Medical management. Presently available options of medical treatment should take into account the levels of plasma biochemistry and x-ray findings, and as a more recently recognized parameter also the dimensions of the largest parathyroid glands, as assessed by ultrasonography. A gland diameter of 5-10 mm or more is considered by some groups as being indicative of autonomous growth which generally is resistant to medical treatment .

Schematically, there are five major medical treatment options which can be combined in some cases, but not in others, namely the restriction of phosphate intake, the administration of calcium supplements, the administration of phosphate binders, and the prescription of vitamin D derivatives and calcimimetics . In dialysis patients the weekly dose of renal replacement therapy is an additional important factor. An optimal dialysis technique allows the control of hyperphosphatemia, the adaptation of the dialysate calcium concentration to each patient’s needs to reduce the occurrence of hypercalcemia, the avoidance of metabolic acidosis and the removal of uremic toxins.

The first treatment goal is to avoid or correct hypocalcemia and to prevent hyperphosphatemia. In patients with well controlled plasma phosphate, this can be achieved by giving either calcitriol or its synthetic analog, alfacalcidol or by administering oral calcium supplements. Until recently, most clinicians would have agreed that calcitriol or alfacalcidol should be the preferred therapy in patients with high to very high plasma intact PTH values and normal to moderatety elevated plasma calcium levels, if plasma phosphorus did not exceed presently recommended levels, namely 1.5 mmol/l for CKD stage 3-4 and 1.8 mmol/l for CKD stage 5, according to the recently published K/DOQI guidelines . However, the administration of vitamin D derivatives often induces hypercalcemia and/or hyperphosphatemia (see below).

Calcimimetics. The introduction of a novel class of therapeutic agents, namely the calcimimetics, will almost certainly lead to a rapid change in the above treatment strategy since they enable a control of 2° hyperparathyroidism without increasing plasma calcium or phosphorus. The calcimimetics act on the CaR cloned by Brown et al to make it more sensitive to extracellular calcium (Figure 16). In initial acute studies in chronic hemodialysis patients it was shown that the calcimimetic cinacalcet was capable of reducing plasma PTH within hours, together with a subsequent rapid decrease in plasma calcium and minor decreases in plasma phosphorus . Moreover, in short-term and long-term studies performed in rats with chronic renal failure the administration of the calcimimetic NPS R-568 at the time of uremia induction allowed the prevention of parathyroid hyperplasia , and more recently the reversal of already established hyperplasia as well . Perhaps more important from a clinical point of view, NPS R-568 also allowed the reversal of osteitis fibrosa in uremic rats .

Recent reports showed that the long-term administration of cinacalcet to chronic hemodialysis patients proved to be superior to «optimal» standard therapy in controlling 2° uremic hyperparathyroidism, in that it was able to induce a decrease in both plasma PTH and the Ca x P product , allowing the achievement of K/DOQI guideline treatment targets in a much larger proportion of dialysis patients than standard therapy does . Moreover, its effect is long-lasting . Finally, the combined analysis of 4 clinical trials showed that randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain . Cinacalcet is given in oral, once daily doses from 30 mg up to 180 mg. It is generally well tolerated, with the exception of gastrointestinal side effects which however cease in the majority of patients with time. Since its administration generally leads to a decrease in serum calcium, a close follow-up is required, at least initially, to avoid hypocalcemia with possible adverse clinical consequences. Cinacalcet can be associated with calcium-containing and non-calcium containing phosphate binders and also with vitamin D derivatives, under the condition that serum calcium and phosphorus remain in the ranges defined by the K/DOQI guidelines. Cinacalcet might well become the first treatment option for this condition in association with elevated plasma calcium levels, and possibly even in patients with normal serum calcium levels. It has been recently marketed in the USA and in Switzerland for the use in dialysis patients. It should become available in the European Union and elsewhere as well, in the coming months.

