frequent UTI’s

Gen - thin WF in NAD

oropharynx dry

bilateral CVA tenderness

exam otherwise unremarkable

WBC 12K with 85% segs, 10% lymphs, 5% monos

U/A pH 7.0, SG 1.025, 1+ protein, nitrite +, leukocyte esterace +, large blood

Urine Micro TNTC wbc’s, TNTC rbc’s, moderate bacteria

Urine GS 2+ GNR

Kidney stones are a common, painful medical condition that often initially present to the general internist. It is estimated that 12% of the U.S. population will have a kidney stone at some time during their lives⁵. For the most part, the initial work-up and management of first time stone patients can be handled by the primary care physician. There are, however, specific circumstances when immediate urological referral should be made. It is the goal of this paper to give a brief, internist-oriented, overview of stone epidemiology and formation, diagnosis, and management.

Although the exact mechanism of stone formation remains unknown, there are several factors that are felt to each play a role, albeit to varying degrees, in the formation of stones. The first factor necessary for stone formation is urinary supersaturation with a particular salt. The solubility of a particular salt is influenced by urine pH; CaPO₄ crystals are less soluble in alkaline urine and uric acid crystals are less soluble in acid urine. Supersaturation can be intermittent, for example, after meals, or during sleep (when there is no fluid consumption). The second factor is the presence or absence of inhibitors of crystal growth, such as citrate and magnesium. Both citrate and magnesium are inhibitors of calcium phosphate crystal growth. The third factor is crystal retention. Retention of crystals allows crystals to grow larger, to the point of actual stone formation. What causes certain patients to retain crystals and other patients to void them is unknown. It is believed that anatomic abnormalities or adherence to the epithelium may play a role. It is the combination of these three factors that ultimately leads to stone formation, and the manipulation of one or more of these factors that forms the basis of stone treatment.

It has long been recognized that there are significant regional differences in the prevalence of kidney stones, both in the United States and world wide. Patients in industrialized nations tend to have stones in the upper urinary tract, whereas those in lesser developed parts of the world tend to have bladder stones¹¹. Epidemiologic data suggests that both climate and diet may play significant roles in the pathogenesis of urolithiasis, and that these factors may help to explain the geographic disparity.

Several regional trends have been identified within the United States. The prevalence of kidney stones increases as one travels from the West coast to the East coast, as well as from the North to the South²⁴. These findings would suggest that the Southeast would have the highest prevalence of stone disease, and this, in fact, is true²⁴. The region that includes North Carolina, South Carolina, and Georgia has come to be referred to as the "stone belt", with the highest prevalence of stones occurring in North Carolina. Within these regional trends, there are also gender and racial trends. The frequency of stones in Caucasians is up to three to four times that of African-Americans ^11,25, and, in general men have a higher incidence of stones than women¹¹.

Epidemiologic studies have been performed in an attempt to explain these regional differences. It has been found that both ambient temperature and sunlight index are independently associated with stone prevalence²⁴. The higher the annual ambient temperature and sunlight index, the higher the prevalence of stone disease. One proposed theory suggests that warmer climates are associated with an increased frequency of dehydration; this, in turn, can cause both the concentration and the acidity of the urine to increase, an subsequently promote stone formation²⁴. Another theory suggests that sunlight exposure influences the occurrence of calcium stones secondary to an increased level of 1,25-dihydroxy vitamin D. Elevated levels of 1,25-dihydroxy vitamin D can enhance intestinal calcium absorption which can lead to hypercalciuria and stone formation. Hypercalciuria has been found to be the most common risk factor for nephrolithiasis²⁴, and, elevated levels of 1,25-dihydroxy vitamin D have been found in some patients with hypercalciuria²⁷.

ANIMAL PROTEIN

SODIUM

The role of dietary sodium is also being evaluated. Increased urinary sodium is directly correlated with increased urinary calcium excretion. There is no definitive evidence, as of yet, that patients with recurrent calcium stones ingest a greater amount of dietary sodium than do controls. It has been suggested that patients with recurrent nephrolithiasis might be more sensitive to the calciuric effects of urinary sodium excretion than are non-stone formers.

