Kidney Biopsy Teaching Case IgG4-Related Tubulointerstitial Nephritis With Membranous Nephropathy Fernando C. Fervenza, MD, PhD, 1 Gregory Downer, MD, 2 Laurence H. Beck Jr, MD, 3 and Sanjeev Sethi, MD, PhD 4 We describe a 67-year-old woman who presented with significant proteinuria and hematuria. Kidney biopsy showed immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (TIN) with concurrent membranous nephropa- thy. IgG4-related TIN is a recently described entity that presents with progressive decreased kidney function and is characterized by a plasma cell–rich infiltrate that is positive for IgG4. It is associated with patchy, often well- localized, tubular atrophy and interstitial fibrosis. Workup for circulating anti–phospholipase A 2 receptor antibodies was negative, suggesting that the membranous nephropathy was not “primary” and may be linked to the IgG4-related disease. The presence of significant proteinuria and hematuria in the setting of IgG4-related TIN should raise suspicion of a glomerular disease. It is important to correctly diagnose IgG4-related TIN and concurrent membranous nephropathy because the lesion responds well to steroid therapy. Am J Kidney Dis. 58(2):320-324. © 2011 by the National Kidney Foundation, Inc. INDEX WORDS: Immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (TIN); immunoglobulin G4 (IgG4)-related sclerosing disease; membranous nephropathy. INTRODUCTION Tubulointerstitial nephritis (TIN) often is second- ary to a hypersensitivity reaction to drugs (eg, antibi- otics or nonsteroidal anti-inflammatory drugs), infec- tions, autoimmune and metabolic diseases, plasma cell dyscrasias, hereditary diseases, and occasionally systemic diseases (eg, TIN with uveitis). 1-4 A less commonly recognized cause of TIN is within the immunoglobulin G4 (IgG4)-related systemic dis- eases. IgG4-related systemic diseases have been ob- served in many organ systems, including pancreas and other gastrointestinal sites, salivary or lacrimal glands, pituitary gland, lung, breast, lymph nodes, and retro- peritoneum (Table 1). 8,19,20 More recently, IgG4- related TIN has been described in the kidney 20-23 and typically presents with a gradual decrease in kidney function over months, with mild or no hematuria and minimal or no proteinuria. 21,24 We describe the case of a patient who presented with significant protein- uria, hematuria, and mildly decreased glomerular fil- tration rate (GFR), for whom kidney biopsy showed IgG4-related TIN concomitant with membranous ne- phropathy. This case represents an uncommon presen- tation of IgG4-related TIN. CASE REPORT Clinical History and Initial Laboratory Data A 67-year-old woman with a 5-year history of diabetes and hypertension presented with worsening proteinuria. Medical his- tory was significant for breast cancer treated 2 years previously, with mastectomy followed by adjuvant radiation therapy. She did not require chemotherapy and was started on anastrozole therapy a few months later. Baseline serum creatinine level was 0.7 mg/dL (61.9 mol/L), and estimated GFR was 60 mL/min/1.73 m 2 (1 mL/s/1.73 m 2 ; calculated using the 4-variable MDRD [Modifica- tion of Diet in Renal Disease] Study equation), with normal urinalysis results. Two years later, she developed fatigue and increasing proteinuria with protein excretion of 2.2 g/24 h. Medica- tions included an angiotensin-converting enzyme inhibitor, anastro- zole, aspirin, a statin, and calcium supplements. Her weight was 70 kg, blood pressure was 170/90 mm Hg, and except for a palpable right submandibular gland, the rest of the physical examination results were unremarkable. An ultrasound of the kidney had normal findings. Urinalysis showed proteinuria (3+) quantitated at protein excretion of 4 g/24 h and blood (3+), including many dysmorphic red blood cells. Laboratory results are listed in Table 2. To determine the cause of the increasing proteinuria, kidney biopsy was performed. Kidney Biopsy The sample submitted for light microscopy contained 27 glom- eruli, of which 9 were globally sclerosed. Seven sclerosed glom- eruli were present in a well-demarcated area of tubulointerstitial scarring and inflammation. Nonsclerosed glomeruli showed a minimal increase in mesangial matrix with no proliferative fea- tures. There was no evidence of crescent formation, endocapillary proliferation, fibrinoid necrosis, or thrombosis. Glomerular base- ment membranes were somewhat thickened; some loops showed pinholes along the capillary walls, but spikes were not present. From the 1 Division of Nephrology and Hypertension, Depart- ment of Internal Medicine, Mayo Clinic, Rochester, MN; 2 West Michigan Nephrology, Muskegon, MI; 3 Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA; and 4 Division of Anatomic Pathology, Department of Laboratory Medi- cine and Pathology, Mayo Clinic, Rochester, MN. Received February 14, 2011. Accepted in revised form May 5, 2011. Originally published online June 27, 2011. Address correspondence to Sanjeev Sethi, MD, PhD, Depart- ment of Laboratory Medicine and Pathology, 200 First St SW, Rochester, MN 55905. E-mail: sethi.sanjeev@mayo.edu © 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.05.006 Am J Kidney Dis. 2011;58(2):320-324 320