Key Points
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Rheumatic syndromes are a common complication of chronic kidney disease (CKD); regardless of renal disease etiology, musculoskeletal symptoms have been reported in up to 82% of patients receiving hemodialysis.
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The pathogenesis of abnormal mineral metabolism in CKD involves inadequate renal conversion of 25-hydroxyvitamin D to its active forms, 1,25-dihydroxyvitamin D, further exacerbated by concomitant nutritional deficiency of 25-hydroxyvitamin D. Deficiencies in vitamin D axis impair dietary calcium absorption and release the parathyroid glands from feedback inhibition.
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Impaired phosphorous excretion with worsening renal function and decreased expression of calcium sensing receptor in the parathyroid gland also promotes increased parathyroid hormone levels, leading to secondary hyperparathyroidism and refractory hyperparathyroidism.
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CKD–mineral and bone disorders are closely interlinked with deposition of calcium-containing crystals, such as basic calcium phosphate, hydroxyapatite, calcium pyrophosphate dihydrate, calcium oxalate, and, to a lesser extent, monosodium urate.
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Calcium oxalate deposition can lead to arthritis and vascular disease, which often are delayed in diagnosis.
Clinical Disease
Chronic kidney disease (CKD) is a growing public health epidemic that affects up to 13% of the U.S. population. CKD exerts a toxic toll in a variety of tissues and other organ system and tissues beginning early in its course, resulting in numerous complications leading to decrease on the quality of life and premature death in affected patients. Rheumatic syndromes are a common complication of CKD; regardless of renal disease etiology, musculoskeletal symptoms have been reported in up to 82% of patients receiving hemodialysis with increasing incidence during long-term maintenance hemodialysis. These rheumatic disorders have been well described and carefully studied for many years ( Table 23-1 ). This chapter will briefly review CKD–mineral and bone disorders (CKD-MBD) and the clinically relevant crystalline disorders with emphasis on oxalate arthropathy.
| NON–CRYSTALLINE-ASSOCIATED DISORDERS |
|---|
| Chronic Kidney Disease–Mineral and Bone Disorders (CKD-MBD) |
| Secondary hyperparathyroidism (sHPP) |
| Osteopenia/osteoporosis |
| Low and high bone turnover |
| Osteomalacia |
| Mixed osteodystrophy (hyperparathyroidism and osteomalacia) |
| Adynamic bone disorder (ABD) |
| Osteoslerosis |
| Soft tissue and vascular calcification (VC) |
| Hemodialysis related |
| Aluminum toxicity |
| β 2 -Microglobulin amyloidosis |
| Upper extremities |
| Scapulohumeral periarthritis |
| Carpal tunnel syndrome (CTS) |
| Flexor tenosynovitis |
| Spine |
| Destructive spondyloarthropathy |
| Periodontoid pseudotumor |
| Extradural amyloid deposits |
| Bone cysts |
| Pathologic fractures |
| Nephrogenic systemic fibrosis (NSF) |
| Avascular necrosis (AVN) |
| Infection |
| Septic arthritis/bursitis |
| Discitis |
| Osteomyelitis |
| Tendon disorder |
| Tendon rupture |
| Tendinitis |
| Olecranon bursitis |
| Uremic myopathy |
| CRYSTALLINE-ASSOCIATED DISORDERS |
| Arthropathy associated with partially carbonate-substituted apatite crystals |
| Calcium pyrophosphate dihydrate |
| Monosodium urate |
| Calcium oxalate |
Chronic Kidney Diseases
Crystal-induced arthropathies and CKD-MBD, as manifest by several laboratory abnormalities, bone diseases, and vascular calcification, are well-recognized complications that occur in all stages of CKD as well as in hemodialysis. The pathogenesis of disordered mineral metabolism in CKD involves inadequate renal conversion of 25-hydroxyvitamin D to its active forms. 1,25-Dihydroxyvitamin D may be further exacerbated by concomitant nutritional deficiency of 25-hydroxyvitamin D. Deficiencies in vitamin D axis impair dietary calcium absorption and release of parathyroid glands from feedback inhibition. Impaired phosphorous excretion with worsening renal function and decreased expression of calcium-sensing receptor in the parathyroid gland also promotes increased parathyroid hormone (PTH) levels leading to secondary hyperparathyroidism and refractory hyperparathyroidism. Furthermore, decrease in circulating 1,25-dihydroxyvitamin D concentrations in early CKD is mediated by fibroblast growth factor 23 (FGF23) by inhibiting the synthetic 1α-hydroxylase and stimulating the catabolic 