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National Kidney Foundation 2006 Spring Clinical Meetings

Chicago, Illinois / April 19-23, 2006

Speakers here agreed that the “overwhelming majority” of patients on dialysis will require a phosphate binder, partly because they have no residual kidney function, and partly because conventional hemodialysis is not carried out often enough to remove the burden of dietary phosphorus patients accumulate throughout the week. However, experts differed in their views of how phosphate binders should be used to treat mineral abnormalities in early-stage chronic kidney disease (CKD).

The case discussed was a young male with stage III CKD with an elevated parathyroid hormone (PTH) level but whose serum calcium and serum phosphorus levels are normal. As explained by Dr. Hartmut Malluche, Robert G. “Robin” Luke Chair in Nephrology, University of Kentucky, Lexington, hyperparathyroidism is “nature’s answer” to the loss of nephron mass. Once the number of functioning nephrons is critically reduced, “nature wants to avoid hyperphosphatemia, so it needs more PTH to increase the fractional excretion of phosphate per remaining nephron,” he indicated. Dr. Rajnish Mehrotra, Associate Professor of Medicine, David Geffen School of Medicine at UCLA, Torrence, California, also argued that even if phosphorus levels are “normal” as in the case under discussion, patients in early-stage CKD may still be retaining phosphorus.

Findings state that phosphorus drives secondary hyperparathyroidism at early stages of CKD. High PTH levels in turn mobilize both calcium and phosphorus from the bone, increasing levels of both minerals. Complicating the picture further, as kidney function fails, levels of 1,25- dihydroxyvitamin D3 or calcitriol—the most active form of vitamin D—gradually fall off as well, resulting in a very high prevalence of 1,25 vitamin D deficiency in early-stage CKD, especially among patients with CKD and diabetes.

“This decline occurs before there is any elevation in serum phosphorus,” Dr. William Goodman, Professor of Medicine, David Geffen School of Medicine, noted. Abnormalities in vitamin D metabolism in turn adversely affect intestinal calcium transport. Thus, in Dr. Goodman’s view, elevations in PTH in early-stage CKD is an appropriate physiological response that helps maintain serum calcium levels. In both healthy individuals as well as in patients with mild to moderate CKD, phosphorus loading impairs the kidney’s production of 1,25-dihydroxyvitamin D3, while restricting phosphorus will increase its production.

The literature suggests that even if phosphorus level is normal, restricting phosphorus in the diet or through the use of phosphate binders will drive up 1,25-dihydroxy-vitamin D3 production and help prevent bone disease. Increases in 1,25-dihydroxyvitamin D3 levels correspond with subsequent reductions in plasma PTH levels, “so it is the change in circulating 1,25-dihydroxyvitamin D3 levels that mediates the reduction in PTH, not phosphorus per se,” Dr. Goodman indicated.

He also argued that patients with earlier-stage CKD are fundamentally different than those on dialysis, largely because they still have residual kidney function and they can excrete phosphorus. In patients who have mild to moderate CKD, serum phosphorus levels are usually normal, while serum calcium levels are typically in the lower range of normal, he added; and the fact that patients with mild CKD excrete relatively little calcium is a sign that the kidney is trying to conserve calcium. “I’m not arguing with the fact that phosphate restriction and phosphate binders are appropriate when serum phosphate levels are elevated,” Dr. Goodman stated.

However, when plasma PTH levels are elevated in earlier-stage CKD, “this is really a biochemical index of inadequate calcium nutrition or inadequate calcium absorption from the gastrointestinal tract. So one of the appropriate physiological interventions to correct this in earlier stages of CKD would be modest calcium supplementation to promote some additional calcium absorption from the gastrointestinal tract, and treatment with vitamin D or one of the new vitamin D analogues. With these interventions, you are targeting what is driving plasma PTH levels up to begin with and that is inadequate calcium coming in from the gastrointestinal tract,” he told delegates.

Dr. Malluche agreed that as soon as a patient becomes hyperphosphatemic, “you have to give a phosphate binder.” However, he also felt a “very cogent case” could be made to initiate phosphate binders in earlier-stage disease if dietary restriction does not bring elevated PTH levels under control.

