37-Year-Old Woman With Bilateral Lower Extremity Edema, Proteinuria, and Microscopic Hematuria

Abstract

A 37-year-old woman with a history of alcohol use disorder, bulimia, and asthma presented to the emergency department with 3 months of bilateral lower extremity edema that started during a trip to Mexico. She first noticed facial swelling after a night of heavy drinking. At that time she endorsed a sore throat but denied nausea, vomiting, diarrhea, fevers, chills, hematuria, dysuria, rashes, or chest pain. She sought medical attention locally in Mexico and was given prednisone, with resolution of the swelling. Records from Mexico were not available; therefore, we were unable to obtain a rationale for treatment with prednisone. However, she subsequently noticed bilateral lower extremity edema that progressively worsened during the following 3 months. She endorsed more than 30 lb of weight gain despite having anorexia. She developed lower extremity pain that she treated with 1800 to 2600 mg of naproxen sodium daily. She denied occupational exposures, animal contacts, or illicit drug use. She denied a history of sexually transmitted infections and was sexually active with 1 male partner. Her home medications included 325 mg of ferrous sulfate daily, as-needed albuterol inhaler, and naproxen sodium as described previously herein. She was admitted to an outside hospital several weeks before this admission for the same concerns. No etiology was found for her diffuse edema. However, notable laboratory values (with reference ranges) were as follows: albumin, 2.4 g/dL (3.5 to 5.0 g/dL) (to convert to g/L, multiply by 10); creatinine, 1.05 mg/dL (0.59 to 1.04 mg/dL) (to convert to μmol/L, multiply by 88.4); hemoglobin, 8.2 g/dL (11.6 to 15 g/dL) (to convert to g/L, multiply by 10); and urinalysis with hematuria and proteinuria. On examination the patient appeared clinically well, without evidence of distress, pallor, or jaundice. Her temperature was 37°C, blood pressure was 124/72 mm Hg, respiratory rate was 18 breaths/min, and oxygen saturation was 97% on room air. Lung sounds were clear to auscultation bilaterally, without crackles or rales, and cardiac examination revealed normal first and second heart sounds, without murmurs, rubs, or gallops. Jugular vein distention was not appreciated. Her face demonstrated bilateral parotid gland enlargement. She had moist mucous membranes, without pharyngeal erythema or exudates. She had pitting edema bilaterally up to the middle of the thigh. She had mild tenderness to palpation in the epigastric region of the abdomen, without any fluid wave present. A smooth, nontender liver was palpated. There was no evidence of rash or musculoskeletal abnormalities. The remainder of the examination findings were normal. Laboratory test results on admission (with reference ranges) were as follows: hemoglobin, 8.5 g/dL (11.6 to 15.0 g/dL); hematocrit, 28.8% (35.5% to 44.9%); mean corpuscular volume, 84.7 fL (78.2 to 97.9 fL), white blood cell count, 5.8×109/L (3.54 to 9.6×109/L); platelet count, 312×109/L (157 to 371×109/L); sodium, 138 mmol/L (135 to 145 mmol/L); potassium, 4.0 mmol/L (3.6 to 5.2 mmol/L); chloride, 104 mmol/L (98 to 107 mmol/L); bicarbonate, 22 mmol/L (22 to 29 mmol/L); random glucose, 122 mg/dL (<140 mg/dL) (to convert to mmol/L, multiply by 0.0555); blood urea nitrogen, 17 mg/dL (6 to 21 mg/dL) (to convert to mmol/L, multiply by 0.357); creatinine, 1.35 mg/dL (0.59 to 1.04 mg/dL); estimated glomerular filtration rate (eGFR) by creatinine, 50 mL/min/body surface area (BSA) (≥60 mL/min/BSA); cystatin C, 2.40 mg/L (0.59 to 0.98 mg/L) with eGFR by cystatin C, 25 mL/min/BSA (≥60 mL/min/BSA); alkaline phosphatase, 188 U/L (35 to 104 U/L) (to convert to μkat/L, multiply by 0.0167); alanine aminotransferase, 14 U/L (7 to 45 U/L) (to convert to μkat/L, multiply by 0.0167); aspartate aminotransferase, 42 U/L (8 to 43 U/L) (to convert to μkat/L, multiply by 0.0167); total bilirubin, 0.7 mg/dL (≤1.2 mg/dL) (to convert to μmol/L, multiply by 17.104); direct bilirubin, 0.3 mg/dL (0.0 to 0.3 mg/dL) (to convert to μmol/L, multiply by 17.104); albumin, 3.5 g/dL (3.5 to 5.0 g/dL); and total protein, 7.6 (6.3 to 7.9 g/dL) (to convert to g/L, multiply by 10). The international normalized ratio was 1.2. Urine dipstick analysis showed 3+ blood and 3+ protein (estimated protein of >300 mg/dL). Urinalysis showed normal-appearing urine with a protein concentration of 184 