1. NEPHROLOGIC CASE CONFERENCE R3 呂建儒

2. Base information 張先生 58 year-old male Nephrotic syndrome, membranous nephropathy (biopsy result from 榮總 ) ESRD on CAPD Gout Personal habits: Allergy:diltiazem, sulindac Smoking (Denied) Betelnut (Denied) Alcohol, quit for years Family history father: HTN mother: athma

3. Chief complaint Multiple small hard nodules over hand and hand joints for 4 months

4. Present illness Multiple small hard nodules over hands and hand joints for 4 months The nodules grows in size, accompanied with limitation of joint movement Weakness of right 4 th finger and left hand(can not grasp tightly), associated with pain recently Persistent hypercalcemia, hyperphosphatemia, and hypoalbuminemia at clinic followup

5. Past history Liver cirrhosis,child B, chronic hepatitis B related, with ascites under Lamivudine treatment Thymoma s/p op in 95-05 in 榮總 Essential hypertension under irregular medical control recently Gout arthritis for more than 10 years Appendicitis s/p op 13 years ago Spontaneous bacterial peritonitis in 2007/07

6. Physical examination T:37.2/ ℃ P:84/min R:18/min BR:160/110/mmHg GENERAL APPEARANCE: Chronic ill-looking CONSCIOUSNESS: Clear, E4V5M6 HEENT: Sclera: not icteric Conjunctiva: mild pale Oral cavity : Intact oral mucosa Normal tongue appearance Throat not injected NECK: Supple No jugular vein engorgement Trachea not deviated No lymphadenopathy CHEST: Breath pattern: smooth, bilateral symmetric expansion No use of accessory muscles Breathing sound:bilateral clear and symmetric breathing sound Wheezing: No wheezing Crackles: No basal crackles HEART: Regular heart beat without audible murmur or gallop ABDOMEN: Soft and flat, No superficial vain engorgement Liver and spleen not palpable No Shifting dullness No tenderness; No rebounding pain No muscle guarding no Murphy's sign Bowel sound: normoactive No visible spider angioma BACK: No knocking pain over bilateral flank area EXTREMITIES: Joint deformity over bilateral hands Freely movable no peripheral edema Multiple nodules over bilateral upper limbs, including hands, wrists, and elbows SKIN: No petechiae or ecchymosis Itching skin rashes over whole body Skin intact

7. Laboratory examination 1/202/213/214/185/206/14 WBC51006900 Hb/Hct8.6/25.37.9/22.77.9/23.28.5/24.57.8/22.58.4/24.9 BUN Cr 92.6 12.9 103.7 10.9 97.3 11.12 98.1 10.72 99 11.37 69.5 10.79 Na13412713212.6129133 K3.8 44.43.63.2 Ca P 12.5 6.7 10.7 6.6 11.7 6.3 11.6 7.8 11.3 7.8 11.1 7.1 Albumin3.032.732.662.472.612.69 iPTH7.85.6 Alk-P138195

8. Image study 6/14

9. Impression Metastatic calcifications, uremic tumoral calcinosis, hyperphosphatemia and hypercalcemia related End stage renal disease on CAPD Liver cirrhosis, child B, HBV related

10. Admission course Whole bosdy CT: no definite tumor or sarcoidosis was found Multiple grouped hyperdense patches in image study Pain control with demoral for severe pain at bilateral upper limbs Pamidronatelow dose steroid6/17: Pamidronate and low dose steroid Consultation of oncologist: PTHrP paraneoplastic syndrome is unlikely CT guided biopsy of right parahumeral mass: Calcinosis Followed Ca/P: ↓, in acceptable range Much improvement of pain and limitation of range of motion Discharge on 7/1

11. Follow-up at clinic 7/097/188/18 Ca/P8.7/6.09.1/6.010.3/6.5 Albumin2.793.0 No pain nor deterioration in local swelling and range of motion at periarticular masses of upper limbs Mild numbness at hands Sometimes muscle cramping

12. METASTATIC CALCIFICATION

13. Extraosseous calcification Calcinosis cutis Dystrophic calcification Metastatic calcification Idiopathic calcification Tumoral calcinosis Iatrogenic calcification Calciphylaxis J Am Acad Dermatol 2011;65:1-12

15. Tumoral calcinosis Familial tumoral calcinosis Dystrophic tumoral calcinosis Metastatic tumoral calcinosis RadioGraphics 2006; 26:871–885RadioGraphics 2006; 26:871–885

