Hyperparathyroidism in chronic kidney disease: complexities within the commonplace

Discussion

Secondary HPT as a consequence of CKD is well recognised. It usually presents with a normal or elevated serum phosphate and low or low-normal serum calcium concentration.¹ Multiple factors mediate the development of hyperparathyroidism in CKD patients. These include hypocalcaemia, decreased 1,25 dihydroxycholecalciferol synthesis and hyperphosphataemia. The differential diagnosis of a raised PTH in the setting of CKD should include primary, secondary and autonomous (tertiary) hyperparathyroidism and, more rarely, FHH and ectopic PTH secretion.

All causes of hypercalcaemia (including primary HPT (pHPT), myeloma, sarcoidosis, hypervitaminosis D and the milk-alkali syndrome) can result in marked renal dysfunction. Hypercalcaemia damages tubular epithelial cells, particularly those in the loop of Henle and in the collecting and distal tubules, eventually leading to dilatation, atrophy, and fibrosis.³ It also down-regulates aquaporin expression which, clinically, can manifest as polyuria, nocturia and reduced urinary concentrating ability.⁴ Hypercalcaemia also has haemodynamic effects, reducing both renal blood flow and glomerular filtration.⁵ Thus, common renal manifestations of pHPT include nephrolithiasis, hypercalciuria and sometimes nephrocalcinosis.⁶ Yamashita and co-workers found that hypercalcaemia was more severe in pHPT patients who had renal insufficiency.⁷ Current guidelines suggest that a parathyroidectomy should be considered for most patients with pHPT, specifically those with any of the following: serum calcium concentration >0.25 mmol/l above the upper limit of normal, a creatinine clearance of <60 ml/min, reduced bone density (especially if in the osteoporotic range) and age <50 years.⁸ In patients with a high surgical risk, medical management with a calcimimetic agent is usually an effective alternative.⁹

Case 1 illustrates the difficulty often encountered by clinicians in distinguishing pHPT from tertiary HPT (tHPT), as both can present with the triad of renal insufficiency, hypercalcaemia and high PTH. Patients with tHPT usually have moderately severe CKD and a prolonged history of sHPT (ie a period of normo- or hypocalcaemia with concurrent hyperparathyroidism). Serum phosphate is typically elevated in tHPT because of severe renal impairment. By contrast, patients with pHPT typically have a low serum phosphate. The reliance on parathyroid imaging to distinguish between pHPT and tHPT has pitfalls. First, multiglandular involvement occurs in up to 25% of patients with pHPT.¹⁰ Second, asymmetric proliferation of the parathyroid glands is common in patients with tHPT and often results in an apparent single focus of intense uptake in imaging studies because of differential tracer retention.¹⁰ Third, there are other local structures that can take up and retain tracer, giving false positive results.¹¹ Thus, multimodal imaging, usually scintigraphy and ultrasound, is recommended.

In Case 2, tHPT was initially considered, but the lack of a prolonged history of CKD and low-normal phosphate on initial presentation argued against this. In addition, PTH was increased only three-fold, whereas in tHPT, elevations are often at least ten-fold. The stability of PTH levels for more than decade is also very atypical of tHPT. This evidence leaves pHPT and FHH as possible diagnoses. It is interesting to note that despite her initial partial parathyroidectomy, the patient's post-operative PTH remained elevated and hypercalcaemia eventually recurred. The failure of surgery to resolve the condition suggests either multi-glandular involvement or the presence of FHH. UCCR is often used as a screening test for FHH, but its validity in CKD patients remains uncertain. Hypocalciuria and 25-hydroxy vitamin D deficiency, both commonly seen in CKD, could potentially increase the false positivity of the test.^12,13 The patient's serum vitamin D level was slightly reduced, but not deficient, and she was on no thiazide diuretics that may have contributed to a low UCCR. The patient's very low UCCR suggested FHH as a potential co-diagnosis,¹² but a corroborative family history was lacking.

FHH is a rare, usually autosomal dominant, condition that is associated with defects in the calcium-sensing receptor (CaSR).¹⁴ The CaSR is expressed in both parathyroid and renal tubular cells,¹⁵ where loss of function results in increased tubular calcium reabsorption, leading to hypocalciuria that persists even after parathyroidectomy. Analysis of the CaSR gene for clinical use is available in some countries. To diagnose FHH, many experts now suggest using UCCR as a screening test. If positive (UCCR <0.02), a follow-up CaSR gene analysis would provide a certain diagnosis if a mutation was detected and 98% sensitivity if no mutations were found.¹⁶

Case 3 was a severe case of sHPT. The largest gland removed was over 150 times the normal volume. The pre-operative localising ⁹⁹Tc-Sestamibi scan revealed only one hyperfunctioning gland with no other abnormal areas of uptake, suggesting an adenoma. This was consistent with the intraoperative finding of one very large gland, but interestingly, the additional gland that was removed was also enlarged, a finding not detected by scintigraphy.