CALCIUM

Restriction of dietary calcium has long been a component of maintenance therapy for recurrent calcium stone formers. However, a prospective study published in the New England Journal of Medicine in 1993 actually showed an apparent protective effect of high dietary calcium intake⁶. Thus, the mechanism by which hypercalciuria occurs is presumed to influenced by more factors than simple excess calcium ingestion and gastrointestinal absorption.

OXALATE

Although hypercalciuria has long been recognized as the most common, and one of the most important risk factors for stone development², some studies have suggested that a mildly elevated urinary oxalate level is a greater risk factor for stone formation than a mildly elevated urinary calcium^1,6,9. Sources of dietary oxalate include tea, chocolate, spinach, peanuts, rhubarb, strawberries, and pepper. Normal urinary oxalate levels are much lower than normal urinary calcium levels. It is proposed that a small increase in urinary oxalate has a more profound effect on crystal precipitation than a comparable increase in urinary calcium. Historically, recurrent calcium oxalate stone formers have been instructed to avoid oxalate-rich foods, as it has been shown that urinary oxalate excretion does indeed increase after ingestion of these items³⁰. This is the basis for the hypothesis that the large amount of iced-tea consumed in the southeastern stone-belt region of the United States may be related to the exceedingly high incidence of stones. However, a case-controlled study from Newfoundland³ found no evidence to support the idea that tea drinking is a risk factor for calcium oxalate stones. Also, a prospective study of beverage use published in the American Journal of Epidemiology in 1996 actually found tea consumption to be associated with a decreased risk of stone formation⁵. This same study showed an increased risk of stones with the consumption of several fruit juices (apple and grapefruit). This finding correlates with the fact that the bulk of urinary oxalate has been shown to be derived from metabolic pathways, in particular, the metabolism of dietary ascorbic acid¹⁶.

WATER

The role that fluid consumption plays in the prevention of stone formation has been given significant importance. Dietary fluid intake needs to be high enough to adequately dilute salts that are prone to precipitate in the urinary tract. Ideally, the fluid ingested to prevent supersaturation of salts should be water. A study published in the Annals of Internal medicine in 1980 was able to show that urinary dilution by ingestion of water reduced the urinary saturation of calcium phosphate, calcium oxalate, and monosodium urate¹⁶. There has been some concern that epidemiologic studies have found that areas of the country that have soft water (e.g. the Carolinas) have a higher incidence of stone disease than regions of the country that have hard water (e.g. the Rockies), thus attempts to flush the urinary tract with large volumes of soft water every day may actually be detrimental. However, a study addressing this concern was published in the Journal of Urology in 1982. This study found that tap water composition (related to calcium, magnesium, and sodium content) had no significant positive or negative association with the development of stone disease²².

Certain medications can significantly alter the composition of the urine and may predispose to stone formation. High doses of aspirin or probenecid are associated with increased excretion of uric acid. Carbonic anhydrase inhibitors, such as Diamox (acetazolamide), can cause a chronically alkaline urine and decreased urinary citrate, predisposing to calcium calculus formation. Triamterene preparations (e.g. Dyazide) and its metabolites have been identified in some urinary stones. Loop diuretics are well known to promote hypercalciuria. More recently, the protease inhibitor Indinavir has been found to have a significant incidence of nephrolithiasis as one of its side effects. Up to five percent of patients during their first year of treatment with Indinavir will develop stones⁷. Indinavir itself can also precipitate in the collecting system and cause obstruction.

Tantamount to understanding how to prevent and treat stone disease is a basic knowledge of the metabolic conditions that can predispose to nephrolithiasis. There many different types of stones, the most common of which are calcium stones (calcium oxalate and calcium phosphate), struvite (i.e. infection) stones, uric acid stones, and cystine stones. It is important to identify both the metabolic and environmental risk factors present in each patient. Calcium containing stones are by far the most common²⁷, and 20-40% percent of patients with recurrent calcium containing stones will have hypercalciuria⁶. Of those patients with calcium stones, only approximately twenty percent will have an identifiable underlying systemic disease as the cause of their stone formation. The remainder of calcium stone patients will diagnosed with idiopathic calcium urolithiasis (ICU)¹¹.