16. Tumoral Calcinosis (Familial tumoral calcinosis) A hereditary condition associated with massive periarticular calcification Typically lobulated, well-demarcated calcifications Most often distributed along the extensor surfaces of large joints

17. Metastatic Calcinosis Hyperphosphatemia Hypercalcemia Gout—calcified tophi

18. METASTATIC CALCINOSIS IN CHRONIC KIDNEY DISEASE

19. Introduction Highly prevalent in patients with chronic kidney disease May contribute to impaired outcomes The most clinically relevant localization of pathological calcification is at cardiovascular sites

20. Mechanism Defective clearance mechanisms of calcified debris fetuin-A-dependent calciprotein particles Osteogenic transdifferentiation Phosphate induced calcification progression and osteogenic transdifferentiation, and calcium synergistically and dramatically potentiated these effects Magnesium: calcification-inhibitory effects

21. Vitamin D and vitamin K have been linked to the regulation of calcification mechanisms Analogue of vitamin D, Warfarin Vitamin K  activation of MGP; inactivation of MGP  arterial medial calcification High dose of active vitamin D analogue or with toxic doses of vitamin D3  vascular and soft tissue calcification Nat. Rev. Nephrol. advance online publication 19 July 2011Nat. Rev. Nephrol. advance online publication 19 July 2011

22. Risk Age, duration of dialysis, diabetes mellitus, hyperphosphatemia and an inappropriate calcium load are major risk factors for progressive calcification in patients with CKD. Am. J. Kidney Dis. 43, 572–579 (2004) A Ca×P product above 60 – 68 mg2/dL2 is well known to facilitate extraosseous (vascular and visceral) calcification J Ren Nutr 2007; 17:389–96.

23. Type / Presentation Extraosseous calcification calcification in median size arteries periarticular (tumoral) calcification visceral calcification (heart, lung, and kidney) The Journal of Clinical Investigation Volume 57 March 1976 692-699The Journal of Clinical Investigation Volume 57 March 1976 692-699 “Uremic tumoral calcinosis” “Calcific uremic arteriolopathy” One subgroup of Calciphylaxis

24. CALCIFIC UREMIC ARTERIOLOPATHY

25. Introduction One of Calciphylaxis Medial calcification of the arterioles leading to ischemia and subcutaneous necrosis 1 month ~12 years after the onset of end-stage renal disease (ESRD), with a median time of 2 years and 9 months Journal of the American Society of Nephrology, vol. 7, no. 7, pp. 978–982, 1996.Journal of the American Society of Nephrology, vol. 7, no. 7, pp. 978–982, 1996.

26. Incidence: 4.1% in dialysis patients Surgery, vol. 122, no. 6, pp. 1083–1090, 1997Surgery, vol. 122, no. 6, pp. 1083–1090, 1997 Other risk factors: obese, Caucasian females, and diabetic patients Kidney International, vol. 61, no. 6, pp. 2210–2217, 2002.Kidney International, vol. 61, no. 6, pp. 2210–2217, 2002. The use of calcium-based phosphate binders and vitamin D analogs for the treatment of severe hyperparathyroidism  increase in incidence recently

27. Clinic features Livedo reticularis Painful, plaque-like subcutaneous nodules Ischemic/necrotic ulcers with eschars Sometimes local infection (erythema, pus)

28. Diagnosis By clinic symptoms/signs Confirmed by skin biopsy May invite further infection or can initiate ulcer formation Image study including plain radiographs, high- resolution computed tomography, bone scans, and X-ray mammography, have nonspecific characteristics

29. Prognosis One-year survival rate of 45.8 % Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569– 579, 2007Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569– 579, 2007 Poor prognostic factors Presence of advanced disease at the time of therapy Rapid progression, local or systemic infection Proximal ischemic lesions Ulceration carries a mortality of greater than 80 percent as a result of local and systemic infections and sepsis Kidney International, vol. 61, no. 6, pp. 2210–2217, 2002.Kidney International, vol. 61, no. 6, pp. 2210–2217, 2002.