24-hydroxylase leading to release of the parathyroids from feedback inhibition and further contributing to secondary hyperparathyroidism. CKD-MBD are closely interlinked with deposition of calcium-containing crystals, such as basic calcium phosphate (BCP), hydroxyapatite (HA), calcium pyrophosphate dihydrate (CPPD), calcium oxalate (CaOX), and, to a lesser extent, monosodium urate (MSU). Deposition of these crystals in and around the joints and soft tissues leads to several clinical presentations, including bursitis, tenosynovitis, synovitis, and arthritis in patients with progressive CKD and hemodialysis. The clinical presentations of crystal-induced arthropathies in CKD and hemodialysis are often similar, requiring diagnostic arthrocentesis, with examination of synovial fluid for crystals undercompensated polarized microscopy and sometimes requires the additional use of special stains for their proper identification. Although the exact molecular mechanisms leading to crystal deposition are not completely understood, murine and human genetic studies have identified many proteins that act as stimulators or inhibitors of crystal formation and could contribute to crystal-induced arthropathies in patients with CKD.
An imbalance between these proteins in uremic and hemodialysis patients may accelerate crystal formation and deposition in the extracellular matrix and may lead to the initiation and propagation of inflammation as these crystals are deposited and released from tissues. In addition, alterations of mineral metabolism in CKD associated with elevated levels of serum calcium (Ca), phosphorus (P), Ca-P product (Ca × P), and PTH are also associated with increased cardiovascular morbidity and mortality. Cardiovascular disease is up to 20-fold more frequent in end-stage renal disease (ESRD) patients and accounts for up to 50% of all deaths, with accelerated atherosclerosis being consistently implicated in this process. Among abnormalities of mineral metabolism, one of the most prominent and relevant is hyperphosphatemia, an event already present in the early phases of renal failure. Elevated serum phosphorous has been related to cardiovascular morbidity and mortality in both hemodialysis and predialysis patients. Vascular and coronary artery calcification have been suggested as the link between abnormal mineral metabolism in general and hyperphosphatemia in particular cardiovascular events in this population. Hyperphosphatemia has been pointed out as the primary culprit in the process of cardiovascular calcification, an event that is present in the early phases of CKD. A significant association between the progression of coronary artery calcification and serum phosphorous concentration was observed in CKD patients, despite serum phosphorous being in the normal range. Faster vascular calcification progression was found in patients with a high-normal serum phosphorous, which was accompanied by more frequent cardiovascular events. However, despite these various findings, the mechanisms by which serum phosphorous contributes to vascular calcification and cardiovascular disease are not completely understood.
Soft Tissue and Vascular Calcification
Calcium and phosphate ions in biologic fluids exist in concentrations near the point at which mineral salt precipitation can occur. The balance between extracellular inorganic pyrophosphate (ePP i ) and extracellular inorganic phosphate (eP i ) levels in local tissues regulates both normal and pathologic mineralization. The normal ratio of ePP i /eP i is tightly regulated and lower values are associated with increased calcification.
Three molecules closely regulate the ePP i /eP i levels: tissue nonspecific alkaline phosphatase, enzyme ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), and the ePP i transporter ANKH (or ank ). Inactivation of ENPP1 in humans markedly reduces plasma PP i levels and results in extensive large artery calcification and variable periarticular calcifications. ENPP1 (ENPP1K121Q) polymorphisms in hemodialysis patients are associated with higher coronary calcification and increased aortic stiffness. PP i is hydrolyzed by extracellular phosphatases, most notably by tissue nonspecific alkaline phosphatase. In patients with calcific uremic arteriolopathy, increased levels of serum alkaline phosphatase activity are observed. The kidney normally clears pyrophosphate but, in patients with stage 5 CKD, plasma pyrophosphate is very efficiently removed by hemodialysis. This contributes to an altered ratio of ePP i /eP i , thereby promoting soft tissue, periarticular, and vascular calcification.
