Vasishta Tatapudi, M.D. October 23rd, 2012.

Case Summary

Chief complaint: 45 year old African American male patient presented with left shoulder pain after minor trauma.

History of present illness: Two months prior to presentation to ER, the patient was treated conservatively for rib fractures after being hit by a bicycle. In the interim period, he developed progressively worsening low back pain, lower extremity weakness, generalized fatigue and significant weight loss.

Past medical history: Hypertension, Diabetes, Depression.

Past surgical history: None.

Medications: Amlodipine 10mg od, glipizide XL 5mg od.

Allergies: None.

Family History: Hypertension, asthma. No family history of kidney disease.

Social history: Former smoker, quit 5 years prior, 10 pack year history of smoking.

Review of systems: No chest pain, palpitations, cough, expectoration, wheezing

or fever. No headache, dizziness, weakness, numbness or LOC. No abdominal pain, vomiting, diarrhea, constipation, blood in

stool. The patient reported 20 lb weight loss in one month and loss

of appetite. Denied nocturia, hesitancy, post-void dribbling of urine,

frequency or dysuria. No history of HIV test in the past.

Vitals: T 100.6, P 117, RR 21 BP 168/108. General: Middle aged male, appearing lethargic. HEENT: mild conjunctival pallor. Neck: No JVD. No cervical lymphadenopathy, supple neck. Chest: clear to auscultation. CVS: Normal S1 S2, regular rhythm, 2/6 systolic murmur at apex. Abdomen: non-distended, normal bowel sounds, soft, non-tender. No mass or organomegaly. CNS : diminished knee jerk and ankle jerk, 3/5 motor strength in muscle groups of bilateral lower extremities. Extremities: No pedal edema, distal pulses palpable.

Hemoglobin 6.9 Sodium 125 Protein 16.4

Hematocrit 19.8 Potassium 3.8 Albumin 3.4

MCV 91.3 Chloride 101 ALT 28

WBC 8.9 Bicarbonate 25 AST 32

Platelets 177 Blood urea 40 ALP 76

PTT 30.9 Creatinine 2.4 Total Bilirubin 0.3

INR 1.51 Glucose 99 Direct Bilirubin 0.1

Calcium 12.1 Corrected Ca 12.2

Anion Gap -1 Corrected AG 1

Urinalysis

Color Yellow Blood Negative

Specific Gravity <1.005 Leuk. Est. Trace

pH 8.0 Nitrite Negative

Protein 1+ RBC 2-5/hpf

Glucose Negative WBC Rare

Bilirubin Negative Bacteria Few

Ketones Negative Epithelial cells Occasional

Casts None

Urine Protein 83 mg/dL P/Cr Ratio 2.8

Urine Creatinine

29mg/dl

EKG: 74 bpm, normal sinus rhythm, non specific ST-T changes, unchanged from prior EKGs.

Chest X Ray: non-displaced left clavicular fracture, osteopenia.

CT chest w/o contrast: notable for multiple healing rib fractures.

The patient was admitted to the medical floor. IV fluids were started for AKI and hypercalcemia. Orthopedics recommended conservative management for fracture of the clavicle.

Hematology evaluated patient and recommended obtaining SPEP, UPEP, serum and urine immunofixation and free light chains. Bone marrow biopsy was done 2 days after admission.

Nephrology consult was requested for management of AKI and hypercalcemia refractory to IV fluids.

SPEP Marked hyperproteinemia, increased alpha 1,2 and beta globulins with a very large peak in the gamma region, compatible with monoclonal gammopathy.

UPEP Two distinct peaks in gamma region that may represent a monoclonal immunoglobulin.

Serum Immunofixation

Ig G: 12739 (694-1618) mg/dL IgA: 13 (81-463) mg/dL IgM: <5 (48-271) mg/dL Ig G Kappa monoclonal protein present.

Bone marrow biopsy: A population of kappa restricted plasma cells (18%) is detected, consistent with plasma cell dyscrasia. A small population of kappa restricted B cells is detected.

Day 1 Day 4 Day 10 Day 16 Day 22 Day 30

Sodium 125 131 128 135 129 128

Potassium 3.8 3.8 3.9 5.0 4.7 4.7

Chloride 101 99 97 108 101 97

Bicarbonate 25 27 22 22 24 28

Blood urea 40 63 47 62 34 33

Creatinine 2.4 3.7 3.2 1.5 0.9 0.7

Glucose 99 99 91 214 224 129

Calcium 12.1 11.7 7.6 7.1 7.6 8.5

Kappa Lambda Kappa/Lambda

Day 4 5690 mg/dL 1.42 mg/dL

4007

Day 18 3810 mg/dL

1.74 mg/dL 2189

Prevalence

Prognostic implications

Types of kidney disease

Cast Nephropathy

Plasmapheresis

Kidney disease is a common problem in multiple myeloma.

