Reducing Cardiovascular Risk and ESRD In Chronic Kidney Disease Patient
By Samuel Snyder, DO and Danielle Thomas, DO
ABSTRACT: Over the last decade, chronic kidney disease (CKD) has become epidemic.1 Greater awareness of CKD and improving survival from cardiovascular disease are partial explanations, as are the increasing prevalence of diabetes mellitus, dyslipidemia, obesity, hypertension, and metabolic syndrome. According to the United States Renal Data Service, prevalence of CKD has risen 84 percent since 2001. But very few of these will progress to End Stage Renal Disease (ESRD), or dialysis dependent renal failure. Instead, the majority will experience cardiovascular death. Most importantly, timely cooperation between primary care physician and nephrologist translates to improved survival. It is the joint responsibility of the primary care physician and the nephrologist to work together to improve this alarming mortality statistic.
Over the last decade, chronic kidney disease (CKD) has become epidemic.1 Greater awareness of CKD and improving survival from cardiovascular disease are partial explanations, as are the increasing prevalence of diabetes mellitus, dyslipidemia, obesity, hypertension, and metabolic syndrome. According to the United States Renal Data Service (USRDS), prevalence of CKD has risen 84 percent since 2001. Medicare expenditures have risen dramatically, and in 2003 were estimated at $37 billion.1
The National Kidney Foundation has established a scheme for staging CKD (Table 1) based on newer understandings of the epidemiology and relative risk of different levels of renal insufficiency.2 Overall, the prevalence of CKD is estimated as 11 percent of the U.S. population, accounting for more than 20 million people.3
But very few of these will progress to End Stage Renal Disease (ESRD), or dialysis-dependent renal failure. As of 2003 USRDS data, there were about 453,000 ESRD patients. Fewer than 1 million persons are thought to be in Stages 4 and 5.1 Most individuals in Stage 3 will never progress. Instead, the majority will experience cardiovascular death.
In validating the staging of CKD, there has been tremendous reconsideration of assessment of renal function. Serum creatinine alone has proven to be too inaccurate. Twenty-four hour urine collections for creatinine clearance better represent renal function better, but are fraught with collection error.
For many years the Cockcroft-Gault equation has been used to estimate creatinine clearance at the bedside. This method is inaccurate at the extremes of renal function, the extremes of age, and when comparing individuals of different race or different muscle mass. Glomerular filtration rate (GFR) is considered the gold standard of renal function, and can be assessed with nuclear scans as iothalamate clearance.
At the bedside, GFR is now most often estimated using the Modified Diet in Renal Disease (MDRD) equation, which is creatinine based, but also includes the influence of age, race, and nutrition (BUN, albumin). However the MDRD equation is still subject to debate, and the best way to assess renal function remains uncertain.
In the 1990’s, the prevailing paradigm in treatment of CKD was renoprotection. Emphasis was placed on use of angiotensin converting enzyme inhibitors, both to treat hypertension, and to reduce the rate of progression of azotemia. As our perspective on CKD has grown, the paradigm has transformed to one that focuses on risk reduction, paralleling the therapeutic momentum in cardiovascular disease. This is reflected in the evidence based recommendations of the Kidney Disease Outcome Quality Initiative (KDOQI), a consensus committee of expert opinion and current evidence in nephrology.4
In this paper, we review the major areas of concern in care of patients with CKD, in whom the dual goals are delay of progression to ESRD, and reduction of cardiovascular risk. These areas include hypertension, use of blockade of the renin-angiotensin system, anemia, lipid lowering therapy, calcium/phosphorus metabolism and secondary hyperparathyroidism, and glycemic control.
Blood Pressure
Cardiovasular disease is the leading cause of mortality among CKD patients.5 Blood pressure control both reduces progression of CKD and reduces cardiovascular mortality risk. In fact, blood pressure control in patients without CKD can minimize age-related decline in GFR.6 The decline in GFR is directly related to systolic pressure.