mg/dL and a large amount of hemoglobin. Microscopic evaluation showed 51 to 100 red blood cells (RBCs) per high-power field without dysmorphic RBCs. The protein to creatinine ratio was 1.19 mg/mg (reference range, <0.18 mg/mg). Renal ultrasonography demonstrated normal echogenicity of the kidneys without hydronephrosis or nephrolithiasis. Hepatic steatosis was noted as well.1.Which one of the following is the most likely cause of acute kidney injury (AKI) in this patient?a.Acute interstitial nephritis (AIN)b.Acute tubular necrosisc.Glomerulonephritisd.Urinary tract obstructione.Renal artery embolism This patient’s creatinine level on presentation was 1.35, up from 1.05 at the outside hospital. This meets the criteria for AKI, which include an increase in serum creatinine level of at least 0.3 mg/dL or at least 50% within 48 hours. Due to her history of an eating disorder and alcohol abuse, we also obtained a cystatin C level, which was elevated at 2.40 mg/L, with eGFR by cystatin C of 25 mL/min/BSA. Cystatin C level is less influenced by conditions that lead to reduced muscle mass, such as eating disorders. Thus, this test is a more accurate measure of eGFR in this patient. Acute interstitial nephritis is caused by drugs, with the most common offending agent being antibiotics; infections; tubulointerstitial nephritis and uveitis syndrome; and systemic diseases such as sarcoidosis and systemic lupus erythematosus. Drug-induced AIN may present with rash, fever, and/or peripheral eosinophilia; however, this is rarely seen as a triad. Eosinophiluria, white blood cell casts, RBCs, and white blood cells may be seen in urine sediment with proteinuria. In patients with white blood cells in their urine sediment in the setting of an elevated serum creatinine level, AIN should be suspected.1Baker R.J. Pusey C.D. The changing profile of acute tubulointerstitial nephritis.Nephrol Dial Transplant. 2004; 19: 8-11Crossref PubMed Scopus (240) Google Scholar Acute tubular necrosis is characterized by urine sediment with muddy brown casts or renal epithelial cells and a fractional excretion of sodium greater than 2%. Typically patients will have a history of dehydration, heart failure, cirrhosis, or sepsis, which leads to tubular damage through renal hypoperfusion, or a history of taking nephrotoxic medications such as aminoglycosides, amphotericin B, and calcineurin inhibitors.2Makris K. Spanou L. Acute kidney injury: definition, pathophysiology and clinical phenotypes.Clin Biochem Rev. 2016; 37: 85-98PubMed Google Scholar The most likely cause of her AKI was thought to be secondary to glomerulonephritis in the setting of proteinuria, hematuria, edema, and hypoalbuminemia as seen at the outside hospital. Patients with urinary tract obstruction may present with pain, decreased urine output, hypertension, hematuria, and an elevated creatinine level. Bladder distention and hydronephrosis may also be present. If chronic obstruction is present, electrolyte abnormalities such as hyperkalemia and distal renal tubular acidosis thought to be due to mineralocorticoid resistance may also be seen. A less common cause of AKI is atheroembolic disease. This should be suspected in patients with a history of arterial catheterization or vascular surgery, especially if livedo reticularis is present on physical examination.3Rahman M. Shad F. Smith M.C. Acute kidney injury: a guide to diagnosis and management.Am Fam Physician. 2012; 86: 631-639PubMed Google Scholar The present patient was admitted for glomerulonephritis of unknown etiology in the setting of edema, AKI, and a history of hypoalbuminemia. Autoimmune serologic tests and urine tests were conducted to help narrow the diagnosis. Serologic test results were as follows: antinuclear antibodies and Scl 70 immunoglobulin (Ig) G were weakly positive. Double-stranded DNA, phospholipase A2 receptor, rheumatoid factor, SS-A/Ro, SS-B/La, anti–smooth muscle, anti-Jo1, anti-ribonucleoprotein, and anti–glomerular basement membrane (GBM) antibodies were all negative. Complement levels (C3 and C4) were normal. Results of human immunodeficiency virus, syphilis, hepatitis B virus, hepatitis C virus, and tissue transglutaminase testing were negative. A 24-hour urine protein sample was collected, and the level was elevated at 575 mg/24 hours (reference range, <229 mg/24 hours). Serum and urine protein electrophoresis results were normal.2.What one finding best supports a diagnosis of glomerulonephritis?a.Hematuria with proteinuria (protein level, >500 mg/day)b.Absence of RBC castsc.Hypoalbuminemiad.AKIe.Bilateral lower extremity edema Hematuria has many etiologies, including bleeding from the kidneys, ureters, bladder, and prostate, and is not specific for glomerular injury,4Bolenz C. Schroppel B. Eisenhardt A. Schmitz-Drager B.J. Grimm M.