1. Types of renal disease in multiple myeloma (myeloma cast nephropathy; myeloma kidney) Seo Mi Seon 2011. 10. 12

2. Introduction 1. Renal disease is a common problem in multiple myeloma  43% (998 pt.) : plasma cr > 1.5 mg/dL [Kidney Int 1995; 48:1347.]  22% (423 pt.) : plasma cr ≥ 2.0 mg/dL [Arch Intern Med 1998; 158:1889.] 2. General correlation between the presence & severity of renal disease and pt survival 1.5 mg/dL 2.3 mg/dL 80 % 50 % Survival figures in the 5th MRC myeloma trial - cohort of 998 patients (< 75 years ) [Kidney Int 1995; 48:1347.]

3. TYPES OF RENAL DISEASE  usually, monoclonal immunoglobulin light chains rare occasions, monoclonal heavy chains or entire Ig non-monoclonal protein-related renal injury  Types of kidney disease by the primary site of injury  Glomerular  Primary (AL or rarely AH) amyloidosis  Monoclonal immunoglobulin deposition (light chain deposition disease, heavy chain deposition disease, and light and heavy chain deposition disease)  Miscellaneous (cryoglobulinemia, proliferative glomerulonephritis, etc)  Tubular  Light chain cast nephropathy (myeloma kidney) : m/c, 40-60% [Nephrol Dial Transplant 1998; 13:1438. ]  Distal tubular dysfunction  Proximal tubule dysfunction or acquired Fanconi's syndrome  Interstitial  Plasma cell infiltration  Interstitial nephritis

4.  Glomerular  Primary (AL or rarely AH) amyloidosis  Monoclonal immunoglobulin deposition (light chain deposition disease heavy chain deposition disease light and heavy chain deposition disease) : nephrotic syndrome urine dipstick : positive (glomerular leak) urine electrophoresis (24hr) : albumin immunofixation : monoclonal light chains amyloidosis : Congo red, B-pleated fibrils LCDD : not form fibrils, Congo red negative  Miscellaneous (cryoglobulinemia, proliferative glomerulonephritis, etc) Type I cryoglobulinemia : rare cause of glomerular disease monoclonal immunoglobulin forms cryoprecipitates → membranoproliferative pattern with intraluminal "thrombi" on renal biopsy both MPGN & RPGN have been described in selected patients (relation to the myeloma : uncertain)

5.  Tubular  Light chain cast nephropathy (myeloma kidney) : m/c, 40-60% [Nephrol Dial Transplant 1998; 13:1438. ]  Distal tubular dysfunction  Proximal tubule dysfunction or acquired Fanconi's syndrome : toxic effect of filtered light chains : limited to tubular dysfunction PT : most prominently affected d/t the reabsorption of filtered light chains & accumulation Fanconi syndrome : proximal renal tubular acidosis & phosphate wasting  Interstitial  Plasma cell infiltration  by itself, rarely severe enough to impair renal function  Interstitial nephritis  associated with light chain deposition in TBM  Immunogold labeling : light chains are deposited in the outer aspect of TBM & lysosomes of tubular epithelial cells Glomerular deposits : absent

6.  only one type of renal disease is clinically manifest in the majority of pts  patients with cast nephropathy rarely develop the nephrotic syndrome d/t amyloidosis, LCDD  patients with amyloidosis, LCDD rarely develop ARF from cast nephropathy  light chain fragments in primary amyloidosis or LCDD : not toxic to the tubules and/or less likely to form intratubular casts  pathologic findings of more than one type of disease : not so uncommon [Am J Kidney Dis 1983; 2:423.] [J Am Soc Nephrol 2001; 12:1482.]

7.  other causes of renal failure or renal disease in multiple myeloma  Volume depletion (as a contributor to cast nephropathy, or d/t acute tubular necrosis)  Hypercalcemia, with or without nephrocalcinosis  15% : plasma ca > 11mg/dL  ↑ bone resorption ( cytokines lymphotoxin, interleukin-6)  Renal failure  by causing renal vasoconstriction  by leading to intratubular calcium deposition  by increasing the toxicity of filtered light chains  Tubulointerstitial nephritis  Plasma cell infiltration of the kidneys  Hyperviscosity syndrome  certain cases, abnormal polymers of IgA, IgG, or kappa light chains are produced → impairment in the microcirculation of CNS, renal failure

8.  ARF may be precipitated by  Nephrotoxic drugs (eg, NSAIDs, ACEI, ARB)  Infection  Intravenous contrast media  Pamidronate  Hyperuricemia  50%  may contribute to acute renal failure  sufficiently rapid tumor turnover is unusual even after chemotherapy overt tumor lysis syndrome : rare

9. myeloma cast nephropathy (myeloma kidney)  monoclonal urinary Ig light chains (Bence Jones proteins) → acute or chronic renal failure  Light chains  molecular weight : 22,000  freely filtered across the glomerulus  largely reabsorbed by the proximal tubular cells  normal rate of excretion : < 30mg/day  overproduction > reasorptive capacity → excretion 100mg – 20g/day  not detected by the urinary dipstick : albumin  sulfosalicylic acid (SSA) : all protein → negative or trace-positive dipstick & markedly positive SSA test → non-albumin proteins (light chains)

10. myeloma cast nephropathy (myeloma kidney) - pathogenesis  urinary light chains lead to renal failure : two factors 1. intratubular cast formation 2. direct tubular toxicity Light chains can precipitate in the tubules → obstructing, dense, intratubular casts in DT, CT (initiate a giant cell reaction) casts contain Tamm-Horsfall mucoprotein (THMP, uromodulin) uncertain function normally secreted by cells of the thick ascending limb of the loop of Henle constitutes the matrix of all urinary casts [Kidney Int 1995; 48:1347.]