The goals suggested by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for CKD patients is 130/80. Unfortunately, according to the National Health and Nutrition Examination Surey, only 11 percent of treated patients are controlled at the level of 130/85.7
Therapeutic lifestyle modifications should always be included in the management of hypertensive patients. Strategies with validated outcomes include sodium restriction to 2.4 g/d, regular aerobic exercise, the DASH diet, moderate weight reduction, reduced alcohol consumption, and smoking cessation.
Many CKD patients have proteinuria, and blood pressure therapy can include attention to this facet of renal damage. Angiotensin converting enzyme (ACE) inhibitor therapy can control blood pressure, reduce proteinuria, and slow progression of CKD. Angiotensin receptor blocking drugs (ARB) have demonstrated similar benefit. So far, ARBs have not been shown to retain any significant advantage over ACE inhibitors.
Hypertension in CKD patients is often complicated, and frequently presents with pressures greater than 20/10 above goal. Thus, many CKD patients requires a minimum of two antihypertensive agents. Because salt and water retention often accompany CKD, diuretics should be a part of blood pressure management.
Thiazide diuretics lose therapeutic effect at lower levels of GFR, so that by the time patients are in the lower range of Stage 3, loop blockers should be used rather than thiazides. Higher doses are often needed to deliver adequate amount of drug to its therapeutic site. Oral absorption of furosemide is quite variable in CKD, ranging from 10 percent to 100 percent, and half-life is relatively short.
Absorption of bumetanide and torsemide are greater and more predictable (80-100 percent), and the latter has a significantly longer half-life. Potassium sparing diuretics should be used with caution in CKD, as they do not provide robust natriuresis, and may cause serious hyperkalemia.
Although beta blockers are often indicated for comorbidities that are common among the CKD population (e.g., post-MI, CHF), they are perhaps underutilized in CKD8,9,10 because of their variable tolerability. They function effectively as antihypertensives, and they may ameliorate the sympathetic hyperactivity present in CKD, which can aggravate the progression of hypertensive nephropathy. Beta blockers have been shown to decrease mortality in heart failure, the leading cause of death in the first year of starting dialysis.
On the other hand, beta blockers may impair glucose delivery, impair insulin resistance, and worsen lipid profiles. These effects may be attenuated by alpha-1 antagonism, which produces opposite effects. Nonselective beta blockers are also more likely to promote hyperkalemia. There are some data to suggest that beta blockers can diminsh free-radical mediated oxidative stress, and thus reduce microalbuminuria.8
Some beta blockers must be dose-adjusted for renal disease; for instance, atenolol should have a 50-75 percent dose reduction. The beta-1 selective drugs atenolol and metoprolol have been most extensively studied in patients with renal disease. Metoprolol does not require any dose adjustment in renal failure.
Labetalol and carvedilol are the two beta blockers with alpha-1 antagonism activity. Studies with labetalol in CKD are few, with small numbers of subjects, and have conflicting data regarding renal blood flow effects. Labetalol is dialyzed and is associated with hyperkalemia. Carvedilol is somewhat better studied in renal disease and clearly attenuates albuminuria, has less hyperkalemia, produces no change in the serum creatinine level, and is not dialyzed.
The renoprotective effects of ACEIs and beta blockers in CKD has been studied. The rate of GFR decline and albuminuria progression is less with ACEIs than with either metoprolol or atenolol.11-15 The effects of these drugs to modify the course of CKD or proteinuria seems to be attenuated in African Americans with hypertensive nephropathy, as evidenced by the African-American Study of Kidney Disease and Hypertension trial.16
Both classes of calcium channel blockers (dihydropyridines and non-dihydropyridines) can be used safely in CKD without dose adjustments. They decrease peripheral vascular resistance and have good absorption. When used in conjunction with an ACEI or an ARB, they may enhance renoprotection, though the individual agents have variable effects on proteinuria.
Many patients with CKD have particularly resistant hypertension, and require multiple drugs. Second and third line agents that can be useful in CKD include the centrally acting alpha-2 agonist clonidine, peripheral acting alpha-1 blockers like prazosin, doxazosin, and terazosin, and the direct vasodilators like hydralazine and minoxidil. These agents may be necessary to control blood pressure in resistant hypertension.
