Ep 146: A 73-Year-Old Female with Lower Extremity Swelling

This episode covers a woman experiencing subacute edema and anasarca due to renal disease, and reviews the possible underlying causes.

Read more on this topic on AccessMedicine.

Harrison's Principles of Internal Medicine, 22nd Edition

Transcript

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[Ms. Heidhausen] This is Katarina Heidhausen, executive editor of Harrison's Principles of Internal Medicine. Harrison's Podclass is brought to you by McGraw Hill's AccessMedicine, the online medical resource that delivers the latest content from the best minds in medicine. And now, on to the episode. 

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[Dr. Handy] Hi, everyone. Welcome back to Harrison's Podclass. We're your co-hosts. I'm Dr. Cathy Handy. 

[Dr. Wiener] And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine. 

[Dr. Handy] Today's episode is about a 73-year-old female with lower extremity swelling. 

[Dr. Wiener] Cathy, today's patient is a 73-year-old previously healthy woman who's brought to clinic by her very worried daughter 'cause her mother has had worsening lower extremity swelling over the last two months. The patient reports that her ankles started swelling and now her thighs are swelling to the point where she can no longer wear her usual hose when she goes out to lunch with her friends. Her past history is only notable for hypertension, controlled with an oral thiazide diuretic. She's diligent about cancer screening, has had her last pap and mammogram last year. The patient said she thought her swelling was related to her hypertension, but doubling the dose of diuretic did not correct the symptoms. She's also noted increasing fatigue and dyspnea on exertion. Carrying her laundry from the basement has become burdensome and she's had to rest one to two times during that time. That's new for her. She denies any fevers, night sweats, anorexia, or weight loss. In fact, her weight has increased by 12 pounds over the last two months. 

[Dr. Handy] Okay, interesting. The new swelling could be a lot of things. Why don't you tell me about her physical exam first? 

[Dr. Wiener] Okay, on exam, she's afebrile. Her heart rate's 80, blood pressure's 130/80. Her respiratory rate's 14 with a resting oxygen saturation of 94%. Her eyelids appear swollen. Neck veins are not elevated. She does have decreased breath sounds at both lung bases with dullness to percussion. Her heart examination is normal, but she has some abdominal distension with possible ascites. She also has notable pitting edema bilaterally to her thighs and it's present on her coccyx. Her skin and her joints are otherwise normal. 

[Dr. Handy] Okay, that was really helpful. What about a POCUS? Was that performed? It does sound like she has some ascites and bilateral pleural effusions. 

[Dr. Wiener] Yeah, POCUS confirms both of those. In addition, you find that she has no interstitial lung disease, a normal-appearing left and right heart. What does that make you think? 

[Dr. Handy] With normal neck veins and POCUS, I don't think this is either left or right heart failure. I am worried that she has nephrotic syndrome or liver disease. Has she noticed any changes in her urine? And I'm assuming you would've told me if she has any jaundice on exam. 

[Dr. Wiener] She does not have any jaundice. On further questioning, she does say that it seems like her urine's more foamy, but she's adamant it has not been discolored. 

[Dr. Handy] Okay, so I think she's going to have nephrotic syndrome without gross hematuria. I do still want to rule out liver disease, but I think the answer is going to be in her urinalysis. 

[Dr. Wiener] Okay. Well, I'll give you some labs. Her labs reveal that her CBC is unremarkable. Her electrolytes are normal, including her creatinine. Liver function tests, including INR, are normal. However, her serum cholesterol is elevated at 300 mg/dL. Her albumin is reduced to 2.8 g/dL. And as you guessed, her urine is notable for 4+ protein with occasional red cell casts and an albumin/creatinine ratio of 300 mg/mL. 

[Dr. Handy] Okay. So she has nephrotic syndrome. A 24-hour urine collection will be the final confirmation. 

[Dr. Wiener] Okay. Well, that brings us to our question. It says, which of the following diagnoses is most likely in this patient? And the options are, A. anti-glomerular basement membrane disease; B. idiopathic membranous glomerulonephritis; C. IgA nephropathy; D. minimal change disease; or E. post-streptococcal glomerulonephritis. 

[Dr. Handy] Let's first do a quick review of the clinical syndromes that glomerular disease may present with and remember that there is some overlap. Patients with nephritic syndrome typically produce one to two grams per 24 hours of proteinuria. They have hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine that's associated with the reduction in glomerular filtration. Nephrotic syndrome, on the other hand, is described by the onset of heavy proteinuria, so over three grams per 24 hours. And patients will also have hypercholesterolemia, hypoalbuminemia, and edema, and anasarca. This is what's described in this patient. The glomerular filtration rate in these patients may initially be normal or rarely, even higher than normal, but with persistent hyperfiltration and continued nephron loss, it typically declines over months to years. I'll also say that our patient is going to need a renal biopsy to determine the exact cause, which will also guide then the appropriate therapy. 

