Arvind K. Garg and Steven Cheng
Hematuria
GENERAL PRINCIPLES
· Hematuria, or blood in the urine, is common in the outpatient setting.
· Concomitant findings, such as pain, renal injury, and proteinuria, help to localize the site of injury along the genitourinary tract.
· Persistent hematuria may be a sign of serious disease and should not be ignored.
Definition
· Hematuria is the presence of red blood cells (RBCs) in urine.
· Gross hematuria is visible to the naked eye and often manifests as red, pink, or cola-colored urine.
· Microscopic hematuria is defined by the American Urological Association (AUA) as the presence of ≥3 RBCs/high-power field (HPF) on microscopic examination of one properly collected, noncontaminated urinalysis in the absence of obvious benign cause.1
· Microscopic hematuria should be confirmed on two out of three midstream clean-catch urine samples before proceeding with further workup.
Classification
· Hematuria is generally categorized based on the source of the blood.
· Blood that enters the urinary content at the glomerular filtration barrier is classified as glomerular hematuria and can be associated with any of the following findings:
o Dysmorphic RBCs
o Cellular casts
o Proteinuria (>0.5 g/24 hours)
· Blood that is introduced to the urinary content at any other site in the urinary tract is classified as nonglomerular.
Epidemiology
· Prevalence of microscopic hematuria ranges between 2.4% and 31.1% depending upon the demographics and the underlying risk factors of study population.1
· Risk of underlying malignancy varies between 2% and 11% with microscopic hematuria as compared to 15% and 22% with gross hematuria.2
Etiology
A brief summary of the causes of hematuria can be found in Table 25-1.3,4
TABLE 25-1 Causes of Hematuria
Data from Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med 2003;348:2330–2338.
Risk Factors
It is impossible to generalize risk factors for hematuria since there are so many different causes. However, common risk factors for hematuria associated with urinary tract malignancy are summarized in Table 25-2.1
TABLE 25-2 Risk Factors for Urinary Tract Malignancy
DIAGNOSIS
The diagnosis of hematuria can be made by serial visual or microscopic assessments of the urine to confirm the persistent presence of blood. The purpose of the ensuing workup is to localize the cause of the hematuria and provide the appropriate treatment.
Clinical Presentation
History
· Although many causes of hematuria are asymptomatic, a detailed history can often identify symptoms that are suggestive of specific causes of hematuria.
· Pain:
o Colicky pain at the costovertebral angle (CVA) or flank with radiation to the groin may indicate a ureteral stone but can be associated with blood clot or sloughed renal papilla.
o A history of dysuria or urinary frequency suggests a urinary tract infection (UTI).
· Urine flow: urinary hesitancy, dribbling, or weak urinary stream accompanies bladder obstruction from an enlarged prostate, stone, or tumor.
· Timing:
o Cyclical hematuria in women raises concern for genitourinary tract endometriosis.
o A history of heavy physical activity may explain transient (<48 hours) microscopic hematuria but does not exclude other underlying pathologic conditions.
· Family history: A family history of hematuria can often be found in individuals with kidney stones, polycystic kidney disease, or congenital disease of the glomerular basement membrane, such as thin basement membrane disease and Alport syndrome.
· Associated illnesses:
o Patients on anticoagulation may have hematuria from nonglomerular sites of bleeding.
o Individuals with sickle cell disease or trait can develop renal diseases with hematuria.
o Infections
§ A history of hematuria 1 to 2 weeks after pharyngitis or skin infection suggests poststreptococcal glomerulonephritis (PSGN).
§ IgA nephropathy can present with episodic gross hematuria in the setting of upper respiratory infections (URI).
§ Bacterial endocarditis, sepsis, abscesses, or infection of an indwelling foreign body can be associated with a proliferative glomerulonephritis. Other infections such as viral hepatitis (hepatitis B and C) and syphilis can also cause a variety of glomerulopathies.
o Autoimmune diseases: immune complex–mediated glomerular diseases such as systemic lupus erythematosus or systemic vasculitis can present with arthritis, arthralgias, fever, or rashes.
