Intra-tubular amyloidosis

A 52-year-old man with a past medical history of asthma, well-controlled diabetes and hypertension was referred to our hospital for acute renal failure. The patient reported a 2-month history of fatigue and arthralgia involving his shoulders, elbows, wrists, metacarpophalangeal joints as well as his knees and ankles. Six weeks before admission, he started naproxen 400 mg twice daily without improvement. Subsequently he was evaluated by a local rheumatologist who suspected rheumatoid arthritis and started him on prednisone 30 mg daily. A month later, his laboratories revealed an elevated serum creatinine (12.3 mg/dl, 1087 mol/l) and potassium (7.9 mEq/l). His serum creatinine was 1.8 mg/dl (159.1 mol/l) 6 weeks earlier and 1.3 mg/dl 7 years earlier (Figure 1). The hyperkalemia was treated with intravenous insulin and dextrose, and he was admitted to our hospital for further management. He denied fever, chills, weight loss, shortness of breath, lower extremity edema, and did not have any uremic symptoms (no nausea, vomiting, hiccups, or itching). He had normal urine output and no dysuria or hematuria. He had hypertension that was diagnosed 13 years earlier and based on records it was well controlled (<135/85) on enalapril 10 mg daily. His diabetes was diagnosed 4 months earlier and treated with rosiglitazone 4 mg once daily. He had not been evaluated for retinopathy. He had no prior urine analysis to assess the presence of albuminuria. His other medications included fluticasone aerosol, albuterol/ipratropium puffs, acetaminophen two tablets at bedtime, and prednisone 30 mg daily. On physical exam his initial blood pressure was 162/70 with a heart rate of 102/min, regular. Orthostatic blood pressure was not checked. He was afebrile. His mucous membranes were moist. His cardiac exam was normal with no pericardial rub and jugular veins were flat. His lungs were clear and abdomen soft with no organomegaly. The skin was normal. His joint exam revealed synovitis in his elbows, wrists, metacarpophalangeal joints, knees, and ankles bilaterally. He had stiffness and decreased range of motion in his elbows, wrists, and ankles. His admission laboratories are shown in Table 1A and 1B. Further tests in the hospital revealed C3 138 mg/dl (normal 75–175), total complement 67 U/ml (30–75), rheumatoid factor <15 IU/ml (<15), antinuclear antibodies 0.2 U (<1), myeloperoxidase antibody less then 5 EU/ml (<5), and proteinase less then 5 EU/ml (<5). Serologies for hepatitis B and C were negative. Serum protein electrophoresis showed a total protein of 6.6 g/dl (normal 6.3–7.9), albumin 3.2 g/dl (3.4–4.7), -1 globulin 0.5 g/dl (0.1–0.3), -2 globulin 1.4 g/dl (0.6–1), -globulin 1 g/dl (0.7–1.2) and -globulin 0.5 g/dl (0.6–1.6). Urinalysis showed a protein to osmolality ratio of 1.17 that corresponds to 24-h urine protein of 1.1 g. The urinary sediment was unremarkable with no red or white blood cell casts. His kidney ultrasound showed no hydronephrosis, normal corticomedullary differentiation, and no renal masses. The left kidney was 13.8 cm and the right 13.6 cm in length. His chest X-ray was unremarkable. The nephrologist felt initially that the acute renal failure was secondary to the combination of NSAID and ACEI toxicities in the setting of chronic kidney disease related to diabetes and hypertension. The anemia was felt to be multifactorial related to chronic kidney disease, iron deficiency, and inflammation. His calcium was not elevated to suggest multiple myeloma. During his hospital course, he was nonoliguric but remained dialysis dependent. In addition, he complained of bilateral hand weakness and numbness (involving the thumb and index finger) and was diagnosed with severe bilateral carpal tunnel syndrome that was confirmed on electromyography. He underwent a carpal tunnel release surgery with significant improvement in his symptoms. A kidney biopsy was performed because of persistence of the renal failure. Congo-red stains showed positive reddish-brown amyloid material with apple-green birefringence staining of the protein reabsorption-like droplets in few tubules (Figure 3a). In a few tubules, casts were also Congo-red positive and showed spicule-like arrangement (Figure 3b). Congo-red stains were negative in the glomeruli, interstitium, and vessels. In the light of the kidney biopsy results, serum immunofixation electrophoresis was performed that showed monoclonal -light chains 908 mg/dl (normal 0.57–2.63 mg/dl), -light chains 2.72 mg/dl (normal 0.33–1.94 mg/dl), and : <0.01. The -2 microglobulin level was markedly elevated at 21.4 g/ml (normal 0.7–1.8 g/ml). The urine protein electrophoresis showed monoclonal M-spike. Urine immunofixation studies also showed monoclonal -light chains. A bone marrow biopsy was performed that showed plasma cell myeloma with focal amyloid deposition. The marrow was slightly hypercellular (70%) with 30% -light chain restricted plasma cells. No radiographic evidence for metastasis or myeloma was detected on a full-body scan. A Cardiac Echo showed normal left