According to the National Institute of Diabetes & Di-gestive & Kidney Diseases (NIDDK), over seven million adult Americans suffer from chronic kidney disease (CKD). The National Kidney Foundation (NKF) estimates that more than 20 million people actually have CKD, and that an equal number are at risk of developing the disease. In 1991, there were about 201,000 Ameri-cans with end-stage renal disease (ESRD); by 2001, the number had reached 406,000.

According to the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), over seven million adult Americans suffer from chronic kidney disease (CKD). The National Kidney Foundation (NKF) estimates that more than 20 million people actually have CKD, and that an equal number are at risk of developing the disease. In 1991, there were about 201,000 Americans with end-stage renal disease (ESRD); by 2001, the number had reached 406,000.

The rise in obesity in the United States has led to an increased incidence of diabetes, the leading cause of CKD.

Back to Physiology 101

The kidneys are responsible for filtering blood, removing wastes and maintaining levels of minerals such as phosphorus, sodium, and calcium. Most of the action takes place in the million or so nephrons, each of which is made up of a glomerulus (a tiny clump of capillaries) and a long tubule. Blood enters the nephron via the glomerulus. Wastes and excess water pass out of the glomerulus and enter the tubule, where minerals are returned to the bloodstream and wastes and excess water are excreted as urine.

Complexity of CKD treatment

Kidney function affects other vital body functions. According to the National Kidney Foundation, the two primary results of CKD are loss of kidney function and the development of cardiovascular disease, outcomes that can be prevented, or at least delayed, when diagnosed and treated early on.

Up to 75% of CKD patients have hypertension. Thus, the NKF recommends antihypertensive therapy for all CKD patients with high blood pressure. Experts at NKF also recommend antihypertensives for the prevention of cardiovascular disease, even in the absence of hypertension.

"Patients with CKD, almost without exception, should be on an ACE inhibitor or an ARB," said George Bailie, Pharm.D., Ph.D., professor of pharmacy practice at Albany College of Pharmacy. These two classes of drugs, recommended as first-line agents in the NKF guidelines for antihypertensive therapy, do several helpful things, Bailie said, but most significantly they decrease the progression of CKD. Patients already on other antihypertensives may need dose reductions or complete discontinuation of one or more of them. Diuretics are recommended second-line agents if the preferred agents are not completely effective.

Patients 20 mmHg or more over their blood pressure goal will probably need to start with both first-and second-line agents. The guidelines suggest that combo products may be useful. However, patients should be stable, and the combo product must contain the appropriate doses needed to maintain BP control. Additional drugs should be chosen based on the type of cardiovascular disease targeted, side effects, drug interactions, and the type of CKD involved.

Another critical function of the kidneys is calcium and phosphorus regulation. Normally functioning kidneys convert vitamin D to its active form, facilitated by parathyroid hormone. Vitamin D increases the absorption of calcium from the intestines. In addition to its role in the activation of vitamin D, parathyroid hormone causes calcium and phosphate to be absorbed into the plasma from bone. It also increases the amount of calcium returned to the bloodstream from the kidneys. At the same time, it inreases the amount of phosphate excreted from the kidneys into the urine.

The battle over calcium regulation

Because the kidneys excrete excess phosphorus, phosphorus levels increase when kidneys begin to fail. The increase in plasma phosphorus, or hyperphosphatemia, causes the parathyroid glands to release more parathyroid hormone, leading to a secondary hyperparathyroidism (SHPT). In SHPT, the excess parathyroid hormone causes calcium to be reabsorbed from bone, weakening bone and leading to bone disease and an excess of circulating calcium, or hypercalcemia. Treating CKD patients with vitamin D can alleviate the SHPT, but because vitamin D increases intestinal absorption of both calcium and phosphorus, this treatment can also lead to hypercalcemia.

Hypercalcemia is serious. Too much calcium can lead to metastatic calcification, said Bailie. Calcium deposits can turn up throughout the body, including the coronary arteries, leading to a much higher cardiovascular death rate.

Regulating calcium and phosphorus in CKD patients is not easy. Vitamin D must be dosed and monitored very carefully. Calcium-based phosphate binders can be administered with each meal, but they must also be dosed carefully because they can cause hypercalcemia, especially when administered with vitamin D.

The importance of controlling calcium and phosphorus levels has left drug manufacturers jockeying for position in a critical market. Of products currently available to treat hyperphosphatemia, calcium carbonate and calcium acetate (PhosLo, Nabi Biopharmaceuticals) are less expensive than most other phosphate binders. At least one study has found calcium acetate more effective than a newer agent, sevelamer (Renagel, Genzyme). However, calcium carbonate and calcium acetate may cause hypercalcemia.

The NKF has recommended that patients limit daily calcium intake to no more than two grams of elemental calcium, no more than 1.5 gm of which should come from phosphate binders. Calcium-based products should not be used in patients with hypercalcemia and are not preferred agents for patients with soft-tissue calcifications. "It really limits the choice of phosphate binders that can be used in that population," said Bailie of the guidelines.