-O. The investigation of hematuria.Dtsch Arztebl Int. 2018; 115: 801-807PubMed Google Scholar although it is typically present with glomerulonephritis. Proteinuria (>500 mg/day) should raise suspicion for a glomerular process leading to kidney damage. Other causes of elevated protein urine levels include orthostatic proteinuria and transient proteinuria, which occurs in the setting of fever and exercise. Glomerular bleeding is suggested by RBC casts and dysmorphic RBCs such as acanthocytes in the urine. Dysmorphic RBCs are thought to arise from both osmotic and mechanical trauma as RBCs pass through the GBM and nephron. Although glomerulonephritis can cause nephrotic syndrome in some patients, leading to hypoalbuminemia, it does not always, and a low serum albumin level is neither sensitive nor specific for glomerulonephritis; given her history of an eating disorder, malnutrition may be a more likely explanation for this finding, although renal loss may have contributed as well. Acute kidney injury can be classified based on the etiology: prerenal, caused by decreased renal perfusion pressure; intrinsic renal, affecting the vessels, glomeruli, or tubules; and postrenal, which is an obstruction of urinary flow. Although glomerulonephritis causes AKI, it is not specific and there are many other causes.5Bennett W.M. Autosomal dominant polycystic kidney disease: 2009 update for internists.Korean J Intern Med. 2009; 24: 165-168Crossref PubMed Scopus (15) Google Scholar Bilateral leg edema can be caused by heart failure, renal disease (including nephrotic syndrome), bilateral deep vein thrombosis, chronic venous disease, liver disease, and malnutrition. Thus, this is not a specific finding for glomerulonephritis. Given the nonnephrotic-range proteinuria and unremarkable antibody investigation, a clear diagnosis could not yet be reached.3.Which one of the following would be the next best step in determining the patient’s disease process?a.Cystoscopyb.Computed tomographic urographyc.Urine cytologyd.Abdominal magnetic resonance imaginge.Renal biopsy Cystoscopy can visualize the bladder and urethra and is often used in patients with hematuria thought to be secondary to malignancy; however, it is not useful in determining the cause of glomerulonephritis. Computed tomographic urography can visualize the kidneys, ureters, and bladder and is performed with contrast to evaluate for nephrolithiasis and hydronephrosis and without contrast to visualize renal and urothelial abnormalities. It is typically performed in patients with unexplained hematuria and thus is not appropriate in this patient in whom we think glomerular disease is the most likely cause. Urine cytology is a noninvasive test performed in patients with suspected bladder cancer; however, it does not help in determining the cause of glomerulonephritis. Abdominal magnetic resonance imaging is useful to evaluate the anatomy of the kidney and can be used in patients who are suspected of having autosomal dominant polycystic kidney disease. However, this test would not help identify the cause of the patient’s glomerulonephritis.6Choyke P.L. Radiologic evaluation of hematuria: guidelines from the American College of Radiology's appropriateness criteria.Am Fam Physician. 2008; 78: 347-352PubMed Google Scholar A renal biopsy would be the best next step to determine the patient’s kidney disease. Renal biopsy is indicated in patients with persistent proteinuria, nephrotic syndrome, increasing serum creatinine level, and systemic disease with renal dysfunction, such as lupus or unexplained chronic kidney disease. It is clear from her evaluation that glomerular disease is the most likely cause of her symptoms. Light microscopic evaluation of the nephrons can reveal the gross structure, and specific immunologic staining can provide an accurate diagnosis, which is essential in deriving a treatment plan. Thus, kidney biopsy is required to characterize the renal involvement as well as to determine the most appropriate therapy and predict long-term prognosis.4.Which one of the following is most likely