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The Case | Proteinuria in a patient with diabetes

Srikanth Kunaparaju1, Chidi Okafor1, Helen Cathro2, Vijay Bhola3, F. Jackson Ballenger4 and Mitchell H. Rosner1 Division of Nephrology, University of Virginia Health System, Charlottesville, Virginia, USA; 2Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, USA; 3Roanoke Memorial Hospital, Roanoke, Virginia, USA and 4Valley Nephrology Associates, Roanoke, Virginia, USA Correspondence: Mitchell H. Rosner, Division of Nephrology, University of Virginia Health System, Box 800133, Charlottesville, Virginia 22911, USA. E-mail: mhr9r@virignia.edu
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Figure 1 | Every glomerulus in the biopsy was globally obliterated by a pale eosinophilic amorphous material. The vessels and interstitium were notably uninvolved. Hematoxylin and eosin 200.

A 49-year-old Caucasian man with type 2 diabetes, hypertension, hyperlipidemia and obesity, and no known renal disease presented with 2 weeks of headache and visual disturbances, and a 6-month history of frothy urine. Diabetes had been diagnosed 3 years previously and had been under excellent control; the most recent Hgb A1c was 7.1%. There was no history of end-organ involvement secondary to diabetes, including retinopathy and neuropathy. Serum and urine protein electrophoresis with immunoxation demonstrated no monoclonal proteins. There was no family history of kidney disease or malignancy. On examination, the patients body mass index was 43 kg/m2, blood pressure was 230/100 mmHg, and the heart rate was 88/min and regular. The rest of the physical examination was signicant for mild periorbital edema and bilateral, 1 pitting

ankle edema. Laboratory testing showed a serum creatinine of 4.55 mg/dl (baseline a year previously was 1.22 mg/dl), blood urea nitrogen of 38 mg/dl, and a 24-h urine total protein excretion of 10.0 g. Urine microscopy showed 12 epithelial cells/high-power eld, but no dysmorphic erythrocytes, cellular casts, or crystals. Serological studies including anti-nuclear antibody, anti-ds DNA, anti-neutrophil cytoplasmic antibody, anti-glomerular basement antibodies, complement levels (C3, C4), and HIV, hepatitis B and C viral studies were all within the reference ranges or negative. Serum and urine protein electrophoresis was negative for monoclonal proteins. A renal ultrasound revealed normal-sized kidneys, normal echogenicity bilaterally, and patent renal vasculature. A renal biopsy was performed for diagnosis. Light microscopic ndings are depicted in Figure 1.

What is the cause of his proteinuria and rapidly declining renal function? How would you confirm your diagnosis?
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S Kunaparaju et al.: Proteinuria in a diabetic patient

The Diagnosis | Hereditary fibrinogen A a amyloidosis

Figure 2 | Specific apple green birefringence on Congo red staining seen in all glomeruli, but neither in the vascular walls nor in the interstitium.

The biopsy revealed obliteration of all glomeruli by amyloid (Figure 1). Severe tubular atrophy was accompanied by severe interstitial brosis. Congo red staining was positive in the glomeruli, demonstrating specic apple green birefringence, but was notably negative in vessels (Figure 2). Immunouorescent analysis revealed segmental smudgy glomerular staining with antisera specic for IgG (trace), IgM (1 ), C1q (1 ), and lambda light chain (1 ). There was no staining with antisera specic for IgA, C3, brin, or kappa light chain. Ultrastructural analysis of a single glomerulus demonstrated no immune complex-type electron-dense deposits. Fine brillary material was present within the capillary basement membranes consistent with amyloid, but was not diagnostic because of suboptimal resolution. The tissue was referred for immunouorescent staining with antibodies against the most common types of hereditary amyloidosis. Although the ndings were suggestive of a diagnosis of brinogen (Fib) A a amyloidosis, the staining intensity was not strong enough for a denitive diagnosis. Tissue was sent for liquid chromatography tandem mass spectrometry protein analysis. Intense signals for Fib A a were seen, which strongly suggested Fib A a amyloid. As Fib A a can be deposited non-specically as part of brin, genetic testing for point mutations was performed. Using polymerase chain reaction amplication and direct DNA sequencing, the common E526V variant was identied, conrming the diagnosis of Fib A a amyloidosis.1 Hereditary Fib A a amyloidosis (also known as AFib amyloidosis) was discovered in 1993.2 It involves an abnormal protein deposition due to the production of a variant of brinogen by the liver. Because of the slow progression of the renal disease, it does not usually present until the fth or sixth decade and its manifestations include proteinuria, uncontrolled hypertension, and renal failure.1,2
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One series found that Fib A a amyloidosis is the most common cause of hereditary renal amyloidosis causing nephrotic syndrome.1 Misdiagnosis as the more common amyloid light-chain amyloidosis can occur, and thus careful diagnostic assessment of the specic type of amyloid deposited in the kidney is critical in ensuring proper therapy.3 In fact, for all newly diagnosed cases of amyloidosis, a careful assessment of amyloid type using tissue staining and polymerase chain reaction amplication and sequencing of mutated genes may be indicated. The rapid progression of renal disease, high levels of new-onset proteinuria, and wellcontrolled diabetes should suggest a diagnosis other than diabetic nephropathy. As synthesis of brinogen is exclusively hepatic, a liver transplant before kidney damage or a combined liverkidney transplant will be required for long-term success.3 Without liver transplantation, the abnormal brinogen synthesis will continue, leading to continued amyloid deposition in the kidney, as well as in the vasculature and heart, leading to poor outcomes.
ACKNOWLEDGMENTS

We thank Dr Maria Picken for performing the immunofluorescent subtyping panel, Dr Ahmet Dogan for performing tandem mass spectroscopy, and Dr Merrill Benson for molecular profiling of this case.
REFERENCES
1. Gillmore JD, Lachmann HJ, Rowczenio D et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20: 444451. Benson MD, Liepnieks J, Uemichi T et al. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet 1993; 3: 252255. Stangou AJ, Banner NR, Hendry BM et al. Hereditary fibrogen A alphachain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 2010; 115: 29983007.
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