«Classical» phosphate binders, oral phosphate restriction, and phosphate removal by dialysis. Calcium salts should be given, preferentially during or at the end of phosphate-rich meals, to patients with uncontrolled hyperphosphatemia who have no hypercalcemia or radiological evidence of soft tissue calcifications. In all other cases of hyperphosphatemia, non calcium-containing phosphate binders should be administered preferentially (see below). Dietary phosphate intake should be examined closely and diminished, if possible. The spontaneous reduction of protein intake with age probably explains the often better control of serum phosphate in elderly ESRD patients, compared with younger ESRD patients, and this might contribute to the relatively low PTH levels of the former and their propensity to develop adynamic bone disease . However, when reducing dietary phosphate intake and concomitantly protein intake, one has to take care to avoid the induction of a protein malnutrition state. In dialysis patients, an attempt should always be made as well to improve the efficiency of the dialysis procedure. Aluminum-containing phosphate binders may be given in some treatment resistant cases, but only for short time periods.

The administration of calcium salts alone may be sufficient for the control of hyperphosphatemia in many instances, particularly in patients with CKD stages 3 and 4. In hemodialysis patients, the efficacy and tolerance of this treatment may be enhanced by the concomitant use of low-calcium dialysate, for instance 1.25 mmol/l, especially if plasma intact PTH levels are not excessively high. However, long-term studies have shown that the continuous use of a dialysate calcium of only 1.25 mmol/l requires close monitoring of plasma calcium because of the risk of inducing excessive PTH secretion . In CAPD patients, the use of calcium carbonate, in the absence of vitamin D, together with a reduction of the dialysate calcium concentration from 1.75 to 1.45 mmol/l prevents the occurrence of hypercalcemia in most patients . However, the addition of daily low-dose alfacalcidol may lead to hypercalcemia, despite a further reduction of dialysate calcium to 1.0 mmol/l. The novel alternative is the use of cinacalcet, certainly in association with higher dialysate calcium concentrations than with the administration of calcium salts and/or vitamin D derivatives.

Oral magnesium hydroxide or carbonate at low doses (2 g/day) can be used in place of or in association with calcium salts for the control of plasma phosphate. The slight increase in plasma magnesium concentration induced by low-dose magnesium treatment probably has no long-term deleterious effects on bone mineralization. Higher doses should not be used in general since they frequently lead to diarrhea and favor the occurrence of hyperkalemia.

Vitamin D. A satisfactory degree of vitamin D repletion should probably be aimed at in case of vitamin D deficiency . Recently, relative vitamin D depletion has been shown to be an independent risk factor for 2° hyperparathyroidism in hemodialysis patients . Repletion with either native vitamin D3 or 25 OH vitamin D3 might allow the achievement of an optimal degree of bone formation and the avoidance of osteomalacia but controlled trials have not been performed in CKD patients. In hemodialysis patients, calcitriol or alfacalcidol can be given either orally or intravenously. The oral administration can be on a daily basis (for instance 0.125 to 0.5 µg) or as intermittent bolus ingestions (for instance 0.5 to 2.0 µg or more for each dose) whereas the i.v. administration is always intermittent (also 0.5 to 2.0 µg or more per injection). The route and mode of administration of calcitriol or alfacalcidol probably play only a minor role. Since the highly active 1α-hydroxylated vitamin D derivatives can easily induce hypercalcemia, intensive resarch has focused on the development of various non-hypercalcemic analogs, including the natural vitamin D compound 24,25(OH)2 vitamin D3, 22-oxa-calcitriol (maxacalcitol), 19-nor-1,25(OH)2 vitamin D3 (paricalcitol), and 1α-(OH) vitamin D2 (hectorol). Despite numerous studies done in many patients, none of them has been shown to have entirely lost the capacity of inducing an increase in plasma calcium or phosphate, and none has been demonstrated thus far to be superior to calcitriol or alfacalcidol in the long run in controlling secondary hyperparathyroidism . Teng et al. showed that paricalcitol administration to a large cohort of hemodialysis patients conferred a remarkable (16%) survival advantage over the administration of calcitriol . However, because of the retrospective and uncontrolled nature of this study it appears to be premature to accept this observation as proof for a superiority of paricalcitol. Moreover, the same group reported subsequently, in another large historical cohort study, that chronic hemodialysis patients who received injectable, active vitamin D (calcitriol or paricalcitol) had a significant survival advantage over patients who did not receive such treatments . We would like to point out that this kind of retrospective studies can only be considered as hypothesis-generating. They need to be confirmed by properly designed, prospective randomized controlled trials .