“You shouldn’t forget that if you give 1,25 hydroxy-vitamin D, you increase intestinal phosphate absorption and actually add to the positive phosphorus balance,” Dr. Malluche reminded the audience. “If the patient needs to excrete extra phosphorus, then think about phosphate binders when dietary restriction doesn’t help.”

Phosphate Binders

A question was also raised as to what type of phosphate binder would be most appropriate in a CKD patient with diabetes whose PTH remains elevated despite treatment with vitamin D, and whose serum phosphorus and serum calcium levels are also high. Here, speakers were concerned about correcting mineral abnormalities without aggravating underlying vascular calcification, which is especially prevalent in CKD patients with diabetes. As was noted, vascular calcification is clearly related to cardiovascular disease (CVD)—the leading cause of death in CKD patients—and may be exacerbated by super-physiological doses of calcium that are usually required to bind sufficient phosphorus.

Data supporting a non-calcium-based phosphate binder strategy are limited but one prospective study—the “treat-to-goal” trial—showed that vascular calcification did not worsen over one year of follow-up in dialysis patients treated with sevelamer, whereas it did progress in patients treated with a calcium phosphate binder. “Theoretically, the use of lanthanum carbonate might have a similar beneficial effect because it is also calcium-free,” Dr. Goodman indicated, although this has not yet been demonstrated in a prospective trial.

However, he stated that the choice of a phosphate binding agent could influence progression of calcification once it is present, even though it is not clear how vascular calcification develops in the first place. Certainly, abnormalities in both phosphorus and calcium can contribute to vascular calcification. As speakers noted, once plasma levels become super-saturated with either mineral, they precipitate out and excess mineral is deposited in soft tissues, including blood vessels.

Culture models suggest that cells grown in the presence of abundant phosphorus may take on a phenotype that causes them to behave as if they were in bone, thereby contributing to vascular calcification as well. Dr. Mehrotra also pointed out that abnormalities in mineral metabolism are predictive of CVD morbidity and mortality and in terms of increased risk, the maximum increase in CVD risk is associated with increasing phosphorus levels.

“There may be no study showing that if you lower serum phosphorus, you reduce mortality risk,” he noted, “but intuitively, if you lower serum phosphorus, you might lower mortality risk.” As corroborated by Dr. Malluche, The National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines indicate that when calcium binders are used, total calcium intake should not exceed 2 g/day, including dietary sources of calcium, so that there will be only about 1200 mg of calcium available for phosphate binding.

“You will not bind a lot of phosphorus with that amount of calcium so you will need another potent phosphate binder,” Dr. Malluche emphasized. Speakers also agreed that calcium-containing phosphate binders are not appropriate for patients whose serum levels of calcium are already elevated, nor for those who are taking vitamin D therapy and whose calcium levels are at the high end of the normal range or elevated.

“Your choice of phosphate binder is going to be influenced very significantly by other biochemical abnormalities,” Dr. Goodman cautioned.

Reducing Pill Burden

The last and not unusual case discussed by panel members involved a young dialysis patient who was hypertensive but who otherwise had no other comorbidities. At a pill count of 30 tablets a day, “he has an inordinately high pill burden,” Dr. Mehrotra reported, “and the single largest pill burden in patients with end-stage renal disease [ESRD] is with phosphate binders”. Certainly, the use of lanthanum carbonate has been shown to reduce pill burden in patients taking either a calcium-based phosphate binder or sevelamer. In an interview, Dr. Goodman also suggested that this agent might be equivalent in potency to the old aluminum-containing binders and more potent than calcium carbonate nor calcium acetate. This potency may likely translate into a lower pill burden and optimally, better compliance.

In a poster session study presented by Dr. Nirupama Vemuri, South Florida Nephrology Group, Coral Springs, 2763 ESRD patients requiring treatment for hyperphosphatemia were switched from their previous phosphate binder to lanthanum carbonate at an initial dose of 1500 mg/day, divided with meals. The dose was titrated up over 12 weeks until a maximum daily dose of 3750 mg/day was reached. The goal was to achieve serum phosphorus levels within the K/DOQI range of 3.5 to 5.5 mg/dL.

