Signs and symptoms

The classic presentation for a patient with acute renal colic is the sudden onset of severe pain originating in the
flank and radiating inferiorly and anteriorly; at least 50% of patients will also have nausea and vomiting.
Patients with urinary calculi may report pain, infection, or hematuria. Patients with small, nonobstructing stones
or those with staghorn calculi may be asymptomatic or experience moderate and easily controlled symptoms.

The location and characteristics of pain in nephrolithiasis include the following:

 Stones obstructing ureteropelvic junction: Mild to severe deep flank pain without radiation to the groin;
irritative voiding symptoms (eg, frequency, dysuria); suprapubic pain, urinary frequency/urgency,
dysuria, stranguria, bowel symptoms
 Stones within ureter: Abrupt onset of severe, colicky pain in the flank and ipsilateral lower abdomen;
radiation to testicles or vulvar area; intense nausea with or without vomiting
 Upper ureteral stones: Pain radiates to flank or lumbar areas
 Midureteral calculi: Pain radiates anteriorly and caudally
 Distal ureteral stones: Pain radiates into groin or testicle (men) or labia majora (women)
 Stones passed into bladder: Mostly asymptomatic; rarely, positional urinary retention

Diagnosis

The diagnosis of nephrolithiasis is often made on the basis of clinical symptoms alone, although confirmatory
tests are usually performed.

Examination of patients with nephrolithiasis includes the following findings:

 Dramatic costovertebral angle tenderness; pain can move to upper/lower abdominal quadrant with
migration of ureteral stone
 Generally unremarkable abdominal evaluation: Possibly hypoactive bowel sounds; usually, absence of
peritoneal signs; possibly, painful testicles but normal-appearing
 Constant body positional movements (eg, writhing, pacing)
 Tachycardia
 Hypertension
 Microscopic hematuria

Testing

The European Association of Urology (EAU) recommends the following laboratory tests in all patients with an
acute stone episode [1] :

 Urinary sediment/dipstick test: To demonstrate blood cells, with a test for bacteriuria (nitrite) and urine
culture in case of a positive reaction
 Serum creatinine level: To measure renal function

Management

Pharmacotherapy and supportive care

Medical treatment of acute stone attacks (renal colic) involves supportive care and administration of agents such
as the following:

 IV hydration
 NSAIDs (eg, ketorolac, ketorolac intranasal, ibuprofen)
 Nonnarcotic analgesics (eg, acetaminophen [APAP])
 PO/IV narcotic analgesics (eg, codeine, morphine sulfate, oxycodone/APAP, hydrocodone/APAP,
dilaudid, fentanyl)
  Alpha blockers (eg, tamsulosin, terazosin) to facilitate stone passage
 Antiemetics (eg, metoclopramide, ondansetron)
 Antibiotics (eg, ampicillin, gentamicin, trimethoprim-sulfamethoxazole, ciprofloxacin, levofloxacin,
ofloxacin)

The following drug classes are used for stone prevention/chemolysis:

 Uricosuric agents (eg, allopurinol)

 Alkalinizing agents (eg, potassium citrate, sodium bicarbonate) - for uric acid and cysteine calculi
 Thiazide diuretics - help treat hypercalcicuria

Surgical options

Stones that are 7 mm and larger are unlikely to pass spontaneously and require some type of surgical procedure,
such as the following:

 Stent placement
 Percutaneous nephrostomy
 Extracorporeal shockwave lithotripsy (ESWL)
 Ureteroscopy
 Percutaneous nephrostolithotomy (PCNL) or mini PNCL
 Open nephrostomy - largely supplanted by less-invasive techniques
 Anatrophic nephrolithotomy - for large. complex staghorn calculi that cannot be cleared by an
acceptable number of PCNLs; typically done via laparoscopic or robotic approach

Pathophysiology

Formation of stones

Urinary tract stone disease is likely caused by two basic phenomena. The first phenomenon is supersaturation of
the urine by stone-forming constituents, including calcium, oxalate, and uric acid. Crystals or foreign bodies can
act as nidi, upon which ions from the supersaturated urine form microscopic crystalline structures. The resulting
calculi give rise to symptoms when they become impacted within the ureter as they pass toward the urinary
bladder.

The overwhelming majority of renal calculi contain calcium. Uric acid calculi and crystals of uric acid, with or
without other contaminating ions, comprise the bulk of the remaining minority. Other, less frequent stone types
include cystine, ammonium acid urate, xanthine, dihydroxyadenine, and various rare stones related to
precipitation of medications in the urinary tract. Supersaturation of the urine is likely the underlying cause of
uric and cystine stones, but calcium-based stones (especially calcium oxalate stones) may have a more complex
etiology.

The second phenomenon, which is most likely responsible for calcium oxalate stones, is deposition of stone
material on a renal papillary calcium phosphate nidus, typically a Randall plaque (which always consists of
calcium phosphate). Evan et al proposed this model based on evidence accumulating from several laboratories.
[5]

Calcium phosphate precipitates in the basement membrane of the thin loops of Henle, erodes into the
interstitium, and then accumulates in the subepithelial space of the renal papilla. The subepithelial deposits,
which have long been known as Randall plaques, eventually erode through the papillary urothelium. Stone
matrix, calcium phosphate, and calcium oxalate gradually deposit on the substrate to create a urinary calculus.

