Nephrolithiasis

I. What every physician needs to know

Stones composed of calcium phosphate or calcium oxalate make up 85-90% of renal stones in the United States. Precipitation of calcium in urine causes these stones, and stones have been linked to hypercalciuria, high salt diets, obesity, hypertension, diabetes, genetic factors, and environmental factors. Uric acid, cystine, and struvite stones occur more frequently in those who have underlying diseases or risk factors.

More than 50% of patients with kidney stones have a first-degree relative with kidney stones. Twin studies demonstrate that genetics significantly alter one’s risk.

II. Diagnostic Confirmation: Are you sure your patient has Nephrolithiasis?

Definitive diagnosis of nephrolithiasis requires that a renal calculus is seen on imaging or identified in urine on urination. If a stone is never isolated for analysis, no risk factors point to alternative etiologies, and if radiology is consistent (in terms of radiodensity of the calculus), most first idiopathic renal stones are calcium-based stones.

A. History Part I: Pattern Recognition

Patients that have pain resembling renal colic should have a full medical history taken, with attention to risk factors and clues for any underlying pathologies or predisposition to renal disease (listed below). Establishing if the patient has previously had episodes of renal colic will help determine if this is recurrent or first time nephrolithiasis. It is important to inquire about history of mysterious flank pain or renal colic-like symptoms that may not have been recognized as such.

Predisposing risk factors for nephrolithiasis that should be investigated include:

Bowel disease or resection
Bariatric surgery, especially gastric bypass procedures
First stone occurring in childhood or adolescence
History of recurrent urinary tract infection
History of prior stones in the family, especially first degree relatives
Gout
Renal structural anomalies
Bone fractures
Chronic kidney disease
Large intake of vitamins C or D
Calcium supplements
Acetazolamide or other carbonic anhydrase inhibitors
Topiramate
Dehydration due to a hot environment, vigorous physical activity, lack of fluid intake
High sodium intake – prepared foods
Eating disorders – laxative use, vomiting
Unusual diets – high protein diets

Location specific pain

Nephrolithiasis presentation differs slightly based on location. Stones in the ureteropelvic junction may cause deep flank pain without radiation to pelvis; pain may be secondary to renal capsular distension. Calculi in the renal pelvis may have vague costovertebral angle discomfort associated, or may be asymptomatic. Stones lodged at the ureter often lead to ureteral spasm, which classically causes deep colicky flank pain radiating to the ipsilateral flank or abdomen, often associated with nausea and/or vomiting. Alternatively the pain may be constant in nature. Most patients experience microscopic or macroscopic hematuria from ureteral or renal pelvis irritation.Renal colic pain often starts at night or in early morning hours, sometimes awakening the sufferer from sleep, and increasing in intensity over 30 min to 6 hours. The peak intensity phase usually lasts only a few hours, during which the patient may present to the emergency room, though this stage may last up to 12 hours. The pain will often suddenly recede as the stone passes into the bladder, no longer irritating the ureters. However, average time to stone passage can be on the order of days; studies have shown average stone passage time of 8 days for 2 mm stones and 22 days for 4-6 mm stones.

Types of stones

Idiopathic calcium stones typically first appear when a patient is between ages 20 and 50. Uric acid stones usually start after 50 years of age, although can start at any time if associated with malignancy, diseases of cell turnover, or in children with genetic disorders affecting purine metabolism. Cystine stones have an average age of onset of 12, as inherited metabolic disorders cause a majority of these stones.

B. History Part 2: Prevalence

Renal stones are increasingly common among the US population. Over the last 30 years, prevalence has increased from 3.8% of the population in 1980 to a current prevalence of 8.8%, or one in eleven US residents (taken from 2007-2010 data). Lifetime risk of developing a kidney stone was measured at 10.6% for men and 7.1% for women in US. Non-Hispanic Caucasians, males, and those with diabetes and obesity report higher rates of renal stones than females, blacks, Hispanics or healthier counterparts.

Globally, prevalence appears to be increasing since 1970, which may be secondary to dietary shifts towards higher sodium intake, increased animal protein intake, and increased high fructose corn syrup intake promoting obesity, a known risk factor for nephrolithiasis. The highest prevalence rates recorded worldwide have been in uranium workers in eastern Tennessee (18.5%) and adults in northern Thailand (16.9%).

C. History Part 3: Competing diagnoses that can mimic nephrolithiasis

Renal colic can mimic alternate conditions. Considering the location of the pain involved can help in developing a differential diagnosis.