New phosphate lowering agents. The development of the novel calcium-free, aluminum-free phosphate binder sevelamer (Renagel®) has been a breakthrough in the control of plasma phosphorus. It is a large molecular-weight resin which is not absorbed by the intestine. It has proved to control hyperphosphatemia successfully in chronic dialysis patients . Its phosphate binding capacity is roughly equivalent to that of Ca carbonate. It increases or decreases serum PTH levels in CKD depending on baseline PTH and it has recently been shown to decrease serum FGF-23 and parathyroid cell hypertrophy in rats with chronic renal failure., In pediatric peritoneal dialysis patients it has been shown to control PTH-induced bone disease as efficiently as calcium carbonate, without increasing serum calcium . Sevelamer offers in addition the advantage to lower serum total cholesterol and LDL-cholesterol and to increase serum HDL-cholesterol. Chertow et al. showed in a prospective, randomized and controlled multicenter study that the administration of sevelamer to chronic hemodialysis patients for one year led to a slower progression of soft tissue calcifications linked to a high Ca x P product or even to their arrest, compared with the administration of calcium carbonate or calcium acetate . An extension of the European arm of this study showed the persistence of the beneficial sevelamer effect after a second year . The long-term administration of sevelamer to uremic rats led to an attenuation of vascular and kidney calcification . Our group recently found that sevelamer also was capable of reducing the progression of atherosclerotic aorta lesions in uremic apolipoprotein E knock-out mice, in addition to reducing aorta calcification.

Another calcium- and aluminum-free oral phosphate binder has been marketed recently in the USA, namely lanthanum carbonate, and the development of still other phosphate binders is in progress. Lanthanum carbonate has a high phosphate binding capacity, similar to that of aluminum-containing binders. The control of hyperphosphatemia with lanthanum carbonate in hemodialysis patients over a 1-year treatment period was as good as with calcium carbonate . At present, no major adverse effects have been observed. In particular, repeat bone biopsies in dialysis patients after one year of treatment did not reveal the induction of low bone turnover disease, in contrast to the effect of calcium-containing phosphate binders . However, since lanthanum is a trace element it remains to be seen which proportion of the massive amounts given to such patients is absorbed from the intestinal lumen and accumulates in various tissues , possibly leading to toxic effects at the level of the liver .

Nicotinamide represents, at least theoretically, a highly interesting compound since it inhibits phosphate absorption from the gut by impairing the intestinal Na,P-cotransporter. The administration of nicotinamide to chronic hemodialysis patients for 12 weeks led to a significant decrease in serum phosphorus concentration, together with a decrease in LDL cholesterol and an increase in HDL cholesterol . Since this drug is absorbed and since its effects are not limited to the intestinal Na,P-cotransporter it remains to be seen whether effects on other organs are well tolerated and without noxious consequences after long-term administration.

A better correction of metabolic acidosis by bicarbonate-buffered dialysate, as compared to acetate-buffered dialysate, probably helps to delay the progression of osteitis fibrosa in hemodialysis patients . A recently proposed mechanism for the beneficial role of acidosis correction is an increase in the sensitivity of the parathyroid gland to plasma ionized calcium.

Table 2 summarizes the main conventional treatment modalities of 2° hyperparathyroidism in chronic renal failure, aimed at correcting major underlying disturbances of calcium-phosphate metabolism.

