Nephrolithiasis/Kidney Stone Disease

Source: 20th Edition Harrison’s Principles of Internal Medicine

 Common, painful, and costly condition.

 Stone may form due to crystallization of lithogenic factors in the upper urinary tract, move into ureter and cause RENAL COLIC (worst pain).
 Preventive treatment: lifelong
 Mixture of crystal types: Calcium oxalate & calcium phosphate
 Stones are composed of medications, such as:
1. Acyclovir
2. Atazanavir
3. Triamterene

Several types of kidney stones:

1. Calcium oxalate 75% (most common)
2. Calcium phosphate 15%
3. Uric acid 8%
4. Struvite 1%
5. Cystine <1%

EPIDIMIOLOGY
 Global disease
 ↑i prevalence due to WESTERNIZATION LIFESTYLE HABITS (e.g., dietary changes, ↑ BMI)
 19% of MEN & 9% of WOMEN: develop at least ONE STONE during their lifetime.
 Prevalence: 50% ↓L black than whites.
 Incidence: varies by AGE, SEX, & RACE
 White men:
Peak annual incidence: 3.5 cases/1000 (age: 40)
Declines: 2 cases/1000 (age:70)
 White women:
Peak annual incidence: 2.5 cases/1000 (age: 30)
Declines: 1.5 cases/1000 (age: 50)

Note: radiographic evidence of a second stone --> should be considered to represent a RECURRENCE, even if the stone has not yet caused symptoms.

ASSOCIATED MEDICAL CONDITIONS

 Systemic disorder
 Conditions predispose to stone formation:
1. GI malabsorption (e.g., Crohn’s disease, gastric surgery)
2. Primary hyperparathyroidism
3. Obesity
4. Type 2 DM
5. Distal RTA
 Medical conditions with history of nephrolithiasis:
1. Hypertension
2. Gout
3. Cardiovascular disease
4. Cholelithiasis

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 5. Reduced bone mineral density
6. CKD
NOTE:
 Nephrolithiasis DOES NOT DIRECTLY CAUSE UTIs.
 Urologic emergency: UTI in the setting of an obstructing stone (“pus under pressure”) --> reruires intervention to establish drainage.

PATHOGENESIS
 Supersaturation: concentration product exceeds the solubility product).
 Urine in most individuals is supersaturated with respect to one or more types of crystals.
 Presence of inhibitors crystallization: prevents from continuously forming stones.
 Urine citrate: most clinically important inhibitor of calcium-containing stones.
 Calculated supersaturation value
- does not perfectly predict stone formation
- useful guide as it integrates the multiple factors that are measured in a 24-h urine collection.
 Renal biopsies: revealed calcium phosphate in the renal interstitium.
 Hypothesis: calcium phosphate deposits at the --> thin limb of the loop of henle --> extends down to the --> papilla --> erodes through --> papillary epithelium.
 Papillary epithelium: provides a site for deposition of calcium oxalate and calcium phosphate crystals.
 Randall’s plaque: majority of calcium oxalate stones grow on calcium phosphate at the tip of the renal papilla.
 Tubular plugs of calcium phosphate: initiating event in calcium phosphate stone development.
 Process of stone formation: begins YEARS before a clinically detectable stone is identified.

RISK FACTORS
1. Dietary Risk Factors
- associated with an ↑I risk of nephrolithiasis: a.) animal protein
b.) oxalate
c.) sodium
d.) sucrose
e.) fructose
- associated with a ↓L risk include; a.) calcium
b.) phosphate
c.) phytate
A. Calcium
- related to a ↓L risk of stone formation.
- reduction in risk associated with HIGHER CALCIUM is due to a reduction in intestinal absorption of dietary oxalate that results in --> lower urine oxalate.
- contraindication: LOW CALCIUM intake --> ↑i risk of stone formation --> contribute to --> ↓L bone density.
- Supplemental calcium: increase the risk of stone formation may be due to to the timing of supplemental calcium intake/higher total calcium consumption --> leading --> higher urinary calcium
excretion.
B. Oxalate
- Urinary oxalate: derived from both endogenous production and absorption of dietary oxalate; strong risk factor for calcium oxalate stone formation.
- oxalate in food may not readily absorbed.
- absorption may be ↑h in stone formers.
- dietary oxalate: weak risk factor for stone formation.
C. Other nutrients
- ↑h intake of animal protein --> lead to --> ↑i excretion of calcium & uric acid --> as well as --> ↓d urinary excretion of citrate.
- ↑h sodium & sucrose intake --> ↑i calcium excretion independent of calcium intake.
- ↑h potassium intake --> ↓d calcium excretion; ↑I urinary citrate excretion due to alkali content.
- low stone risk factors: magnesium & phytate.

