Clinical Heterogeneity of Calcium–Phosphate Disorders in Advanced CKD

1. Renal Osteodystrophy

Renal osteodystrophy (ROD) represents the skeletal manifestations of CKD-MBD and itself encompasses a heterogeneous group of abnormalities in bone turnover, mineralization, and volume that arise as kidney function declines [38,41]. It represents one of the major contributors to the markedly increased fracture risk, disability, and mortality observed in patients with advanced CKD. Historically considered synonymous with secondary hyperparathyroid bone disease, ROD is now recognized as a spectrum of histological phenotypes hence requiring a bone biopsy for precise diagnosis [17,38,41].

2. Vascular Calcification

Vascular Calcification (VC) in advanced CKD is a highly prevalent, cell-mediated process that is a major driver of cardiovascular mortality and morbidity [21,42,61]. The development of VC requires both a permissive systemic biochemical milieu characterized by calcium-phosphate supersaturation and an active cellular program that promotes osteogenic transformation of vascular smooth muscle cells [42,61]. VC is classified into intimal calcification, closely associated with atherosclerotic plaque and chronic vascular inflammation, and medial (Mönckeberg) calcification, characterized by diffuse and continuous deposition of hydroxyapatite in the tunica media. Hence, CKD confers a specific risk for medial calcification, although both types are found in advanced CKD since the same risk factors for atherosclerotic disease exist in adult CKD patients [42,61]. CT coronary artery calcium scan remains the gold standard to identify and prognosticate vascular calcification, while newer diagnostic tools such as pulse wave velocity testing strongly correlates with advanced CKD and vascular calcification [4,22,68].

Pathophysiology of Vascular Calcification in Advanced CKD

The hallmark of VC in CKD is the active osteogenic transformation of vascular smooth muscle cells (VSMCs), rather than passive precipitation of calcium–phosphate complexes. As kidney function declines, chronic phosphate retention, oxidative stress, uremic toxins, and persistent inflammation create a pro-calcific environment that drives VSMCs to lose their normal contractile phenotype and acquire characteristics of osteoblast-like cells. Elevated phosphate directly promotes this phenotypic transition by activating NF-κB signaling and upregulating the osteogenic transcription factor RUNX2, leading to expression of bone-associated proteins such as osteocalcin and osteopontin and ultimately promoting hydroxyapatite deposition within the vascular wall [21,28,61]. Hyperphosphatemia also increases tissue non-specific alkaline phosphatase (TNAP), which degrades pyrophosphate, a potent endogenous inhibitor of calcification, thereby further favoring mineral deposition [21,61]. Although hyperphosphatemia is considered the principal driver of osteogenic differentiation, experimental evidence also suggests that elevated PTH may directly contribute by activating PTH1 receptors expressed on VSMCs, increasing expression of RUNX2 and Osterix and further promoting osteogenic transformation [51].

Under physiological conditions, the vasculature possesses several endogenous defense mechanisms that actively inhibit ectopic mineralization. Calcification inhibitors including matrix Gla protein (MGP), Gla-rich protein (GRP), fetuin-A, and pyrophosphate bind calcium-phosphate complexes, suppress osteogenic differentiation, and facilitate the safe transport and clearance of mineral particles [31,58,71]. In CKD, however, these protective systems become progressively impaired through vitamin K deficiency, chronic inflammation, reduced protein activity, and an overwhelming mineral burden. In addition, vascular smooth muscle cells express the calcium-sensing receptor (CaSR), whose activation maintains the contractile phenotype and suppresses osteogenic signaling. Reduced CaSR expression observed in advanced CKD further shifts the balance toward vascular mineralization by promoting loss of the contractile phenotype and increasing RUNX2-mediated osteogenic differentiation [1].

Importantly, systemic disturbances in calcium and phosphate homeostasis alone do not fully explain the marked variability in vascular calcification observed among patients with advanced CKD. Many individuals with similar serum phosphate, calcium, PTH, and FGF23 concentrations develop vastly different degrees of vascular calcification, suggesting that local vascular biology plays an equally important role. Differences in vascular inflammation, oxidative stress, extracellular matrix composition, expression of calcification inhibitors, and susceptibility of VSMCs to osteogenic transformation likely determine whether hydroxyapatite deposition occurs once a permissive systemic mineral environment has been established [21,42,61]. This concept of tissue-specific susceptibility provides one explanation for the remarkable clinical heterogeneity of calcium-phosphate disorders observed in CKD.