CALCIUM STONES

ICU is a diagnosis of exclusion, thus, conditions that are known to cause hypercalcemia and/or hypercalciuria, such as primary hyperparathyroidism, sarcoidosis, Cushing’s Syndrome, hyperthyroidism, and immobilization must first be ruled out. Of all of the aforementioned conditions, primary hyperparathyroidism is the most common hypercalcemic condition associated with urolithiasis, and accounts for stone formation in five percent of patients¹¹. Elevated levels of parathyroid hormone cause increased bone resorption, renal reabsorption, and intestinal absorption of calcium, thus increasing serum calcium levels and supersaturating the urine with calcium salts. Patients are diagnosed with the finding of an elevated serum calcium level in conjunction with an inappropriately elevated PTH level. Eighty percent of these patients will be found to have a single adenoma¹¹.

Many patients will have hypercalciuria without hypercalcemia. Most of these patients will have idiopathic hypercalciuria secondary to excessive gastrointestinal absorption. However, hypercalciuria can also be secondary to administration of loop diuretics, excessive sodium ingestion, familial hypercalciuria, or type I distal renal tubular acidosis (RTA).

Seventy percent of patients with distal RTA will develop nephrolithiasis¹¹. The diagnosis of a type I RTA is made in a patient found to have a systemic acidosis and a urine pH > 6. These patients are unable to lower their urine pH despite being systemically acidotic and having a normal ability to reabsorb bicarbonate. Excess serum acid is buffered by calcium from bone, which is then excreted in the urine. This hypercalciuria, particularly in the setting of an alkaline urine (which favors calcium phosphate precipitation) and hypocitraturia (citrate inhibits calcium phosphate crystal formation) favors the formation of stones.

In addition to calcium complexing with phosphate, calcium can also complex with oxalate to form stones. Primary hyperoxaluria is an extremely rare disorder with approximately fifty percent of patients dying of renal failure by the age of twenty. This disease diagnosis should be considered in the very young patient who has evidence of large calculi on plain abdominal films, a positive family history for stone disease, and an elevated urinary oxalate level upon laboratory testing. A somewhat more common oxalate disorder is enteric hyperoxaluria. Enteric hyperoxaluria is most commonly associated with patients who have small bowel disorders. Patients with inflammatory bowel disease or chronic pancreatitis, or patients who are status post small bowel resection or jejunoileal bypass for obesity can have problems with fat malabsorption. This increased intestinal fat binds calcium, thus less calcium is available to bind oxalate present in the gut predisposing to hyperoxaluria and stone formation. Patients with inflammatory bowel disease have been found to have a two to three percent incidence of nephrolithiasis, while those who are status-post ileal resection have a ten percent incidence of stone disease⁸.

URIC ACID

STRUVITE

Struvite stones, also called infection stones, are composed of magnesium ammonium phosphate. Infection stones account for 15-20% of all urinary stones. It is believed that these stones are the consequence of infection of the urinary tract with urease-producing bacteria, such as Proteus species. Klebsiella, Pseudomonas, and Staphylococci can also produce urease. These organisms are able to hydrolyze urea to produce ammonia, which then causes alkalinization of the urine. An alkaline urine then promotes the preciptation of magnesium, ammonium, and phosphate. Struvite stones are usually found in the setting of other stone disease upon which a urinary tract infection has been superimposed. If the infection is silent and the stones are allowed to grow, large staghorn calculi can be formed; these stones can form a cast of the calyceal system and cause complete obstruction requiring surgical intervention.

CYSTINE

Cystine stones are extremely rare and are the result of the inherited disorder cystinuria. Cystinuria is an autosomal recessive disorder in which there is a defect in the renal tubular resorption of cystine. Cystine is relatively insoluble in acid urine. Because of the heritable nature of the disease, cystine nephrolithiasis is usually diagnosed in children and is an uncommon cause of first time stones in adults.

HISTORY AND PHYSICAL

The initial step in diagnosing nephrolithiasis is clinical suspicion. Classically, most patients will initially present with excruciating episodic colic related to intermittent ureteral spasm from the obstructing stone. The location of the pain depends on the location of the stone. As the stone travels down the urinary tract, the pain can radiate into the groin and patients may complain of testicular or labial pain. The pain may be associated with nausea and/or vomiting, as well as urinary frequency and dysuria. The patient may report a change in the color of the urine, particularly if there is significant hematuria. The most helpful piece of history is history of a previous kidney stone. Stones can also present "silently" as persistent or recurrent UTI’s, or as isolated hematuria found incidentally on urinalysis. A family history, dietary history, and medication history should also be taken.

