Clin Kidney J (2012) 5: 130–132 doi: 10.1093/ckj/sfs004 Advance Access publication 8 March 2012 Exceptional Case

Amyloid proximal tubulopathy: a novel form of light chain proximal tubulopathy

Christopher P. Larsen1, G. Scott Borrelli2 and Patrick D. Walker1

1Nephropathology Associates, Little Rock, AR, USA and 2East Tennessee Nephrology, Knoxville, TN, USA Correspondence and offprint requests to: Christopher P. Larsen; E-mail: [email protected]

Abstract Light chain proximal tubulopathy is a paraproteinemic-related kidney disease most commonly seen in patients with a plasma cell dyscrasia. The classic description is that of proximal tubules with kappa-restricted intracytoplasmic crystals in a patient with a clinical Fanconi’s syndrome. Recently, other variants of light chain proximal tubulopathy have been described including those without crystal formation. We expand the morphologic spectrum in this report of a patient who presented with acute renal failure, proteinuria and hematuria. Biopsy revealed proximal tubulopathy in which the proximal tubules show intracytoplasmic amyloid formation. This is the first description, to our knowledge, of amyloid proximal tubulopathy.

Keywords: amyloid; kidney biopsy; light chain proximal tubulopathy; multiple myeloma

Background and simvastatin for hyperlipidemia. The physical examination was unremarkable. When laboratory studies returned 2 days after the visit, the patient was called to the hospital for Kidney disease is a common manifestation of multiple admission in order to evaluate an elevated serum crea- myeloma and the second leading cause of death in myeloma tinine (Cr) at 6.7 mg/dL (592.3 lmol/L) with an estimated patients [1]. The most common paraprotein-related diseases glomerular filtration rate (GFR) of 8 mL/min/1.73m2 of the kidney are amyloidosis, light chain deposition disease (0.133 mL/s/1.73m2). and light chain cast nephropathy. Less common forms of Further questioning on admission revealed a 3- to 4-week paraproteinemic disease in multiple myeloma include cry- history of fatigue and poor appetite as well as increased oglobulinemic glomerulonephritis and light chain proximal thirst and recent nocturia. He also reported taking occa- tubulopathy. sional ibuprofen for mild back discomfort. He denied fever, Light chain proximal tubulopathy is a form of proximal chills, shortness of breath, nausea, vomiting and diarrhea. tubule injury secondary to increased filtration of pathogenic Physical examination was again unremarkable and vital light chains. The classic and most widely recognized form of signs were within normal limits. A repeat serum Cr at the this disease has kappa-restricted intracytoplasmic crystals time of admission was 8.5 mg/dL (751.4 lmol/L) with a GFR on renal biopsy and the clinical manifestation of a Fanconi’s of 6 mL/min/1.73m2 (0.100 mL/s/1.73m2). He was also found syndrome [2]. In recent years, the pathologic spectrum to be hyperkalemic with a potassium level of 6.6 mEq/L has been expanded to include cases with fibrillary cytoplas- (6.6 mmol/L) and to have mild thrombocytopenia with a mic inclusions [3] and those showing light chain restriction platelet count of 137 3 103/lL(1373 109/L). Urinalysis within the lysosomes without inclusions [4]. was positive for protein and showed moderate blood. A free AL amyloidosis deposition has been described in all lambda light chain was detected in the serum and urine by compartments of the kidney and is frequently seen in immunofixation. The remaining laboratory values were un- the glomeruli, arterial walls and interstitium. Amyloid is remarkable with a normal hemoglobin and hematocrit seen in the tubular lumens in cases of light chain cast nephr- at 14.1 g/dL (141 g/L) and 43.0%, respectively. The re- opathy when the casts prove to be Congo red positive [5]. maining electrolytes were within normal limits with sodium We lengthen the list of possible locations for renal amyloid of 139 mEq/L (139 mmol/L), chloride of 106 mEq/L deposition and further expand the spectrum of lesions in (106 mmol/L) and calcium of 9.2 mg/dL (2.3 mmol/L). He light chain proximal tubulopathy in this report detailing had normal liver function with alkaline phosphatase of the first description of amyloid proximal tubulopathy. 79 U/L, aspartate aminotransferase of 15 U/L, alanine amino- transferase of 15 U/L, total bilirubin of 0.3 mg/dL (5.1 lmol/L), albumin of 4.1 g/dL (41 g/L) and normal coagulation studies Case report with a prothrombin time of 13.6 s and an International Nor- malized Ratio of 1.05. Serologies for anti-nuclear antibodies, A 67-year-old Caucasian male presented for a routine anti-neutrophil cytoplasmic antibodies and anti-glomerular checkup. Medications included lisinopril for hypertension basement membrane antibodies were negative. The urine

