EVOLVEing past Cinacalcet

One of the regular criticisms of nephrology is the lack of good quality randomized controlled trials. This is particularly the case in the world of renal bone disease where we target surrogate endpoints without necessarily knowing for certain what the effect this has on the most important outcome - patient survival. The EVOLVE trial was once such trial which examined the role of cinacalcet in preventing all-cause and cardiovascular mortality. The results of this trial were somewhat ambiguous in that the overall results were negative but this could have been affected by the slightly older age of the treatment group (after adjustment for age, there was a benefit to cinacalcet). There was, however, a wonderful rebuttal to this particular argument in a letter to the editor published later in the NEJM by Giovanni Tripepi.

Overall, the number needed to treat to prevent a single death was 500 and this is balanced by a 62% drop-out rate in the treatment group. There was also a lower rate of parathyroidectomy in the treatment group.

Last month NDT published and ERA-EDTA position statement on the use of calcimimetics in patients on dialysis. Based on a meta-analysis (which was largely derived from the EVOLVE trial), they made the definitive statement that cinacalcet should not be used in patients on dialysis to reduce cardiovascular or all-cause mortality. Further, they pointed out that although the original trials showed that PTH could be successfully lowered using these drugs and that this could reduce the rate of parathyroidectomies, there is no evidence that this has any benefits either beyond the prevention of surgery. They called for a randomized trial of parathyroidectomy vs. cinacalcet for the treatment of intractable hyperparathyroidism with hard endpoints. I second that call.

Hypocalcemia - What's the diagnosis - Answer

This was an interesting case. A woman with a previous history of hyperparathyroidism and multiple neck surgeries who developed severe, symptomatic hypocalcemia 3 hours following a parathyroidectomy was thought to have failed because of a persistently elevated PTH level. This suggests that did in fact successfully remove her parathyroid gland and that there was an issue with the assay.

In the hospital referred to in this case, the assay used was a Roche Elecsys PTH STAT assay. This is an antibody-based assay that uses two murine antibodies - a "capture" antibody and a "signal" antibody. In patients who have been previously exposed to murine tissue, anti-mouse antibodies can be present in the serum that bind to both of these antibodies giving a false positive result on the assay. In this case, the patient had received OKT3 in the past which has been associated with a prevalence of anti-mouse antibodies of up to 26%. Her PTH level was repeated using an alternative assay - her pre-op PTH was 18 pg/ml and her post-op PTH was 5 pg/ml. Unfortunately, she required long-term treatment with vitamin D and calcium supplementation. In retrospect, the normal calcium and phosphate in a patient with this degree of apparent hyperparathyroidism and normal kidney function was a clue that there may have been an issue with the test although, of course, it is easy to say that knowing the answer.

Congratulations to "anonymous" for getting the correct answer. The complete case report can be found here.

Hypocalcemia - What's the Diagnosis?

A 36yr old woman with a history of PCKD was referred for surgical treatment of hyperparathyroidism. She had a history of two prior failed kidney transplants following which she had been on dialysis for more than 10 years. She had a third renal transplant 10 years prior to this presentation which was still functional. At the time of her transplant, she had received OKT3 and was currently maintained on tacrolimus and prednisone. She had a long history of hyperparathyroidism. Six years prior to her transplant, she had a subtotal (3.5 glands) parathyroidectomy. The year of her transplant, she had another neck exploration with the removal of 8 nests of hypercellular parathyroid tissue.

At the time of this presentation, her PTH was 3,300 pg/ml despite treatment with cinacalcet. Her ionized calcium was normal (1.2 mmol/L) but she complained of poor concentration, fatigue and depression. Serum phosphorous and creatinine were normal. She had a normal sestamibi scan but an US revealed hyperplastic parathyroid tissue in her neck.

During the parathyroidectomy, frozen section revealed hypercellular parathyroid tissue that was removed. However, pre-op, intra-op and post-op PTH levels were elevated at >1700 pg/ml. Because of the persistently elevated PTH, it was considered a failed operation and calcium supplementation was not started post-op. However, within 3 hours of the operation, she developed perioral numbness, tetany and muscle spasms in her legs. Her ionized calcium was low (0.9 mmol/L) and her symptoms resolved after treatment with iv calcium. Her PTH remained elevated at 3000 pg/ml.

What is the reason for her acute hypocalcemia in this setting? Answer in the comments please.