Nephrolithiasis

Definition, Etiology, PathogenesisTop

Nephrolithiasis refers to the presence of insoluble stones in the urinary tract, which form in a complex cascade of events when the concentration of stone-forming salts in urine exceeds the threshold of solubility and precipitation occurs. These precipitates form crystals or nuclei that may become retained in the kidney or flow into the urinary tract and become a nidus for stone aggregation and growth.

The main factors contributing to the formation of kidney stones depend on the underlying etiology, with the common factors being:

1) High urine concentrations of lithogenic substances, such as oxalate, calcium, phosphate, uric acid, and cystine.

2) Impaired urinary flow.

3) Urinary tract infection (UTI).

Most frequently kidney stones are formed of calcium oxalate, less commonly of calcium phosphate, urate, struvite (magnesium ammonium phosphate), or cystine. Etiology and pathogenesis of main types of nephrolithiasis: Table 1.

The stones may form at various levels of the urinary tract, most frequently in the renal calyces and renal pelvis. They may subsequently move downstream to the ureters and the bladder, where they may either continue to grow or be passed with urine. Some stones reach considerable sizes, but stones of any size can lead to obstructive uropathy resulting in kidney injury.

Clinical Features and Natural HistoryTop

Nephrolithiasis typically manifests as renal colic, that is, flank pain referred to the pubic region, genitalia, and inner thighs; in patients with urethral obstruction, the pain is referred to the suprapubic region. The pain starts when the stone passes through the narrow lumen of the ureter. It may be accompanied by nausea and vomiting, urinary urgency, urinary frequency, rigors, fever, hypotension (sepsis), and even syncope (in patients with severe pain). Hematuria is also occasionally observed. In patients presenting with rigors, fever, or hypotension, care must be taken to exclude urosepsis secondary to obstructive uropathy, which is associated with significant mortality if unrecognized and will require urgent urologic consultation and management. Physical examination reveals flank pain and increased muscle tone on the side of the colic. The pain is relieved when urine flow is restored (as a result of passage of the stone to the bladder and/or spontaneous passage of the stone with urine).

The underlying cause of stone formation determines the risk for disease recurrence. A highly recurrent disease is observed in 10% of patients with nephrolithiasis. Approximately half of all patients with stone formation will have a subsequent recurrence of renal colic within the next 10 years.

DiagnosisTop

Diagnosis of Acute Nephrolithiasis

Diagnosis is based on the clinical signs and symptoms from detailed medical history and physical examination as well as results of imaging studies. In some patients kidney stones are diagnosed incidentally, when imaging studies are performed for unrelated reasons.

In patients evaluated for acute flank pain, initial diagnostic imaging studies should include ultrasonography or noncontrast computed tomography (CT). Ultrasonography is the first-line imaging study of choice for pediatric patients and patients who are or may be pregnant. A noncontrast CT scan offers better sensitivity and specificity compared with ultrasonography but has risks associated with radiation exposure. In patients with a body mass index (BMI) <30 kg/m2, a low-dose CT scan should be offered, which substantially decreases radiation exposure while maintaining high specificity and sensitivity. A contrast-enhanced CT may be used to assess for suspected anatomic renal collecting system abnormalities as part of operative planning.

Other diagnostic tests evaluated during an episode of acute nephrolithiasis include urinalysis and blood testing (complete blood count [CBC] and evaluation of serum electrolytes and creatinine). On urinalysis, three-quarters of patients show microscopic or gross hematuria, and ~3% have leukocyturia and bacteriuria due to a coexisting UTI. No specific abnormalities in blood tests are typical for nephrolithiasis. An elevated creatinine level may be observed in patients with acute renal injury secondary to obstructive uropathy particularly in patients with a solitary kidney.

Differential Diagnosis

Differential diagnosis should include cholelithiasis, acute abdomen, acute pyelonephritis, and other causes of urinary tract obstruction (eg, thrombi or necrotic fragments of renal parenchyma in patients with acute renal papillary necrosis or tuberculosis).

Diagnosis of Causes of Nephrolithiasis

All patients with first-time stone formation should undergo a limited metabolic evaluation to exclude potential systemic disorders as an underlying cause of stone formation. Patients with clearly identifiable risk factors for recurrent stone formation should undergo a more thorough metabolic evaluation.

Risk factors for recurrent stone formation include stones in children (<18 years of age); bilateral or multiple stones; recurrent stones (having ≥2 kidney stone episodes in the past); noncalcium stones (eg, uric acid, cystine); pure calcium phosphate stones; any complicated stone episodes that resulted in severe acute kidney injury (AKI); sepsis; hospitalization or complicated hospital admission; any stones requiring percutaneous nephrolithotomy treatment (usually staghorn stones—stones involving the entire renal pelvis and extending calyces); stones in the setting of a solitary kidney (anatomic or functioning); patients with chronic kidney disease; and history of kidney stones and a systemic disease that increases the risk of kidney stones, such as gout, osteoporosis, bowel disorders with associated malabsorptive states, hyperparathyroidism, renal tubular acidosis, and type 2 diabetes mellitus.

