This PDF has been corrected to include a missing author. VA BOSTON MEDICAL FORUM A Veteran Presenting With Leg Swelling, Dyspnea, and Proteinuria Madeline DiLorenzo, MD; Jonathan X. Li, MD; Judith Strymish, MD; Jeffrey William, MD; and Anthony C. Breu, MD Madeline DiLorenzo Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, un- is a Resident in the Department of Internal detectable viral load), epilepsy, and hypertension presented to the VA Boston Health- Medicine at Boston care System (VABHS) emergency department with 1 week of bilateral leg swelling and University Medical exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspi- Center in Massachu- ration and orthopnea. There was no personal or family history of pulmonary embolism. He re- setts. Anthony Breu is a Hospitalist and the ported weight gain but was unable to quantify how much. He also reported flare up of chronic Director of Resident knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for sev- Education at VA Boston eral weeks. His physical examination was notable for a heart rate of 105 beats per minute and bi- Healthcare System and an Assistant Professor of lateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which Medicine at Harvard was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of University in Massa- 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstruct- chusetts. He supervises ing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury. the VA Boston Medical Forum chief resident case conferences. Jonathan Li, MD, Chief Medical Resi- is defined by a constellation of findings that in- All patients or their dent, VABHS and Beth Israel Deaconess clude renal insufficiency (often indicated by an surrogate decision Medical Center (BIDMC). Dr. William, based elevation in blood urea nitrogen and creatinine), makers understand and have signed appropriate on the degree of proteinuria and edema, a diag- hypertension, hematuria, and subnephrotic patient release forms. nosis of nephrotic syndrome was made. How is range proteinuria. In practice, patients may This article has received nephrotic syndrome defined, and how is it dis- fulfill criteria of both nephrotic and nephritic an abbreviated peer review. tinguished from glomerulonephritis? syndromes, but the preponderance of clinical Correspondence: evidence often points one way or the other. In Anthony Breu Jeffrey William, MD, Nephrologist, this case, nephrotic syndrome was diagnosed ([email protected]) BIDMC, Assistant Professor of Medicine, based on the urine protein-to-creatinine ratio of Harvard Medical School. The pathophysi- 7.8 mg/mg, hypoalbuminemia, and edema. ology of nephrotic disease and glomerulone- phritis are quite distinct, resulting in symptoms Dr. Li. What would be your first-line and systemic manifestations that only slightly workup for evaluation of the etiology of this overlap. Glomerulonephritis is characterized patient’s nephrotic syndrome? by inflammation of the endothelial cells of the trilayered glomerular capillary, with a result- Dr. William. Rather than memorizing ing active urine sediment with red blood cells, a list of etiologies of nephrotic syndrome, it white blood cells, and casts. Nephrotic syn- is essential to consider the pathophysiology drome mostly affects the visceral epithelial cells of heavy proteinuria. Though the glomeru- of the glomerular capillary, commonly referred lar filtration barrier is extremely complex and to as podocytes, and hence, the urine sediment defects in any component can cause protein- in nephrotic disease is often inactive. Patients uria, disruption of the podocyte is often in- with nephrotic syndrome have nephrotic-range volved. Common disease processes that chiefly proteinuria (excretion of > 3.5 g per 24 h or a target the podocyte include minimal change spot urine protein-creatinine ratio > 3.5 g in disease, primary focal and segmental glo- the steady state) and both hypoalbuminemia merulosclerosis (FSGS), and membranous (< 3 g/dL) and peripheral edema. Lipiduria and nephropathy, all by differing mechanisms. Min- hyperlipidemia are common findings in ne- imal change disease and idiopathic/primary phrotic syndrome but are not required for a clin- FSGS are increasingly thought to be at differ- ical diagnosis.1 In contrast, glomerulonephritis ing points on a spectrum of the same disease.2 420 • FEDERAL PRACTITIONER • SEPTEMBER 2019 mdedge.com/fedprac Secondary FSGS, on the other hand, is a pro- TABLE 1 Laboratory Results at Admission, gressive disease, commonly resulting from First Hospitalization longstanding hypertension, diabetes mellitus, Blood Tests Result Reference