An elderly suffering from acute renal failure Speaker: Dr C W Chow Chairperson: Dr W T Wong Intensive Care Unit Caritas Medical Centre 24th July 2012

Our Patient M/79 Hypertension Old cerebrovascular accident, CT brain: left internal capsule old infarct Benign Prostatic hypertrophy First presented to CMC Medical Clinic in Dec 2008 for renal impairment.

History of multiple myeloma Renal impairment Ur: 8.2mmol/L Cr: 202umo/L Normochromic Normocytic anaemia Hb: 7.6g/dL Reverse A/G ratio Albumin 23g/L, Globulin 96g/L

Previous work up for multiple myeloma Serum electrophoresis and immunofixation Monoclonal IgG/Lambda detected. IgG: 7070mg/dl (819-1725mg/dl) IgA: 24mg/dl (70-386mg/dl), IgM: 16mg/dl (55-307mg/dl) BMA/Trephine Biopsy: Well differentiated myeloma cell content about 20% of all cells

Treatment of multiple myeloma 10 cycles of Melphalan and Prednisolone Every Cycle M&P for 5 days Melphalan 4mg daily Prednisolone 60mg daily Treatment from 2/2009 to 3/2010

1/09 9/09 2/10 3/10 6/11 IgG 7070 1950 2170 2650 Alb 22 28 31 Glob 90 46 50 52 62 Ur 9.8 5.4 6.8 7.2 8.0 Cr 194 147 126 150 139 Hb 7.6 9.3 9.7 9.6 <---- MP ---> Globulin level and Immunoglobulin level came down after cheomtherapy treatment with steroid and alkylating agent, Methalan Renal function slightly improved after treatment and remained static afterwards.

This admission Presented to medical ward for diarrhoea and decreased urine output on 6th September 2011. Blood test found acute renal failure. Transferred to ICU for acute renal failure and suspected myeloma kidney

This admission 7 Sep 2011 Albumin Globulin Urea Cr Hb HCO3 K+ 21 Globulin 58 Urea 19 Cr 729 Hb 7.7 HCO3 13.9 K+ 4.0 Serum protein electrophoresis Paraprotein in mid gamma region Serum Immunofixation IgG-Lambda paraprotein Urine Protein 3.67g/L Free lambda light chains Urine immunofixation Finding similar to the previous work up, this time likely to be recurrent multiple myeloma with acute renal failure

XR skull, pelvis and chest found no bony lesion

Bone marrow aspiration and trephine biopsy result

Progress USG kidney confimred no evidence of obstructive uropathy. Renal suggested to consider plasmapharesis. Performed Renal Biopsy after stabilization Transferred to ICU

Ig G Albumin Globulin Urea Cr Hb HD Plasma 7/9 8/9 9/9 10/9 11/9 13/9 14/9 Ig G 3110 Albumin 21 20 23 Globulin 58 41 37 29 31 36 30 Urea 19 11 6.2 15 9.4 Cr 729 905 974 596 465 811 529 Hb 7.7 8.1 7.5 7.1 6.5 HD 4hrs Plasma 2.1L 2.4L

Progress PMH Haematology consultation Started on dexamethasone 20mg daily on 16 September. Plan to transfer to PMH Haematology ward for chemotherapy with renal support in PMH.

Deterioration Develop severe abdominal pain with peritoneal sign on 17 September. Surgical team consulted and urgent plain CT abd performed.

Operative record 1L blood stained peritoneal fluid Fibrous band stemming from anti-mesenteric border of sigmoid colon attaching to left pelvic side wall leading to internal herniation and ischemia of small bowel. 80cm full thickness infarct of small bowel Small bowel resection and primary anastomosis

Pathology report Small intestine pathology on 19 Sep Bone marrow smear and trephine biopsy on 14 Sep

Progress Gradual deterioration in renal function again after operation. Decided to try High Cut off Haemodialysis with special large pore dialyser membrane rather than plasmapharesis with intermittent HD.