As mentioned, the spontaneous formation of Ca 2+ :PO 4 –3 solid phases in extracellular fluids may be prevented by a number of proteins that inhibit precipitation or sequester ions to reduce their bioavailability. In bone, normal mechanisms inhibiting mineral deposition are blocked in a carefully regulated manner. It is thought that, under normal physiologic states, similar proteins expressed in soft tissues and in blood vessels prevent precipitation of calcium with other minerals. However, this process is believed to be dysregulated in stage 5 CKD. Prominent among these many inhibitors are matrix c-carboxyglutamic acid protein (MGP) in the extracellular matrix and α 2 -Heremans-Schmid glycoproteins/fetuins in serum ( Table 23-2 ). MGP can directly sequester calcium, acting as a buffering agent, but it also serves as an inhibitory partner of bone morphogenic protein (BMP)-2. BMP-2, a potent morphogen of the transforming growth factor-β superfamily, normally functions during skeletal development, but under unusual circumstances, it can induce ectopic cartilage and bone formation in soft tissues. Interestingly, serum concentrations of BMP-2 in uremic patients are twice those found in normal serum. Local concentrations of MGP seem important in reducing ectopic calcification. In situ hybridization and immunohistochemistry studies of MGP in vascular smooth muscle cells demonstrate downregulation of this molecule in calcific human tissue and in animal models of calcification. MGP knockout mice develop overwhelming vascular calcification of the vascular tree, an effect that appears to be regulated locally in cells in an autonomous manner. Warfarin, which is administered to patients undergoing hemodialysis, inhibits vitamin K–dependent c-carboxylation of MGP and results in reduced MGP function. Finally, MGP polymorphisms are of prognostic significance in predicting progression to stage 5 CKD, cardiovascular mortality, and vascular calcification in patients with CKD. Another systemic factor that functions as a potent inhibitor of HA crystal formation is α 2 -Heremans-Schmid glycoprotein-A produced by the liver. Fetuin-A binds calcium and phosphorus in extracellular fluids and helps maintain the solubility of calcium in plasma. Fetuin-A plasma levels are reduced in patients with stage 5 CKD compared with healthy control subjects.
| Name/Class | Chemistry | Production/Distribution | Action | Null Mice | Notes |
|---|---|---|---|---|---|
| PP i inorganic | Chain of P linked through oxygen plasma solute | VSMCs, chondrocytes osteoblasts/ubiquitous | Inhibits mineralization, oxalate crystallization | Hydrolyzed by TNAP | |
| MGP GLA protein | Noncollagenous bone protein, 84 amino acids; 14 kDa 5 g-GLA residues | VSMCs, chondrocytes/calcified tissues (cartilage, vessels) | Inhibits calcification | Arterial calcification, aortic rupture, osteopenia, fractures | Requires vitamin K–dependent g-carboxylation |
| BMP-7 TGF-β superfamily | Protein, 431 amino acids; 7-cystatin-residue ring | Adult: kidney Embryo: skeleton, kidney, eye, CV/collecting tubules, glomerulus, adventitia | Cell proliferation/ differentiation/apoptosis; osteoblasts, VSMC differentiation | Uremia | Anti-TGF-β, anti-inflammatory effect (IL-1,-6,-8 inhibition) |
| OPG TNF-R superfamily | Glycoprotein 40 amino acids; 60 kDA M; 120 kDa D | Heart, arteries, veins, bone, marrow, lung, kidney, intestine/ several tissues (bone, vessels); cytokine receptor glomerulus, adventitia | Inhibits osteoclastogenesis, protective for vascular (endothelial cell survival factor) | High turnover, osteoporosis, VC |
The toxic environment associated with late-stage CKD can induce trans-differentiation of vascular smooth muscle cells into an osteoblastic phenotype with subsequent deposition of BCP and HA into tissues through matrix vesicles. This occurs when genes for regulatory transcription factors, such as Cbfa1/Runx2, Msx2 , and Sox9, which are pivotal to determine chondroblastic and osteoblastic differentiation, are induced. A number of key mechanisms, including hyperphosphatemia, BMP-7, and osteoprotegerin (OPG), contribute to the induction of these genes. Elevated phosphate concentrations, such as those in patients with late-stage CKD, may increase intracellular phosphate levels through Pit-1, a type II sodium/phosphate cotransporter that induces Cbfa1 expression and vascular smooth muscle cell trans-differentiation. BMP-7 deficiency in CKD further contributes to the differentiation and transformation of vascular smooth muscle cells into cells with an osteoblastic phenotype. OPG, a soluble protein inhibitor of the RANK/RANKL system, maintains a balance between bone formation and bone breakdown; increased levels of OPG lead to increased bone formation. Deletion of OPG in mice results in osteoporosis and also, surprisingly, to extensive vascular calcification. Concentrations of soluble plasma OPG are significantly higher in patients undergoing hemodialysis compared to age-matched healthy volunteers. OPG is upregulated at sites of tissue calcification, which supports a role for local tissue phenotype-determining factors in promoting aberrant ectopic calcification.