Proteinuria
Proteinuria can be glomerular or tubular in origin, or, the result of overproduction. Persistent proteinuria is an independent risk factor for cardiovascular disease, and its presence correlates with the progression of chronic kidney disease. In diabetes, microalbuminuria is an early indicator of nephropathy. The most convenient way to quantify asymptomatic proteinuria is the spot urine protein to creatinine ratio, which serves as a good surrogate for 24h protein excretion in grams/day.17
Microalbuminuria, most often monitored for diabetic nephropathy, is defined as the presence of 30-300mg/day, whereas proteinuria is defined by the presence of >300 mg protein/24h. The presence of proteinuria is not only an indicator of CKD, but it is also thought to play a role in perpetuating CKD. The Kidney Disease Outcomes Quality Initiative (K/DOQI) goals for proteinuria are to reduce it to less than 500-1000mg/day. The treatment of proteinuria in chronic kidney disease will be discussed here.
It is well established that the use of ACEIs minimizes the progression of proteinuria in CKD, especially in diabetic nephropathy.17 The mechanism is thought to be two-fold, by reducing intraglomerular pressure and also possibly by enancing podocyte permselectivity. Low sodium diets enhance this reduction in proteinuria.
A recent meta-analysis addressed the use of ACEIs versus ARBs to reduce proteinuria in CKD.18 The findings suggest equivalent reduction in proteinuria between ACEIs and ARBs, but a greater reduction in proteinuria from a combination of the two. Even patients with advanced CKD, e.g. Stage IV, should be started on ACEI or ARB therapy. The drugs should be started at low doses and titrated upward, monitoring within the first week for the development of hyperkalemia or a sharp increase in serum creatinine. Small increases in creatinine are tolerated, even expected, indicating the usual mechanism of the drug.
Statins have been proposed to halt the progression of CKD. This was based on several post hoc analyses of studies that did not include CKD progression as a primary outcome. Currently, there is not enough evidence to support the use of statins specifically for decreasing CKD progression. Importantly, CKD patients are candidates for statin therapy to reduce cardiovascular risk.
With respect to dietary protein restriction and the progression of renal disease, the MDRD study is the largest trial to date, studying 585 patients. After an initial sharp decline in GFR associated with the low protein diet within the first four months, only a very modest long term reduction in GFR decline was sustained (2.8mL/min/year), compared to 3.9mL/min/year in the control group.19 Some have expressed concern that protein restriction might increase the risk of malnutrition as CKD progresses. The use of protein restricted diets has waned since the advent of ACEIs and ARBs.
Anemia
Normocytic normochromic anemia typically begins as GFR falls below 60mL/min. Decreased erythropoietin production is the primary cause. In addition, red cell life span is diminished; this may be linked to elevated blood viscosity.20 All CKD Stage III, IV, and V patients should be screened for anemia.
Anemia evaluation includes red cell indices, reticulocyte count, iron, percent saturation of transferrin, and ferritin, and exclusion of anemia from another cause, for instance, GI bleeding or deficiency of folate or B-12. If iron deficiency is detected, it should be further evaluated and treated. Long standing anemia can cause increased LV mass, which aggravates cardiovascular risk.
Once iron is replete, the mainstay of treatment for CKD anemia is an erythropoiesis stimulating agent (ESA), such as erythropoietin alpha, beta, or darbepoietin. Ongoing iron supplementation is usually required to avoid a functional iron deficiency because of defective iron transport in CKD.