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 - Vitamin C supplements: associated with an ↑i risk of calcium oxalate stone formation in men due to raised levels of oxalate in urine.
- male calcium oxalate stone formers: advised to avoid vitamin C supplements.
- ↑h doses of supplemental vitamin B6: beneficial in selected patients with type 1 hyperoxaluria.
D. Fluids & beverages
- ↑i risk of stone formation: ↓d urine volume.
- urine output <1L/d: risk factor of stone formation MORE THAN DOUBLES.
- fluid intake: main determinant of urine volume.
-associated with a reduced risk of stone formation: coffee, tea, beer, wine, and orange juice.
- sugar-sweetened beverage: ↑i risk.

2. Nondietary Risk Factors

- important risk factors: a.) age
b.) race
c.) body size
d.) environment
- incidence: ↑h in middle-aged men; can form from infants & elderly.
- weight gain: ↑i the risk of stone formation.
- lead to urine volume: a.) working in a hot environment
b.) lack of ready access to water or a bathroom

3. Urinary Risk Factors

A. Urine volume
- ↓L urine volume --> results --> ↑h concentration of lithogenic factors; common and readily modifiable risk factor.
- effective: ↑h fluid intake in ↑i urine volume & reducing the risk of stone recurrences.
B. Urine calcium
- ↑h urine calcium excretion → ↑i formation of calcium oxalate & phosphate stones.
- hypercalciuria: condition of elevated calcium in the urine.
- levels of urine calcium excretion → ↑h with a history of nephrolithiasis.
C. Urine oxalate
- ↑h urine oxalate excretion → ↑i calcium oxalate stone formation.
- relation of urine oxalate & stone risk: continuous
- simple dichotomization of urine oxalate excretion: not helpful in assessing risk.
- 2 sources of urine oxalate: a.) endogenous generation
b.) dietary intake
- dietary oxalate: major contributor; source that can be modified.
- ↑h dietary calcium intake → reduces GI oxalate absorption and thereby reduces urine oxalate.
D. Urine citrate
- natural inhibitor of calcium-containing stones
-↓L urine citrate excretion → ↑i risk of stone formation.
- citrate reabsorption: influenced by the intracellular pH of proximal tubular cells.
- metabolic acidosis due to ↑h animal flesh intake → lead to → ↓r in citrate excretion → by → ↑i reabsorption of filtered citrate.
E. Urine uric acid
- ↑h urine levels of uric acid: risk factor for uric acid stone formation; found with excess purine consumption & rare genetic conditions → lead to → overproduction of uric acid.
F. Urine pH
- influences the solubility of some crystals.
- uric acid stones: form only when the urine pH is ≤5.5 or lower.
- calcium phosphate stones: form when urine pH is ≥6.5 or higher.

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 - cystine: more soluble at higher urine pH.
- calcium oxalate stones: not influenced by urine pH.

4. Genetic Risk Factors

- more than 2fold greater in individuals with a family history of stone disease.
- monogenic disorders → cause nephrolithiasis.
- 2 most common & well-characterized rare monogenic disorders that lead to stone formation: a.) primary hyperoxaluria
- autosomal recessive disorder that causes excessive endogenous oxalate generation by the liver
with consequent calcium oxalate deposition in the kidney can eventually lead to renal failure.
b.) cystinuria
- autosomal recessive disorder that causes abnormal reabsorption of filtered basic amino acids.
- ↑e urinary excretion of cystine (poorly soluble) → lead to → cystine stone formation.
- cystine stones: visible on plain radiographs; often manifest as staghorn calculi or multiple bilateral stones.
- repeat episodes of obstruction & instrumentation: cause a reduction in the GFR.