and obesity in adults. Membranous nephrop- athy can also be either primary or secondary. Sodium, mEq/L 138 135-145 Primary membranous nephropathy is chiefly Potassium, mEq/L 4.4 3.5-5.0 caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type Chloride, mEq/L 105 100-110 phospholipase A2 receptor), whereas second- Bicarbonate, mEq/L 24 20-30 ary membranous nephropathy can be caused Blood urea nitrogen, mg/dL 34 7-25 by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus er- Creatinine, mg/dL 2.5 0.5-1.5 ythematosus), certain malignancies, chronic Glucose, mg/dL 104 70-105 infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti- Calcium, mg/dL 9.4 8.5-10.5 3-5 inflammatory drugs (NSAIDs). Paraprotein Magnesium, mg/dL 1.8 1.6-2.6 deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria. Phosphorous, mg/dL 2.5 2.5-5.0 Given these potential diagnoses, a careful his- White blood cells, K/uL 8.0 4.0-11.0 tory should be taken to assess exposures and re- Hemoglobin, g/dL 12.0 14.0-18.0 cent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syn- Hematocrit, % 38.2 40-52 drome to determine if there is an underlying ne- Platelets, K/uL 208 150-440 phritic process. Select serologies may be sent to look for autoimmune disease, such as systemic Mean corpuscular volume, fL 83.4 82-98 lupus erythematosus and common viral expo- International normalized ratio 1.0 0.9-1.1 sures like hepatitis B or C. Serum and urine pro- tein electrophoreses would be appropriate initial Alanine aminotransferase, IU/L 17 0-40 tests of suspected paraprotein-related diseases. Aspartate aminotransferase, IU/L 22 0-40 Other serologies, such as antineutrophil cyto- Albumin, g/dL 2.0 3.4-4.8 plasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be Alkaline phosphatase, IU/L 354 39-117 indicated here given the lack of hematuria and Total bilirubin, mg/dL 0.5 0-1.5 presence of nephrotic-range proteinuria. Thyroid-stimulating hormone, u/mL 4.5 0.-5.0 Dr. Li. The initial evaluation was nota- Total cholesterol, mg/dL 179 0-199 ble for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinu- Triglycerides, mg/dL 239 0-149 clear antibody (ANA) titer of 1:40. The re- High-density lipoprotein cholesterol, mg/dL 20 40-60 mainder of his initial workup did not reveal an Low-density lipoprotein cholesterol, mg/dL 111 0-129 etiology for his nephrotic syndrome (Table 3). Hemoglobin A , % 5.5 4.0-5.6 Dr. William, is there a role for starting ur- 1c gent empiric steroids in nephrotic syndrome Brain natriuretic peptide level, pg/mL 38 5-100 while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or Troponin I, ng/mL 0.0 0.0-0.3 is this determination based on something else? are serious thrombotic complications requir- Dr. William. Edema is a primary symptom ing anticoagulation, and a renal biopsy is of nephrotic syndrome and can often be man- deemed to be too risky, then empiric steroid aged with diuretics alone. If a clear medication- therapy may be necessary. Children with new- mediated cause is suspected, discontinuation onset nephrotic syndrome are presumed to have of this agent may result in spontaneous im- minimal change disease, given its prevalence provement without steroid treatment. However, in this patient population, and are often given in cases where an etiology is unclear and there empiric steroids without obtaining a renal mdedge.com/fedprac SEPTEMBER 2019 • FEDERAL PRACTITIONER • 421 MEDICAL FORUM TABLE 2 Urine Results at Admission, First Hospitalization noglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for Tests Result Reference IgG1, IgG2, and IgG3, and were weakly pos- Osmolality , mOsm/Kg H2O 301 280-300 itive for the PLA2 receptor. Focal intimal ar- Sodium, mmol/L 109 Not established teritis in a small interlobular vessel was seen. Dr. William, the pathology returned sug- Creatinine, mg/dL 21 Not established gestive of lupus nephritis. Does the overall Blood Negative Negative clinical picture fit with lupus nephritis? Red blood cells 1 0-3 Dr. William. Given the history and a Protein:creatinine ratio 7.8 < 0.2 rather low ANA, the diagnosis of lupus ne- phritis seems unlikely. The lack of IgG4 and Free κ, mg/L 310 0.1-32.7 PLA2R staining in the biopsy suggests that Free λ, mg/L 95 0.5-5.0 this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, Urine protein electrophoresis Negative Negative but further investigation should be pursued. TABLE 3 Additional Tests, First Hospitalization Dr. Li. The patient was discharged after Tests Result Reference the biopsyROUND with- a planned outpatient ne- phrologyTABLE follow-up to discuss results and C-reactive protein 43 Not established treatment.