Calculi located near or in the renal pelvis typically cause lumbar or flank pain, which may be similar to the pain of cholecystitis, cholangitis or biliary colic on the right side, or peptic ulcer disease or acute pancreatitis on the left side. Flank pain with hematuria and costovertebral angle tenderness is also concerning for pyelonephritis, and not infrequently these problems will co-exist.

Stones in the mid-ureter cause pain that radiates anteriorly and caudally and may be mistaken for diverticulitis or radicular nerve pain from vertebral compression on either side, or appendicitis when on the right. In older patients who have unclear mid-abdominal pain, abdominal aortic aneurysm should be considered. Stones in the distal ureter may cause pain radiating into the groin, testicles, or labia majora if the stone irritates the ilioinguinal or genitofemoral nerves. This may mimic pelvic inflammatory disease, urinary tract infections, epididymitis, or other testicular diseases.

Once a calculus reaches the bladder, the patient’s painful episode generally resolves quickly, over 30 minutes to several hours, though occasionally if a large stone is present in the bladder, the patient will describe positional retention with urination as the stone creates a urethral blockage.If renal colic is still highly suspected, further history, imaging, and lab work should be done to evaluate potential calcium phosphate, calcium oxalate, cysteine, uric acid, or struvite stones.

D. Physical examination findings

In general, history, labs and imaging are more useful than physical exam in diagnosing nephrolithiasis. However, a few key points should be noted.

Vital signs during an episode of renal colic may indicate hypertension and tachycardia, but patients should not be febrile. Fever may suggest UTI, pyelonephritis or even pyonephrosis if kidney is obstructed.
Patients with nephrolithiasis usually appear to be moving around on the bed or pacing, rather than immobile. Peritoneal signs should be absent.
Nausea and vomiting are common.
Patients may complain of testicular pain, but testicular exam should not be remarkable or show tender testicles.
If patient is older with unclear etiology of abdominal pain, assess for abdominal aortic aneurysm.

E. What diagnostic tests should be performed?

Non-contrast computed tomography (CT) of the abdomen is the gold standard.
Plain film radiography can diagnose many stones.

See imaging section for further details.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

During renal colic, initial lab work should include a complete blood count (to assess infection), serum chemistries (to assess dehydration, derangements from vomiting or impaired renal function) and urinalysis. Urinalysis from first AM urine can assess pH (>7.0 indicates urea-splitting organism, associated with struvite calculi) and hematuria, pyuria or signs of infection. Spin the urine for sediment, checking for crystals to differentiate calcium oxalate, cysteine, and uric acid crystals.

In addition to basic chemistry panel, first time stone formers should have serum calcium and phosphorus evaluated to screen for renal tubular acidosis (low serum bicarbonate with elevated urine pH), hyperparathyroidism and hyperphosphaturia.

Possibly most importantly, locate a mesh net and ask the patient to urinate into a mesh net, catching any stones that may pass during the episode. A stone analysis completed on a stone excreted while urinating (caught in a mesh net for example) would provide definitive data that would help determine treatment. Sometimes crystals from urinalysis sediment can provide this diagnostic information as well.

If the patient has recurrent renal stones, or a non-calcium based stone is identified, or the patient is highly interested further metabolic testing should be completed. This should include assessment for supersaturation of urine with a 24-hour collection of urine to measure urine volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium and creatinine (normal values listed below). This testing can suggest the likelihood of recurrence. However, testing for systemic diseases should be guided by history, physical findings, or abnormal initial lab tests (listed below).

Blood tests that may be useful in evaluating nephrolithiasis (normal ranges):

Calcium (8.3-10.3 mg/dl)
Phosphate (2.5-5.0 mg/dl)
Creatinine (0.6-1.2 mg/dl)
Bicarbonate (20-28 mmol/liter)
Chloride (95-105 mmol/liter)
Potassium (2.5-5.0 mmol/liter)

Urine studies that may be helpful (normal ranges):

24-hour urine studies (normal ranges)
Urine volume (>1.5 liter/day)
Creatinine (20-25 mg/kg in men; 15-20 mg/kg in women)
Urea (g/day multiplied by 6.25/weight in kg = estimated protein intake; 0.8-1.0 g/kg per day)
Calcium (<300 mg/day in men; <250 mg/day in women; <140 mg/g creatinine per day)
Oxalate (<40 mg/day)
pH (5.8-6.2)
Phosphate (500-1500 mg/day)
Citrate (>450 mg/day in men; >550 mg/day in women)
Uric acid (<800 mg/day in men; <750 mg/day in women)
Sodium (50-150 mmol/day)
Potassium (20-100 mmol/day)
Magnesium (50-150 mg/day)
Sulfate (20-80 mmol/day)
Ammonium (15-60 mmol/day)
Spot urine protein level
Cystine (cyanide nitroprusside test; negative result indicates cystine <75 mg/liter)

