 4 involves GFR of 15 to 29 mL/min/1.73m2 and Stage 5 is characterised by a GFR of under 15 mL/min/1.73m2. British guidelines distinguish between stage 3A (GFR 45-59) and stage 3B (GFR 30-44) for purposes of screening and referral. Lab results may now reflect this.

Kidney function declines by, on average,  0.5 to 1 mL/min/1.73m2 each year, from the age of 25 onwards. For most people, their kidney peak was in their mid-20s and 30s. By the time a person gets to the age of 60, he or she is on average running on a GFR of 75 to 80. By the time a person gets to 70, the GFR is in the 60s. If a 75-year-old patient is losing 0.5 to 1 mL/min/1.73m2 each year and has a GFR of 55, GFR might be expected to be reasonable when that patient reaches the age of 95. If a person is 35 years old and the GFR is 55mL/min/1.73m2, that presents problems, Prof Mellotte said.

The eGFR value that clinically defines chronic kidney disease is 60ml/min/1.73m2. There needs to be two abnormal results. Guidelines now also support Protein Creatinine Ratio (PCR) — a ratio of urinary protein to urinary creatinine — as being equivalent to 24-hour urine collections. A morning sample will be used. Proteinuria is defined as a protein/creatinine ratio greater than 45mg/mmol.

A study by Liam Glynn et al in the west of Ireland (IMJ 2002) found that most CKD was unrecognised in general practice. The vast majority of patients with CKD remain outside specialist centres as only a small number will ever end up on dialysis.

Dr George Mellotte: 'Something needs to be done to prevent risk of dying through a cardiovascular epidemic'

For each 1mL/min decrease in creatinine clearance, a 1 per cent increase in mortality was observed (McAlister FA et al, Circulation 2004). An independent, graded association has been observed between a reduced eGFR and the risk of death, cardiovascular events, and hospitalisation (Alan S. Go et al, NEJM 2004). The risk increases exponentially. This highlights the clinical and public health importance of chronic renal insufficiency.

Something needs to be done to prevent risk of dying through a cardiovascular epidemic, Dr Mellotte said. Preserving kidney function is very important.

Untreated hypertension shortens life expectancy by five years. Blood pressure of 140/90 in people with kidney disease is associated with a loss of GFR of 6 to 8 per cent per annum. By bringing blood pressure down to 130/80 or less, the loss of GFR is two per cent per annum.

Management guidelines
NICE (UK National Institute of Clinical Excellence) guidelines on clinical management of primary hypertension in adults, published in August, recommend that for all people with hypertension, there should be a test for the presence of protein in the urine. Hypertension is a continuum, Dr Mellotte said. The AASK  study (NEJM, Sept 2010) concluded that very intense control does not have the same benefit in people who do not have proteinuria. As a first step, the recent NICE guidelines suggest offering people aged under 55 years antihypertensive treatment with an angiotensin-converting enzyme (ACE) inhibitor or a low-cost angiotensin-II receptor blocker (ARB). If an ACE inhibitor is prescribed and is not tolerated (for example, because of cough), an ARB should be offered.

An ACE inhibitor should not be combined with an ARB to treat hypertension in these patients. Step 1 antihypertensive treatment with a calcium-channel blocker (CCB) should be offered to people aged over 55 years and to black people of African or Caribbean family origin of any age, NICE said. If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, a thiazide-like diuretic should be offered. If treatment with three drugs is required, the combination of ACE inhibitor or angiotensin II receptor blocker, calcium-channel blocker and thiazide-like diuretic should be used.

Prof Mellotte has an issue with using thiazide diuretics in patients with GFR of less than 45. Thiazide diuretics are not effective in people with severe renal impairment. Treatment of resistant hypertension involves A + C + D, as well as low-dose spironolactone (if the blood potassium level is <4.5mmol/l) or an alpha blocker or a betablocker. The problem with spironolactone in people with  renal disease is that severe hyperkalaemia can arise, so potassium has to be watched.

Excess salt
Excess salt is probably the biggest problem in resistant hypertension. Excess alcohol intake is another major issue. In people with kidney disease, NSAIDs negate the impact of the ACEs and the ARBs.

Secondary causes of hypertension include renal artery stenosis and primary hyperaldosteronism. There is a link between loss in GFR and mortality. The target is a 60 per cent reduction in proteinuria or less than 50mg of protein per mmol of creatinine. The aim is to prevent cardiovascular disease. Most kidney disease patients, especially where there is  proteinurea, have raised LDL and high triglycerides. Many kidney disease and dialysis patients do not experience typical cardiovascular deaths. Many are sudden deaths (one in four patients on dialysis die this way).

SHARP study
There is evidence supporting lipid-lowering therapy in the Study of Heart and Renal Protection (SHARP) by Prof Colin Baigent et al (Lancet, 2011). This randomised, placebo-controlled trial examined the effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease.

This showed a 17 per cent proportional reduction in major atherosclerotic events if you used that combination, compared to placebo. The guidelines are now reflecting that.

There are other risk factors. Nearly all severe renal disease patients are vitamin D deficient. Low vitamin D levels have been associated with increased cardiovascular risk. Anaemia is a risk factor but overtreating it can be a problem.

In summary, it is important to look at risk factors and examine medical history. If a person is diabetic and hypertensive and is over the age of 55,that person has a one in three chance of having significant kidney disease. Urinalysis for proteinurea in important. Serum creatinine and eGFR should be measured. If patients are in the ‘at-risk’ group with hypertension, they should be reassessed every one to two years.

If a person is on a dialysis, their life expectancy decreases by 80 per cent. Most CKD patients should  have their hypertension treated aggressively because it slows progression of kidney disease and it improves the prognosis.

In ischaemic stroke patients, HbA1c on admission was an independent significant predictor for neurological and functional outcomes, Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke — a study by Dr Masahiro Kamouchi et al based at the Department of Medicine and Clinical Science in Kyushu University, Fukuoka, Japan — has found.

Diabetes mellitus is an established risk factor for stroke. However, it has been uncertain whether prestroke glycaemic control (PSGC) status affects clinical outcomes of acute ischaemic stroke. The aim of this study was to elucidate the association between PSGC status and neurological or functional outcomes in patients with acute ischaemic stroke.

The age- and sex-adjusted odds ratios (ORs) for neurological improvement were lower, and those for neurological deterioration and a poor functional outcome were higher in patients with poorer PSGC status. After adjusting for multiple confounding factors, these trends were unchanged. These findings were comparable in patients with non-cardioembolic and cardioembolic infarctions.

Stroke. 2011;42:2788-2794