Nephrology Grand Rounds Vasishta Tatapudi, MD March 26th, 2013.

History • C/C: A 60 year old Chinese female patient with edema and 6.9g proteinuria in a 24 hour urine collection. • HPI: Patient was seen in clinic 1 month prior to admission with c/o generalized fatigue, shortness of breath, occasional palpitations and lower extremity swelling for 3-4 months. Initial labs showed Microalb/Cr ratio of 6.7g/g, hypoabuminemia and elevated cholesterol levels. She returned to clinic 3 weeks later, 24 hour urine collection for protein was ordered. She was followed up one week later. EKG showing premature atrial complexes prompted transfer to ER.

Medical history: None. Surgical history: None. Medications: Lasix 40mg bid, crestor 10mg daily. Allergies: None.

• Health maintenance: Mammogram and pap smear in May 2012, both normal. Never had a colonoscopy. • Family History: Father had heart disease. Sister had breast cancer at age of 60. • Social History: Works as a receptionist and lives with her husband. No history of smoking, alcohol or drug use.

Review of Systems • • • • • • •

Denied history of chest pain. No history of cough, expectoration, wheezing, fever. Never observed blood in urine or frothy urine. Did not notice decreased urine output or a change in urinary habits. No skin rash, oral ulcers, joint pain. No changes in bowel habits, dark or bloody stool. No decrease in appetite, night sweats or weight loss.

Physical Exam General: Elderly female patient, lying in bed, 1 pillow, no distress. Vital signs: 98 F, HR 98, RR 16, BP 110/55. HEENT/Neck: No JVD, no lymphadenopathy. RS: CTA. CVS: S1, S2 normal, no added sounds. Abdomen: No distention, no organomegaly. CNS: No focal deficits. Normal reflexes. Extremities: Pitting edema upto b/l knees. Skin: No rash, purpura.

Laboratory Data Hemoglobin 13.4

Sodium

134

Protein

5.6

Hematocrit

39.8

Potassium

2.9

Albumin

2.7

MCV

93.7

Chloride

90

ALT

25

White count

6.7

Bicarbonate

37

AST

61

Platelets

464

Blood urea

19

ALP

132

Eosinophils

0.4%

Creatinine

0.9

Total Bili.

0.4

Glucose

87

Direct Bili.

0.1

Calcium

8.5

AG

7

Lipid Panel

Urinalysis

Tot. Chol.

586

Color

Yellow

LDL

493

Specific Gravity

1.010

HDL

25

pH

6.5

Glucose

Negative

Bilirubin

Negative

Trig.

340

BNP

1220

Ketones

Negative

Troponin

0.4980

Blood

Negative

Protein

3+

Leuk. Est.

Negative

Nitrite

Negative

RBC

2-3

WBC

0-2

Casts

Negative

Bacteria

Negative

Urine Protein/Creatinine U. Prt.

150.5

U. Cr.

31.2

P/Cr

4.8g/g

• EKG: normal sinus rhythm. • Chest x-ray: clear lung fields, cardiomegaly, no mass. • Echo: LA is severely dilated, myocardium of the LV is severely thickened, hyperdynamic LV wall motion and EF(75%). Myocardium of RV is thickened. No evidence of pulmonary hypertension. • Renal U/S: Increased parenchymal echogenicity bilaterally. Upper normal sized kidneys, right-13, left 13.1. No hydronephrosis, calculi. Patent renal artery and veins.

Work-up HbA1c

5.5

HIV rapid test

Negative

HBsAg

Negative

ANA

Negative

HBsAb

Negative

C3

157(75-140)

HBcAb

Negative

C4

35(10-34)

HCV Ab

Negative

Work-up • SPEP: Marked hypoproteinemia, marked hypoalbuminemia, increased alpha 2 globulins and decreased gamma globulins. • UPEP: Albumin and other proteins observed, compatible with non selective proteinuria. • Serum IF: Faint band in Lambda is present against a dense polyclonal background. • Urine IF: Free Kappa band present. Ig Levels Serum Free Light Chains IgG

484(694-1618)

Kappa

675(3.3-19.4)

IgA

246(81-463)

Lambda

19(5.7-26.3)

IgM

172(48-271)

K/L Ratio

34.1(0.3-1.65)

Work-up • Skeletal Survey: No definite lytic or sclerotic osseous lesions or areas of erosion or aggressive appearing bone destruction are identified.

Differential Diagnosis • Primary amyoidosis • Monoclonal immunoglobulin deposition disease Membranous nephropathy-primary/secondary FSGS-primary/secondary Minimal change disease Lupus Nephritis-Class V

Kidney Biopsy

Courtesy Dr. Ming Wu.

Primary Amyloidosis

Amyloid • Rudolph Virchow used the term amyloid to describe ‘waxy eosinophilic’ tissue deposits, believed to be polysaccharide derivatives. • Amylum is Latin for Starch. • In 1959, electron microscopic examination of ultrathin sections of amyloidotic tissues revealed the presence of fibrils.