Certain lab abnormalities indicate metabolic risks for renal stones, and an opportunity for primary prevention from further nephrolithiasis. Patients can be treated with regimens to decrease the risk of future renal stones.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A non-contrast computed tomography (CT) of the abdomen has >95% sensitivity and specificity for detecting not only renal stones, but their size, number and location if the patient has ongoing symptoms. The CT can differentiate uric acid stones from calcium-based stones based on radiodensity, can visualize all types of renal calculi, and can identify hydronephrosis. To lower radiation doses in repeat stone formers who may receive multiple CT scans, some facilities offer a low-dose radiation protocol CT (low-dose stone-protocol CT) for stone detection.

Plain film radiography of kidneys/ureters/bladder (KUB) is an excellent test for calcium oxalate and calcium phosphate calculi, however uric acid and cysteine stones are radiolucent and do not show up. Struvite calculi can variably be radiolucent or radiopaque. Overall sensitivity and specificity for plain x-rays in diagnosing renal calculi is 45-59% (sensitivity) and 71-77% (specificity) respectively. This can be a valuable test for following known radiopaque stones, especially as it minimizes radiation compared to CT and is inexpensive, but it does not allow one to rule out nephrolithiasis if no stone is seen.

Renal ultrasound has overall sensitivity of 70% and specificity of 94% for detecting renal calculi. It is less useful when assessing the upper ureter, the most likely location of symptomatic stones. The test eliminates radiation, therefore it may be useful as a first-line screening test, for following radio-opaque stones when location is known or for assessing pregnant patients. It has good sensitivity for evaluating hydronephrosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

If a patient has a single, isolated idiopathic calcium stone with no further stones on plain film radiograph/CT, no history of previous stones, and no concerning risk factors (patient has one kidney, patient has marked electrolyte abnormalities), no further evaluation beyond basic blood and urine evaluation suggested above is required.

III. Default management

Management will include evaluating for emergency complications of nephrolithiasis first, then addressing pain and considering additional medications that can be used for active expulsive therapy. Urology should be consulted in complicated cases such as a larger stone (greater than or equal to 6mm) that is less likely to spontaneously pass, a urinary tract infection with obstruction and when patient will need prompt follow up. Admission can be considered in complicated cases (see Immediate management). Lastly, nephrolithiasis prevention must be addressed prior to discharge.

A. Immediate management

Evaluate for emergency complications of nephrolithiasis. Urology should be involved in care if any of these complications are present:

Urinary Tract Infection – often associated with nephrolithiasis. Do consider antibiotics if patients have signs or symptoms of a urinary tract infection such as abnormal urinalysis, fever, leukocytosis. Collect urine culture prior to antibiotic use, knowing that if infection is proximal to an obstructing stone the culture will not always be positive.
Renal outflow obstruction from calculi or pyonephrosis – while debate exists about whether IV fluids may harm an obstructed kidney by increasing preload pressure, if volume status is low (which is often the case if patient has been nauseated or vomiting), IV fluids and prevention of dehydration are critical for perfusing an obstructed kidney.
Refractory pain – see pain management pathway below.
Acute Renal Failure – if present, attempts should be made to avoid further renal damage by avoiding contrast-induced nephropathy (especially in setting of azotemia) and reno-toxic medications, identifying high risk patients such as those with one functional kidney, diabetes, dehydration or multiple myeloma.

The below complications typically require admission to the hospital:

Infected hydronephrosis – a UTI proximal to the obstructing stone
One functional kidney
Immunocompromised status
Pregnancy
Extravasated perinephric urine
Nausea/vomiting or pain that cannot be managed outpatient, usually in stones >5 mm

Pain management

Mild pain

Acetaminophen and observation can be adequate for small stones.

Moderate or severe pain

Parenteral or oral opiates, NSAIDS, and anti-emetics can be used alone or in combination in these cases. When dosing parenteral narcotics, remember that renal colic is one of the most painful human conditions, and also that overdosing causes respiratory depression, sedation, constipation and nausea/vomiting.

