Extraosseous Calcification in Kidney Disease: Strategies for Management
Nephrologists describe management of extraosseous calcification, which can occur in patients with chronic and end-stage kidney disease.
By Korey Bartolomeo, DO; Xin Yee Tan, MD; and Richard Fatica, MD
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Editor’s note: This is part two of a two-part series on extraosseous calcification in kidney disease. Part one of the series focuses on pathogenesis, presentation and diagnosis. The original article, including a full list of references, was published in the Cleveland Clinic Journal of Medicine and can be accessed here.
Most of the research has focused on therapies directed at vascular calcification, given its clinical implications with cardiovascular disease in end-stage kidney disease.
Given the central role of elevated phosphate and FGF-23 in the pathogenesis of extraosseous calcification, controlling serum phosphate levels, first through dietary phosphate restriction and then with intestinal phosphate binders, is a logical and low-cost management choice in preventing vascular calcification.
The most commonly used phosphate intestinal binders are calcium-based (e.g., calcium carbonate, calcium acetate) and are used extensively in patients with chronic and end-stage kidney disease for many indications. However, earlier studies demonstrated a relationship between higher calcium intake and higher rates of vascular calcification,33 and subsequent studies called attention to this association, leading to recommendations for using non–calcium-based intestinal phosphate binders to restore normal phosphate levels while limiting calcium intake to maintain normal serum calcium.34,35
A number of randomized trials over the last 20 years have attempted to settle the debate on calcium-based vs non–calcium-based phosphate binders and cardiovascular disease, many of them using vascular calcification as a surrogate end point.
The IMPROVE-CKD trial36 (Impact of Phosphate Reduction on Vascular End-points in Chronic Kidney Disease) tested lanthanum use in patients with advanced chronic kidney disease (eGFR < 30 mL/min/1.73 m2) and evaluated changes in aortic calcification and arterial stiffness. It did not find statistically significant differences with lanthanum compared with placebo. Of note, the trial was limited by recruitment, including patients with normal phosphate levels and excluding those with end-stage kidney disease.36
The Treat-to-Goal study37 in patients with end-stage kidney disease on hemodialysis found less coronary artery and aortic calcification and a lower incidence of hypercalcemia in those randomized to sevelamer compared with calcium acetate. These results may correlate with improved all-cause survival rates in patients newly started on hemodialysis, despite lower rates of normophosphatemia when sevelamer is used.15,38 Subsequent studies comparing lanthanum carbonate with calcium carbonate in patients newly starting on hemodialysis did not find statistically significant differences in calcification scores in heart valves.39
The LANDMARK trial 40 (Outcome Study of Lanthanum Carbonate Compared With Calcium Carbonate on Cardiovascular Mortality and Morbidity in Patients With Chronic Kidney Disease on Hemodialysis), published in 2021, looked at patients with end-stage kidney disease in Japan who had risk factors for vascular calcification who were randomized to receive lanthanum or calcium carbonate. It did not find any statistically significant differences in rates of all-cause mortality or cardiovascular events between the two groups, though the event rates were low. Further, compared with the United States, Japan has lower dietary calcium intake, higher use of arteriovenous fistulas for dialysis access, and different cardiovascular screening practices, which could limit wide applicability of the results.40
In sum, data conflict regarding whether non–calcium-based intestinal phosphate binders are superior to calcium-based binders in preventing vascular calcification and cardiovascular events.
Pyrophosphates (bisphosphonates), the most commonly used class of drugs for preventing bone resorption, inhibit the activity of osteoclasts, and some of these drugs also induce apoptosis. Bisphosphonates are either retained in the bone or cleared by the kidney.