Clinical Manifestation of Vascular Calcification

Medial calcification is particularly prominent in CKD and leads to progressive loss of arterial compliance [4,42,68]. As elastic arteries stiffen, there is a rise in systolic blood pressure with a concomitant fall in diastolic pressure, resulting in widened pulse pressure. This altered hemodynamic profile increases left ventricular afterload and promotes the development of LVH and diastolic dysfunction [36,68]. In addition, arterial stiffening accelerates pulse wave velocity and causes early return of reflected waves during systole, further augmenting systolic pressure and myocardial workload [36,68]. The reduction in diastolic pressure impairs coronary perfusion, predisposing to subendocardial ischemia, even in the absence of obstructive coronary artery disease. Clinically, patients may present with difficult-to-control systolic hypertension, exertional dyspnea, or features of heart failure with preserved ejection fraction.

Intimal calcification contributes to luminal narrowing and plaque burden [42,61]. In CKD, calcified plaques are common and may be more diffuse and rapidly progressive. Coronary artery calcification is strongly associated with coronary artery disease, including stable angina, acute coronary syndromes, and myocardial infarction [22,56]. Similarly, calcification within the carotid and cerebral vasculature increases the risk of ischemic stroke and transient ischemic attack. Notably, CKD patients frequently exhibit a combination of medial and intimal calcification, resulting in both impaired vascular compliance and atherosclerotic complications, which together amplify cardiovascular risk [42,61]. Vascular calcification in peripheral arteries contributes to peripheral arterial disease, manifesting as claudication, reduced exercise tolerance, and in advanced cases, critical limb ischemia [47]. Impaired perfusion, combined with microvascular dysfunction and uremia-related factors, contributes to poor wound healing, ulcer formation, and increased risk of limb amputation [47].

Treatment of Vascular Calcification

The treatment of vascular calcification in advanced CKD is primarily directed at reducing phosphate burden and controlling secondary hyperparathyroidism, similar to the management of CKD-MBD as above [30,42]. Emerging strategies targeting calcification inhibitors, such as vitamin K repletion, and novel agents that inhibit hydroxyapatite formation show promise but remain under investigation [55,58]. Despite these approaches, no therapy has been definitively shown to reverse established vascular calcification, and current management focuses on slowing progression and mitigating cardiovascular risk [42,55,61]. Coronary calcification presence justifies aggressive cardiovascular risk reduction with statin-based therapies and lower blood pressure targets [2]. An important consideration to keep in mind is the role of magnesium in opposing vascular calcification. Interestingly, however, hypomagnesemia is common in CKD and dialysis patients and a role for magnesium supplementation in this scenario has been debated [75].

3. Valvular Calcification

Valvular calcification exists on a continuum with vascular calcification but possesses unique structural and biomechanical characteristics that influence its pathogenesis and clinical manifestations. The aortic valve and the mitral annulus are most commonly affected. When compared to the non-CKD population, patients with advanced CKD develop valvular calcification earlier, more rapidly, and with greater severity [37,57,72]. The prevalence of valvular calcification is 8 times greater in patients undergoing hemodialysis than the general population [57,72]. Diagnosis involves non-invasive imaging, usually echocardiography as first line showing defects in leaflet thickening, echogenic calcifications, or reduced mobility; this modality is also used to assess the functional consequences (aortic stenosis or mitral regurgitation) [3].

Pathophysiology of Valvular Calcification

The basic pathophysiology of valvular calcification in advanced CKD is analogous to CKD-MBD maladaptive osteogenic transformation described above in vascular tissue. Phosphate retention, elevated PTH, increased FGF23 and reduced calcitriol, chronic inflammation and oxidative stress all promote osteogenic signalling and mineral deposition through osteogenic differentiation of valvular interstitial cells (VICs), the principal resident cells of the cardiac valves [43,49,57]. What makes valves uniquely susceptible is their exposure to mechanical stress, especially the aortic valve [43,49]. Repetitive shear and pressure, along with a rich extracellular matrix of collagen and elastin, promote activation of inflammatory pathways and osteogenic differentiation of VICs, making the aortic valve and the mitral annulus more prone to mineral deposition [43,49]. The resulting valve injury perpetuates local inflammation, fibrosis, and progressive mineral deposition, driving the development of clinically significant valvular disease. The avascular structure of valves limit the regenerative capacity once injury and inflammation have progressed [43,49].