Discordance between imaging and pathological findings is not uncommon in sHPT; hence there is continuing debate on the value of preoperative imaging, with some authors using it only for recurrent or persistent disease.¹⁷ Indeed, the choice of modality that is best for imaging parathyroid glands is also contentious. Imaging of the normal parathyroid gland is difficult as this tissue is not easily distinguished from surrounding tissue. As the gland expands and increases in cellularity, however, it becomes increasingly easy to detect by ultrasound. High-resolution colour Doppler ultrasound now also enables more accurate assessment of changes in parathyroid volume.^{18 99}Tc-Sestamibi imaging helps to localise parathyroid tissue but provides little anatomical localisation and often must be used in combination with another imaging modality.¹⁹ Thyroid uptake of radiotracers can also be a source of error and some authors advocate a subtraction scan by imaging with ¹²³I or ⁹⁹Tc-Pertechnetate. Previous studies have demonstrated the poor sensitivity of various imaging techniques in identifying all affected glands.¹⁷ Some authors advocate a combination of ⁹⁹Tc-Sestamibi single photon emission computed tomography (SPECT) with CT to gain high sensitivity and accuracy gland localisation.¹⁹ MRI can also be helpful, especially when combined with scintigraphy.²⁰

Another noteworthy lesson from Case 3 was the fact that severe secondary hyperparathyroidism can occur early in CKD: recent guidelines suggest that PTH concentrations should be monitored when the GFR falls below 60 ml/min/1.73 m².²¹ The ideal target for PTH is not known, but the current Kidney Disease Outcome Quality Initiative (KDOQI) guidelines suggests that the PTH should be kept at between 3.85 and 7.7 pmol/l in Stage 3 CKD, and between 7.7 and 12.1 pmol/l in Stage 4 CKD.²² The interpretation of PTH concentration is further complicated by the high intra-individual biological variation in PTH secretion in CKD patients; a single measurement rarely provides an accurate picture of parathyroid activity.²³ Indeed, PTH itself might not be the best molecule to measure in early CKD. The hormone fibroblast growth factor-23 (FGF-23) could be a more appropriate measure when assessing bone and mineral disorders. FGF-23 is a phosphaturic hormone that down-regulates the activation of vitamin D in the kidney. This hormone is elevated long before changes are seen in calcium, phosphate or PTH,²⁴ but because of its instability in plasma samples, it is not easy to measure.²⁵

In the past decade, parathyroidectomy in dialysis patients has been substantially delayed by the introduction of calcimimetic agents. Parathyroidectomy continues to be performed, but at a markedly decreased frequency. The role of calcimimetics in non-dialysis patients is less well defined. In randomised, controlled, placebo-controlled trials, cinacalcet treatment reduced PTH levels, but it did so at the cost of significant hypocalcaemia and hyperphosphataemia.²⁶ Thus, early routine use of calcimimetics in CKD is currently neither recommended nor licensed. Nevertheless, there may be individual cases in which pre-dialysis use might help to prevent severe secondary hyperparathyroidism.

The last case presents a common scenario of hypercalcaemia post renal transplantation. Secondary HPT occurs frequently in CKD patients and, although pHPT cannot be excluded completely without histology, the symmetrical uptake and excretion of tracer in the parathyroid scan in this case argues against this. Although renal transplantation eventually corrects the sHPT for many, the correction can take time and is incomplete in 50% of recipients.²⁷ As demonstrated in this patient, marked hypercalcaemia can cause graft dysfunction and nephrocalcinosis. Traditionally, hyperparathyroidism post transplantation has been managed with phosphate supplementation, bisphosphonates and, in refractory cases, parathyroidectomy. In some cases, this procedure has been shown to be deleterious to graft function.²⁸ Numerous case series have now reported the effectiveness of cinacalcet in reducing serum PTH and calcium after transplantation (see review by Copley²⁹). There are, however, at least three case reports of graft dysfunction resulting from nephrocalcinosis after the initiation of cinacalcet treatment.^29–32 CaSR is present in both parathyroid tissues and renal tubules.³³ In addition to the suppression of PTH secretion, cinacalcet can also interact directly with the CaSR expressed in renal tubules, resulting in increased calcium excretion that is independent of PTH's action on renal tubules.¹⁴ Therefore, cinacalcet might exert hypercalciuric effects through both PTH-dependent and-independent mechanisms. With these concerns in mind, the results of a randomised placebo-controlled trial (see clinicaltrials.gov NCT 00975000, due for completion in 2013) will hopefully provide a more definitive answer on the efficacy and safety of cinacalcet in this setting.

In conclusion, renal dysfunction and hyperparathyroidism often co-exist. Although usually caused by secondary hyperparathyroidism, incongruent biochemistry can challenge both the diagnosis and treatment of these conditions.