It is frequently the presenting manifestation in multiple myeloma.

The pathology is very heterogeneous and may involve a variety of different mechanisms.

Sanders PW et al Lab Invest. 1991;64(4):527.

The frequency with which kidney disease occurs varies with the definition used for renal insufficiency.

In two large series, 43 percent of 998 patients had a plasma creatinine concentration above 1.5 and 22 percent of 423 patients had a plasma creatinine concentration ≥2.0 mg/dL.

Winearls CG, Kidney Int. 1995;48(4):1347. BladéJ, Fernández-Llama P, Arch Intern Med. 1998;158(17):1889.

There is a general correlation between the presence of renal disease and patient survival.

One-year patient survival of 80 percent in those with a plasma creatinine concentration below 1.5 mg/dL versus 50 percent in those with a plasma creatinine concentration above 2.3 mg/dL at disease presentation.

Winearls CG, Kidney Int. 1995;48(4):1347.

The response of the renal disease to therapy has prognostic value.

Recovery of renal function is associated with greater survival.

BladéJ, et al, Arch Intern Med. 1998;158(17):1889.

Renal involvement in multiple myeloma is usually the result of monoclonal immunoglobulins.

Non-monoclonal protein-related renal injury may also occur.

The types of kidney disease can be classified by the primary site of injury.

Primary (AL or rarely AH) amyloidosis Monoclonal immunoglobulin deposition Collapsing FSGS due to drugs

Light chain cast nephropathy (myeloma kidney) Proximal tubule dysfunction or acquired Fanconi's syndrome Distal tubular dysfunction

Interstitial

Plasma cell infiltration Interstitial nephritis

Volume depletion (as a contributor to cast nephropathy, or due to acute tubular necrosis)

Hypercalcemia NSAIDs, angiotensin converting enzyme inhibitors or receptor

blockers Intravenous contrast media Hyperuricemia Hyperviscosity syndrome

In autopsy or biopsy studies, myeloma cast nephropathy is the single most common finding among patients with multiple myeloma.

Iványi B, Acta Morphol Hung. 1989;37(3-4):235. Nasr SH, et al Am J Kidney Dis. 2012;59(6):786.

In an autopsy study of 81 patients with multiple myeloma, 41 patients had clinical renal disease. Among these, 27 (65 percent) had cast nephropathy.

In a biopsy series, among 190 patients with multiple myeloma who underwent a kidney biopsy, cast nephropathy, monoclonal immunoglobulin deposition disease, and amyloidosis were present in 33, 22 and 21 percent of patients, respectively.

Iványi B, Acta Morphol Hung. 1989;37(3-4):235. Nasr SH, et al Am J Kidney Dis. 2012;59(6):786.

Infusion of monoclonal light chains from individual patients

into mice produces the same form of renal disease.

The biochemical characteristics of the individual light chain appear to be a major determinant of which disease (if any) will be seen.

Solomon A, et al N Engl J Med. 1991;324(26):1845.

Solomon A, et al N Engl J Med. 1991;324(26):1845.

Solomon A, et al N Engl J Med. 1991;324(26):1845.

Observations regarding the importance of light chain characteristics and clinical experience have led to the notion that only one type of renal disease is clinically manifest in the majority of patients.

In practice, however, pathologic findings of more than one type of disease are not uncommon.

In a series of 190 patients with multiple myeloma who underwent kidney biopsy, 12 patients had 2 distinct paraprotein-associated lesions.

One patient has been described to have developed cast nephropathy, AL amyloidosis and light chain deposition disease in the same kidney.

Nasr SH, et al, Am J Kidney Dis. 2012;59(6):786. Lorenz EC et al, Nephrol Dial Transplant. 2010;25(4):1340.

Lorenz EC et al, Nephrol Dial Transplant. 2010;25(4):1340.

Lorenz EC et al, Nephrol Dial Transplant. 2010;25(4):1340.

The term myeloma kidney or myeloma cast nephropathy refers to a disorder in which monoclonal urinary immunoglobulin light chains (Bence Jones proteins) lead to acute or chronic renal failure.

They are freely filtered across the glomerulus and then largely reabsorbed by the proximal tubular cells.