Local injection of alcohol and active vitamin D derivatives. Since in advanced forms of 2° hyperparathyroidism the hyperplasia of parathyroid glands is asymmetrical, with some glands being grossly enlarged and others remaining relatively small, local ethanol injection has been proposed as an alternative therapy in patients who become resistant to medical treatment. The procedure is performed by fine needle injection of small amounts of ethanol under Doppler-ultrasonography guidance, targeted at the largest gland(s). In many instances a second and a third injection is required to decrease plasma PTH levels adequately. In the experience by Kakuta et al, parathyroid function could be maintained within target range in 38 of 46 patients (80.4%) at 1 year after percutaneous ethanol injection, followed by appropriate medical therapy. Surgical parathyroidectomy was not required in any patient. Conversely, in the eight remaining patients with recurrent hyperparathyroidism who required subtotal parathyroidectomy, plasma iPTH levels recovered in only 50% of them at 1 year after ethanol injection. Thus this technique can allow one to set a new stage for the successful treatment with 1α-hydroxylated vitamin D compounds, at least in highly specialized institutions. However, it has not reached at present a widespread use in clinical practice outside of Japan since other research groups were unable to obtain equally convincing results.

Recently, the direct injection of maxacalcitol into parathyroid glands of dialysis patients and uremic rats was shown to lead to a rapid, significant decrease in circulating PTH. In the rats, the injection of vehicle solution alone did not induce a change in plasma PTH levels. The ultimate contribution of the administration of active vitamin D derivatives via this invasive route to the control of severe 2° uremic hyperparathyroidism remains to be seen.

Despite major advances in the medical treatment of mineral and bone metabolism disturbances in uremic patients the achievement of the targets for plasma calcium, phosphorus, Ca x P product, and PTH as defined by the K/DOQI guidelines was far from being optimal in the DOPPS patient population for the years 2002-2004 . It was actually rare in the dialysis patients of this international cohort to fall within recommended ranges for all four indicators of mineral metabolism.

Surgical treatment. The surgical correction remains the final, symptomatic therapy of the most severe forms of 2° hyperparathyroidism which cannot be controlled by medical treatment. The most important issue is to prevent or correct the development of major clinical complications associated with this disease. The presence of a severe form of overfunction must be proved by clinical, biochemical and radiological evidence. Thus in general neck surgery should only be done in case plasma intact PTH values are greatly elevated (> 600-800 pg/ml), together with an increase in plasma total alkaline phosphatases (or better bone-specific alkaline phosphatase), and only after one or several medical treatment attempts have been unsuccessful in decreasing plasma iPTH with active vitamin D derivatives or if their use is absolutely contraindicated, namely in presence of persistent hypercalcemia or hyperphosphatemia. Bone histomorphometry examination is rarely needed. Clinical symptoms and signs such as pruritus and osteoarticular pain are non specific and therefore are no good criteria for operation by their own. Similarly, an isolated increase in plasma calcium and/or phosphorus, even in case of coexistent soft tissue calcifications, is not a sufficient criterion alone for surgical PTX. However, in the presence of a high plasma PTH the latter disturbances may contribute to favor the decision to proceed to the surgical correction of parathyroid overfunction. The results can be spectacular, including the complete disappearance of soft tissue calcifications (see Figure 13 above). A concomitant aluminum overload should be excluded or treated, if present, before performing surgery.

Two main surgical procedures are generally used, namely either subtotal parathyroidectomy or total parathyroidectomy with immediate autotransplantation. There is no substantial difference of operative difficulties and treatment results between the two procedures. We found that the long term frequency of recurrence of hyperparathyroidism was similar . Moreover, in contrast to reports by others, the claimed superiority of total parathyroidectomy in terms of long-term control of parathyroid overfunction has been questioned recently . We do not recommend the performance of total parathyroidectomy without autotransplantation in uremic patients since subsequently permanent hypoparathyroidism and adynamic bone disease may develop.

The frequency of parathyroidectomy has not changed significantly during the past few years according to a survey done in Northern Italy some years ago . In the USA, PTX was associated with higher short-term mortality, but lower long-term mortality among chronic dialysis patients . Measures to attenuate 2° hyperparathyroidism may play an important role in reducing mortality among patients with end-stage renal disease.