Physical Examination
· Thorough physical examination including vital signs (especially blood pressure) and assessment of volume status is important. The presence of edema and hypertension favors a glomerular cause of hematuria.
· Fever, CVA tenderness, or suprapubic tenderness may suggest infection.
· Polycystic kidney or distended bladder may be palpable on abdominal examination.
· Skin rashes, arthritis, or heart murmurs can often be seen with systemic vasculitis, autoimmune glomerulonephritis, and infectious glomerulonephritis.
· Digital rectal examination helps with diagnosis of prostate enlargement, masses, or tenderness.
· Vaginal examination should be performed in women to exclude vaginal bleeding.
Diagnostic Testing
An overview of the workup for hematuria is summarized in Figure 25-1.
Figure 25-1 Algorithm for the evaluation of microscopic hematuria.
Laboratories
· The urinalysis (dipstick and micro) is the initial test for diagnosis and confirmation of hematuria. The urinalysis is able to distinguish true hematuria from urine that is discolored due to chemical pigments, food metabolites, or medications (e.g., bilirubin, porphyrins, beets, blackberries, blueberries, levodopa, metronidazole, nitrofurantoin, pyridium, phenytoin, rifampin).5
· The urine evaluation can also help differentiate glomerular from nonglomerular hematuria.
o The dipstick is able to detect significant excretion of negatively charged proteins. While it may miss microalbuminuria seen in the earliest stages of nephropathy, a positive urine dipstick is suggestive of glomerular damage and should be further assessed by an estimate of renal function and quantification of proteinuria.
o Urine microscopy can detect the presence of dysmorphic RBCs and cellular casts. When coupled with proteinuria (≥0.5 g/day) and/or renal insufficiency, it suggests renal parenchymal disease and warrants further nephrologic workup.
· Further laboratory testing can be guided based on history, physical examination, and initial lab testing.
o Urine culture is indicated if pyuria or bacteriuria is present. Repeat urinalysis 6 weeks after appropriate antimicrobial therapy.
o Hemoglobin electrophoresis evaluates for suspected sickle cell disease or trait.
o Antinuclear antibody, antineutrophil cytoplasmic antibody, antiglomerular basement membrane antibodies, complement levels, cryoglobulins, HIV testing, and viral hepatitis serology are used for evaluation of glomerular hematuria.
o Urine cytology is used for patients at risk for genitourinary malignancies but not for routine screening. If positive, cystoscopy is warranted.
Imaging
· Imaging should be performed in patients with no evidence of glomerular hematuria.
· CT scan with and without intravenous (IV) contrast is currently the preferred initial imaging modality. It has excellent sensitivity for stones and solid masses. In patients with a contraindication to CT (contrast allergy, pregnancy, renal insufficiency), MRI with and without IV contrast can be considered.
· Ultrasonography is an effective and safe imaging modality in patients with contraindications to CT/MRI and is preferred in pregnancy.
· Retrograde pyelogram (RPG) provides an alternative for the evaluation of upper genitourinary tracts.
· Intravenous urography (IVU) was traditionally the initial imaging modality of upper urinary tracts but has been largely replaced by other methods.
Diagnostic Procedures
· Per the 2012 AUA guidelines, cystoscopy should be performed on all patients with hematuria ≥35 years old, with or without risk factors for urinary tract malignancy. Patients <35 years should have cystoscopy if underlying risk factors for malignancy are present.1
· Referral to nephrology with a possible kidney biopsy is indicated if glomerular pathology is suspected.
TREATMENT
· The treatment of hematuria is entirely dependent on the cause.
· See Chapter 24 for treatment of glomerulonephritis.
FOLLOW-UP
· A patient with a history of persistent microscopic hematuria and two consecutive negative annual urinalyses does not need any further urinalysis or other evaluation.1
· For persistent microscopic hematuria after negative workup, yearly urinalysis should be conducted.1
· Repeat evaluation in 3 to 5 years should be considered for persistent or recurrent microscopic hematuria after initial negative workup.1
Nephrolithiasis
GENERAL PRINCIPLES
Kidney stones are crystalline structures in the urinary tract that have achieved sufficient size to cause symptoms or be visible by radiographic imaging techniques.