20/9 21/9 22/9 23/9 24/9 28/9 Alb 18 15 16 14 21 Glob 35 37 33 34 38 Cr 653 620 237 307 169 291 FLC 3820 3100 1150 HCO-HD 8hs Free light chain level decreased by more than 60% after 2 sections of High cuff off haemodialysis. Replacement fluid during HCO HD: formula 4 dialysate, no extra albumin infusion given, albumin level static after treatment. (Regional Citrate was used for anticoagulation )

Progress Renal function remained static. Dialysis independent. Transferred to PMH Haematology on 30 September. Completed consolidation chemotherapy with high dose dexamethasone and Bortezomib and discharge on 12 Oct

Progress After finishing consolidation chemotherapy IgG level down 14-25g/L Hb level around 9g/dL Cr static around 280umol/L Tholidomide as maintenance since Jan 2012 IgG level remained low. Cr static around 200umol/L

High cut-off haemodialysis (HCO HD) in a patient with multiple myeloma

Multiple Myeloma Multiple myeloma is a cancer of plasma cells. Intact immunoglobulin Isolated clonal free light chain (FLC)

Free Light Chain (FLC) Accurate immunoassay found all myeloma patients have detectable free light chain secretion. Serum FLC level depends on level of synthesis by plasma cells and clearance by kidney.

Mechanism of myeloma kidney Production of FLC in normal individual is approximately 500mg per day. Rapidly cleared and metabolized by the kidney within the proximal tubules, half-life of 2-6 hours. In myeloma patient, excessive synthesis of FLC occurs which overwhelm the absorption limit of proximal tubules Dimopoulos MA, Kastritis E, Rosinol L, Blade J, Ludwig H. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 2008;22:1485-93

Cast nephropathy FLC enter the distal tubules causing cast formation and direct cellular damage. Distal tubular casts and interstitial inflammation. Tubular cast is formed by FLC and Tamm-Horsfall protein, a glycoprotein synthesized in medullary thick ascending limbs of loop of Henle Cockwell P, Hutchison CA. Management options for cast nephropathy in multiple myeloma. Curr Opin Nephrol Hypertens 2010;19:550-5

Extracorporeal removal of FLC Free light chain is the culprit of myeloma cast nephropathy. Decrease in serum FLCs should lower renal exposure and slow renal tubular injury. Direct removal of FLCs from the blood is a theoretical attractive treatment option. Benefit will only be achieved in the presence of effective chemotherapy.

Molecular size Kappa light chain 22kDa Lambda light chain 45kDa

High Cut off dialysis Cut off for conventional high flux dialyser in blood is around 10kD. Cut off for HCO HD dialyser is around 45kD. Cut off for plasmafilter is even bigger.

High Cut off dialysis Haemodialysis using conventional or high flux dialyser is ineffective for the removal of FLC due to the small pore size. High cuff off dialyser membrane is characterized by very large pores, 3 times the size of a normal high flux filter. Gondouin B, Hutchison CA. High cut-off dialysis membranes: current uses and future potential. Adv Chronic Kidney Dis 2011;18:180-7.

HCO dialyser membrane HCO membranes offer significantly increased removal of molecules with molecular weights of 15 -60kDa as compared with conventional high flux membrane. Pore size of HCO membrane is adequate for removal of free light chains Gondouin B, Hutchison CA. High cut-off dialysis membranes: current uses and future potential. Adv Chronic Kidney Dis 2011;18:180-7.

Plasma exchange Plasma exchange involve withdrawal of venous blood, separation of blood from plasma and reinfusion of cell plus plasma or replacement fluid. Plasma and blood are separated by centrifugation or membrane filtration Plasma exchange has been suggested for treatment of myeloma kidney by rapidly reducing the plasma concentration of myeloma protein.