The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: [email protected] Amyloid proximal tubulopathy 131 was negative for eosinophils. Renal ultrasound revealed sym- of the Congo red-positive bodies, which showed 21 staining metric kidneys that were normal in size with no hydroneph- by lambda. Kappa was negative within the tubular cyto- rosis and renal cortical echotexture within normal limits. plasm (Figure 1C). The tubular casts stained equally with A renal biopsy was performed. Ten glomeruli were kappa and lambda. The tubular basement membranes were available for light microscopic evaluation and all were un- negative by kappa and lambda. remarkable. There was severe tubular injury with tubular Electron microscopy was performed on a section of renal nuclei showing prominent nucleoli and the proximal tubular cortex. The evaluated glomerulus was unremarkable. There cytoplasm showed frequent thinning with loss of the apical were no deposits in the glomerulus or along the tubular brush border. Approximately 30% of the proximal tubules basement membranes. Glomerular epithelial foot processes had small round amorphous intracytoplasmic bodies. These were intact. Focal proximal tubules had intracytoplasmic bodies were periodic acid-Schiff negative, slightly silver pos- aggregates of small, non-branching overlapping fibrils with itive and blue on trichrome stain. A Congo red stain was a surrounding membrane (Figure 1D). These fibrils had a positive in these intracellular bodies and showed green bi- mean diameter of 9 nm. The renal biopsy was diagnosed refringence upon polarization (Figure 1A and B). Congo red as lambda light chain proximal tubulopathy consistent was negative throughout the remaining tissue including with amyloid proximal tubulopathy. glomeruli, tubular lumens, arterial walls and interstitium. The results of the kidney biopsy prompted the clinical One core of renal cortex was submitted for immuno- evaluation for multiple myeloma. A bone marrow biopsy fluorescence evaluation. Sections were stained for IgA, was performed and showed increased cellularity largely IgG, IgM, C3, C4, C1q, fibrinogen, albumin, kappa and lambda consisting of atypical plasma cells. The overall cellularity light chains. All stains were negative within the six intact was 95%, ~90% of which consisted of plasma cells. Immu- glomeruli. There was 31 staining for lambda within the noperoxidase stains demonstrated lambda restriction within proximal tubule cytoplasm protein resorption droplets and these plasma cells. A Congo red stain was performed on the focal tubules had larger inclusions corresponding to the size bone marrow tissue and was negative. The bone marrow

Fig. 1. Amyloid proximal tubulopathy. (A) Proximal tubules with intracytoplasmic inclusions (arrowheads) that stain blue on Masson’s trichrome stain (original magnification 3400). (B) The inclusions (arrowheads) show green birefringence under polarized light on Congo red stain (original magnification 3600). (C) There is lambda restriction present in the proximal tubular cytoplasm inclusions (arrowhead) (fluorescein-conjugated anti-human lambda; original magnification 3400). (D) Transmission electron photomicrographs showing intracytoplasmic inclusion in the proximal tubule cytoplasm which appears to be membrane bound (arrowhead) and are composed of overlapping fibrils (unstained; original magnification 335 000). 132 C.P. Larsen et al. biopsy was diagnosed as plasma cell myeloma. A skeletal of the kidney. We believe this lesion is best termed ‘amyloid survey was performed and did not reveal any lesions in the proximaltubulopathy’andshouldbeconsideredapart bones. of the broadening spectrum of light chain proximal tubul- The patient was treated after diagnosis with plasma- opathy. It is likely a rare form of the disease as we have pheresis to decrease his light chain burden and bortezo- seen 21 cases of isolated proximal tubulopathy in our mib 1.3 mg/m2/dose along with oral dexamethasone laboratory over the past 3 years (13 of which were re- 40 mg weekly for his multiple myeloma while hospital- ported in a previous publication [7]) and this is the only ized. He was discharged on hospital Day 24 with a serum case with intracytoplasmic amyloid formation. Cr of 2.4 mg/dL (212.2 lmol/L) and a GFR of 27 mL/min/ 2 2 1.73m (0.450 mL/s/1.73m ). As an outpatient, lenalidomide Conflict of interest statement. None declared. 10 mg, 2 weeks on and 1 week off, was added to his treatment. His 4-month follow-up serum Cr was 3.8 mg/dL (335.9 lmol/L) with a GFR of 19 mL/min/1.73m2 (0.317 mL/s/1.73m2). References

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