30. One-year survival rate: 45% (control: 90%) Five-year survival rate: 35% (control: 60%) Kidney International, Vol. 60 (2001), pp. 324–332Kidney International, Vol. 60 (2001), pp. 324–332

31. Therapies Medical treatment: Calcium-Phosphate control Diet control Ca contained phosphate binder  non-Ca phosphate binder Control of secondary hyperparathyroidism (SHPT) Surgical treatment: Local debridement / Amputation Parathyroidectomy for hyperparathyroidism Renal transplantation

32. Therapies Sodium Thiosulfate Dissolve insoluble calcium salts embedded in tissue into soluble calcium thiosulfate Reversal of endothelial dysfunction and increased vasodilatation through its antioxidant properties No determined regimen; some reports: 5~25 gm IV, 3~4/week, for 6~24 months Side effect: sodium retention causing increased anion gap metabolic acidosis American Journal of Kidney Diseases, vol. 43, no. 6, pp. 1104–1108, 2004.American Journal of Kidney Diseases, vol. 43, no. 6, pp. 1104–1108, 2004. Seminars in Dialysis, vol. 23, no. 3, pp. 258–262, 2010.Seminars in Dialysis, vol. 23, no. 3, pp. 258–262, 2010.

33. Bisphosphates A powerful inhibitor on osteoclast activity and bone resorption Osteoporosis, tumoral hypercalcemia, Paget’s disease Exert an inhibitory effect on macrophage activity and local proinflammatory cytokine production Nephrology Dialysis Transplantation, vol. 19, no. 8, pp. 2130–2132, 2004.Nephrology Dialysis Transplantation, vol. 19, no. 8, pp. 2130–2132, 2004.

34. Hyperbaric Oxygen Therapy(HBO) Healing impaired when tissue oxygen tension falls below 20mmHg Hypoxia hinders with the oxygen-dependent polymorphonuclear leukocyte-mediated bacterial killing in wound infections Disadvantage Costly and not readily available May increase the pain and remain ineffective with organ involvement Journal of Nephrology, vol. 15, no.6, pp. 676–680, 2002.Journal of Nephrology, vol. 15, no.6, pp. 676–680, 2002.

35. Steroid Controversial Stabilization or improvement in nonulcerating lesions Disadvantage Predispose the patients to systemic infection in long term use Kidney International, vol. 61, no. 6, pp. 2210–2217, 2002.Kidney International, vol. 61, no. 6, pp. 2210–2217, 2002. Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569– 579, 2007.Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569– 579, 2007.

36. Sterile Maggot Therapy Larvae of the species Lucilia sericata Some enzymes: Liquefy necrotic tissue Secrete phenylacetic acid and phenylacetyl aldehyde: antibacterial activity Almost painless Journal of Dermatological Treatment, vol. 12, no. 4, pp. 211–214, 2001.Journal of Dermatological Treatment, vol. 12, no. 4, pp. 211–214, 2001.

37. Anticoagulation therapy Low-dose tissue plasminogen activator Substitution of warfarin with LMWH American Journal of Kidney Diseases, vol. 32, no. 3, pp. 384–391, 1998.American Journal of Kidney Diseases, vol. 32, no. 3, pp. 384–391, 1998. Limb revascularization Still progressing in some cases Poor outcome? Primary amputation American Surgeon, vol. 68, no. 7, pp. 591–592, 2002.American Surgeon, vol. 68, no. 7, pp. 591–592, 2002.

38. UREMIC TUMORAL CALCINOSIS

39. Introduction Periarticular mass Solitary or multifocal In HD also in PD “The most important pathogenic factors in UTC are an increased Ca P product and hyperphosphoremia, which is not necessarily related to hyperparathyroidism.” Journal of Rheumatology 2006;33:119–26Journal of Rheumatology 2006;33:119–26

40. Incidence: 0.5% to 3% in uremic patients on hemodialysis Journal of Rheumatology 2006; 33:119–26Journal of Rheumatology 2006; 33:119–26 1.6% in PD Perit Dial Int 2011; 31(4):430-439Perit Dial Int 2011; 31(4):430-439 Time from dialysis start to the development of UTC: HD: PD = 63.3 months : 45.3 months Perit Dial Int 2011; 31(4):430-439Perit Dial Int 2011; 31(4):430-439

41. Clinical features Periarticular tumors that sometimes reduce the range of motion Lesions not painful unless impinging on a local nerve Ulcerative? Usually nonulcerative Shallow skin ulcer only because of repetitive abrasion at the late status

42. Radiologic features Radiography a lobulated calcific mass within soft tissues usually affects extensor surfaces CT lobulated cystic calcifications, which communicate with the bursa in many cases

43. MRI T1-weightedMR imaging inhomogeneous lesions with low signal intensity T2-weightedMR imaging (a) a diffuse lower-signal-intensity pattern or (b) a bright nodular pattern with alternating areas of high signal intensity and signal void T1 CT

44. Characterization of calcific deposits Components Calcium phosphate Hydroxyapatite (HAP) Carbonate-substituted apatite A mixture of carbonate apatite and calcium carbonate HAP is the most stable and least soluble among calcium-phosphate salts, whereas carbonate- substituted apatite is much more soluble.