Robust data exist for using this drug class in bone disorders in patients in the early stages of chronic kidney disease (eGFR > 35 mL/min/1.73 m2), but data are significantly limited in those with stage 4 or 5 chronic kidney disease or end-stage kidney disease, and there are theoretical safety concerns.41 Bisphosphonates are less frequently prescribed in these latter populations, possibly due to concerns about toxicity, as these drugs are excreted by the kidney.42 Reports of worsening kidney disease or kidney injury exist for most drugs in the bisphosphonate class, but larger observational trials have found oral bisphosphonates to be reasonably safe in advanced chronic kidney disease, though bisphosphonate users had a 14% higher risk of progression of chronic kidney disease.43
Zoledronic acid, a potent intravenous formulation, should be avoided if the eGFR is less than 30 mL/min/1.73 m2, in view of stronger associations with direct tubular injury, acute kidney injury, and worsened eGFR.44,45 Pamidronate is generally the preferred intravenous formulation for patients with advanced chronic kidney disease, usually given at a lower dose or infused over a longer time. Rarely, collapsing focal segmental glomerulosclerosis can occur.44,45
Bisphosphonates have been shown to reduce both overall vascular calcification and all-cause mortality in certain groups (eg, patients with osteoporosis or cancer), but not the rate of cardiovascular events.46 Etidronate, a first-generation bisphosphonate now discontinued due to high rates of osteomalacia, was used to treat soft tissue calcifications.47–49 Etidronate also reduced vascular calcification in rat models of chronic kidney disease, while human studies showed reduced coronary artery calcification in patients with advanced chronic kidney disease and end-stage kidney disease.49–51 Newer bisphosphonates have limited data on their effects on vascular calcification in end-stage kidney disease, with one study of alendronate showing no improvement in coronary artery calcification score.52
Denosumab, a RANK ligand inhibitor (RANK stands for receptor activator of nuclear factor kappa B) that prevents osteoclast maturation, has not been studied in soft tissue calcification. Small pilot studies have looked at denosumab’s effects on vascular calcification in humans and have suggested it may slow coronary artery calcification, but this has been challenged in other studies.52,53 More studies are needed to determine the clinical significance of these findings. We are not aware of any studies that have looked at denosumab in soft tissue calcification or calciphylaxis.
Teriparatide is a synthetic formulation of PTH. The only evidence for using it to treat tumoral calcinosis comes from case reports, and no major studies have looked at using it in end-stage kidney disease to prevent vascular calcification.54
Calcimimetics are drugs that bind allosterically to the calcium-sensing receptor on parathyroid cells to suppress PTH release for a given serum calcium level.
Cinacalcet, the most common drug in this class, has been studied extensively in secondary hyperparathyroidism in 2 trials, the EVOLVE55 (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events) and ADVANCE56 (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Heemodialysis). It did not show improvement in aortic calcification or reduction in cardiovascular outcomes or all-cause mortality despite improvements in serum PTH levels.55,56 In contrast, a more recent meta-analysis of cinacalcet use in end-stage kidney disease did find a benefit in terms of lower rates of all-cause mortality and cardiovascular mortality.57 Other calcimimetics have been studied only in animal models, and thus their clinical effect in humans is undetermined.
Sodium thiosulfate is an older medication with antioxidant properties that has been used off-label for years in calcium disorders including vascular calcification and calciphylaxis. It was recently systematically reviewed in treating calciphylaxis, with conflicting results.58,59 More recently, a randomized clinical trial60 showed reduction of iliac artery calcification and arterial stiffness with sodium thiosulfate compared with placebo in calciphylaxis. Ongoing prospective and randomized trials will hopefully provide clarity of the benefit of sodium thiosulfate in vascular calcification and calciphylaxis. In a small case series, the drug has shown improvement in symptom burden in soft tissue calcification of the shoulder and hip, with partial size regression.61
Vitamin K is an essential cofactor for carboxylation of numerous proteins, including some that inhibit vascular calcification, such as matrix G1a protein.62 Evidence that lack of vitamin K may be involved in vascular calcification includes a high prevalence of vitamin K deficiency in this population and improvement in carboxylation surrogate markers with supplementation.63,64
Warfarin, a vitamin K antagonist, accelerates medial arterial calcification, particularly in end-stage kidney disease.65 Furthermore, warfarin has been identified observationally as a risk factor for calciphylaxis, and low levels of carboxylation of matrix G1a protein are associated with calciphylaxis in end-stage kidney disease.66 The suspected mechanism by which warfarin may contribute to calciphylaxis is by inhibiting vitamin K-dependent carboxylation of matrix G1a protein, a mineral-binding extracellular matrix protein that prevents calcium deposition in arteries.
Several phase 3 trials are being conducted to determine the benefit of vitamin K supplementation in vascular calcification and calciphylaxis, though a recent trial in patients with stage 4 chronic kidney disease67 did not show improvement in vascular stiffness with vitamin K supplementation. There are no current studies looking at tumoral calcinosis and vitamin K supplementation.
SNF472, a myoinositol hexaphosphate that inhibits hydroxyapatite growth, has shown promise in early clinical trials in reduction of coronary artery calcium volume, while tissue-nonspecific alkaline phosphatase inhibitors are in earlier stages of development.68,69
Magnesium and vitamin D supplementation in chronic and end-stage kidney disease has had varying degrees of success in preventing vascular calcification, though more studies are needed to confirm its clinical utility.70,71 With particular relevance to soft tissue calcification, surgical debridement and hyperbaric oxygen therapies hold significant promise as adjunctive therapies to the aforementioned medical therapies.72–74
Dr. Fatica has disclosed working as an advisor or review panel participant for Natera Inc and REATA Pharmaceuticals. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.