Abstract
Kidney damage is manifested by loss of the integrity of the filtration barrier, impairment of tubular function, or other processes that interfere with normal kidney function. Urinalysis and urine sediment examination are useful tools to detect this damage, and both hematuria and proteinuria are important biomarkers of kidney disease. The appearance of red blood cells (RBCs) in the urine and the presence and type of proteinuria may point to the site of nephron damage and qualify the diagnostic evaluation. The persistence of hematuria and the level of proteinuria provide prognostic information as well as an assessment of continued disease activity and response to treatment. This chapter explores the significance of hematuria and proteinuria, the mechanisms of their development, the evaluation of these findings, and treatment options.
Keywords
proteinuria, albuminuria, hematuria, acanthocyte, red blood cell (RBC) cast, chronic kidney disease (CKD), glomerular basement membrane (GBM), urinalysis
Kidney disease is recognized as a reduction in the glomerular filtration rate (GFR) or damage to kidney structure or function. This damage is manifested by loss of the integrity of the filtration barrier, impairment of tubular function, or other processes that interfere with normal kidney function. Urinalysis and urine sediment examination are useful tools to detect this damage, and both hematuria and proteinuria are important biomarkers of kidney disease. The appearance of red blood cells (RBCs) in the urine and the presence and type of proteinuria may point to the site of nephron damage and qualify the diagnostic evaluation. For example, blebs on the surface of RBCs in the urine sediment indicate glomerular bleeding as these cells undergo morphologic changes when forced across the glomerular basement membrane (GBM); albuminuria often reflects damage to the filtration barrier with a loss of the charge and size selectivity of the membrane; and low-molecular-weight proteinuria, such as β-2-microglobulin, identifies a failure of proximal tubular protein reabsorption or excessive filtration of pathologic molecules. The persistence of hematuria and the level of proteinuria provide prognostic information as well as an assessment of continued disease activity and response to treatment.
As early kidney damage may occur without clinical correlations, screening for hematuria and proteinuria is encouraged in high-risk populations, such as those with diabetes, hypertension, autoimmune conditions, or a family history of kidney disease. The detection of abnormal levels of these biomarkers warrants a full and complete evaluation by a trained clinician. This chapter explores the significance of hematuria and proteinuria, the mechanisms of their development, the evaluation of these findings, and treatment options.
Hematuria
Hematuria is the presence of RBCs in the urine. This can be divided into macroscopic (also known as gross or visible) and microscopic hematuria. Macroscopic hematuria is detected by the naked eye while microscopic hematuria needs either evaluation with a urine dipstick or microscopic urine sediment evaluation. As little as 1 mL of blood in a liter of urine can result in discoloration of the urine. Urine can appear on a spectrum from light pink to dark red/cola colored depending on the concentration of RBCs.
Definition
On microscopic evaluation, the presence of three or more RBCs per high-power field in a centrifuged urine sample is generally considered abnormal. However, there is no absolute cutoff, and lowering this threshold will result in more false-positive results, while increasing this threshold will result in more false-negative results.
Etiology
The many different causes of hematuria are outlined in Table 5.1 . Microscopic hematuria can come from glomerular or nonglomerular sites, with evaluation based on the RBC morphology in the urine sediment and the presence and amount of albuminuria. The most common glomerular causes of asymptomatic hematuria include IgA nephropathy and thin basement membrane disease (TBMD). In about half of affected individuals, immunoglobulin A (IgA) nephropathy can present with gross hematuria following upper respiratory tract infections, although this should be differentiated from postinfectious glomerulonephritis (PIGN). PIGN typically has a longer lag than IgA nephropathy between the infection and the onset of hematuria. TBMD results from genetic defects in type IV collagen that make up the GBM. The inheritance pattern is autosomal dominant, resulting in multiple family members with microscopic hematuria without progressive kidney disease. Glomerular hematuria can be found in healthy individuals after intense exercise, which is benign in nature. Conversely, a family history of hematuria and progressive kidney disease, hearing loss, and ocular abnormalities can indicate Alport syndrome, a genetic condition similar to TBMD in which affected individuals can progress to kidney failure.
| Glomerular |
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| Tubular/Interstitial |
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| Urothelial |
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| Medications |
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| Structural Kidney Diseases |
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| Other Causes |
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| Rare Causes |
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Inflammatory diseases of the glomerulus also cause glomerular hematuria. These include lupus nephritis, membranoproliferative glomerulonephritis (MPGN), pauci-immune vasculitis, and antiglomerular basement membrane disease, among others. Direct barotrauma in the setting of hypertensive emergency can result in hematuria. Glomerular diseases that lack significant inflammation but result in increased GBM permeability, such as focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy, primarily cause proteinuria, but they can also result in hematuria. Hematuria has also been reported as an uncommon finding in diabetic nephropathy.