Approach to the Patient

- requires weeks to months for a kidney stone to grow to a clinically detectable size.
- stone formation and growth → characteristically clinically silent.
- Note: stone can remain asymptomatic in the kidney for years or even decades before signs or symptoms become apparent.
E.g. signs (hematuria) & symptoms (pain)
-onset of symptoms → attributable → stone moving into the ureter.

Clinical Presentation & Differential Diagnosis

- 2 common presentations with an acute stone event: a.) renal colic
b.) painless gross hematuria
- renal colic: misnomer due to pain that is typically does not subside completely rather it varies intensity.
- when stone moves into ureter, discomfort often begins with a sudden onset of → unilateral flank pain.
- intensity of the pain can ↑i rapidly; this pain is accompanied often by nausea & occasionally by vomiting that may radiate depending on the location of the stone.
- if stone lodges:
Upper part of the ureter → pain may radiate ANTERIORLY.
Lower part of the ureter → pain may radiate IPSILATERAL TESTICLE (men) & IPSILATERAL LABIUM (women).
Occasionally, patient has HEMATURIA WITHOUT PAIN.
Right ureteral pelvic junction → symptoms may mimic those of ACUTE CHOLECYSTITIS.
Right pelvic brim → symptoms may mimic ACUTE APPENDICITIS.
Left pelvic brim → symptoms may mimic ACUTE DIVERTICULITIS.
Ureterovesical junction → experience urinary urgency & frequency. In female patients, may lead → incorrect diagnosis of bacterial cystitis (urine may contain RBC & WBC) urine culture is negative.
Obstructing stone with proximal infection → present as ACUTE PYELONEPHRITIS.
- UTI in the setting of ureteral obstruction
 Medical emergency that requires immediate restoration of drainage by placement of a ureteral stent/percutaneous nephrostomy tube.
- differential diagnosis: 1. muscular or skeletal pain
2. herpes zoster
3. duodenal ulcer
4. abdominal aortic aneurysms
5. gynecologic conditions
6. ureteral structure
7. Ureteral obstruction by materials other than stone (blood compression & obstruction)
- extraluminal process can lead to → ureteral compression & obstruction

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Diagnosis and Intervention
- serum chemistry → typically normal; WBC may be elevated.
- examination of urine sediment: reveal RBCs & WBCs; occasionally crystals.
- basis of diagnosis: history, physical examination & urinalysis.
- Note: calcium oxalate dihydrate crystals → bipyramidally shaped not necessary to wait for radiographic confirmation before treating the symptoms.
Cystine crystals → hexagonal
- Helical computed tomography (CT)
 confirmed by this imaging study; highly sensitive and allows visualization of uric acid stones(radiolucent) and does not require radiocontrast.
 Detects stones as small as 1mm that may be missed by other imaging modalities.
 Reveals a ureteral stone or evidence of recent passage (e.g., perinephric standing or hydronephrosis).
- Plain abdominal radiograph (KUB)
 Can miss a stone in the ureter or kidney even if it is radiopaque.
 Does not provide information on obstruction.
- Abdominal ultrasound
 Offers the advantage of avoiding radiation and provides information on hydronephrosis.
 Not as sensitive as CT
 Images only the kidney & possibly the proximal segment of the ureter.
 Most ureteral stones are not detectable by ultrasound.
- NSAIDs (ketorolac): effective as opiods in relieving symptoms ; have fewer side effects.
- excessive fluid administration → has no been shown to be beneficial. GOAL: maintain euvolemia
- Use of an alpha blocker may ↑i the rate of spontaneous stone passage.
- Urologic intervention
 Should be postponed unless there is evidence of UTI, a low probability of spontaneous stone passage (e.g., stone measuring ≥6mm or an anatomic abnormality) or intractable pain.
- Ureteral stent: placed cytoscopically; requires general anesthesia; can be quite uncomfortable; cause gross hematuria and may ↑i risk of UTI.
- if an intervention is indicated, selection of most appropriate intervention is determined by: a.) size
b.) location
c.) composition of the stone
d.) urinary tract anatomy
e.) experience of urologist
- Extracorporeal shockwave lithotripsy (ESWL)
- least invasive option
- uses shock waves generated outside the body to fragment the stone; used less frequently.
- Endourologic approach
- more frequently used than ESWL
- remove a stone by basket extraction or laser fragmentation
-large upper-tract stones → percutaneous nephrostolithomy: has the highest likelihood of rendering the patient stone-free.
-open surgical procedures: a.) ureterolithotomy
b.) pyelolithotomy

