Commentary by Sarah Berry MD, PGY-3 and Joseph Weisstuch, MD Clinical Assistant Professor of Medicine, Divsion of Nephrology
Case: Mr. K is a 59 year old gentleman with a past medical history of hypertension, non-insulin dependent diabetes mellitus, dyslipidemia and worsening chronic kidney disease (CKD) over the last six years, despite compliance with his medications and optimized glucose and blood pressure control. His current medication regimen includes metoprolol, hydrochlorothiazide, aspirin, simvastatin, glyburide, and monopril. Mr. K’s most recent lab work indicates that his serum creatinine is 1.7mg/dl, potassium 4.6mmol/l, sodium 141mmol/l, magnesium 1.7mg/dl, calcium 9.4mg/dl, phosphate 3.5mg/dl, HgA1c 7.1%. His calculated GFR (via the Cockroft Gault formula) is 50ml/min, meeting the definition of Stage 3 CKD.
At a glance, Mr. K’s electrolytes look fine, with no apparent metabolic effects due to his chronic kidney disease as of yet. Are there any interventions to be made today?
The answer is yes. Abnormal phosphate retention is known to begin as early as Stage 2 (GFR 60-90ml/min). A compensatory elevation in serum intact parathyroid hormone (iPTH) initially prevents hyperphosphatemia by decreasing proximal tubule phosphate reabsorption. However, this physiologic compensation over time causes hyperplasia and hypertrophy of the parathyroid gland, setting the stage for secondary hyperparathyroidism and the wide array of metabolic, vascular, rheumatologic, and cardiac complications that accompany its onset.
Therefore, in patients with early stage CKD, measurement of serum iPTH is a better benchmark for action by physicians. This fact is emphasized in the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease published in 2003. These guidelines specifically delineate goal iPTH values, varying by the severity of the CKD. In patients with Stage 3 CKD, such as Mr. K, goal iPTH is 35-70pg/ml. For patients with Stages 4 and 5 CKD, goal iPTH is 70-110pg/ml and 150-300pg/ml, respectively. 
On measurement, Mr. K’s iPTH level is 95pg/ml, significantly above the K/DOQI recommended value and an indication that he is progressing towards hyperparathyroidism. The K/DOQI guidelines also outline strict goals for serum phosphorus values: 2.7-4.6 for patients with stage 3 and 4 disease, and 3.5-5.5 for patients with Stage 5 CKD. How important is normalization of serum phosphorus? The evidence is mixed. In 2005, the data from 840 patients in the Modification of Diet in Renal Disease study showed that neither serum phosphate nor calcium-phosphate product were significantly associated with increased mortality in non-dialysis dependent patients.  However, a recent VA study of nearly 3490 veterans refuted those findings, showing that serum phosphate >3.5mg/dL in non-dialysis dependent patients was an independent marker for increased mortality at 2 years. Additionally, mortality increased linearly with each 0.5mg/dL increase in serum phosphate. 
With this possible mortality benefit in mind, what are the options for intervention? Dietary phosphate restriction is the first step. Animal studies have shown that phosphate restriction in subjects with CKD and normal serum phosphate levels will prevent a rise in serum iPTH, even as GFR continues to decline. Phosphate intake should be in the range of 800-1000mg daily, which is accomplished via protein restriction. Early involvement of a renal dietician has proven to be the cornerstone of success in maintaining compliance.
For patients who are dialysis dependent, co-existing malnutrition is a complicating factor, and protein restriction is not always recommended. This makes adequate phosphate restriction an impossibility in many patients. In these patients, as well as in patients who fail an initial trial of phosphate restriction, initiation of oral phosphate binders is indicated. Dosed at mealtime, these agents bind phosphate in the gastrointestinal tract, preventing its absorption. Some examples: calcium carbonate, calcium acetate, sevelamer hydrochloride, and lanthanum carbonate. (Aluminum hydroxide has fallen out of favor due to aluminum toxicity). It’s reasonable to start with the economical calcium based binders at a low dose that can be titrated up to achieve goal iPTH and phosphate levels. However, keep in mind that this will contribute to increased total calcium intake, the metabolism of which should also be precariously balanced in patients with CKD. Considering the theoretical risk of increased vascular calcification if either serum calcium or the calcium-phosphate product rises above the normal range, the dose of calcium-based binders should be decreased or stopped entirely. Sevelamer (Renagel), while significantly more expensive, is an excellent alternative in these patients.
Vitamin D sterol therapy is an additional consideration. Vitamin D deficiency due to CKD has also been shown to play a role in the development of secondary hyperparathyroidism, and supplementation with calcitriol should be considered if a patient’s serum iPTH is above target.
In general, all of the above interventions can significantly affect serum electrolytes, including magnesium, phosphorus, and calcium. In this regard, these electrolytes as well as serum iPTH should be measured monthly after a new intervention, and every 3 months thereafter in patients stable on therapy.
To summarize, secondary hyperparathyroidism is a marker for increased mortality in patients with CKD, and early intervention can prevent it. As most early stage CKD is managed by internists, it is our responsibility to recognize the indications and the options for intervention at the appropriate time.
1. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Diseases 2003; 42(Suppl 3):S1
2. Menon, Vandana, et al. Relationship of Phosphorus and Calcium-Phosphate Product with Mortality in CKD. Am J Kidney Diseases, 2005. 46:455
3. Kestenbaum, B, Sampson, JN, Rudser, KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrology 2005; 16:520 http://jasn.asnjournals.org/cgi/content/full/16/2/520
4. Slatopolsky, E, Caglar, S, et al. Phosphate Restriction Prevents Hyperparathyroidism in Renal Failure. J Clin Invest 1971; 50:492 http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=5545116
Image Courtesy of Gray’s Anatomy