Epidemiology
· Nephrolithiasis is a common condition that affects men twice as often as women (lifetime risk of 12% vs. 6%).6
· The peak age of onset is the third decade, with increasing incidence until age 70.
· Prevalence is influenced by age, sex, race, body size, and geographic distribution.
Classification
· Calcium stones account for approximately 80% of all stones and are composed of calcium oxalate, calcium phosphate, or both.7 Calcium stones are usually idiopathic but can occur with primary hyperparathyroidism, medullary sponge kidney, or distal renal tubular acidosis.
· Uric acid and struvite stones comprise the majority of the remainder.
· Uric acid stones form in the setting of uric acid overproduction, low urinary volume, and persistently acidic urine pH.
· Struvite stones (triple phosphate) occur under conditions of high urinary pH and increased ammonia production, reflecting infection with urea-splitting organisms (e.g., Proteus mirabilis, Klebsiellaspp.). Escherichia colidoes not produce urease.8,9 Struvite stones are usually composed of magnesium ammonium phosphate (struvite) or carbonate apatite and are often in the shape of a staghorn, as they grow rapidly and typically extend to involve more than one calyx. They often occur in paraplegic or quadriplegic patients because of increased predisposition to UTIs. Staghorn calculi are associated with increased rates of chronic kidney disease.
· Rarely poorly soluble drugs (e.g., triamterene, indinavir) can form stones.
Risk Factors
Risk factors for nephrolithiasis include family history, primary hyperparathyroidism, renal tubular acidosis, recurrent UTIs, inflammatory bowel disease, obesity, gout, diabetes, hot climates, high-protein and high-sodium diet, low fluid intake, and perhaps a high dietary fructose.6,10
DIAGNOSIS
Clinical Presentation
· The clinical spectrum of nephrolithiasis ranges from incidental radiologic diagnosis of otherwise asymptomatic disease to severe symptoms, such as flank pain (renal colic), hematuria, UTIs, or even renal failure.
· Asymptomatic disease: Patients with nephrolithiasis may be asymptomatic for years.
· Renal colic: Renal colic is typically abrupt in onset, colicky in nature, and localized to the flank area. The pain often radiates into the groin and the testicles or labia. Hematuria, urinary frequency, urgency, nausea, and vomiting are common associated symptoms. Staghorn calculi do not generally present in this fashion.8
· Hematuria: Passage of a stone through the urinary tract may lead to hematuria (gross or microscopic). It can occur even in otherwise asymptomatic patients.
· Renal failure: Acute renal failure may result if the obstruction is bilateral or if it obstructs a solitary functional kidney. Chronic obstruction or recurrent nephrolithiasis can lead to chronic kidney disease.
· Patients with staghorn calculi may be asymptomatic but can present with recurrent UTIs, gross hematuria, abdominal pain, fever, and urosepsis.8
· It is important to remember that renal colic can mimic other etiologies of acute abdomen (e.g., acute appendicitis, intestinal obstruction, ectopic pregnancy, cholecystitis). They should be ruled out in the appropriate clinical setting.
Diagnostic Testing
Laboratories
· In the acute setting, laboratory studies should include an assessment of renal function with serum creatinine and serum electrolytes.
· As calcium-based stones occur most frequently, the initial evaluation involves an assessment of calcium homeostasis, beginning with serum calcium and intact parathyroid hormone levels.
· Serum uric acid can be checked if uric acid stones are suspected.
· A microscopic assessment of the urine and/or passed stone fragment is mandatory to identify crystals in the urine.
o Calcium oxalate: envelope-shaped crystals
o Triple phosphate: coffin lid–shaped crystals
o Calcium phosphate: small rosettes
o Cystine: hexagons
o Uric acid: polymorphic (rhomboid, rosettes, lemon shaped or four-sided whetstones)
· Metabolic evaluation:
o Patients with recurrent calcium stones or a single noncalcium stone should undergo more extensive evaluation, including at least two 24-hour urine studies for measurement of urine volume, pH, calcium, citrate, creatinine, and sodium. This evaluation identifies metabolic characteristics that put the patient at risk for recurrent stone formation.
o These urine studies should not be performed within 3 to 4 weeks of an acute stone episode or in the presence of a UTI.
o A quantitative 24-hour urine for cysteine should be collected if the composition of the stone is unknown.
