1. Department of Nephrology Hypercalcemia R4 Song Se-bin

2. Calcium regulation

3. Etiology

4. Clinical manifestations  Mild hypercalcemia ( to 11-11.5 mg/dL)  Asymptomatic, trouble concentration, depression, nephrolithiasis …  Severe hypercalcemia ( > 12-13 mg/dL)  Lethargy, stupor, or coma, GI Sx (nausea, anorexia, constipation, or pancreatitis), polyuria, polydipsia, bone pain, pathologic Fx.  Bradycardia, AV block, short QT interval

5. Diagnosis If albumin<4.1mg/dl Alb. 1.0 Ca 0.8 Chronic hypercalcemia Low phosphorus PTH resistant Family Hx ① Albumin ② Intact PTH ③ PTHrp ④ 1,25 or 25 Vit. D ⑤ TFT ⑥ SPEP, UPEP ⑦ Ca/Cr clearance ratio

6. Treatment  4-6L iv hydration for first 24hr  Loop diuretics  CHF…  Sodium and calcium excretion  Not initiated until volume status to normal  Bone resorption inhibition (bisphophonate)  Malignancy or severe hyperparathyroidism  Onset : within 1-3 days, normalization in 60-90% patients  Zoledronic acid (4mg iv over ~30min)  Pamidronate (60-90mg iv over 2-4hr)  Etidronate (7.5mg/kg per day for 3-7 days)

7.  Glucocorticoids  1,25(OH) 2 D-mediated hypercalcemia  Decrease 1,25(OH) 2 D production  IV hydrocortisone (100-300mg daily) or  oral PDL (40-60mg daily) for 3-7 days  Ketoconazole, chlorquine, hydroxychloroquine  Decrease 1,25(OH) 2 D production  Calcitonin, rarely used  Dialysis, occasionally

9. Renal disease in multiple myeloma Department of Nephrology R4 Song Se-bin

10. Introduction  Common problem in multiple myeloma  Renal insufficiency  In 43% of 998 patients, Cr > 1.5mg/dL  In 22% of 423 patients, Cr > 2.0mg/dL Winearls et al. Kidney Int 1995;48:1347 Blade et al. Arch Intern Med 1998;158:1889  General correlation between presence and severity of renal disease and patient survival.  1 yr survival -> 80% in Cr 2.3mg/dL  Renal fuctional recovery in 26% of those with renal insufficiency  Median survival of 28 months vs 4 months in those with irreversible renal failure Blade et al. Arch Intern Med 1998;158:1889

11. Types of renal disease  Glomerular  Primary (AL or rarely AH) amyloidosis  Monoclonal immunoglobulin deposition (light chain or heavy chain deposition disease, and light & heavy chain deposition disease)  Miscellaneous (cryoglobulinemia, proliferative GN, etc)  Tubular  Light chain cast nephropathy (myeloma kidney) m/c  Distal tubular dysfunction  Proximal tubule dysfunction or acquired Fanconi's syndrome  Interstitial  Plasma cell infiltration  Interstitial nephritis

12.  clinical renal disease in 41 of 81 patients  cast nephropathy in 27 (65%), light chain deposition disease in 2 (5%), amyloidosis in 3 (7%) Ivanyi et al. Acta Morphol Hung 1989  Myeloma cast nephropathy  40~60% of renal disease in MM  Significant renal dysfunction  May be negative with urine dipstick for protein  Presenting manifestation in MM  Amyloidosis or light chain deposition disease  Presenting nephrotic syndrome  positive with dipstick

13.  Other cause of renal disease or renal failure in MM  Volume depletion (as a contributor to cast nephropathy, or due to acute tubular necrosis)  Hypercalcemia, with or without nephrocalcinosis  Tubulointerstitial nephritis  Plasma cell infiltration of the kidneys  Hyperviscosity syndrome

14. Renal amyloidosis

15. Light chain deposition disease

16. Myeloma cast nephropathy  Light chains  MW about 22,000  Freely filtered across glomerulus and reabsorbed by proximal tubular cells  General, Light chain excretion less than 30mg/day  In MM, 100 mg to 20 g/day

17. Pathogenesis in cast nephropathy  Intratubular cast formation in distal and collecting tubules -> tubular obstruction  Filtered light chains + Tamm-Horsfall mucoprotein  Contributor to cast formation  Loop diuretics by increasing luminal sodium chloride  Increased urinary calcium  Radiocontrast media, which may interact with light chains and promote intratubular obstruction

18.  Tubular injury  Proximal tubular injury  Filtered light chain-> resorption into proximal tubular cells -> accumulation within cells -> interfere with lysosomal function -> decrease proximal light chain reabsorption  Tubular injury in loop of Henle  Increase in tubular fluid sodium chloride conc. -> increase aggregation of light chain  Light chain characteristics  Specific binding site for Ig light chains on THMP  High affinity for THMP -> increase cast formation  Cationic BJ proteins + anionic THMP  Reducing by urine alkalinization

19. Diagnosis in cast nephropathy  Acute or subacute kidney injury -> dipstick protein (-) but quantitative urine protein (+) -> serum / urine protein electrophoresis and immunofixation, free light chain assay  Kidney biopsy (definitive diagnosis)

23. Treatment in cast nephropathy  Dexamethasone based chemotherapy  thalidomide and dexamethasone, or bortezomib, thalidomide, and dexamethasone) initiated as rapidly as possible to decrease light chain production  Plasmapheresis + chemotherapy  Volume replacement and maintenace high urine output(>3L/day)  Hypercalcemia Tx  Hydration  Bisphosphonate (Ca>14mg/dL or unresponsive hypercalcemia)  Bone resorption inhibition (bisphophonate)  Onset : within 1-3 days, normalization in 60-90% patients  Zoledronic acid (4mg iv over ~30min)  Pamidronate (60-90mg iv over 2-4hr)  Etidronate (7.5mg/kg per day for 3-7 days)