After 12 and 16 weeks of therapy, tablet burden, total daily dose and the effect of the phosphate binder on serum phosphorus levels were assessed. “At the end of the 12-week titration period, there were significant reductions in the mean average daily tablet burden and in total daily dose compared with previous phosphate-binder therapy, and there were further reductions in pill burden and in a daily dose at week 16 compared with week 12 for all groups as well,” investigators reported. At baseline, patients prescribed a calcium-based binder were taking a mean of 8.3 pills/day while those taking sevelamer were on a mean of 9.6 pills/day. Those requiring combination therapy were on a mean of 14.9 pills/day. At the end of week 16, the mean tablet count was 5.8 in patients who were previously taking a calcium-based binder and a mean of 5.9 for those previously taking sevelamer. The mean daily tablet count in those previously on combination therapy was 6.5, or a 56% reduction in tablet burden compared with prior combination therapy, investigators noted.

Serum phosphorus levels were either maintained or approximated levels achieved with prior phosphate binder use; the same percentage of patients whose serum phosphorus levels were controlled (approximately 40%) also remained constant from study entry to week 16. “Patient satisfaction also markedly increased,” Dr. Vemuri said in an interview, “and both patient and physician satisfaction were similar, with a substantial majority of patients (73%) indicating they preferred lanthanum carbonate over their previous medication.”

A new formulation of lanthanum carbonate that offers a reduced tablet size and which will allow most patients to take a single pill per meal may further reduce tablet burden, investigators confirmed. Dietitian Cathi Martin, Renal Care Group, Springfield and East Nashville, Tennessee, also reminded delegates that patients may eat only two meals a day and snack in between, “so you have to tailor your phosphate binder according to their diet and food patterns.”

She also emphasized that patients who eat out often or consume mostly commercially prepared foods are going to ingest substantial quantities of phosphorus, “so you have to make small incremental changes that are going to benefit patients,” she suggested.

Dr. Mehrotra also recommend that healthcare providers need to be sensitive to culturally diverse diets. “If you practice in a large Hispanic community and you tell patients they have to eat non-Mexican foods, it’s not going to happen, so we need to be aware of cultural sensitivities to diet.” Physicians also need to ascertain just how adherent—or non-adherent—dialysis patients may be. Otherwise, they risk thinking the medication is not suitable, are likely to increase the dose, and patients will end up taking a lot of pills, as Dr. Malluche suggested. He explained: “You want to design a regimen that has the lowest number of pills... so we need to make it as easy as possible for patients to adhere to the regimen.”

Questions and Answers

This question-and-answer section is based on interviews with Dr. Rajnish Mehrotra, Associate Professor of Medicine, David Geffen School of Medicine at UCLA, Torrence, California; and Dr. Hartmut Malluche, Robert G. “Robin” Luke Chair in Nephrology, University of Kentucky, Lexington.

Q: Why is pill burden becoming an important issue now in nephrology?

Dr. Mehrotra: We know that the number of medications prescribed for ESRD patients runs about 10 prescriptions per patient. Criteria like age, presence or absence of diabetes or modality—whether its hemodialysis or peritoneal dialysis—will not make any difference. The minimum of pills a patient has to take is 30 a day. The nephrology community has never addressed this issue—namely, the number of pills we ask our patients to take—and how it affects adherence to therapy, not just to medication but to dialysis and all the lifestyle changes we impose on our patients as well. So if there are more potent phosphate binders—for example, lanthanum carbonate—that have the potential to reduce the pill burden, I would argue that this has significant potential towards improving adherence as well as the outcome. Q: Have any long-term toxicity issues emerged with lanthanum carbonate?

Dr. Malluche: There is a certain accumulation of lanthanum in bone but I can state that at least with the two-year data, we did not see any aluminum-like effects. As a matter of fact, bone turnover in lanthanum-treated patients tended to be better: there was increased bone formation rate and a clear-cut trend towards increased bone mass, which would address the problem of osteoporosis that we see in our dialysis patients. So from the data we have now, there is no evidence of toxicity.