Extracellular phosphate levels are tightly regulated through the activity of multiple secreted signaling peptide hormones. Fibroblast growth factor 23 (FGF23) is a recently identified hormone regulator of mineral and vitamin D metabolism. FGF23 is an osteoclast-derived secreted protein that works in conjunction with PTH to induce phosphaturia; levels of FGF23 are markedly elevated in CKD. The principal actions of FGF23 are to inhibit sodium-dependent phosphate reabsorption and to suppress circulating 1,25(OH) 2 -vitamin D levels. Mutations in the gene for FGF23 result in hyperphosphatemic familial tumoral calcinosis. In stages 3 and 4 CKD, FGF23 levels are quite elevated to compensate for persistent phosphate retention, which results in reduced renal production of 1,25-dihydroxyvitamin D and thereby stimulate secretion of PTH, suggesting its critical role in the pathogenesis of altered mineral homeostasis in CKD. Furthermore, it has recently been shown that FGF23 directly acts on parathyroid gland and mediates secretion of PTH. It has been postulated that, as the major phosphaturic hormone, this may be a counterbalancing mechanism to increase the fractional excretion of phosphate by the reduced mass of functioning kidney. To function, FGF23 must bind to an FGF receptor complexed to its cofactor Klotho, which is a 130-kilodalton transmembrane glucuronidase, the expression of which in the kidney is reduced in CKD. Besides its function in the proximal tubule of the kidney, FGF23 signals in the parathyroid glands to reduce PTH gene transcription and translation in rats. This result is paradoxical, because transgenic mice overexpressing FGF23 develop hyperparathyroidism. However, greater understanding of the mechanism by which FGF23 regulates extracellular phosphate levels may allow development of targeted therapies to better control hyperphosphatemia in stages 4 and 5 CKD. Whether FGF23 also has local effects that contribute to calcium-containing crystal formation and deposition has not yet been studied.
Crystal-Induced Inflammation and Chronic Inflammation in CKD
Crystal release from soft tissue and joints induces inflammation through mechanisms that involve innate immunity and interleukin (IL)-1β. Conflicting data have been reported regarding the role of TLRs in crystal-induced inflammation (see Chapter 5 ), although some of the observed differences may be accounted for by the different animal models from which these disparate data were derived. However, the IL-1 receptor (IL-1R), which signals through its TLR adaptor protein myeloid differentiation factor 88 (MyD88), is critical for mediating inflammation induced by MSU, CPPD, and HA crystals. These crystals stimulate the activation of mononuclear phagocytes involving the NLRP3 inflammasome (see Chapter 5 ). The pivotal role of the inflammasome and IL-1 signaling in response to certain crystals has been exploited by successful use of the IL-1R antagonist (anakinra, rilonacept, canakinumab) to treat refractory cases of gout and pseudogout. Similar studies have not been performed in other crystal arthropathies such as CaOX crystal deposition disease, which likely use similar inflammatory mechanism.
Interestingly, an attenuated inflammatory response to MSU crystals has been observed in patients receiving chronic hemodialysis, with decreased monocyte release of IL-1α, IL-6, and tumor necrosis factor as compared with individuals having normal renal function. In addition, it is possible to speculate that the increased P i concentration seen in CKD may also trigger phosphorylation-driven signaling inflammatory cascade that correlates with chronic inflammatory state seen in patients with CKD as one the pivotal factor contributing to increased cardiovascular risk.