to be identified on renal biopsy?a.Focal segmental glomerulosclerosisb.Increased mesangial expansion and deposition of IgA antibodies in the glomerulusc.Linear deposition of IgG along the glomerular capillariesd.Pauci-immune glomerulonephritise.Membranoproliferative glomerulonephritis Primary focal segmental glomerulosclerosis typically presents with nephrotic syndrome characterized by proteinuria in the nephrotic range (>3.5 g/24 hours), hypoalbuminemia, and edema. The present patient does not meet the criteria for proteinuria in the nephrotic range, with less than 1 g/day of proteinuria. IgA mesangial staining is classically seen in IgA nephropathy. Other pathologic findings may include mesangial expansion and endocapillary hypercellularity. The present patient with microscopic hematuria, mild proteinuria, and possible upper respiratory tract infection coinciding with the onset of symptoms most likely has IgA nephropathy. Linear deposition of IgG along the glomerular capillaries is pathognomonic of anti-GBM antibody disease (formerly Goodpasture disease). Anti-GBM antibody disease typically presents with alveolar hemorrhage and acute renal failure, with proteinuria, dysmorphic RBCs, white blood cells, and RBC casts. Although pulmonary symptoms are variably present, this was not a likely diagnosis. Pauci-immune glomerulonephritis is a pathologic finding in microscopic polyangiitis and granulomatosis with polyangiitis, which are antineutrophil cytoplasmic antibody–positive vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis present with systemic signs such as fatigue, fevers, weight loss, cough, dyspnea, purpura, and a rise in serum creatinine level with hematuria and cellular casts. This patient did not have systemic signs, making this diagnosis less likely. Membranoproliferative glomerulonephritis is caused by cryoglobulins and immune complex deposition in the kidney and is typically associated with cryoglobulinemia and hepatitis C virus infection in adults. Kidney biopsy was performed and demonstrated IgA nephropathy with predominantly mesangial proliferative features (Oxford: M1, S0, E0, T0, C0).5.Which one of the following treatments would be most appropriate for this patient?a.Dialysisb.Kidney transplantc.Glucocorticoidsd.Angiotensin-converting enzyme (ACE) inhibitore.Tonsillectomy Renal replacement therapy with dialysis plays no role in the management of IgA nephropathy apart from the standard indications for dialysis, which this patient does not have. Should her renal function continue to decline, it may become an appropriate supportive measure. Patients who progress to end-stage renal disease can be treated with kidney transplant, although at this time it would not be indicated in a patient with relatively preserved renal function. Glucocorticoid therapy should be considered in patients with proteinuria greater than 1 g/day and persistent hematuria. ACE inhibitor therapy is recommended in proteinuric kidney diseases and works through decreasing blood pressure and intraglomerular pressure, which, in turn, leads to decreased protein excretion. Because she has proteinuria, ACE inhibitor therapy would be most appropriate for long-term therapy. Tonsillectomy has not been shown to prevent recurrent episodes of IgA nephropathy. Glomerular disease can manifest with hematuria, proteinuria, renal insufficiency, hypertension, edema, hypercoagulability, and systemic symptoms. These diseases are classified based on the pattern of urinary abnormalities and the degree of renal dysfunction. Classically, nephrotic syndrome is associated with greater than 3.5 g/day of protein excretion and hypoalbuminemia with peripheral edema, hyperlipidemia, and lipiduria. Nephritic syndrome (glomerulonephritis) is characterized by hematuria, variable degrees of proteinuria, and leukocyturia, although patients may also present with peripheral edema and hypertension.7Madaio M.P. Harrington J.T. The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome.Arch Intern Med. 2001; 161: 25-34Crossref PubMed Scopus (51) Google Scholar IgA nephropathy was first characterized by Berger and Hinglais in 1968 and is also known as Berger disease.8Trimarchi H. Barratt J. Monteiro R.C. Feehally J. IgA nephropathy: "state of the art": a report from the 15th International Symposium on IgA Nephropathy celebrating the 50th anniversary of its first description.Kidney Int. 2019; 95: 750-756Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Immunoglobulin