Imaging
· Helical CT scan (without contrast) is currently the gold standard for diagnosis of nephrolithiasis and has largely replaced other modalities.
· Plain radiography may visualize radiopaque stones, but it is clearly limited by its inability to detect radiolucent stones (e.g., uric acid stones) or provide additional data regarding the urinary tract.
· IVU is more sensitive but entails administration of nephrotoxic contrast.
· Ultrasound is an alternative imaging modality for the diagnosis of nephrolithiasis and hydronephrosis, especially in patients who cannot receive radiation. Presence of small stones may go undetected, and the exact level of obstruction may not be clearly delineated with ultrasound.
TREATMENT
Acute Management
· The treatment of acute renal colic consists of analgesia, relief of obstruction, and control of infection (if present).
· The urine should be strained to retrieve the stone for analysis.
· The rate of spontaneous stone passage is dependent on stone size and location.
o If the stone is <5 mm, conservative management is adequate, as 80% to 90% of these stones pass spontaneously.9,11
o Stones 5 to 7 mm pass spontaneously only 50% of the time, and stones >7 mm rarely pass spontaneously.
o Stones <7 mm can be managed conservatively if there is no evidence of obstruction or infection, and the pain can be controlled with oral analgesic agents.
· Fluid administration should be titrated to achieve a urine output of roughly 2.5 L/day to assist with passage of stone.
· Nifedipine and peripheral β-blockers may improve the rate of stone passage (referred to as medical expulsive therapy).12
· If there is evidence of hydronephrosis or multiple stones, a follow-up imaging study, such as helical CT, is warranted.12
· Complete obstruction, UTI, urosepsis, and uncontrollable pain are indications for expedited stone removal.
o A urology consultation should be obtained.
o Treatment modalities include extracorporeal shockwave lithotripsy, percutaneous nephrolithotomy, ureteroscopic removal, surgery, and chemolysis.12
Lifestyle/Risk Modification
· Dietary counseling should be provided to all patients with kidney stones to prevent further stone formation.
· Fluid intake should be increased to maintain adequate urine flow rates and to lower the urine solute concentration. Suggested target urine volume for patients with nephrolithiasis is >2.5 L/day.
· Dietary calcium intake should be kept within the normal range (800 to 1,000 mg/day). Calcium restriction may result in impaired bone mineralization and may actually increase the risk for nephrolithiasis by increasing the absorption and urinary excretion of oxalate.7,13
· Low-sodium diet (100 mEq or 2.3 g/day) should be followed to decrease urinary calcium.7
· A low-oxalate diet may decrease urinary oxalate.8 Oxalate is present in beets, rhubarb, spinach, greens, okra, tea, chocolate, cocoa, and nuts.
· A low-protein diet increases urine pH, decreases uric acid excretion, and may also decrease urinary calcium excretion.7
Chronic Management
Calcium Stones
· Hypercalciuria (>4 mg/kg/day) is most often due to increased gastrointestinal absorption of calcium but may also be caused by impaired renal tubular calcium reabsorption or excessive skeletal resorption as in primary hyperparathyroidism.
o Patients should maintain a normal calcium intake (800 to 1,000 mg/day).
o They should ensure adequate fluid intake and consume a salt-restricted diet.
o Thiazide diuretics (e.g., hydrochlorothiazide 25 to 50 mg PO daily) increase calcium reabsorption and are frequently used in this setting.7,14
· Hypocitraturia (<250 mg/day) is a frequent finding.
o Citrate is a potent inhibitor of calcium oxalate precipitation.
o Citrate excretion can be enhanced by therapy with potassium citrate, starting at a dose of 10 mEq two to three times daily.