Evaluation for Stone Prevention

- more than half of first-time stone formers will have recurrence within 10 years.
History
- patients medical history should cover a.) UTI
b.) bariatric surgery
c.) gout
d.) hypertension
e.) DM

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 - family history of stone disease → reveal a genetic predisposition.
- ROS should focus on etiologic factors related to ↓L urine volume (↑h insensible losses) & GI malabsorption; how frequently the patient voids during the day and overnight.

Physical Examination
- should assess a.) weight
b.) BP
c.) costovertebral angle tenderness
d.) lower-extremity edema
e.) signs of other systemic conditions (such as primary hyperparathyroidism & gout).

Laboratory Evaluation
- the following serum levels should be determined: a.) electrolytes (uncover hypokalemia & RTA).
b.) creatinine
c.) calcium
d.) uric acid
- PTH level: measured if indicated by high-normal or ↑ serum & urine calcium concentration.
- 25-hydroxy vitamin D: measured with PTH to investigate possible role of secondary ↑ PTH levels in the setting of vitamin D insufficiency.
- asymptomatic residual renal stones → RBC & WBC are frequently present in urine.
- possibility of an infection → CULTURE should be performed.
- sediment: reveal crystals; help identify the stone type; provide prognostic information
- crystalluria: strong risk factor for new stone formation.
- 24-h urine collection: serve as a cornerstone on which therapeutic recommendations are based.
- recommendations on lifestyle modifications → should be deferred until urine collection is complete.
- baseline assessment → patient should collect at least 24-h urine samples while consuming their usual diet and usual volume of fluid.
- following factors that should be measured: a.) total volume d.) uric acid g.) potassium j). creatinine
b.) calcium e.) oxalate h.) phosphorus
c.) citrate f.) sodium i.) pH
- specialized testing (calcium loading/restriction) → NOT RECOMMENDED as it does not influence clinical recommendations.
- stone composition analysis → essential if a stone or fragment is available.
- stone type → cannot be determined with certainty from 24-h urine results.
- puric acid stones → identified by low Hounsfield units on CT.

Imaging
- helical CT without contrast: GOLD STANDARD diagnostic test.
- low-dose CT → should be considered to establish the baseline stone burden.
- CT → provides the best information; radiation dose is higher than from other modalities; performed only if the results will lead to a change in clinical recommendations.
- renal ultrasound → used to minimize radiation exposure; less sensitive.

Prevention of New Stone Formation

- recommendations for preventing stone formation → depend on the stone type & results of metabolic evaluation.
- all stone types: consistently diluted urine → reduces the likelihood of crystal formation.
- urine volume → at least 2L/d
- educate patients about how much more they need to drink in light of their 24-h urine volume.
E.g., Daily urine volume: 1.5 L
Patient should be advised to drink at least 0.5L more per day in order to ↑i urine volume to the GOAL of 2L/day.