In the absence of colic, the physical examination is usually unremarkable. When colic is present, the patient is usually restless and uncomfortable. Costo-vertebral angle tenderness or diffuse abdominal tenderness may be present, however, there should be no signs of peritoneal irritation. The physical exam is also the initial screen for underlying occult systemic disease, such as the finding of erythema nodosum (suggesting sarcoid), evidence of gouty arthritis, or findings worrisome for malignancy.

LABORATORY EVALUATION

Patients presenting with their first kidney stone should have a basic laboratory workup which includes blood chemistries (to assess renal function, calcium, phosphorus, uric acid, and systemic acid base status), and a baseline CBC. A urinalysis should be performed to assess urine pH (acid pH is associated with uric acid and cystine stones; alkaline pH is associated with struvite and calcium phosphate stones, or may suggest the diagnosis of type I distal RTA). A urine microscopic exam should be performed to look for crystals, bacteria, and hematuria. Finally, a urine culture should be performed to evaluate for occult infection. All urine should be strained so that if the stone is passed, spectrometry can be performed to identify the stone composition

In addition to the aforementioned workup, patients presenting with recurrent stone disease should undergo a 24 hour urine collection to assess urinary volume, creatinine clearance, calcium, oxalate, uric acid, citrate, and sodium excretion.

RADIOGRAPHIC IMAGING

Approximately 90% of stones are radiodense and can be seen on plain X-ray. Pure calcium phosphate and calcium oxalate stones are the most dense, and calcium oxalate stones may have a spiculated or "jackstone" appearance. Struvite stones have low radiodensity when pure, but are usually complexed with calcium and have a laminated appearance. Struvite stones are also called staghorn calculi because of the branched appearance the stone takes on when it fills the renal pelvis. Cystine stones are the least radiodense and uric acid stones are radiolucent.

A KUB of the abdomen, as well as plain film tomograms, can give a quick idea of stone size and location. Tomograms, by eliminating shadows that are not in the plain being imaged (for example, bowel gas), permit stone detection as small as 2mm. Typically, stones < 5mm will pass spontaneously, stones between 5-10mm have a 50% chance of passing, and stones >10mm usually require surgical removal. In addition to a KUB and tomograms, patients with acute renal colic should undergo intravenous pyelogram (IVP). IVP will aid in the diagnosis of radiolucent stones, as well as identify any anatomic abnormalities or the presence of obstruction. Currently, the standard radiographic evaluation in acute renal colic includes KUB and IVP.

Other imaging modalities include CT scan and ultrasound. CT imaging is felt to be the most sensitive study for stone detection. The most accurate evaluation is obtained before intravenous contrast is administered; however, obstruction, abcess, or urine extravasation are best seen after IV contrast. Newer spiral CT techniques are further enhancing the value of CT scan in acute renal colic; this technique can virtually eliminate respiratory-induced changes in renal position. At NCBH, the cost of an IVP and spiral CT are relatively similar, each approximately $600.

Ultrasound, while readily available and non-invasive, has not traditionally been the study of choice in acute renal colic. While ultrasound can accurately diagnose caliceal stones larger than 5mm, stones in this location are rarely the cause of symptoms. It is unclear whether sonography is a reliable modality for detecting stones in locations that are typically associated with symptom, such as at the ureteropelvic junction or in the mid to upper ureter. Three recent studies have attempted to address the role for ultrasound in acute renal colic. Two of these studies have concluded that ultrasound, when combined with KUB radiography, is an acceptable alternative to IVP ^10,14, particularly in patients with contraindications to IVP, such as renal insufficiency, allergy to contrast, or pregnancy. The third study, a prospective study published in the Journal of Urologic Radiology in 1992, found that ultrasound alone can be used for the detection of intrarenal stones, but that KUB and tomography is a more sensitive imaging examination for determination of size and number of small stones³⁰.