Glenner GG. N Engl J Med. 1980;302:1283-1292. Jean D. Sipe, Alan S. CohenVolume 130, Issues 2–3, June 2000,

Ultrastructure

Glenner GG. N Engl J Med. 1980;302:1283-1292. Merlini, Bellotti, N Engl J Med 2003;349:583-96.

Cross β Pleated Sheet Structure of Filaments

Pauling, Proc Natl Acad Sci U S A. 1951 November; 37(11): 729–740.

Amyloidosis • Amyloidosis is a generic term for a family of diseases defined by morphologic criteria. • The diseases are characterized by the deposition in extracellular spaces of a proteinaceous material. • Amyloidoses may be classified based on precursor proteins.

Ronco et al, Renal Amyloidosis, Comprehensive clinical nephrology.

Merlini, Bellotti, N Engl J Med 2003;349:583-96.

Apolipoprotein A1-Cardiac Amyloid

Merlini, Bellotti, N Engl J Med 2003;349:583-96.

Amyloidogenesis

Merlini, Bellotti, N Engl J Med 2003;349:583-96.

SAP Scintigraphy

Hazenberg et al, The American Journal of Medicine, Vol 119, No 4, April 2006

Monoclonal Ig Related Disease • The glomerular capillaries are a favorite site for the deposition of abnormal proteins.

• Categorization based on electron microscopy. • Amyloidosis, cryoglobulinemic and immunotactoid glomerulonephritis GN. • Monoclonal immunoglobulin deposition disease (MIDD). Ronco et al, Renal Amyloidosis, Comprehensive clinical nephrology. Sanjeev, Sethi, N Engl J Med 2012;366:1119-31.

AL Amyloidosis • Free immunoglobulin subunits, mostly light chains, secreted by a single clone of B cells, are the cause of the most frequent and severe amyloidosis affecting the kidney. • In AL amyloidosis, there is a striking overrepresentation of the λ isotype, which is twofold to fourfold more frequent than the κ isotype. • The incidence of AL amyloidosis is nine per million per year. • Fewer than one of four patients with AL amyloidosis is considered to have an overt immunoproliferative disease.

Pathology-AL Amyloidosis

Diagnostic Atlas of Renal Pathology: A Companion to Brenner & Rector's The Kidney, 9th edition , Agnes B. Fogo. Ronco et al, Renal Amyloidosis, Comprehensive clinical nephrology.

Clinical Features

Merlini, Bellotti, N Engl J Med 2003;349:583-96.

Diagnosis • Particular vigilance should be maintained in patients with multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS), especially of the λ isotype. • Biopsy of an affected organ is usually diagnostic, but less invasive alternatives should be preferred first. • Indications to look for hereditary causes of Amyloidosis. • MGUS and Hereditary Amyloid may co-exist.

Proteomic Analysis • Although renal biopsy can type AL and AA amyloidosis, some cases pose problems in accurate typing of amyloid, and ancillary tests including genetic analysis are often required. • Accurate typing of amyloidosis has implications for prognosis, genetic counseling, and treatment. • Laser microdissection (LMD) and tandem mass spectrometry (MS)– based proteomic analysis is a sensitive and specific tool for the diagnosis of amyloidosis.

Sanjeev Sethi et al, Kidney International (2012) 82, 226–234.

Treatment

• Goal: To demonstrate that high-dose melphalan would improve the survival rate compared to standard therapy. • Study Design: Multicenter, randomized, controlled trial. • Included 100 patients. • Treatment: Melphalan+Dexamethasone vs HDM+ASCT. • M/Dex: 10mg/m2+40mg/d x 4 days for 12 to 18 months. • HDM+ASCT: 200mg/m - day zero+ 2x106 CD34+ cells – day two. • Primary outcome: Overall survival.

Baseline Characteristics

Jaccard A, Moreau P, Leblond V, et al. N Engl J Med. 2007;357:1083-1093.

Results

Jaccard A, Moreau P, Leblond V, et al. N Engl J Med. 2007;357:1083-1093.

Hematologic Response

Jaccard A, Moreau P, Leblond V, et al. N Engl J Med. 2007;357:1083-1093.

Survival In the intention-to-treat analysis, the Kaplan– Meier estimate of median overall survival was 56m (M/Dex) vs 22m (HDM/ASCT)

Jaccard A, Moreau P, Leblond V, et al. N Engl J Med. 2007;357:1083-1093.

Conclusions of Study • High-dose melphalan plus autologous stem-cell rescue was not superior to the outcome with standard-dose melphalan plus dexamethasone. • Treatment-related mortality in the HDM group (24%) was higher than that reported in single-center studies from amyloidosis referral centers (4% to 14%). • The high mortality was likely due to enrollment of patients who had severe organ dysfunction and would not be eligible for HDM/ASCT at many referral centers.

Jaccard A, Moreau P, Leblond V, et al. N Engl J Med. 2007;357:1083-1093.

Thank you.