Hematuria and Proteinuria

Definition

On microscopic evaluation, the presence of three or more RBCs per high-power (400×) field in a centrifuged urine sample is generally considered abnormal. However, there is no absolute cutoff, and lowering this cutoff results in more false-positive results, while increasing this cutoff will result in more false-negative results for any given etiology.

Etiology

Hematuria can be due to RBC loss anywhere along the genitourinary tract, ranging from the glomerulus to the urethra ( Table 5.1 ). Glomerular hematuria may be distinguished from other causes of hematuria using 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 macroscopic hematuria following upper respiratory tract infections, although this should be differentiated from post-infectious 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, often without progressive kidney disease. Conversely, a family history of hematuria and progressive kidney disease, hearing loss, and ocular abnormalities suggest Alport syndrome, a genetic condition similar to TBMD in which affected individuals can progress to kidney failure.

Inflammatory diseases of the glomerulus also cause glomerular hematuria. These include lupus nephritis, membranoproliferative glomerulonephritis (MPGN), antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, and antiglomerular basement membrane disease, among others. 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 can also have hematuria. Hematuria has been reported as an uncommon finding in diabetic kidney disease. In addition, direct barotrauma in the setting of hypertensive emergency can result in hematuria. Lastly, glomerular hematuria can be found in healthy individuals after intense exercise; this is a diagnosis of exclusion and typically benign in nature.

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. 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 (non-glomerular) origin, with the risk of malignancy generally increasing 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 crystalluria and nephrolithiasis, such as hypercalciuria and hyperoxaluria, have also been identified as causes of microscopic hematuria. Anticoagulation 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 several chemotherapeutic agents. Conversely, many medications cause discoloration of urine without actual RBCs or free heme pigment in the urine ( Table 5.2 ). Causes include certain foods such as beets and metabolites such as porphyrins, bile pigments, and methemoglobin.

Mechanical trauma to the genitourinary tract, including with instrumentation such as the placement of a bladder catheter, 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

Evaluation typically starts with a urine dipstick test 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 heme in the urine in the form of intact RBCs or heme pigment from either free hemoglobin (e.g., intravascular hemolysis) or myoglobin (e.g., rhabdomyolysis) in the urine. False-positive results can be due to the presence of semen, bacterial peroxidase, or highly alkaline urine, or after cleaning the perineum with oxidizing agents. False-negative results can occur in cases of high vitamin C intake.