Oral iron can be supplied as ferrous sulfate 325mg (65mg elemental) TID. Goals for iron therapy are to maintain the percent transferrin saturation above 20 and the ferritin above 100ng/mL. The target Hb level for CKD was re-evaluated in the 2006 KDOQI recommendations. The current target is greater than 11g/dL but no higher than 13g/dL.21 Neither observational data or results from randomized controlled trials provide evidence to support the idea that hemoglobin should be normalized in advanced CKD.22
Lipids
The majority of CKD patients die from cardiovascular disease. For this reason alone, reducing cardiovascular risk is paramount in this population. Although elevated LDL has been shown to promote glomerulosclerosis in rats,23 this has not been translated to human studies. Post-hoc analyses have, however, linked dyslipidemia to a decline in GFR. There are some data to suggest that lipid control may curb GFR decline.22 While there is no robust evidence that improved lipid control reduces CKD progression, CKD is a coronary heart disease (CHD) risk equivalent and these patients should be screened and treated aggressively.24,25,26
Dyslipidemia with elevated LDL is most common among the diabetic CKD population. In nondiabetic CKD patients, hypertriglyceridemia is almost universal below a GFR of 30mL/min.24 This is most likely due to low lipoprotein lipase activity.23 Triglycerides are also elevated in transplant patients secondary to immunosupressant therapy. Nephrotic CKD patients typically have elevated total cholesterol, LDL, and triglycerides secondary to dimished catabolism of LDL and triglycerides.25
Reasonable goals for LDL in CKD have been extrapolated from the ATP-III data. For patients with CKD, LDL<100mg/dL is recommended; for patients with diabetes and CKD, the more stringent goal of <70mg/dL is recommended.25,26 The treatment approach is similar to non-CKD patients, with dietary and therapeutic lifestyle modifications serving as a necessary starting point.
Statins are the most effective class of drugs to achieve LDL goals in CKD. Dose reduction by 50 percent is recommended in CKD Stage 4 for lovastatin, fluvastatin and simvastatin24; in practice, this might not be possible for these particular statins without sacrificing therapeutic efficacy. P450 inhibitors will elevate serum levels of the statin and caution should be used when prescribing such drugs as fibrates, nicotinic acid, warfarin, SSRIs, non-dihydropyridine calcium channel blockers, azoles, and macrolides.
For patients inadequately controlled on a statin alone, the addition of a bile acid sequestrant is probably the best choice in CKD, as long as the triglycerides are not elevated. The phosphate binder sevelamer has been documented to reduce LDL in CKD patients.28,29 Triglyceride control is best achieved after TLC with either a fibrate or niacin. Niacin has the additional benefit of reducing phosphorus in CKD late Stage IV and V patients.30 Gemfibrozil is the least likely of these agents to affect BUN and creatinine, and can be used without dose alteration throughout the range of CKD. Fish oil reduces triglycerides in the general population, but has not been specifically studied in CKD.
Calcium, Phosphorus, Bone and Secondary Hyperparathyroidism
The development of secondary hyperparathyroidism in CKD is insidious. It is dependent on the interplay between hyperphosphatemia, hypocalcemia, and calcitriol (1,25-dihydroxycholecalciferol). Reduction in GFR leads to hyperphosphatemia that increases the production and release of parathyroid hormone (iPTH). The reduced ability of the failing kidney to activate Vitamin D into calcitriol also elevates serum iPTH via poor calcium absorption and decreased PTH transcription. Elevated PTH results in a variety of bone mineral diseases.
Monitoring for the development of secondary hyperparathyroidism should begin in CKD III. Guidelines for the treatment of PTH include specific GFR—or CKD stage--related goals. Achieving iPTH lower than 150pg/mL in ESRD is not recommended, as this can promote adynamic bone disease. One parameter of treatment is the calcium-phosphate product; in ESRD, this should be less than 55 mg2/dL2. An elevated Ca-Phos product is associated with calciphylaxis, myopathy, and vascular calcifications.
The treatment of secondary hyperparathyroidism has evolved with the advent of non-metallic based phosphate binders and the novel medication cinacalcet. Dietary modifications to reduce phosphate intake generally result in further protein malnutrition in this already population whose nutritional status is already compromised; but the intake of no more than 800mg phosphorus is reasonable.
The two most common non-calcium based phosphate binders are sevelamer and lanthanum. Neither promotes the vascular calcifications seen with calcium based phosphate binders. Nutritional Vitamin D deficiency (25(OH)-Vitamin D, calcidiol) is common in CKD, and the administration of ergocalciferol to replete calcidiol is increasingly popular. Randomized controlled trials on the development of bone mineral disease are needed to evaluate the efficacy of this approach.