The normal rate of light chain excretion is less than 30 mg/day.

However, reabsorptive capacity can be exceeded due to overproduction in multiple myeloma, resulting in an increase in light chain excretion that can range from 100 mg to more than 20 g/day.

Mechanisms of injury:

Intratubular cast formation

Direct tubular toxicity Contributing Factors for cast formation: Volume depletion, tubular sodium and calcium, radio contrast

media, NSAIDs.

Sanders PW, J Lab Clin Med. 1994;124(4):484.

Comprehensive Clinical Nephrology: Expert Consult - Jürgen Floege, Richard J. Johnson, John Feehally

Comprehensive Clinical Nephrology: Expert Consult - Jürgen Floege, Richard J. Johnson, John Feehally

Light chains can precipitate in the tubules, leading to obstructing, dense, intratubular casts in the distal and collecting tubules.

In addition to precipitated light chains, these casts contain other filtered proteins and Tamm-Horsfall mucoprotein.

The limitation of obstructing casts to the distal nephron may reflect the requirement of the excreted light chains to aggregate with THMP derived from the loop of Henle.

Sanders PW, Booker BBJ Clin Inves. 1992;89(2):630.

Patients with multiple myeloma who have AKI with a course and findings consistent with myeloma cast nephropathy should receive chemotherapy.

Plasmapheresis, to rapidly lower the level of circulating free light chains, may be indicated for patients with myeloma cast nephropathy.

The evidence evaluating the effectiveness of plasmapheresis in patients with AKI due to myeloma is conflicting.

• Single center, prospective, randomized, controlled trial.

• Enrolled 29 consecutive patients with multiple myeloma and kidney disease between 1980 and 1986.

• 15 patients underwent plasma exchange together with corticosteroids, cytotoxic drug, hemodialysis only when needed.

• 14 patients underwent peritoneal dialysis together with corticosteroids and cytotoxic drug.

Zucchelli P et al, Int. 1988;33(6):1175.

Zucchelli P et al, Int. 1988;33(6):1175.

Zucchelli P et al, Int. 1988;33(6):1175.

Zucchelli P et al, Int. 1988;33(6):1175.

• Randomized, controlled trial, conducted from 1998 to 2004.

• Hospital plasma exchange units in 14 Canadian medical centers.

• 104 patients between 18 and 81 years of age with acute renal failure at the onset of myeloma.

• Study participants were randomly assigned to conventional therapy plus 5 to 7 plasma exchanges or conventional therapy alone.

• The primary outcome was a composite measure of death, dialysis dependence, or glomerular filtration rate less

30 mL/min per 1.73 m2.

Clark WF et al Ann Intern Med. 2005;143(11):777.

Clark WF et al Ann Intern Med. 2005;143(11):777.

Primary outcome occurred in 69.2% patients in the control group versus 57.9% patients in the plasma exchange group (difference between groups, 11.3% [95% CI, -8.3% to 29.1%]).

The cumulative survival for the 2 groups was similar; 33.3% in the control group and 32.8% patients in the plasma exchange group died by 6 months.

The authors concluded that there was no statistically significant nor clinically meaningful difference in outcomes, although the wide confidence interval of the difference did not exclude the possibility of benefit or harm.

Clark WF et al Ann Intern Med. 2005;143(11):777.

Although Clark’s study was the largest of the three

trials, the number of patients in Clark’s study was still small and was at risk for beta error.

Composite outcome disadvantaged PLEX because patients who died with improved renal function were considered failures.

Renal pathology was not verified due to the low biopsy rate.

No method was employed to assess the adequacy of treatment.

• Retrospective study to investigate the effectiveness of PLEX in the treatment of CN, when the diagnosis is confirmed by renal biopsy and the treatment is guided by serum-free light-chain levels.

• Forty patients met the inclusion criteria.

• Twenty-eight (70%) patients underwent renal biopsy without any serious complications.

Leung N et al, Kidney Int. 2008;73(11):1282.

Leung N et al, Kidney Int. 2008;73(11):1282.

CN was identified in 18 (64.3%) patients.

14 of 18 patients with CN had sFLC measured before and after PLEX.

Renal response occurred in 77.8% (7/9) whose sFLC was reduced by 50% or more.

None of the five patients with <50% reduction in sFLC had a renal response.

Leung N et al, Kidney Int. 2008;73(11):1282.

Leung N et al, Kidney Int. 2008;73(11):1282.

Leung N et al, Kidney Int. 2008;73(11):1282.

Thank you