Clinical Manifestation of Valvular Calcification

Calcification of the aortic valve leads to progressive leaflet thickening, reduced mobility, and ultimately aortic stenosis, characterized by obstruction to left ventricular outflow [3,49]. In early stages, patients may be asymptomatic or present with subtle exercise intolerance. As disease progresses, the classic clinical triad of exertional dyspnea, angina, and syncope emerges [3].

Mitral annular calcification (MAC) involves deposition of calcium within the fibrous annulus of the mitral valve, most commonly affecting the posterior annulus [16,20]. While often asymptomatic in early stages, progressive calcification can impair valvular function and disrupt adjacent cardiac structures. The most common functional consequence is mitral regurgitation, resulting from impaired leaflet coaptation due to annular rigidity. Less commonly, extensive calcification may encroach on the valve orifice and produce mitral stenosis [20]. Beyond valvular dysfunction, MAC has important electrophysiologic implications due to its proximity to the cardiac conduction system. Patients may develop conduction abnormalities, including varying degrees of atrioventricular block, as well as atrial arrhythmias, particularly atrial fibrillation [16,20]. Hemodynamically significant mitral valve disease may lead to left atrial enlargement, pulmonary congestion, and symptoms of heart failure.

Treatment of Valvular Calcification

Medical management of valvular calcification in advanced CKD follows the same tenets of CKD-MBD, involving phosphate control, management of PTH, and avoiding hypercalcemia [30,35]. In this population, given the increased risk of surgical intervention, transcatheter aortic valve replacement is preferred, while surgical mitral valve repair or replacement remains the standard of practice for mitral valve disease [67,70]. Emerging therapies include targeting mineralization pathways (hydroxyapatite inhibitors), Vitamin K repletion (similar to vascular calcification), and anti-inflammatory strategies [55,58].

4. Calciphylaxis (Calcific Uremic Arteriolopathy)

Calciphylaxis is a rare and life-threatening thrombotic vasculopathy that results from the calcification of the arteriolar microvasculature of the deep dermis and subcutaneous adipose tissue in central (visceral) or peripheral presentations. Mortality remains exceptionally high, with reported one-year mortality rates approaching 40–80%, largely driven by infectious complications and sepsis arising from progressive skin ulceration and tissue necrosis [8,39,46].

The diagnosis of calciphylaxis is often clinical and based on the presence of characteristic painful violaceous plaques, retiform purpura, or necrotic ulcerative lesions in patients with advanced CKD or ESKD [45,46]. Definitive diagnosis remains histopathologic confirmation on skin biopsy demonstrating medial calcification of small dermal and subcutaneous arterioles with associated microvascular thrombosis, fat necrosis, and septal panniculitis. Additional findings may include intimal hyperplasia and endothelial injury [23,45]. However, biopsy is frequently avoided because of the risks of poor wound healing, ulcer propagation, infection, and worsening necrosis [8,46].

Imaging may provide important supportive evidence when biopsy is deferred. Plain radiographs and CT imaging can demonstrate subcutaneous calcification, while technetium-99m bone scintigraphy has demonstrated high sensitivity for calciphylaxis and frequently shows increased tracer uptake in affected tissues [19,50].

Calciphylaxis Pathophysiology

Although calciphylaxis shares many of the osteogenic mechanisms described in vascular calcification, including phosphate-driven vascular smooth muscle cell transformation and upregulation of osteogenic transcriptional pathways, it is increasingly recognized as a pathophysiologically distinct entity rather than simply an advanced form of vascular mineral deposition [8,46,73]. In contrast to conventional vascular calcification, which primarily affects large and medium-sized arteries and manifests clinically through arterial stiffness and cardiovascular disease, calciphylaxis preferentially involves the dermal and subcutaneous microvasculature and is characterized by a profound superimposed vasculopathic and thrombotic component resulting in tissue ischemia and necrosis [23,46,73].

The osteogenic transformation pathways implicated in vascular calcification, including activation of RUNX2, BMP-2, alkaline phosphatase, and osteocalcin signaling, are similarly observed in calciphylaxis and contribute to medial calcification of small dermal arterioles [21,28]. However, calciphylaxis appears to involve a more severe disruption in endogenous anti-calcification defenses. Deficiencies in matrix Gla protein (MGP), fetuin-A, and pyrophosphate are thought to play particularly important roles, with the strong association between calciphylaxis and warfarin exposure highlighting the importance of impaired vitamin K-dependent activation of MGP [31,59,73]. Reduced fetuin-A levels, frequently observed in inflammation, malnutrition, and advanced CKD, may further impair buffering of calcium-phosphate nanocrystals and promote uncontrolled microvascular calcification [31].