Plasma exchange A randomised study in 1988 found patient treated with plasma exchange on top of steroid and cytotoxic therapy had benefit in renal recovery and survival. Another small randomised trial found only more significant lowering of myeloma protein without significant benefit in renal recovery and survival. Comparison of survival Upper graph: treatment group: steroid + cytotoxic drug + plasma exchange + prn dialysis Lower graph: Control grout: Steroid + cytotoxic drug + prn dialysis Renal recovery similar finding Only 15 patients in treatment gp and 14 patients in control group

Plasma exchange Failure of removal of free light chain by plasma exchange is due to the high extravascular distribution and synthetic rate. PE of one plasma volume remove 65% of the intravascular compartment FLC. FLC rapidly reequilibrates with the extravascular reservoir and only 13% of total body load of FLC removed. Extended filtration is not possible for PE. Lower figure: One case study recorded the change in free light chain level after repeated section of plasma change. This study found that fLC level dropped by 30-60% after one section of plasma exchange, but rebound within 10hrs Upper figure: Despite multiple sections of PE, fLC level was gradually rising rather than dropping. fLC level drops only after initiation of chemotherapy.

HCO Dialysis vs Plasma exchange Effective removal of FLC can be achieved by extended HD with HCO dialyser, up to 8hours per section. Mathematical model showed that HCO HD is more effective than PE for removal of FLC. 3: 3.5L PE x6 sections over 12 days 4: HCO HD 3x / week Hutchison CA, Cockwell P, Reid S, et al. Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 2007;18:886-95.

FLCs removal by HCO HD Serum free kappa and lambda light chains are efficiently cleared by High Cut off HD. Two dialyser in series can improve the efficiency of removal of FLCs. Hutchison CA, Cockwell P, Reid S, et al. Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 2007;18:886-95.

Renal recovery Fourteen of the 19 patients who received FLC removal HD became independent of dialysis at a median of 28 d (range 13 to 120) Hutchison CA, Bradwell AR, Cook M, et al. Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 2009;4:745-54

Renal recovery and FLCs removal Renal recovery depends on early reduction of serum FLCs. Renal recovery associates with survival advantage. Hutchison CA, Bradwell AR, Cook M, et al. Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 2009;4:745-54

Disease Specific Treatment (chemotherapy) Early chemotherapy should be commenced to halt further production of FLCs. Traditional treatment Melphalan and prednisolone VAD (Vincristine, Doxorubicin and Dexamethadone) Effect on FLC load in the first few weeks of treatment may be slow. Too slow to prevent irreversible kidney injury.

Bortezomib/Velcade Proteasome inhibitor Proteasome is responsible for the degradation of the vast majority of intracellular proteins, including proapoptotic proteins, and thus affects multiple signaling pathways within cells.

Thalidomide Immunomodulatory effect. Anti-angiogenic properties Birth defect is the most important side effect

Novel chemotherapy agents Novel chemotherapy agents in combination with dexamathadone will obtain the fastest and deepest response. The drugs used should have demonstrated safety and efficacy in renal failure, including dialysis dependent patient. The chemotherapy used should not impaired collection of peripheral blood stem cells for future stem cell transplant. Limited evidence for an optimal chemotherapy regimen for patients with multiple myeloma and acute renal failure Study of bortezomib based regimes for myeloma patient with acute renal failure Most patient (10/17) >50% decreased in Cr level in 35 days Roussou M, Kastritis E, Migkou M, et al. Treatment of patients with multiple myeloma complicated by renal failure with bortezomib-based regimens. Leuk Lymphoma 2008;49:890-5.

Take home message Multiple myeloma with renal impairment at presentation should be considered as medical emergency Prompt diagnosis and treatment of myeloma cast nephropathy is a critical determinant of renal recovery and survival. High cut off haemodialysis combined with novel chemotherapy agents may be the future direction of treatment while awaiting further evidence. Physical removal of free light chain by extra-corporeal method, plasma exchange or HCO haemodialysis, should be seriously considered.

Thank You Questions? Routinue measurement of free light chain level in other hospital