The presence of pyuria in the setting of hematuria, along with specific symptoms, can point to infection or inflammation being the cause. Numerous bacterial pathogens can cause infectious cystitis. Patients taking immunosuppressant medications can develop infectious cystitis from viruses such as BK polyomavirus. Without infectious symptoms and with sterile cultures, acute or chronic tubulointerstitial disease should be considered, with the latter including analgesic nephropathy. Although rare in the United States, infections such as tuberculosis or schistosomiasis can cause pyuria and hematuria with sterile bacterial cultures in endemic countries.
Macroscopic hematuria with passage of blood clots in the urine is most often of urothelial origin, and the risk of malignancy generally increases in older individuals. Other risk factors for urothelial carcinoma include exposure to cigarette smoking, occupational carcinogens, radiation, or medications such as cyclophosphamide. In older men, prostatic hypertrophy can be a cause of hematuria, but caution should be used to exclude malignancy. Hematuria associated with renal colic can be from nephrolithiasis; however, blood clots causing urinary obstruction can cause similar pain. Risk factors for nephrolithiasis, such as hypercalciuria and hyperoxaluria, have also been identified as causes of hematuria. Overanticoagulation can result in hematuria originating in the urothelial tract and has also been implicated, albeit rarely, in glomerular bleeding.
Medications that directly cause hematuria are uncommon, with the exception of a few specific chemotherapeutic agents. Conversely, many medications cause discoloration of urine without actual RBCs or free heme pigment in the urine ( Table 5.2 ). This holds true for certain foods such as beets and for metabolites such as porphyrins, bile pigments, and methemoglobin.
| Red |
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| Red-Brown |
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| Brown |
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| Dark Appearing |
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| Red-Orange |
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Instrumentation and trauma to the genitourinary tract is commonly associated with hematuria. Similarly, papillary infarction or necrosis (more frequently seen in individuals with sickle cell disease and in a subset of individuals with analgesic nephropathy), kidney infarcts, damage from radiation, or structural kidney disease can all result in hematuria. In addition to causes already mentioned, hematuria in kidney transplant patients can be due to BK polyoma virus infection, rejection, recurrence of original kidney disease (if associated with hematuria), trauma, or structural/anastomotic problems.
Detection
Identification of microscopic hematuria is commonly performed with a urine dipstick. The dipstick is performed when there is discoloration of the urine or when there is concern for hematuria. The dipstick relies on the peroxidase activity of the heme molecule, which results in a detectable change in color on an impregnated indicator pad. This sensitive reaction can detect very small amounts of blood in the urine. Positive results can also be present in the setting of free heme pigment from hemoglobin or myoglobin in the urine without intact RBCs (e.g., rhabdomyolysis). False-positive results can be due to the presence of semen, bacterial peroxidase, highly alkaline urine, or after cleaning the perineum with oxidizing agents. False-negative results can occur in cases of high vitamin C intake.
Evaluation of Hematuria
The evaluation of hematuria ( Fig. 5.1 ) begins with a careful personal and family history that can provide clues to the possible etiology. Personal history should include prior episodes of hematuria, antecedent travel, upper respiratory tract infection before the onset of hematuria, recent strenuous exercise, history of renal colic or previous nephrolithiasis, passage of blood clots in the urine, pelvic radiation, recent trauma or instrumentation, and initiation of new medications or use of anticoagulants. Hematuria in the setting of menstruation should always be interpreted with caution because of the risk of contamination of the urine sample. Family history should include the presence of hematuria, hearing or ocular disorders, progressive kidney disease, and hematologic abnormalities such as sickle cell disease/trait or coagulation disorders. Physical examination should explore signs of infection (for pyelonephritis, cystitis, or prostatitis), severe hypertension, edema pointing to possible accompanying hypoalbuminemia from nephrotic syndrome, masses in the setting of kidney or prostatic malignancy, or enlarged kidneys from polycystic kidney disease (PKD).