A major distinguishing feature of calciphylaxis is the central role of endothelial dysfunction and thrombosis. Whereas vascular calcification may progress over years without overt tissue infarction, calciphylaxis lesions demonstrate endothelial injury, fibrointimal hyperplasia, luminal narrowing, and fibrin thrombi within small dermal and subcutaneous arterioles [23,45]. Hypercoagulability appears to contribute substantially to disease progression, with reported associations including protein C deficiency, protein S deficiency, antiphospholipid antibodies, systemic inflammation, and hypoalbuminemia [8,46]. This thrombotic microangiopathy-like process likely explains the severe pain, rapid lesion progression, and ischemic necrosis characteristic of calciphylaxis. Proposed "second-hit" mechanisms including local trauma, injections, surgery, infection, and hypotension may precipitate tissue infarction in an already sensitized calcified microvasculature [46,73].

Another defining feature of visceral calciphylaxis is its striking tissue tropism toward adipose-rich regions such as the abdomen, thighs, buttocks, and breasts. This distribution is not typical of conventional vascular calcification and suggests that local tissue-specific factors contribute importantly to disease pathogenesis. Obesity is among the strongest identified risk factors for calciphylaxis, particularly for proximal lesions [45,46]. Several mechanisms have been proposed to explain this fat predilection. Adipose tissue is relatively hypovascular and prone to local hypoxia, potentially increasing susceptibility to ischemic injury once microvascular compromise develops. Mechanical stress and tension within subcutaneous septa may further predispose to vascular injury in areas of increased adiposity. In addition, adipocytes produce inflammatory cytokines including TNF-α and IL-6, which may amplify endothelial dysfunction, oxidative stress, and osteogenic signaling locally within affected tissues [73]. Experimental studies have also demonstrated that adipocytes exposed to elevated phosphate concentrations may themselves undergo calcific transformation, suggesting that adipose tissue may actively participate in the calcific milieu rather than serving solely as a passive target [73]. Furthermore, adipocytes express MGP, raising the possibility that regional dysregulation of local calcification inhibitors contributes to selective tissue vulnerability [59,73].

Treatment of Calciphylaxis

Treatment of calciphylaxis focuses on interrupting the calcific-thrombotic cascade, limiting tissue ischemia, preventing infection, and optimizing wound healing [46,69].

Warfarin discontinuation is a key intervention whenever feasible given its inhibition of vitamin K–dependent activation of matrix Gla protein (MGP), an important endogenous inhibitor of vascular calcification [59]. This association further supports the concept that calciphylaxis represents profound local failure of anti-calcification defense mechanisms within the microvasculature.

Parenteral administration of sodium thiosulfate (STS) remains the most widely used pharmacologic therapy [12,69]. Proposed mechanisms for STS benefits include calcium chelation, antioxidant effects, vasodilation, and inhibition of hydroxyapatite formation [12,69]. Early case series suggested improvements in pain and wound healing, though more recent observational studies and meta-analyses have not consistently demonstrated clear mortality or wound-healing benefit [69]. Nevertheless, because of biologic plausibility and limited alternatives, STS remains standard adjunctive therapy in many centers. Common adverse effects include nausea, metabolic acidosis, and volume overload that can be addressed with anti-emetics and intensification of dialysis therapy. BEAT-Calci is an ongoing randomized, adaptive, multi-center, platform trial that will evaluate multiple interventions, including STS and other drug therapies as well as different dialysis regimens to establish high-quality evidence on the effect of a range of interventions in patients with ESRD and newly diagnosed calciphylaxis [24].

Newer therapies target calcification more directly. SNF472 (myo-inositol hexaphosphate) inhibits hydroxyapatite crystal growth, thereby targeting the final common pathway of ectopic calcification [55]. Magnesium-based therapies and vitamin K supplementation similarly aim to restore endogenous anti-calcification pathways and reduce crystal formation [55,59]. Despite these emerging approaches, treatment remains largely supportive, with meticulous wound care, hyperbaric oxygen, infection control, and pain management remaining central to outcomes.