· Hyperoxaluria (>40 mg/day) often responds to dietary restriction.
o Patients with small bowel malabsorption due to intrinsic disease (e.g., inflammatory bowel disease) or jejunoileal bypass may absorb excessive oxalate, resulting in enteric hyperoxaluria.
o Dietary restriction of oxalate and oxalate binders such as oral calcium carbonate or cholestyramine may be useful. Follow-up 24-hour urine collection should be obtained within 2 to 4 weeks of initiating supplemental calcium therapy to monitor for hypercalciuria.
o Primary hyperoxaluria is due to a genetic enzyme defect in amino acid metabolism in which excess oxalate is produced. These patients have nonenteric hyperoxaluria that does not respond to dietary manipulation.
o Hyperuricosuria (>750 mg/day) may also result in calcium stone formation as uric acid crystals can serve as a nidus for calcium oxalate or calcium phosphate precipitation. Allopurinol has been shown to decrease calcium stone formation in the setting of hyperuricosuria.7
Uric Acid Stones
· Conservative therapy involves maintenance of urine volumes of >2.5 L/day through oral hydration, dietary protein/purine restriction (e.g., meat, fish, and poultry), and alkalinization of urine to pH 6.5 to 7.0 with an oral alkali preparation, such as potassium citrate.
· Allopurinol, 300 mg PO daily, can be used to achieve target excretion of uric acid <600 mg/day.
· Probenecid and other uricosuric drugs should be avoided, as they may increase the risk of uric acid or calcium stones.
Cystine Stones
· In general, a nephrologist should follow patients with cystine stones.
· High fluid intake (3 to 4 L/day) and consistent alkalinization (pH >7.5 using potassium citrate, sodium citrate, and sodium bicarbonate) are required to increase solubility and prevent stones.
· Cystine-binding drugs (e.g., penicillamine, tiopronin, and captopril) may be necessary.15
Struvite Stones
· For antimicrobial therapy to be effective, the infected stone must be removed surgically, percutaneously, or by extracorporeal shockwave lithotripsy.
· For poor surgical candidates, chemolysis is possible, but it is unlikely to be effective on its own.9
REFERENCES
1.Davis R, Jones JS, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline 2012. J Urol 2012;188: 2473–2481.
2.Gkougkousis EG, Jain S, Mellon JK. Urologic issues for the nephrologist. In: Floege J, Johnson R, Feehally J., eds. Comprehensive Clinical Nephrology, 4th ed. Missouri, MO: Elsevier; 2010:720–723.
3.Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med 2003; 348:2330–2338.
4.Juran PJ. Approach to hematuria. In: Cheng S, Vijayan A., eds. Nephrology Subspecialty Consult, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:31–38.
5.Emmett M, Fenves AZ, Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, Chertow GM, eds. Brenner and Rector’s the Kidney, 9th ed. Philadelphia, PA: Elsevier; 2012:844–847.
6.Curhan GC. Epidemiology of stone disease. Urol Clin North Am 2007;34:287–293.
7.Delvecchio FC, Preminger GM. Medical management of stone disease. Curr Opin Urol 2003;13:2–33.
8.Healy KA, Ogan K. Pathophysiology and management of infectious staghorn calculi. Urol Clin North Am 2007;34:363–374.
9.Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol 1999;162:688–690.
10.Tracy CR, Pearle MS. Update on the medical management of stone disease. Curr Opin Urol 2009;19:200–204.
11.Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol 2002;178:101–113.
12.Preminger GM, Tiselius HG, Assimos DG, EAU/AUA Nephrolithiasis Guideline Panel. 2007 guideline for the management of ureteral calculi. J Urol 2007;178:2418–2434.
13.Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002;346:77–84.
14.Escribano J, Balaguer A, Pagone F. Pharmacological interventions for preventing complications in idiopathic hypercalciuria. Cochrane Database Syst Rev 2009;(1):CD004754.
15.Mattoo A, Goldfarb DS. Cystinuria. Semin Nephrol 2008;28:181–191.