Nonsteroidal anti-inflammatory drugs

Ketorolac is the only intravenous NSAID approved for use; intranasal or oral forms of ketorolac are available though less well-studied for renal colic. Ketorolac provides effective pain relief with less sedation than opiates though it may have increased risks in patients with peptic ulcer disease, renal failure, or gastrointestinal bleeding.

Ketorolac: 30-60 mg IM or 30 mg IV initial dose, followed by 30 mg IV or IM every 6-8 hours. Lower to 15 mg for pts >65yrs old.

Morphine

Morphine is a common choice (meperidine causes more nausea/vomiting and is contraindicated in the presence of impaired kidney function).

Morphine: Standard dosing – 10 mg/70 kg every 4 hrs SQ or IM, or doses of 4-10 mg IV in small increments to avoid respiratory depression.

Metoclopramide

Metroclopramide is the only antiemetic that has been studied for renal colic and therefore is a common choice. Conveniently, this medication works both for pain relief and as an anti-emetic in these patients. It is not, however, an anxiolytic or sedative. Other options not as well-studied include promethazine, prochlorperazine, or hydroxyzine.

Metoclopramide: 10 mg IV or IM q 4-6 hours. Effect onset within 3 minutes IV, 15 minutes IM.

Additional pain management therapy

Antidiuretic therapy – Desmopressin has been shown to have dramatic efficacy in renal colic.. Studies showed a dramatic effect on pain by recipients. In one study of 126 patients with acute renal colic, 50% had complete relief of pain 30 minutes after receiving DDAVP and did not require any analgesic medicine. The medication has fast onset and no adverse effects were seen in this study. It is thought to work by lowering intraureteral pressure, but also may relax pelvic and ureteral musculature. Can be given as a nasal spray or injection (usual dose is 40 mcg nasally or 1ml IV).

Medical expulsive therapy and alternatives

The size of the renal calculus gives an indication as to whether it will pass successfully through the ureter without further intervention. Studies show that stones 4 mm or less have a 95% spontaneous passage rate, especially in the distal ureter, while those larger than 8 mm have an only 20% spontaneous passage rate. Despite these statistics, stone shape and a patient’s renal anatomy also help predict the success of a stone spontaneously passing through the ureter.

For stones 3-10 mm in size, urologists often recommend active medical expulsive therapy (MET), or additional medications that can increase stone passage rate by up to 65%. Medications on this list include calcium channel blockers, shown to relax ureteral smooth muscle, and alpha 1 adrenergic antagonists, shown to relax ureteral and lower urinary tract musculature. One should not conduct MET for more than 10-14 days, and all patients should have prompt urologic follow-up scheduled in case this therapy is not successful.

A typical outpatient regimen for a patient with an intermediate-sized stone might include:

1-2 narcotic/acetaminophen tabs q 4-6 hrs prn pain

600-800 mg ibuprofen q8 hrs

30 mg nifedipine ER daily OR 0.4 mg tamsulosin daily OR 4 mg terazosin daily

Pregnancy and renal stones

Acetaminophen and observation is the treatment of choice for mild to moderate pain in pregnant women. Opioids may also be used. They are class C in pregnancy, and because they do cross the blood-brain barrier and can depress the respiratory system they should be avoided if near delivery.

B. Physical Examination Tips to Guide Management.

Patients’ pain levels should correlate to passage of the renal stone. Pain usually resolves within a short time frame (30 min to 2 hours) of stone passage.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Lab tests are not indicated to confirm that a patient has recovered from nephrolithiasis. Imaging can be helpful, however (see Imaging section above). Most patients do not need more than basic lab screening as mentioned above. However, certain lab abnormalities can suggest specific treatments – see below.

D. Long-term management.

If this is a patient’s first idiopathic renal stone, they should receive conservative treatment. A step-wise approach to the prevention of further renal stones is appropriate.

All patients with a renal stone should increase their fluid intake to 2.5 L/day – especially emphasizing water, because fluids high in sugar or sodium might make calcium stones precipitate more frequently. Trials have shown that increased fluid intake resulted in markedly lower recurrence rates for idiopathic first time calcium stone formers.
Diet: Sodium, sugar, and animal proteins have all been shown to exacerbate calcium stone formation. Tailored dietary guidelines can prevent further stone development:Calcium stones: limit sodium intake, consume adequate dietary calcium (1000-1200 mg per day, and not advisable to take calcium pills as these may increase precipitation of calcium).
Calcium stones with low urinary citrate: increase intake of fruits and vegetables and limit non-dairy animal protein.

Calcium stones with high urinary uric acid OR uric acid stones: limit intake of non-dairy animal protein.