[Dr. Wiener] Do you have enough information to answer our question? 

[Dr. Handy] I know which is most likely, but again, the renal biopsy will be definitive. She most likely has B. idiopathic membranous glomerulonephritis. 

[Dr. Wiener] Why do you say that? 

[Dr. Handy] Well, first, let me rule out some of the other options. Patients with anti-glomerular basement membrane disease or anti-GBM disease have autoantibodies against the glomerular basement membrane. If they present with renal and pulmonary disease, we call it Goodpasture syndrome. Older patients with anti-GBM disease typically present with a rapidly progressive glomerulonephritis and acute renal failure rather than indolent nephrotic syndrome. 

[Dr. Wiener] What about IgA nephropathy? Why'd you rule that out? 

[Dr. Handy] IgA nephropathy is one of the most common forms of glomerulonephritis worldwide. There is a male predominance and a peak incidence in the second and third decades of life. IgA nephropathy is a relatively benign disease for the majority of patients. 5-30% of patients go into complete remission. Others will have hematuria, but well-preserved renal function. Histologically, you see deposition of IgA in the mesangium. The two most common clinical presentations of IgA nephropathy are recurrent episodes of macroscopic hematuria during or immediately following an upper respiratory infection. And that's often accompanied by proteinuria and persistent asymptomatic microscopic hematuria. Nephrotic syndrome though is uncommon, so I don't think our patient fits that picture either. 

[Dr. Wiener] Okay, we're narrowing it down. What about minimal change disease and post-streptococcal glomerulonephritis? 

[Dr. Handy] Minimal change disease does present with nephrotic syndrome. It causes 70-90% of nephrotic syndrome in childhood, but only 10-15% of nephrotic syndrome in adults. Minimal change disease usually presents as a primary renal disease, but it can be associated with several conditions. And there are some that are associated with allergies and some medications like NSAIDs or lithium. Minimal change disease though is named as such because on renal biopsy there are no glomerular lesions by light microscopy and it's generally negative for deposits by immunofluorescence. Again, the renal biopsy will be necessary for a definitive diagnosis, but because this is a less common cause of nephrotic syndrome than membranous glomerulonephritis in older adults, I'm going to say that it's less likely. 

[Dr. Wiener] Okay, well, what about post-streptococcal glomerulonephritis? 

[Dr. Handy] So the classic presentation there is an acute nephritic picture with hematuria, pyuria, red blood cell casts, edema, hypertension, and oliguric renal failure. And this may be severe enough to appear as rapidly progressive glomerulonephritis. Systemic symptoms would be headache, malaise, anorexia, and flank pain. And that's usually due to swelling of the renal capsule and that can be reported in up to about 50% of cases. There can be nephrotic range proteinuria and our patient did not have anything to suggest a recent streptococcal infection. Skin and more commonly, throat infections typically precede the glomerular disease but interestingly, antibiotic therapy does not reduce the recurrence of nephritis. Post-streptococcal glomerulonephritis due to pharyngitis develops one to three weeks after infection and about two to six weeks after impetigo. 

[Dr. Wiener] Okay, so we're going to say our patient likely has membranous GN. Tell me a little bit more about that one. 

[Dr. Handy] Membranous GN or membranous nephropathy, as it's sometimes called, accounts for about 25% of cases of nephrotic syndrome in adults. Idiopathic membranous GN is the most common cause of nephrotic syndrome in the elderly and that's why I picked it for our patient. Also, in 20-30% of cases, membranous GN is secondary and may be associated with solid tumors or an infection, or rheumatologic disorders such as lupus or rheumatoid arthritis. And importantly, although thrombotic complications are a feature of all nephrotic syndromes, membraneous GN has the highest reported incidences of renal vein thrombosis, pulmonary embolism, and deep vein thrombosis. Prophylactic anticoagulation is controversial, but it has been recommended for patients with hypoalbuminemia. So that will be a consideration for our patient. 

[Dr. Wiener] Great. So to summarize, the teaching points in this case are that broadly speaking, glomerular diseases may present clinically with a nephritic or a nephrotic presentation, but there's a great deal of overlap. Idiopathic or secondary membranous glomerulonephritis is the most common cause of nephrotic syndrome in the elderly, but the definitive diagnosis typically requires further testing, including renal biopsy, that will help define further therapy. 

[Dr. Handy] And you can find this question and others like it in the Harrison's Self-Review book, and online. And read more about this in the Harrison's chapter on membranous glomerular disease. Visit the show notes for links to helpful resources, including related chapters and review questions from Harrison's, available exclusively on AccessMedicine. If you enjoyed this episode, please leave us a review, so we can reach more listeners just like you. Thanks so much for listening. 

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