ventricular chamber size with a calculated left ventricular ejection fraction of 60% and no evidence of cardiac amyloidosis. Because of the multiple joints synovitis, a synovial aspiration of the left knee was performed and stained with Congo red. Amyloid was focally present within the monocytic/histiocytic cells. In addition, patient complained of recurrence of hand weakness and noted bilateral paresthesias in the soles of his feet bilaterally and proximal toes. An electromyography was repeated and showed evidence of a length-dependent predominantly axonal sensorimotor peripheral neuropathy. There was evidence of median and ulnar neuropathy on the right which had slightly progressed from the previous study. The neurologist felt that the polyneuropathy was likely due to amyloidosis. In summary, the patient had the following new diagnoses: (1) multiple myeloma and (2) systemic AL amyloidosis with renal, joint and probable nerve involvement. He was started on high-dose dexamethasone on days 1–4, 9–12, and 11–20, every 28 days. He reported on the 3rd day of treatment that he felt remarkably improved and was able to walk with minimal difficulty. At the time of submission of the manuscript, he was still dialysis dependent and was undergoing an evaluation for bone marrow transplantation. We present a case of acute renal failure with rather unusual renal biopsy findings in a patient with hypertension, diabetes, and recent polyarthralgia presumed to be secondary to rheumatoid arthritis (RA). The initial clinical impression was that the renal insufficiency was due to the effects of the NSAID and ACEI in the setting of diabetes mellitus and hypertension. However, a renal biopsy was obtained because of lack of improvement of renal function. The renal biopsy showed chronic interstitial inflammation along with rather extensive tubulo-interstitial scarring. Based on these findings, the initial renal biopsy impression was that of chronic interstitial nephritis, secondary to NSAID and ACEI. The biopsy also showed few casts that stained for -light chains, suggesting a component of cast nephropathy/myeloma kidney. The case was unusual in that the casts did not appear histologically like those in cast nephropathy and that tubules contained PAS-negative droplets that did not appear like protein reabsorption droplets. They were much larger; some were free in the lumen, others in the epithelial cells and some between the epithelial cells. In isolated tubules, the PAS-negative casts were surrounded by the droplets. Surprisingly the casts and droplets stained for -light chains, and furthermore showed bright apple-green birefringence on Congo-red stains suggesting that they were made of amyloid fibrils. Electron microscopy confirmed the diagnosis of amyloidosis: amyloid fibrils were present in tubules, both free in the lumen comprising the casts, and within and between tubular epithelial cells forming protein reabsorption-like droplets. A search of the literature at this time revealed a single report of amyloid casts in the tubules.1 Light chain deposition was not seen along the tubular or glomerular basement membranes. The thickening of the glomerular and tubular basement membranes was likely due to diabetes and ischemic changes from hypertension. The tubulo-interstitial scarring was likely due to multiple etiologies including chronic interstitial nephritis due to NSAID or ACEI, tubular amyloidosis, diabetes, and/or hypertension. Amyloid can be found anywhere in the kidney, but glomerular deposition typically predominates. By light microscopy, glomerular amyloid appears as amorphous material in the mesangium and capillary loops.7 The mesangial involvement usually leads to the formation of PAS-negative mesangial nodules. The glomerular capillary walls are infiltrated with amyloid resulting in the thickening of the glomerular basement membranes. On silver stains, spicules can be seen. When the glomerulus is involved, almost 50% of the cases present with renal insufficiency and more then 70% have proteinuria.4, 7 Vessels are also commonly involved, initially in the media. Less commonly, amyloid deposits in the tubular basement membrane leading to tubular atrophy and interstitial fibrosis.4 When amyloid is confined to the tubulointerstitium or vasculature, proteinuria is minimal and reduced glomerular filtration rate is the principal clinical manifestation.7 In our case there was no glomerular or vascular involvement. To the best of our knowledge there has been one previously reported case of intratubular amyloidosis (discussed below).1 To summarize, we present an unusual case of AL amyloidosis where amyloid was noted within renal tubules as droplets and casts. From the pathology standpoint, intra-tubular amyloidosis is rare but should be in the differential diagnosis when tubular casts or protein reabsorption-like droplets in tubular epithelial cells are PAS negative and are comprised of monoclonal light chains on immunofluorescence studies. Congo-red stains and electron microscopy are then required to confirm the diagnosis.