45. Differential diagnosis Causes of dystrophic calcification Connective tissue diseases Progressive systemic sclerosis Mixed connective tissue disease Dermatomyositis Polymyositis Systemic lupus erythematosus Neoplastic diseases Synovial sarcoma Osteosarcoma Chondrosarcoma Metaplasia Synovial osteochondromatosis Degenerative diseases Calcium pyrophosphate deposition disease Calcific tendonitis Calcific bursitis Causes of metabolic calcification Hyperphosphatemia Chronic renal failure Hypercalcemia Primary hyperparathyroidism Milk alkali syndrome Hypervitaminosis D Sarcoidosis Hydroxyapatite deposition disease Hyperuricemia Tophaceous gout

46. Therapies Medical treatment: Dietary phosphorus restriction Non-Ca phosphate binder Calcimimetics Optimal control of secondary hyperparathyroidism (SHPT) Bisphosphate Intensive HD with low-Ca dialysate Surgical treatment: Local excision Parathyroidectomy Renal transplantation Am J Kidney Dis 2004; 43:712–20

47. Aggressive medical measures combined with intermittent HD has been reported to achieve complete resolution of UTC in a PD patient Kidney Int 2006; 70:1887. Some reports showed that combined therapy with bisphosphate and steroid would be successful treatment of uremic tumoral calcinosis. Nephrol Dial Transplant (1999) 14: 2716-2719Nephrol Dial Transplant (1999) 14: 2716-2719 Clinical and Experimental Nephrology, Volume 15, Number 1, February 2011, 154-158Clinical and Experimental Nephrology, Volume 15, Number 1, February 2011, 154-158

49. Follow-up Scintigraphy Help in screening multiple lesions CT scan Help in identifying the extent of a localized lesion such as joint involvement Ultrasound Showed localized multiloculated fluid accumulation within hyperechoic masses and perifocal interstitial fluid collection Can help to determine the activity of the lesion Journal of Clinical Imaging 30 (2006) 66–68Journal of Clinical Imaging 30 (2006) 66–68

50. A risk of CUA(Calcific Uremic Arteriolopathy)? No literature discussed about it One case report showed a hemodialysis patient suffered from UTC and CUA simultaneously.

51. Peritoneal Dialysis International, Vol. 31, pp. 430-439Peritoneal Dialysis International, Vol. 31, pp. 430-439

52. ABOUT HYPERPARATHYROIDISM

53. “Hyperparathyroidism is not a prerequisite for calciphylaxis” Nephrol Dial Transplant 1993; 8: 1270–1273Nephrol Dial Transplant 1993; 8: 1270–1273 A case in hemodialysis suffered from tumoral calcinosis, without hyperparathyroidism. Adv Perit Dial. 2008;24:132-6.Adv Perit Dial. 2008;24:132-6.

54. Some reports showed that there was no benefit from parathyroidectomy in some patients with calciphylaxis. Metastatic calcification in CKD including the severe types such as uremic tumoral calcinosis and calcific uremic arteriolopathy may be multifactorial etiology.

55. IN THE FUTURE

56. Calciprotein particles calcium-regulatory proteins including fetuin-A (α-2-HS-glycoprotein), osteopontin and matrix Gla protein (MGP) Pyrophosphates system activation of pyrophosphate synthesis or transport inhibition of pyrophosphate degradation pyrophosphate and adenosine replacement

57. BACK TO OUR PATIENT

58. Bisphosphates + Steroid Short term hemodialysis Followup Laboratory examination Image: X-ray, CT scan Ultrasound??

59. SUMMARY

60. Metastatic calcification in chronic kidney disease Presentation Cardiovascular disease is common Uremic tumoral calcinosis(UTC) Calcific uremic arteriolopathy(CUA) Risk factors Ca x P product: above 60 – 68 mg2/dL2 & hyperphosphatemia Use of calcium-based phosphate binders and vitamin D analogs Hyperparathyroidism: not prerequisite Treatment Control of Ca x P product and hyperphosphatemia +/- hyperparathyroidism Much new idea for mechanism and novel therapies

61. Thanks for attention