11. HPF, PAS stain, tubular casts in myeloma kidney bottom two tubules → casts composed of PAS-negative Ig light chains middle tubule (probably hyaline) → primarily composed of PAS-positive THMP classic features of cast nephropathy 1)obstructed tubule with a fractured dense cast 2) giant cell reaction in the lower left part of the tubule 3) interstitial infiltrate IF with anti-human lambda antiserum variable staining of intratubular Ig light chain casts multiple myeloma excreting monoclonal lambda light chains

12.  contributor to cast nephropathy  volume depletion : important  promote cast formation by slowing flow within the tubules by promoting the formation of large aggregates  Loop diuretics  by increasing luminal sodium chloride  Increased urinary calcium  as a result of hypercalcemia  Radiocontrast media  interact with light chains  promote intratubular obstruction

13.  Role of tubular injury cast formation is relatively minor in some pt. degree of renal failure correlates best with tubular damage & atrophy Reabsorption of filtered light chain into tubular cell → tubular injury (PT) → interfere with lysosomal function Tubular injury → promote the development of renal failure PT dysfunction →↓ proximal light chain reabsorption → ↑ delivery to the distal nephron (cast formation can occur) interfere with tubular function in the loop of Henle → ↑ tubular fluid sodium chloride concentration → ↑ aggregation of light chains with THMP → ↑ cast formation [Kidney Int 1995; 48:1347.]

14.  Light chain charicterics  Excrete > 1g of light chain/day  Much larger quantities are excreted w/o substantial change in renal function  Different light chains have a variable nephrotoxic potential  Infusion of light chains into mice produce the same form of renal disease  Cast nephropathy  one important determinant of the potential of a particular light chain to form intratubular casts : affinity of its binding to THMP  specific binding site for immunoglobulin light chains : linear sequence of nine amino acids  Light chains with high affinity : more likely to produce obstructing intratubular casts [N Engl J Med 1991; 324:1845.] [J Clin Invest 1997; 99:732.]

15.  Genesis of myeloma kidney [Kidney Int 1995; 48:1347.] Intratubular cast formation Tubular injury Volume depletion Loop diurectics Increased urinary calcium Radiocontrast media Light chain characteristics Binding affinity to THMP

16. myeloma cast nephropathy (myeloma kidney) - Diagnosis  urine dipstick  primarily senses albumin  negative or only trace positive for protein  sediment : typically bland  sulfosalicylic acid (SSA)  detects all proteins  markedly positive SSA test with a relatively negative dipstick : highly suggestive of the presence of non-albumin proteins (such as light chains (Bence Jones protein))  serum protein electrophoresis, immunofixation, free light chain assay (24-hour urine collection and serum)  based on suggestive clinical features and the presence of elevated quantities of monoclonal free light chains in both the plasma and urine  definitive diagnosis requires a kidney biopsy

17. Treatment of renal failure in multiple myeloma  20% : renal failure [Arch Intern Med 1998; 158:1889.]  acute renal failure : multifactorial  hypercalcemia, volume depletion, hyperuricemia, hyperviscosity (rare), toxicity d/t IV radiocontrast media, NSAIDs, ACEI, ARB → Specific treatment is directed at the cause of ARF 1. Chemotherapy : MM, myeloma cast nephropathy, ARF bortezomib, thalidomide, and dexamethasone or thalidomide and dexamethasone (Grade 1B) as rapidly as possible to decrease light chain production hematopoietic cell transplantation

18. 2. Intravenous fluids  to treat volume depletion, hypercalcemia, hyperuricemia  vigorous intravenous fluid therapy → mainstay of therapy of ARF  goal : to decrease the light chain concentration within the tubular lumen and produce a high urine flow rate to minimize light chain precipitation  isotonic or one-half isotonic saline (Grade 1B) at an initial rate of 150 mL/h urine output at 100 to 150 mL/h (3 L/day)  loop diuretics (fluid overload)

19. 3. Hypercalcemia Tx.  corrected serum calcium < 14mg/dL (4 mmol/L)  treat initially with the fluid regimen  If persists despite 6 to 12 hours of fluids  bisphosphonate  zoledronic acid : 4 mg IV over 15 minutes  pamidronate : 60 - 90 mg over 2-3 hours  corrected serum calcium ≥ 14mg/dL (4 mmol/L)  Bisphosphonate immediately (Grade 1B)  Fluid regimen 4. Hyperuricemia  if present, should be treated 5. NSAIDs, ACEI, ARB should be stopped radiocontrast dye avoided if possible