5. Tumoral Calcinosis

Tumoral calcinosis (TC) is an uncommon but striking manifestation of severe CKD-MBD characterized by the development of large periarticular calcium-phosphate deposits within soft tissues [40,48,66]. In patients with advanced CKD or ESKD, tumoral calcinosis represents a form of metastatic calcification driven primarily by chronic hyperphosphatemia, elevated calcium-phosphate product, and severe secondary hyperparathyroidism [40,66]. Although historically described as a hereditary disorder involving FGF23 pathway abnormalities in patients with normal kidney function, tumoral calcinosis in CKD occurs as an acquired complication of dysregulated mineral metabolism and prolonged dialysis exposure [48,66].

Pathophysiology of Tumoral Calcinosis

The pathophysiology of tumoral calcinosis in advanced CKD reflects profound disturbances in phosphate homeostasis and failure of normal inhibitory mechanisms that prevent extraskeletal calcium-phosphate deposition [40,66]. Persistent phosphate retention due to declining renal clearance serves as the principal initiating abnormality. As serum phosphate concentrations rise, the calcium-phosphate product exceeds its solubility threshold, favoring precipitation of hydroxyapatite crystals within periarticular soft tissues [13,40].

At the molecular level, CKD-associated tumoral calcinosis shares many osteogenic pathways observed in vascular and valvular calcification as above. Unlike vascular calcification, which develops within the vessel wall, tumoral calcinosis demonstrates a striking predilection for periarticular soft tissues subjected to repetitive mechanical stress. Recurrent microtrauma may provide a nidus for hydroxyapatite crystal nucleation and progressive enlargement of calcific masses. Once established, these lesions incite a chronic foreign-body inflammatory response characterized by macrophages, multinucleated giant cells, and fibrous encapsulation, contributing to continued lesion expansion [48,66]. Histologically, lesions consist of lobulated calcific masses containing hydroxyapatite crystals separated by fibrous septae with surrounding macrophages, multinucleated giant cells, and chronic inflammatory infiltrates [40,48].

Clinical Manifestations of Tumoral Calcinosis

Tumoral calcinosis typically presents as a slowly enlarging, firm periarticular tumor-like masses that may initially be painless but progressively cause pain, stiffness, reduced mobility, and functional impairment depending on lesion size and location [40,48,66]. The hips, shoulders, and elbows are among the most frequently involved sites. Lesions may become massive and mechanically limit joint movement or compress adjacent neurovascular structures. In severe cases, patients may develop difficulty ambulating, impaired upper extremity mobility, or debilitating pain.

Overlying skin may become erythematous, ulcerated, or inflamed, particularly when lesions enlarge rapidly or undergo secondary infection [40,66]. Spontaneous extrusion of chalk-like calcium material through the skin has also been described. Imaging typically demonstrates large multilobulated periarticular calcified masses with cystic or "cloud-like" calcium deposition patterns on radiography or CT imaging [48]. Bone involvement is usually absent, helping distinguish tumoral calcinosis from primary osseous neoplasms.

Treatment of Tumoral Calcinosis

Successful treatment depends on sustained reduction of phosphate burden and regression of the calcium-phosphate product, although complete resolution may require prolonged therapy. Intensification of dialysis, strict dietary phosphate restriction, optimization of phosphate binder therapy, and control of secondary hyperparathyroidism have all been associated with regression of lesions in selected patients [40,66].

Surgical excision may be considered for patients with severe pain, neurovascular compression, recurrent infection, or major functional impairment [48,66]. However, recurrence is common if the underlying metabolic abnormalities remain uncontrolled. Because lesions are often highly vascular and poorly circumscribed, surgery may also be technically challenging. Emerging therapies targeting hydroxyapatite formation and calcification signaling pathways remain investigational. Consequently, sustained correction of phosphate homeostasis through optimization of dialysis, phosphate-lowering therapy, and control of secondary hyperparathyroidism remains the cornerstone of management.

6. Ocular Calcifications (Corneal and Conjunctival)

Clinical Manifestations

Ocular calcification is an underrecognized manifestation of CKD-MBD resulting from metastatic calcium-phosphate deposition within the conjunctiva and cornea. Although frequently asymptomatic, these lesions may cause significant ocular discomfort and visual impairment when advanced [52,53]. The most common manifestations are conjunctival calcification and corneal calcification (band keratopathy). Many patients are identified incidentally on slit-lamp examination, where lesions appear as small, punctate, chalky-white plaques. As calcification progresses, patients may develop blurred vision, foreign-body sensation, ocular pain, and photophobia. When accompanied by ocular surface inflammation, the classic finding of the "red eye of uremia" may produce painful conjunctival irritation that clinically mimics conjunctivitis [52,53].