Once the presence of a stone is diagnosed, a decision must be made regarding outpatient versus inpatient therapy. Indications for hospitalization include intractable nausea and vomiting, evidence of significant dehydration, or inability to provide adequate analgesia. In addition, there are several indications for urgent urological consultation:

1) fever - suggests infection proximal to the obstructing stone

2) non-functioning kidney - evidence of a completely obstructed ureter

3) solitary kidney with a partially obstructed ureter

4) urine extravasation

5) stone larger than 10mm - unlikely to pass spontaneously

MEDICAL MANAGEMENT

Most patients can be managed in the ambulatory setting. The acute management for renal colic should include:

1) forced hydration of 2-3 liters of fluid per day

2) straining of the urine for future stone analysis

3) analgesia, e.g. oxycodone

4) phenothiazines for nausea

5) weekly KUB to follow stone progression

6) urological consultation if stone has not passed by 6 weeks

SURGICAL MANAGEMENT

URETEROSCOPY

When a stone is unable to be passed spontaneously, several surgical options are available for stone removal. Stones in the lower ureter can be removed with transurethral ureteroscopy. This procedure is generally well tolerated and requires regional or general anesthesia, but can be performed on an outpatient basis. Ureteroscopy has been gaining increasing therapeutic applications with the development of smaller, flexible ureteroscopes. Small stones <5mm can be removed with basket retrieval. Larger stones can be treated with direct contact fragmentation devices. The most common complication or ureteroscopy is ureteral stricture at the site of local trauma, and the risk of this complication is related to surgical skill.

ESWL and PNL

Stones that are located higher in the urinary tract can often be managed with one of two newer surgical techniques that have been developed as an alternative to open surgical stone removal, and thus have less associated morbidity. These techniques are extracorporeal shock wave lihotripsy (ESWL) and percutaneous nephrolithostomy (PNL).

ESWL is felt to be the treatment of choice for uncomplicated stones in the upper urinary tract. ESWL can usually be performed as an outpatient and is tolerated well. The patient is sedated, the stone is located under fluoro, and the lithotripter focuses a shock wave on the stone and shatters it. The stone fragments are then passed in the urine, this can be associated with a mild amount of colic. Acute complications of ESWL are usually related to parenchymal injury from the shock wave. Complications can range from mild hematuria to more serious perinephric or retroperitoneal hemorrhage. Long term complications may include worsening of pre-existing hypertension or the development of new hypertension, the mechanism of which is not yet understood¹⁴.

Percutaneous nephrolithostomy is usually performed in patients whose outcomes with ESWL therapy are suboptimal, or in patients with renal stones >2.5cm. In PNL the patient is sedated, a percutaneous nephrostomy tube is placed under fluoroscopic guidance, the tract is dilated, and the stone is retrieved. Large staghorn calculi can often be managed with a combination of PNL (for initial debulking) followed by ESWL, but may require multiple percutaneous access tracts and ancillary procedures depending on the amount of stone burden, as retained fragments are a nidus for reinfection.

Prevention of recurrent stone disease is a lifelong process. The backbone of all preventive strategies is adequate fluid intake and urine volume to prevent supersaturation of salts and to keep the kidneys flushed. If stone analysis has been performed, then more specific therapies can be employed.

For patients with calcium stones, the role of dietary calcium restriction remains controversial. Its intent is to decrease hypercalciuria, the most common risk factor in calcium stone formation. However, recent studies have actually shown an apparent protective effect of high dietary calcium intake⁶. Other dietary modifications include limiting the intake of animal protein (which increases urinary calcium and uric acid excretion), as well as possibly avoiding oxalate-rich foods (yet unproven). Medication adjuncts to dietary modification include thiazide diuretics (to decrease urinary calcium excretion), potassium citrate (to alkalinize the urine and to increase the excretion of the inhibitor citrate). Allopurinol can be used in hyperuricosuric patients with calcium or uric acid stones, particularly when alkalization of the urine by itself is not sufficient.

Kidney stones are a common problem that often present to the general internist and can usually be managed in the ambulatory setting. The exact mechanism of stone formation remains unknown, however it appears that environmental, dietary and metabolic factors all play a role. Calcium stones are by far the most common and are also the most radiodense. Newer radiologic techniques, such as spiral CT, allow rapid detection of stones as small as 2mm. Stones that are less than 5mm can usually be passed spontaneously, in conjunction with forced hydration and analgesia. The internist must be aware of the indications for urgent urological referral, which include fever, complete obstruction, partial obstruction with a solitary kidney, extravasation of urine, and stones larger than 10mm. Newer urological techniques, ESWL and PNL, have the benefit of stone removal without the morbidity of open surgical removal. Once treated, prevention of recurrent stone disease becomes a lifelong process, the cornerstone of which is adequate fluid intake.

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