20. 6. Plasmapheresis for the removal of toxic circulating free light chains from the plasma in ARF and suspected myeloma cast nephropathy (Grade 2B) Efficacy of plasmapheresis in multiple myeloma Serum protein electrophoresis before (left panel) and after (right panel) four consecutive daily plasma exchanges in a patient with multiple myeloma and acute renal failure monoclonal peak representing the circulating light chains (arrow) : essentially disappeared

21.  randomized trials  efficacy of plasmapheresis  29 patients  multiple myeloma  acute renal failure  significant Bence Jones proteinuria (24 : required dialysis)  randomly assigned  to plasma exchange + glucocorticoids, cytotoxic drugs + hemodialysis (if required)  to glucocorticoids, cytotoxic drugs, peritoneal dialysis (if required) (—) renal failure requiring dialysis; (— — —) renal failure not requiring dialysis; (...) serum creatinine <2.5 mg/d 13/15 (87%) vs 2/14(14%) : recovered renal function Kidney Int 1988; 33:1175.

22. Kidney Int 2008; 73:1282. Renal response by reduction of sFLCs Patient survival based on renal response. Median survival 31.8M vs 11M  retrospective study  40pt  biopsy-proven cast nephropathy  serum free light chains measured before and after plasmapheresis  renal response : 50 percent reduction in serum creatinine  dialysis independence at 180 days in 7/9 (77.8 %) (>50% light reduction)

23.  Indications  Patients with cast nephropathy on kidney biopsy  highly suggestive clinical presentations high levels of free monoclonal light chains in the serum or urine, even in the absence of a renal biopsy  Protocol  5-7 exchanges within 7-10 days  + dexamethasone- containing chemotherapy to reduce the rate of light chain production → repeat monoclonal light chain assay (to monitor recurrent light chain accumulation) → 1-2 days after completing the initial course of plasma exchange → recurrence of excess light chain production → repeat a course of plasma exchange

24. 7. Dialysis (Grade 2C)  remove circulating light chains  but the efficiency is much less than that with plasmapheresis  net light chain removal in 50 liters of peritoneal dialysate : only 2 grams  one five liter plasma exchange : 17 grams  both standard and high-flux hemodialysis unlikely to remove substantial amounts of light chains  until more evidence is available dialysis should be initiated for the usual indications (eg, fluid overload, hyperkalemia, uremia) not for the removal of free light chains  plasmapheresis using citrate anticoagulation → alkalemia → should be performed after plasmapheresis to correct the alkalemia

25. Clin J Am Soc Nephrol 2009; 4:745. 19 dialysis-dependent patients c multiple myeloma& cast nephropathy 13 pts extended dialysis + chemotherapy Gambro HCO 1100 hemodialysis membrane 8hrs/day (5d), 8hrs/QOD (12d), 6hrs/3times/week 6pts : chemotherapy Comparison of reductions in serum FLC concentrations Renal recovery rates 81% 63% 39% 94% 15% 30% independent of dialysis at a median of 28 d (range 13 to 120) Vs 1: recovery of renal function by 105 days

26. Prognosis  no clinical predictive factors at presentation  significant renal dysfunction at presentation tend to have worse outcomes  reported rates of improvement in kidney function range : 50 – 80%  dense cast formation and significant tubular damage : less likely to recover kidney function [Kidney Int 1988; 33:1175.][Am J Kidney Dis 1987; 10:28.] [Arch Intern Med 1990; 150:1693.]

27. Chronic renal failure  Optimal therapy is less certain in slowly progressive disease  Improvement is much less likely in diffuse, dense intratubular cast formation on kidney biopsy  insufficient evidence of benefit from plasmapheresis generally suggest chemotherapy alone to reduce light chain production [Am J Kidney Dis 1987; 10:28.]

28. ESRD  ESRD d/t multiple myeloma, survive the first two months  actuarial survival : 45 % at one year 25 - 30 % at 2-3 years  ESRD who respond to chemotherapy with a reduction in light chain  mean survival : 47 months versus only 17 months in nonresponders [Q J Med 1989; 73:903.] [Am J Kidney Dis 1990; 16:216.]

29. Survival curves for patients receiving dialysis and for patients with renal failure of lesser degree (milder RF). Am J Kidney Dis 1997; 30:786. One retrospective study 140 patients with multiple myeloma 7 ± 4 mL/ min : requiring dialysis 30 ± 14 mL/min : milder renal impairment Survival in the two groups is identical (median, 22 months).

30. Kidney transplantation  limited to case reports and case series  < 50 patients being reported  review of eight case reports  renal and patient survival : 14 to >96 months  retrospective review 7 patients with LCDD, renal transplantation  1 : died shortly after transplant of progression of multiple myeloma  5 : LCDD recurred after a median of 33 months (range 2 to 45) (4 : died shortly after recurrence)  1 : successful transplant outcome [Transplantation 1996; 62:1577.] [Am J Kidney Dis 2004; 43:147.]