HA and BCP Disease
HA and other forms of BCP (i.e., carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate) may cause significant extraskeletal calcification in patients with late-stage CKD by depositing in periarticular tissue, viscera, and arteries. HA may deposit in the small joints of the hands, wrists, elbows, hips, and ankles, but the shoulders are the joints most commonly affected. Prospective studies conducted during the years soon after the introduction of hemodialysis found the prevalence of extraskeletal calcification to be 52%, a number that has decreased gradually over time with more aggressive management of hyperphosphatemia and secondary hyperparathyroidism. This reduction in the prevalence of extraskeletal calcification among patients with CKD has resulted from a reduction of the elevated calcium × phosphorus quotient, as well as from changes in the local (tissue) and circulating (serum) levels of calcification-inhibitory and calcification-stimulatory proteins.
CPPD Deposition Disease (Pseudogout)
Acute attacks of pseudogout occur when CPPD crystals are shed from hyaline cartilage and fibrocartilage into joints or periarticular tissues, inducing a sterile inflammatory response. CPPD crystal–induced arthritis affects large or medium-sized joints, including the knees, wrists, hips, and shoulders, although small joints can also be involved. The prevalence of CPPD deposition disease increases with age, both among patients with late-stage CKD and among the remainder of the general population. One study reported a prevalence of CPPD arthropathy as high as 43% among patients receiving chronic dialysis.
Patients with late-stage CKD and CPPD deposition disease may develop secondary osteoarthritis due to crystal-induced activation of MMP-13 mediated by IL-1β. In the setting of CPPD deposition disease, degenerative changes may occur in atypical joints such as the metacarpophalangeal joints. Accelerated spinal osteoarthritis could also occur, the appearance of which may be remarkably similar to that of Charcot-type joint involvement. The frequent occurrence of metabolic abnormalities common to CPPD deposition disease and CKD (e.g., hypercalcemia, hyperphosphatemia, vitamin D deficiency with secondary and tertiary hyperparathyroidism, and iron overload) accounts for the higher prevalence and greater severity of attacks of CPPD-induced arthritis among patients receiving hemodialysis. In contrast, attacks of MSU crystal–induced arthritis are much less frequent and less severe among patients receiving dialysis treatment, compared with those with CKD who have not yet initiated dialysis. Chondrocalcinosis in patients with CKD is not pathognomonic of CPPD deposition disease, as similar calcifications can be seen in radiographs of patients with CKD who have deposition of CaOX or HA crystals. Thus, diagnostic arthrocentesis is critical when evaluating an inflamed joint in a patient with CKD.
MSU Deposition Disease (Gout)
The clinical presentation of gout is similar to that of pseudogout, although small joints such as the first metatarsophalangeal joints are commonly affected. Gout disproportionately affects persons with CKD, because declining GFR reduces urate clearance and results in hyperuricemia. Hyperparathyroidism, a common complication of moderate to severe CKD, can also promote hyperuricemia by enhancing urate absorption. MSU crystal–induced arthritis continues to develop after the onset of uremia; however, symptoms are milder than before its onset. In hemodialysis patients, hyperuricemia is attenuated by urate removal, especially when high-flux hemodialysis membranes are used. Further descriptions of CPPD and MSU in relationship to CKD are described in their respective chapters.
Calcium Oxalate Deposition Disease
Oxalate is a metabolic end product of glycine, serine, other amino acids, and ascorbic acid. Large amounts of oxalate are also present in certain foods, such as spinach and rhubarb. Oxalate is readily absorbed after ingestion, cannot be metabolized in mammals, and is primarily eliminated through renal excretion. Oxalate is freely filtered by the glomerulus and is secreted by the tubules. Hyperoxalemia, hyperoxaluria, oxalate kidney stones, and crystalline tissue deposits may result from several contributing factors that may affect oxalate metabolism. Familial or primary hyperoxaluria (PHs) are rare genetic disorders of glyoxylate metabolism in which specific hepatic enzyme deficiencies result in the overproduction of oxalate by the liver leading to severe hyperoxaluria, recurrent urolithiasis or progressive nephrocalcinosis, ESRD, and tissue deposition. Secondary oxalosis results from either dietary or other exposures to large amounts of oxalate or oxalate precursors or underlying disorders such as ESRD, inflammatory bowel disease, or infections ( Table 23-3 ).
| FAMILIAL |
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| ACQUIRED |
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