A nephropathy is characterized by the predominance of circulating immune complexes consisting of aberrantly glycosylated IgA deposition in the glomerular mesangium, leading to kidney injury. Immunoglobulin A nephropathy is the leading cause of glomerulonephritis in the United States, and even so, its prevalence is likely underreported. It is believed that IgA nephropathy is a disorder of the mucosal immune system as evidenced by its association with celiac disease and the observation that hematuria tends to worsen after an upper respiratory tract infection.9Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (705) Google Scholar The classic presentation of IgA nephropathy is episodic gross hematuria occurring after an upper respiratory tract infection. Diseases associated with IgA nephropathy include cirrhosis, celiac disease, and human immunodeficiency virus. The differential diagnosis is broad and includes Henoch-Schonlein purpura, postinfectious glomerulonephritis, lupus nephritis, and membranoproliferative glomerulonephritis. An evaluation including urinalysis with microscopic analysis and a 24-hour urine protein should be performed and the diagnosis confirmed by renal biopsy if indicated.10Trimarchi H. Barratt J. Cattran D.C. et al.Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group.Kidney Int. 2017; 91: 1014-1021Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar It remains possible that this patient had IgA nephropathy related to underlying liver cirrhosis secondary to her past alcohol use. Liver disease is the leading cause of secondary IgA nephropathy via impaired clearance of IgA by the Kupffer cells in the liver, which predisposes these patients to IgA complex deposition. Because of this mechanism, patients with cirrhosis can have IgA complex deposition detectable on kidney biopsy even in the absence of clinically relevant renal dysfunction, and most have no signs of glomerular involvement.11Floege J. Rauen T. Eitner F. Intensive supportive care plus immunosuppression in IgA nephropathy.N Engl J Med. 2016; 374: 992-993PubMed Google Scholar Immunoglogulin A nephropathy has a heterogenous risk of kidney function decline as evidenced by studies in which the risk is anywhere from 5% to 60%. Current guidelines recommend risk stratifying patients with IgA nephropathy so that immunosuppression can be targeted toward high-risk individuals. The STOP-IgA trial did not find any benefit of immunosuppression in patients with IgA nephropathy with moderate proteinuria and chronic kidney disease stages 1 through 3.1Baker R.J. Pusey C.D. The changing profile of acute tubulointerstitial nephritis.Nephrol Dial Transplant. 2004; 19: 8-11Crossref PubMed Scopus (240) Google Scholar The MEST score is one such risk stratification associated with renal outcomes. This scoring system includes 4 histologic components: mesangial (M), endocapillary hypercellularity (E), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T). A recent study by Barbour et al12Barbour S.J. Coppo R. Zhang H. et al.Evaluating a new international risk-prediction tool in IgA nephropathy.JAMA Intern Med. 2019; 179: 942-952Crossref PubMed Scopus (99) Google Scholar investigated clinical, limited, and full models to predict which patients will benefit from immunosuppressive therapy. These prediction models take into account both the MEST score and clinical data and have been accurate in helping clinicians improve the management and treatment of IgA nephropathy.12Barbour S.J. Coppo R. Zhang H. et al.Evaluating a new international risk-prediction tool in IgA nephropathy.JAMA Intern Med. 2019; 179: 942-952Crossref PubMed Scopus (99) Google Scholar Using this scoring system, her risk of progression to end-stage renal disease was predicted to be less than 6% in 5 years. Currently there are 2 nonimmunosuppressive mainstays of therapy for IgA nephropathy: ACE inhibitors or angiotensin receptor blockers to control blood pressure and progression of the renal disease by minimizing proteinuria. Statin therapy can also be initiated in patients with elevated low-density lipoprotein cholesterol levels to lower cardiovascular disease risk, although the utility in slowing the progression of renal disease remains unclear. The present patient was started on the ACE inhibitor lisinopril 2.5 mg and will continue to follow up with nephrology as an outpatient to ensure remission of her proteinuria and hematuria.