The use of Vitamin D3 analogs is generally reserved for patients with very high iPTH, and they are administered with close attention to the calcium-phosphate product. The available Vitamin D3 analogs include calcitriol, paracalcitol, and doxercalciferol. The latter two are less likely to cause hypercalcemia than calcitriol.
Dosing schedules vary and must be adjusted, and vitamin D analogs can be used concomitantly with calcimimetic therapy. A novel calcimimetic medication, cinacalcet, actually sensitizes the parathyroid gland receptors to calcium. This has excellent efficacy in reducing both the iPTH and Ca-Phos product, and is indicated in patients with iPTH >300pg/nL.31 Attention to secondary hyperparathyroidism and nutritional Vitamin D deficiency is an integral part of managing CKD.
Glycemic Control
CKD is associated with altered insulin and glucose metabolism. Insulin resistance is seen in earlier stages of CKD. With the development of uremia, peripheral skeletal muscle uptake of glucose is impaired, resulting in hyperglycemia.32 This can be mitigated or reversed with aerobic exercise. In addition, metabolic acidosis and calcitriol deficiency both reduce circulating insulin.33,34
As GFR declines, the clearance of insulin diminishes, anorexia and malnutrition are more common, and patients may have a greater tendency toward hypoglycemia. Insulin requirements change again when patients are placed on renal replacement therapy. In diabetics without CKD, tight glycemic control has been shown to reduce the development of nephropathy. 34,35
The use of metformin in patients with a GFR below 60mL/min may increase the risk of lactic acidosis. Additionally, the metabolism of sulfonylureas is reduced in CKD; therefore, it is prudent to dose these drugs conservatively. Of the sulfonylureas, glipizde is primarily metabolized through the liver and has the least active metabolite.
nsulin doses are not usually adjusted until CKD III, when a GFR below 50mL/min generally demands a 25-50 percent reduction in insulin. The initiation of dialysis enhances insulin clearance, demanding attention to insulin adjustment. Attention to nutrition, exercise, oral and insulin therapy is necessary to maintain a hemoglobin A1C of less than 7 percent in CKD patients.
Summary
The epidemic of CKD and the progression to ESRD threaten to become economically overwhelming in the coming decades. Stemming this tide requires the cooperative efforts of primary care physicians and nephrologists. And yet, “a National Institute of Health consensus conference reported that only 20-25 percent of patients were referred to a nephrologist prior to onset of ESRD”.35
Benefits of timely intervention in CKD patients may include the following: slowing progression to ESRD, improved nutrition, reduced rate of metabolic complications, and modification of cardiovascular risk factors. And if patients do progress to ESRD, it is hoped that placement of dialysis access can be done in a timely manner, since fistula use lowers dialysis mortality; and that transplant rate will be increased.
Most importantly, timely cooperation between primary care physician and nephrologist translates to improved survival. “Patients who saw a nephrologist [for the first time] less than 90 days before onset of dialysis had a 36 percent greater mortality rate compared with those who had their first nephrology visit earlier”.36 It is the joint responsibility of the primary care physician and the nephrologist to work together to improve this alarming mortality statistics.
| Table 1. Stages of CKD | ||
| Stage | Description | GFR (ml/min/1.73m2) |
| 1 | Kidney damage, normal or GFR | >90 |
| 2 | Kidney damage, mild GFR | 60-89 |
| 3 | Moderate decrease in GFR | 30-59 |
| 4 | Severe decrease in GFR | 15-29 |
| 5 | Kidney failure | <15 or dialysis |
Dr. Snyder is a 1980 graduate of Philadelphia College of Osteopathic Medicine. He is board certified in Internal Medicine and Nephrology, and is chair of Internal Medicine at Nova Southeastern University College of Osteopathic Medicine. Dr. Thomas is a 2006 graduate of Des Moines University College of Osteopathic Medicine, and is currently a resident in Internal Medicine at Mt. Sinai Medical Center, Maimi Beach, FL.
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