Calcium oxalate stones with high urinary oxalate: limit oxalate-rich foods (spinach, chocolate, almonds, buckwheat), but maintain normal calcium consumption.

If a patient does not follow dietary and hydration recommendations, he or she is likely to have repeat attacks in the future. Rates of recurrence if untreated: 45% of patients will have another attack within 5 years, 50% within 10 years, and 75% within 20 years.

Patients who have recurrence, or are unable to follow dietary or hydration recommendations, may benefit from pharmacologic therapy.

Recurrent calcium-based stones with or without primary hypercalciuria: Thiazide diuretics are a mainstay of therapy; shown in several randomized controlled trials to decrease the recurrence of calcium stones. Can stimulate renal calcium reabsorption and are linked with increased bone mineral density. Options include one of these agents: Hydrochlorothiazide 12.5-25 mg/day (bid dosing most effective); indapamide 1.25-2.5 mg/day; chlorthalidone 12.5-50 mg/day; give with potassium supplementation or spironolactone or amiloride to increase potassium retention.
Recurrent calcium stones with hypocitraturia: Because citrate inhibits crystallization of calcium-oxalate and calcium-phosphate, low urinary citrate can be a risk factor for calcium stones. Potassium citrate replacement is one method for preventing calcium-based stones, and can work even if urinary citrate is normal. Unfortunately, increasing urinary pH with citrate supplementation can paradoxically supersaturate calcium phosphate in urine, so patients should emphasize adequate fluid intake if using this therapy. Dispense potassium citrate 20-30 mEq, taken 2 to 3 times/day.
Calcium oxalate stones: Magnesium replacement works by forming complexes with oxalate, thereby reducing formation of calcium-oxalate crystals. Few randomized controlled trials done for magnesium in this setting; may be useful in low urinary magnesium excretion situations. Some data also exists for using pyridoxine, or vitamin B6, which has been shown in non-randomized trials to lower urinary oxalate and stone formation. Lastly, patients who have hyperuricosuria and normal urinary calcium should consider daily allopurinol therapy.
Uric acid stones: The main strategy is alkalinisation of the urine (goal urine pH 6.5-7.46), which can be accomplished with potassium citrate 20-30 mEq, taken 3 times/day (initial dose – titrate to goal) or sodium bicarbonate 1300 mg bid. Monitor potassium levels closely in patients on potassium citrate. For patients whose urine does not alkalinize easily, allopurinol 300 mg/day can be given as second-line therapy to lower endogenous uric acid production; dose should be adjusted downward for low eGFR
Cystine stones: Treatments include dilution, alkalinisation of urine with potassium citrate, thiol drugs, and chelation therapy. Initially, patients should start with aggressive hydration, including waking up at least once in the night to drink water, and taking 10-20 mEq urinary citrate tid to keep urine pH greater than or equal to 7. If stones then recur, additional therapies such as alpha-mercaptopropionylglycine should be considered.
Struvite stones: Often surgically managed because of size. Long-term low-dose antibiotic regimens can help eliminate postoperative fragments. Acetohydroxamic acid (AHA) may be offered to reduce stone growth and formation after surgical options are exhausted.

Clinicians should obtain a 24-hour urine specimen within 6 months of initiating treatment, either dietary or medical, to evaluate response to therapy.

After this, at least an annual assessment of a 24-hour urine specimen should be performed to monitor risk.

E. Common Pitfalls and Side-Effects of Management.

Fifteen to twenty percent of patients will require further management by urology for non-resolving renal calculi. Occasionally urology will opt for definitive management initially based on obstruction, stone size, or infection. The type of intervention is decided based partially on stone size, among other factors:

Ureteral stones no larger than 1 cm in proximal ureter – first-line therapy is extracorporeal shock wave lithotripsy, with percutaneous nephrolithotomy or ureteroscopy as alternatives.
Ureteral stones greater than 2cm, or an obstructing stone – percutaneous nephrolithotomy, open or laparoscopic stone removal.

IV. Management with Co-Morbidities.

For complications, hospitalists can and should involve urologists, dietitians, pharmacists (to monitor eGFR levels on allopurinol, HCTZ), and/or nurses (counseling for lifestyle, diet) to improve patients’ care. Further resources are available in the clinical practice guidelines section of the American Urological Association website: www.auanet.org

A. Renal Insufficiency.

While renal stones are associated with increased risk of renal insufficiency and even end-stage renal failure, mild renal insufficiency would not change standard management. In moderate to severe renal insufficiency one should be more cautious with volume repletion.