Sevelamer lowers phosphate levels and LDL cholesterol-an advantage in the CKD population. It does not cause hypercalcemia because it does not contain calcium. It reduced vitamin D levels during clinical trials, so dose adjustments of vitamin D may be necessary during treatment. Some experts believe it may be safer than lanthanum carbonate (Fosrenol, Shire Pharmaceuticals), another drug for hyperphosphatemia. Lanthanum binds to phosphate in the intestines and is then excreted. It has proven effective in lowering phosphate levels and preventing bone disease caused by hyperphosphatemia. It is calcium free, so hypercalcemia is not a problem. There is some concern that lanthanum not bound to phosphate may be absorbed into the bloodstream. The Food & Drug Administration considers it approvable, and Shire expects to have lanthanum on pharmacy shelves late this year.

Then there is Cinacalcet (Sensipar, Amgen), the first of a new class of drugs called calcimimetics. Cinacalcet is approved for SHPT in dialysis patients. By activating calcium receptors on the parathyroid glands, cinacalcet can lower parathyroid hormone, calcium, and phosphorus levels. It may be given with vitamin D and phosphate binders. Bailie said cinacalcet looks promising.

The NKF recommends another group of drugs, the vitamin D analogs, when necessary, but close monitoring of parathyroid hormone, calcium, and phosphorus levels is required. Calcitriol is a D3 analog that has proven effective, but hypercalcemia can be a real problem.

Paricalcitol injection (Zemplar, Abbott), currently the most widely used vitamin D in dialysis patients, is indicated for preventing and treating SHPT associated with chronic renal failure. It does not cause hyperphosphatemia but can increase the risk for hypercalcemia, said Laura Williams, M.D., MPH, global project head for the renal team, Global Pharmaceutical Research & Development, at Abbott. However, Williams prefers paricalcitol because it has a wider therapeutic window than other vitamin Ds. It has lowered mortality rates in dialysis patients during clinical trials, compared with calcitriol injection. It also recently received approval for pediatric use. Of the 40 million or so Americans not on dialysis who have CKD, or who are at risk, there is a subset with SHPT who could benefit from treatment.

Doxercalciferol (Hectorol, Bone Care International) is a D2 analog. Said Keith Crawford, assistant director of marketing for Bone Care, this pro-hormone is not active until absorbed. This prevents concentration of active vitamin D in the gut, which in turn precludes the development of hypercalcemia and hyperphosphatemia.

With the lowered risk of hypercalcemia associated with doxercalciferol, clinicians may be able to take advantage of some of the other benefits of vitamin D in a host of disorders, including anemia, diabetes, psoriasis, cancer, and cardiovascular disease. Doxercalciferol is now available in three different forms: an intravenous product for hemodialysis patients, a 2.5-mcg capsule primarily for peritoneal dialysis patients, and a new 0.5-mcg capsule for patients in earlier stages of CKD.

"Dialysis patients need huge amounts of iron," said Bailie. Loss of kidney function can decrease production of red blood cells, causing anemia. Many patients take one of the epoetin alfas (Procrit by Ortho Biotech or Epogen by Amgen). Bailie said a work group for the NKF is reviewing anemia management research now, and guidelines for therapy will be available next year.

The development of darbepoetin alfa (Aranesp, Amgen) for anemia management is especially exciting, according to Bailie. It can be dosed once-weekly or biweekly, and one study concluded that anemia in CKD patients could be controlled with a once-monthly injection.

Injectable iron can also be useful for anemia, Bailie said. Two relatively new and promising intravenous iron products are iron sucrose injection (Venofer, American Regent) and sodium ferric gluconate complex (Ferrlecit, R & D Labs).

Who pays for all of this?

Medicare covers the majority of patients with end-stage renal disease. In a June 2004 report to Congress, the Government Accountability Office summed up Medicare reimbursement for dialysis treatment. GAO concluded that overall reimbursement for ESRD treatment (dialysis, nursing, lab tests, and drugs) was about 3% over the actual cost of providing this treatment. However, dialysis providers bill Medicare at a composite rate for dialysis services, and they bill separately for certain drugs not included in the dialysis composite rate. It turns out that reimbursement for dialysis services is 11% below actual provider cost, on average. Even more interesting, reimbursement for separately billed drugs exceeds the drug cost by 16%. "Because of this imbalance," the report states, "providers have an incentive to maximize the use of profitable, separately billed drugs to compensate for inadequate payments under the composite rate."

The Centers for Medicare & Medicaid Services is redesigning the payment system for ESRD. The agency is developing a plan for a broader payment system that would combine both dialysis treatment and drug treatment for ESRD in one reimbursement.

As for the earlier stages of kidney disease, third-party payers are acknowledging the importance of managing chronic kidney disease. Blue Cross & Blue Shield of Minnesota, for example, has partnered with American Healthways to expand their CKD program. The program is designed to prevent or delay the progression to ESRD.

Researchers at the University of Minnesota College of Pharmacy found that Medicare patients with CKD have fairly stable costs of care through the early stages of the disease. However, in the months just before these patients require dialysis, there is a spike in treatment costs. Most of the increased costs appear to be due to hospitalizations.

Researchers concluded that patients with CKD and risk factors for CKD need to be managed more appropriately. Diagnosing CKD early on and keeping it under control could help prevent some of the complications of the disease, reduce costs, and possibly delay the onset of ESRD.

Medicare's new drug benefit plan may help early-stage CKD patients get the medications they need to control their disorder. Manufacturers, including Genzyme, maker of sevelamer, are looking to increased sales to Medicare beneficiaries.

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