Drug-induced stone disease

A number of medications or their metabolites can precipitate in urine causing stone formation. These include the
following [8, 9, 10] :
  Indinavir
 Atazanavir
 Guaifenesin
 Triamterene
 Silicate (overuse of antacids containing magnesium silicate)
 Sulfa drugs, including sulfasalazine, sulfadiazine, acetylsulfamethoxazole, acetylsulfasoxazole, and
acetylsulfaguanidine
 Ceftriaxone (rarely) [11]

A population-based case-control study from the United Kingdom found that use of any of the following five oral
antibiotic classes 3–12 months before the index date was associated with nephrolithiasis:

 Sulfas - Adjusted odds ratio (OR) 2.33 (95% confidence interval [CI] 2.19-2.48)
 Cephalosporins – OR 1.88 (95% CI 1.75-2.01)
 Fluoroquinolones – OR  1.67 (95% CI 1.54-1.81)
 Nitrofurantoin/methenamine – OR  1.70 (95% CI 1.55-1.88)
 Broad-spectrum penicillins – OR 1.27 (9% CI 1.18-1.36)

Associations were greatest for exposure at younger ages (P< 0.001) and exposure 3–6 months before the index
date (P< 0.001). With all but broad-spectrum penicillins, the risk remained statistically significant 3–5 years
from exposure. [12]

Genetic factors

Nephrolithiasis is known to have a familial nature and significant heritability, and genes that may be involved in
renal stone formation have been identified. Genome-wide association studies and candidate gene studies have
implicated genes involved in renal tubular handling of lithogenic substrates, such as calcium, oxalate, and
phosphate, and of inhibitors of crystallization, such as citrate and magnesium. [13]

Using whole-exome sequencing, Daga et al detected monogenic causative mutations in 15 of 51 families with
members who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of
nephrocalcinosis. Identified mutations were in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19,
GRHPR, SLC3A1, SLC12A1), one dominant gene (SLC9A3R1), and one gene (SLC34A1) with both recessive
and dominant inheritance. [14]

In patients with idiopathic hypercalciuria and calcium-containing kidney stones, genetic screens of
nephrolithiasis determinants have identified candidates involved in renal calcium handling, such as the transient
rec eptor potential vanilloid 5 (TRPV5), which is an important player in Ca2+ homeostasis. TheTRPV5 channel
also plays a role in renal calcium transport, and may be the future target of therapies for individuals at risk for
nephrolithiasis. [15]

Serious complications of urinary tract stone disease include the following:

 Abscess formation
 Serious infection of the kidney that diminishes renal function
 Urinary fistula formation
 Ureteral scarring and stenosis
 Ureteral perforation
 Extravasation
 Urosepsis
 Renal loss due to long-standing obstruction

overactive

Signs and symptoms

Clinical manifestations of overactive bladder OAB include the following:

 Urinary urgency (hallmark symptom)

 Urgency urinary incontinence (may or may not be present)
 Urinary frequency and nocturia (usually present)

Management

The three main treatment approaches are as follows:

 Behavioral therapy (eg, bladder training, biofeedback, pelvic floor muscle therapy, pelvic floor
electrical stimulation)
 Pharmacologic therapy (eg, anticholinergic/antimuscarinic agents)
 Surgical therapy (eg, neuromodulation and augmentation cytoplasty [rarely necessary])

Treatment guidelines

Guidelines for the treatment of OAB by the AUA/SUFU include the following recommendations [2] :

 First-line therapy: Behavioral therapies and education should be offered first; starting antimuscarinic
agents at the same time as behavior therapies may prove clinically beneficial
 Second-line therapy: Antimuscarinics; extended-release preparations should be used instead of
immediate-release preparations when possible; transdermal oxybutynin can also be used
 Third-line therapy: Sacral neuromodulation or peripheral tibial nerve stimulation (PTNS) for carefully
selected patients with severe refractory OAB symptoms or those who are not candidates for second-line
therapy and are willing to undergo a surgical procedure; intradetrusor injection of onabotulinumtoxinA
is another option

Pathophysiology

OAB appears to be multifactorial in both etiology and pathophysiology. Symptoms of OAB are suggestive of
underlying detrusor overactivity. Overactivity of the detrusor muscle—neurogenic, myogenic, or idiopathic in
origin—may result in urinary urgency and urgency incontinence. [5]

The role of the M2 receptor in the human bladder is not well established. Data from small studies demonstrating
up-regulation of the M2 receptor in certain pathologic states suggest that it may have a role in detrusor
overactivity related to obstruction and spinal cord injury.

Binding of acetylcholine to the M3 receptor activates phospholipase C via coupling with G proteins. This action
causes the release of calcium from the sarcoplasmic reticulum and contraction of the bladder smooth muscle.
Increased sensitivity to stimulation by muscarinic receptors may lead to OAB. Leakage of acetylcholine from
the parasympathetic nerve terminal may lead to micromotion of the detrusor, which may activate sensory
afferent fibers, leading to the sensation of urgency.

Sensory afferent nerves may also play a role in OAB. Activation of normally quiescent C sensory fibers may
help produce symptoms of OAB in individuals with neurologic and other disorders. Several types of receptors
identified on sensory nerves may have a role in OAB symptoms. These include vanilloid, purinergic, neurokinin
A, and nerve growth factor receptors. Substances such as nitric oxide, calcitonin gene-related protein, and brain-
derived neurotropic factor may also have a role in modulating sensory afferent fibers in the human bladder. [6, 7]

Once thought to be biologically inert, the urothelium may also have a role in OAB (see the image below). The
urothelium communicates directly with suburothelial afferents acting as luminal sensors. Low pH, high
potassium concentration, and increased osmolality in the urine can influence sensory nerves. Activation of
suburothelial afferent fibers without changes in the smooth muscle may lead to urgency. Activation of the
suburothelial afferents in the presence of enhanced smooth-muscle coupling may lead to urgency and unstable
detrusor contractions. [8, 9]