Pathophysiology

The systemic biochemical milieu underlying ocular calcification is similar to that responsible for other manifestations of CKD-MBD, with chronic calcium-phosphate supersaturation promoting metastatic mineral deposition. However, local ocular factors appear to determine tissue susceptibility. Localized alkalosis within the interpalpebral zone, chronic ocular surface irritation, and minor epithelial injury related to dialysis-associated volume depletion promote hydroxyapatite precipitation within the conjunctiva and cornea [52,53]. Iatrogenic factors may further contribute, as many patients with advanced CKD suffer from dry eye disease and frequently use topical ophthalmic preparations. Some artificial tears and glaucoma medications contain phosphate-containing buffers or preservatives, increasing the local phosphate burden and further promoting hydroxyapatite deposition [53].

Treatment

Management consists of optimization of systemic mineral metabolism together with local ophthalmologic therapy. The primary treatment for symptomatic band keratopathy is epithelial debridement followed by EDTA chelation, resulting in improvement in visual acuity in approximately 80% of patients [53]. Phototherapeutic keratectomy has also been utilized for selected patients, although it may produce corneal surface irregularity and further studies are needed to better define its efficacy and long-term outcomes [52,53].

7. Cutaneous Calcification and Pruritus

Clinical Manifestations

Cutaneous calcification represents an uncommon manifestation of metastatic calcification in advanced CKD and may contribute to localized skin irritation and pruritus. More broadly, chronic kidney disease-associated pruritus (CKD-aP) is one of the most common symptoms experienced by patients receiving dialysis, affecting quality of life, sleep, and psychological well-being. Although many patients have no visible skin calcification, abnormalities in mineral metabolism have been associated with an increased risk of pruritus. In the Chronic Renal Insufficiency Cohort (CRIC), elevated PTH concentrations (>65 pg/mL) were associated with a higher incidence of pruritus, whereas lower serum calcium concentrations (<9 mg/dL) were associated with a lower risk, supporting a contribution of CKD-MBD to symptom development [74].

Pathophysiology

The pathogenesis of CKD-associated pruritus is multifactorial and remains incompletely understood. Calcium-phosphate deposition within the skin has historically been proposed to irritate cutaneous nerve endings and contribute to itching in patients with severe CKD-MBD. However, current evidence suggests that mineral metabolism represents only one component of a broader process involving systemic inflammation, immune dysregulation, peripheral neuropathy, and alterations in opioid receptor signaling. Consequently, disturbances in calcium-phosphate homeostasis may amplify rather than solely cause pruritus.

Treatment

Management includes optimization of CKD-MBD parameters, particularly control of hyperphosphatemia and secondary hyperparathyroidism, in patients with evidence of mineral dysregulation. However, because CKD-associated pruritus is multifactorial, symptom-directed therapies including emollients, gabapentinoids, κ-opioid receptor agonists, ultraviolet B phototherapy, and optimization of dialysis adequacy are frequently required.

Progression of Kidney Disease and Kidney Stones

Beyond its role in CKD-MBD, increasing evidence suggests that phosphate retention itself may contribute to progression of kidney disease. Extensive experimental studies have demonstrated that high dietary phosphate intake accelerates kidney injury and fibrosis, whereas dietary phosphate restriction attenuates progression of established CKD [25,29,34]. In humans, there have been a few epidemiological studies that show an association between serum phosphate levels and rate of progression of kidney disease in CKD patients [10,60]. Although these studies are associations that are hypothesis generating, no interventional studies have shown reducing serum phosphate improves kidney function. Dietary intake of ultraprocessed foods associated with high phosphate intake is a potential unifying explanation for these findings. Nutritional management of CKD with a healthy diet, emphasizing plant-based patterns with low phosphate and ultra processed food intake, could prevent the development of CKD-MBD and all the manifestations of calcification presented.

The majority of idiopathic kidney stones in the Western world are made up of calcium oxalate and only a smaller fraction contain phosphate, but calcium phosphate may be important as a predisposing factor for calcium oxalate kidney stone formation. Idiopathic calcium oxalate stones are thought to form from Randall plaques, which are subepithelial deposits of calcium phosphate in the renal papilla [15,32,33]. It has been postulated that deposition of calcium phosphate in the renal interstitium, and its growth into a Randall plaque formation, is similar to pathological biomineralization seen elsewhere in the body. Once this plaque is exposed to urine, which is metastable with respect to calcium oxalate, calcium oxalate stone formation begins.