Work-up hematuria with confidence. Learn what you should be worrying about, what tests are worth considering, and how to figure out if this is a job for a urologist or nephrologist.
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Hematuria often initially presents in the primary care setting as asymptomatic, microscopic hematuria. Urine microscopy that shows 3 or more red blood cells per high-powered field should prompt a work-up. The major thrust of the work-up should be evaluating whether the source of the blood is a urologic/non-glomerular or a nephrologic/glomerular etiology.
Gross (visible) hematuria is more likely to be malignancy, and the presence of clots in the urine is much more suggestive of a non-glomerular source. The American Urologic Association hematuria guidelines categorize hematuria as high risk in patients with age greater than ≥ 60 years, > 30 pack years of tobacco smoking, >25 RBC/HPF on single urinalysis, and a history of gross hematuria as high risk for malignancy. Male sex, prior pelvic radiation therapy, prior cyclophosphamide chemotherapy, and occupational exposures to benzene chemicals also confer higher risk of urothelial cancer (Barocas et al. 2020). Aristolochic acid, a naturally occurring plant compound found in some herbal medicinal products, has also been implicated in bladder cancer (Chen et al. 2012). Beet consumption can lead to pseudohematuria/beeturia in up to 14% of the population (Watson et al. 1963). Rifampin and pyridium can also lead to pseudohematuria, while long-term NSAID use can lead to tubular necrosis.
Importantly, anticoagulation does not cause spontaneous hematuria. In fact, hematuria in these patients may occur earlier in malignancy and lead to an earlier diagnosis (Moschini et al. 2016). Exercise-induced hematuria also exists, and the mechanism behind it is uncertain. Delightfully, some researchers believe it comes from foot strike trauma while running, resulting in hemolysis (Varma et al. 2014).
Concern for a urologic source should prompt questions such about flank pain, back pain, dysuria, and clots, in addition to asking about risk factors for urothelial cancer. Concern for a nephrologic cause should lead to questions about systemic diseases such as lupus or other rheumatologic disease. This means asking about symptoms like eye irritation, malar rash, palpable purpura, and joint pain.
For gross hematuria or patients with high risk for malignancy, Dr. Fine begins with imaging, which is typically CT urography. This can identify masses, stones, cysts, and other anatomic abnormalities. The American Urological Association guideline recommends renal ultrasound for patients at low and intermediate risk for malignancy. This may reveal cysts, hydronephrosis, and certain anatomical abnormalities, but resolution on CT is far greater. Intermediate and high risk patients will also typically undergo cystoscopy as well. If a clear etiology cannot be elucidated, additional angiographic imaging could be considered to rule out vascular anomalies. A negative evaluation in low- and intermediate-risk patients should prompt a repeat urinalysis in 6-12 months.
While gross hematuria is more commonly associated with urologic causes, it can be seen in IGA nephropathy and thin basement membrane disease, where the hematuria typically manifests without proteinuria. Point of care urinalysis is generally not accurate enough to truly quantify proteinuria. A protein:creatinine ratio or albumin:creatinine ratio can be used to do this, and the latter is more sensitive and accurate. Dr. Fine will often check both. Albuminuria can be suggestive of glomerular protein, so if there is a substantial difference between the two, he will start to think about tubular proteins, which impacts his differential. Red blood cell casts are suggestive of a glomerular source, but may not be reported in routine laboratory analysis. Crystals seen on urinalysis may indicate the presence of a urinary stone disease, but may also simply mean the urine is concentrated.
Key point: Proteinuria or a rising creatinine are suggestive of a renal process that should prompt a thorough work-up for glomerular causes of hematuria. A rising creatinine raises the concern for a rapidly progressive glomerulonephritis, which is potentially the most serious nephrologic issue. Dr. Fine breaks down glomerulonephritis into three groups: Anti-glomerular basement membrane diseases (anti-GBM, formerly Goodpasture’s), ANCA or pauci-immune glomerulonephritis, and immune complex glomerulonephritis.
Anti-GBM is unlikely in the absence of rapidly progressive renal failure. The ANCA glomerulonephritides are not necessarily rapidly progressive. Initial work-up includes testing for ANCA antibodies, which include anti-MPO and anti-PR3 antibodies. If both are present, consider drug induced ANCA glomerulonephritis (Radic et al. 2012).
The differential for immune-complex glomerulonephritis is longer, and Dr. Fine sub-categorizes these into low complement and normal complement disease. For low complement disease, Dr. Fine considers three broad groups: infection-related, lupus, and membranoproliferative glomerulonephritis. For normal complement disease, Dr. Fine considers IgA vasculitis (formerly Henoch-Schonlein). However, all of these disease states can present with normal complement levels.
There are also several mimickers of rapidly progressive glomerulonephritis, including HIV nephropathy and hepatitis C related disease, although these typically do not present with hematuria. Scleroderma can cause thrombotic microangiopathy with hemolytic anemia and thrombocytopenia.
If there is little proteinuria and the patient has stable disease, Dr. Fine may consider deferring biopsy. But in general, he favors early biopsy for diagnostic confirmation of glomerular disease, particularly in patients with low risk of bleeding complications. He also favors biopsy in patients with renal transplantation, and there appears to be a lower complication rate in biopsies of transplanted kidneys compared to native kidneys (Whittier et al. 2018).
Listeners will develop a framework to evaluate hematuria, and to determine whether it is glomerular or non-glomerular in etiology.
After listening to this episode listeners will…
Dr. Fine reports no relevant disclosures. The Curbsiders report no relevant financial disclosures.
Williams, PN, Fine DM, Watto MF. “#404 Hematuria with Dr. Derek Fine”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast July 17, 2023.
Producer and writer: Paul Williams, MD, FACP
Show Notes, Infographic, and Cover Art: Paul Williams, MD, FACP
Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP
Reviewer: Emi Okamoto, MD
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP
Technical Production: PodPaste
Guest: Derek Fine, MD
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