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 Recommendation for Specific Stone Types
Calcium Oxalate
- risk factors: a.) ↑h urine calcium
b.) ↑h urine urine oxalate
c.) ↓L urine citrate
- insensitive to pH in the physiologic range.
- ↑h urine calcium excretion → absorb a ↑h percentage of ingested calcium.
- men with ↑h urine calcium & recurrent calcium oxalate stones → diet containing 1200 mg calcium & ↓L intake of sodium & animal protein → reduced stone formation from that ↓L calcium diet (400
mg/day.
- ↑e calcium intake (>1200 mg/d) → should be avoided
- thiazide diuretic
- treat hypertension; ↓L urine
- chlorthalidone → ↓r calcium oxalate stone by recurrence by 50%.
- when it is prescribed → dietary sodium restriction is essential to obtain the desired ↓r in urinary calcium excretion & minimize urinary potassium losses.
- biphosphonates
- ↓r urine calcium excretion
- cannot recommended solely for stone prevention
- used to treat with low bone density.
- ↓r in urine oxalate → ↓r supersaturation of calcium oxalate
- avoiding high-dose vitamin C supplements → only known strategy that reduces ENDOGENOUS oxalate production.
- oxalate: metabolic end product.
- reducing absorption of exogenous oxalate involves 2 approaches:
a.) avoidance of foods that contain ↑h amounts of oxalate (spinach, rhubarb, almonds & potatoes).
b.) extreme oxalate restriction → does not reduce stone recurrence; harmful to over-all health.
- absorption of oxalate → ↓r by ↑h calcium intake; influenced by intestinal microbiota depending on the presence of oxalate-degrading bacteria.
- citrate: natural inhibitor of calcium oxalate & calcium phosphate stones.
- ↑h-level consumption of foods rich in alkali (I.e., fruits & vegetables) → ↑i urine citrate.
- supplemental alkali (i.e., potassium citrate or bicarbonate) → lead to an → ↑i urinary citrate excretion
- sodium salts (sodium bicarbonate) → avoided due to adverse effects of sodium on urine calcium excretion.
- urine pH → does not influence calcium oxalate stone formation.
- ↑h-level of urine uric acid → ↑i risk factor of calcium oxalate stones.
- allopurinol: reduced stone recurrence in patients with calcium oxalate stones & ↑h urine uric acid levels.
- dietary modifications may be beneficial in ↓r stone recurrence:
a.) restriction of nondairy animal protein (meat, chicken, seafood) → result in ↑h excretion of citrate & ↓L excretion of calcium.
b.) reducing sodium intake to <2.5 g/day → ↓d urinary excretion of calcium
c.) sucrose & fructose intake → SHOULD BE MINIMIZED
- DASH diet → reduce BP

Calcium Phosphate
- share risk factors with calcium oxalate stones including → ↑h conc’n of urine calcium & ↓L conc’n of urine citrate.
- ↑h-urine phosphate levels & ↑h urine pH → associated with an ↑i of calcium phosphate stone formation.
- MORE COMMON IN PATIENTS WITH DISTAL RTA & PRIMARY HYPERPARATHYRODISM.
- thiazide diuretics (with sodium restrictions) → used to ↓r urine calcium.
- ↓r of dietary phosphate → beneficial by ↓r urine phosphate excretion.

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 Uric Acid
- 2 main risk factors: a.) ↓L urine pH
b.) ↑h uric acid excretion
- urine pH: predominant influence on uric acid solubility
- mainstay of prevention of uric acid stone formation → ↑i urine pH.
- alkalinizing the urine → achieved by ↑i intake of foods rich in alkali (fruits & vegetables) and ↓r intake of foods that produce acid (e.g., animal flesh).
- supplementation with bicarbonate or citrate salts → used to reach the recommended PH GOAL of 6.5 throughout the day & night.
- end product of purine metabolism.
- xanthine oxidase inhibitor (allopurinol & febuxostat) → reduce urine uric acid excretion by 40-50%.

Cystine
- focus for cystine stone prevention: ↑i cystine solubility.
- GOAL: tx with medication that covalently binds to cystine (tiopronin or penicillamine) & medication that ↑r urine pH.
- tiopronin → preferred choice due to better adverse event profile.
- preferred alkalinizing agent to achieve a urine pH of 7.5 is → potassium citrate/bicarbonate → as sodium salts → ↑i cystine excretion.
- cystinuria → maintaining ↑h urine volume is an essential componentt of the preventive regimen.

Struvite
- aka as infection stones or triple-phosphate stones.
- form only when upper urinary tract is infected with urease-producing bacteria such as Proteus mirabilis, Klebsiella pneumoniae or Providencia species.
- urease-producing bacteria → hydrolyzes urea & ↑el the urine pH to → supraphysiologic level (>8.0).
- grow quickly & fill the renal pelvis (staghorn calculi).
- require complete removal by a urologist.
- patients with recurrent UTIs → urease inhibitor acetohydroxamic acid can be considered (used with caution because of potential side effects).