NEPHROLOGIC CASE CONFERENCE R3 呂建儒. Base information 張先生 58 year-old male Nephrotic syndrome, membranous nephropathy (biopsy result from 榮總 ) ESRD on.

NEPHROLOGIC CASE CONFERENCE

R3 呂建儒

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

Chief complaint

• Multiple small hard nodules over hand and hand joints for 4 months

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 4th finger and left hand(can not grasp tightly), associated with pain recently

• Persistent hypercalcemia, hyperphosphatemia, and hypoalbuminemia at clinic followup

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

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

Laboratory examination

1/20 2/21 3/21 4/18 5/20 6/14

WBC 5100 6900

Hb/Hct 8.6/25.3 7.9/22.7 7.9/23.2 8.5/24.5 7.8/22.5 8.4/24.9

BUNCr

92.612.9

103.710.9

97.311.12

98.110.72

9911.37

69.510.79

Na 134 127 132 12.6 129 133

K 3.8 3.8 4 4.4 3.6 3.2

CaP

12.56.7

10.76.6

11.76.3

11.67.8

11.37.8

11.17.1

Albumin 3.03 2.73 2.66 2.47 2.61 2.69

iPTH 7.8 5.6

Alk-P 138 195

Image study6/14 6/14

Impression

• Metastatic calcifications, uremic tumoral calcinosis, hyperphosphatemia and hypercalcemia related

• End stage renal disease on CAPD• Liver cirrhosis, child B, HBV related

Admission course

Follow-up at clinic

7/09 7/18 8/18

Ca/P 8.7/6.0 9.1/6.0 10.3/6.5

Albumin 2.79 3.0

• No pain nor deterioration in local swelling and range of motion at periarticular masses of upper limbs

• Mild numbness at hands• Sometimes muscle cramping

METASTATIC CALCIFICATION

Extraosseous calcification

• Calcinosis cutis• Dystrophic calcification• Metastatic calcification• Idiopathic calcification

• Tumoral calcinosis

• Iatrogenic calcification• Calciphylaxis

• J Am Acad Dermatol 2011;65:1-12J Am Acad Dermatol 2011;65:1-12

• Tumoral calcinosis• Familial tumoral calcinosis• Dystrophic tumoral calcinosis• Metastatic tumoral calcinosis

• RadioGraphics 2006; 26:871–885RadioGraphics 2006; 26:871–885

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

Metastatic Calcinosis

• Hyperphosphatemia• Hypercalcemia• Gout—calcified tophi

METASTATIC CALCINOSIS IN CHRONIC KIDNEY DISEASE

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

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

• 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

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)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.J Ren Nutr 2007; 17:389–96.

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

CALCIFIC UREMIC ARTERIOLOPATHY

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, Journal of the American Society of Nephrology, vol. 7, no. 7, pp. 978–982, 1996.1996.

• 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

Clinic features• Livedo reticularis

• Painful, plaque-like subcutaneous nodules

• Ischemic/necrotic ulcers with eschars

• Sometimes local infection (erythema, pus)

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

Prognosis

• One-year survival rate of 45.8 %• Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569–Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569–

579, 2007579, 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.

• 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

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

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.

• 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.

• 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.

• 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–Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 569–

579, 2007.579, 2007.

• 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.

• 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.

UREMIC TUMORAL CALCINOSIS

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

• 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):430-439 Perit 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):430-439 Perit Dial Int 2011; 31(4):430-439

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

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

• 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

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.

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

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; 43:712–20Am J Kidney Dis 2004; 43:712–20

• 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.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-Clinical and Experimental Nephrology, Volume 15, Number 1, February 2011 , 154-158158

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

• 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.

ABOUT HYPERPARATHYROIDISM

• “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.

• 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.

IN THE FUTURE

• 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

BACK TO OUR PATIENT

• Bisphosphates + Steroid• Short term hemodialysis

• Followup• Laboratory examination• Image:

• X-ray, CT scan• Ultrasound??

SUMMARY

• 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

Thanks for attention