Diagnostic Tests

1. Limited metabolic evaluation: A basic evaluation including urinalysis, culture, and blood tests should be done for all patients with acute renal colic. Stone analysis should be completed for any collected stones to determine their composition. Following the first episode of renal colic, a limited metabolic stone workup should be performed in all patients in the absence of risk factors for recurrent stone disease. This basic workup is done when the patient is free of the acute symptoms of colic, usually 2 to 3 months after the episode or urologic intervention due to renal colic (the patient should follow their usual diet) and in persons incidentally diagnosed with asymptomatic kidney stones:

1) Urinalysis: Presence of specific crystals such as uric acid, cystine, calcium oxalate, or calcium phosphate in urine may indicate the type of renal stones.

2) Urine culture: Confirms or excludes a concomitant infection.

3) Serum levels of creatinine, sodium, potassium, bicarbonate, calcium, phosphorus, and uric acid.

2. In-depth metabolic evaluation: In addition to the limited metabolic evaluation, patients with risk factors for recurrent stone disease as well as occupational risk factors, where public safety is at risk (pilots, air traffic controllers, police officers, firemen, military personnel), should undergo an in-depth metabolic evaluation including the following:

1) Two 24-hour urine collections: Urine collections should be evaluated for volume, creatinine, calcium, sodium, potassium, oxalate, citrate, uric acid, magnesium (and cystine in case of suspected cystine stones or if stone analysis has identified cystine).

2) Spot urine collection: pH, specific gravity, urinalysis.

3) Serum levels of creatinine, sodium, potassium, chloride, calcium, albumin, uric acid, bicarbonate, parathyroid hormone (PTH) (if serum calcium level is elevated), and vitamin D (if serum calcium is low or if serum PTH is elevated).

Stone analysis of any captured kidney stones should be performed whenever possible to determine stone composition. Further evaluation may be needed depending on the underlying etiology of the formed stones (Table 1). Repeat imaging studies may be required in patients at high risk of stone recurrence to assess stone burden.

TreatmentTop

The principles of treatment for acute renal colic are recognition of any emergent sequelae of the stones requiring urgent management, pain control, and identification and treatment of the underlying causes.

Indications for an urgent urologic consultation and treatment include:

1) Signs or symptoms of sepsis with obstruction.

2) Oliguria or anuria.

3) Obstructing stones in a solitary kidney.

4) Failure to control pain using pharmacotherapy.

Specific treatment of various types of nephrolithiasis: Table 2.

Medical Treatment of Acute Renal Colic

The management of pain should not be delayed. It should follow a stepwise fashion with nonsteroidal anti-inflammatory drugs (NSAIDs) being the first option whenever possible.

1. Acute treatment of pain:

1) Oral or rectal NSAIDs, for example, ketoprofen 50 to 100 mg, ibuprofen 600 to 800 mg, diclofenac 50 to 100 mg, naproxen 500 to 750 mg.

2) Oral acetaminophen (INN paracetamol) 325 to 650 mg every 4 hours.

3) Alpha-blockers, for example, oral tamsulosin 0.4 mg once daily (this allows for an increased rate of stone passage and decreases overall analgesic use).Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (subgroup analysis). Hollingsworth JM, Canales BK, Rogers MA, et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ. 2016 Dec 1;355:i6112. doi: 10.1136/bmj.i6112. Review. PMID: 27908918; PMCID: PMC5131734.

2. Acute treatment of severe pain:

1) Oral acetaminophen and NSAIDs should be first-line options whenever possible.

2) IV or IM NSAIDs, for example, ketoprofen 100 mg, diclofenac 75 mg, or ketorolac 30 mg, are as effective as opioids in relieving severe renal colic and additionally reduce edema and inflammation surrounding a blocked stone. Relieving pain may facilitate the passage of the stone downstream to the bladder. Care must be taken in patients with AKI when prescribing NSAIDs, as these agents may exacerbate AKI.

3) Opioids:

a) IV or IM tramadol 100 mg.

b) IV morphine sulfate 2 to 5 mg every 4 hours, with extra doses for breakthrough pain used as necessary.

c) IV hydromorphone 0.5 to 2 mg every 4 hours, with extra doses for breakthrough pain used as necessary.

Conservative Treatment

Depending on stone location and size as well as the patient’s tolerance, conservative management of nephrolithiasis may be an option. Natural history of kidney stones depending on size and likelihood of spontaneous passage: Table 3.

Active Treatment

1. Extracorporeal shock wave lithotripsy (ESWL): In situ fragmentation of stones in the kidney or other part of the urinary tract using external (electrohydraulic, electromagnetic, or piezoelectric) shock waves. The procedure is performed under sedation with analgesia, usually in an outpatient setting. Contraindications: pregnancy, bleeding disorders (anticoagulants and antiplatelet drugs should be temporarily discontinued), poorly controlled hypertension. Special caution is needed in patients with a cardiac pacemaker or abdominal aortic aneurysm.

2. Ureteroscopic lithotripsy (URSL): Manipulation and removal of stones using a ureteroscope (an endoscope introduced through the urethra and the bladder into the ureter).

3. Percutaneous nephrolithotomy (PCNL): Removal of stones from the kidney or upper urinary tract using an endoscope (nephroscope) introduced directly into the renal pelvis. PCNL is reserved for patients with large stone burden (particularly patients with staghorn stones) or those in whom it is not possible to perform ESWL or URSL.

4. Surgical removal of the stone (in exceptional cases total nephrectomy may be needed; rarely done).

PrognosisTop

In patients with incidentally diagnosed urinary stones, the 5-year risk of developing symptomatic nephrolithiasis is ~50%. The risk of a second episode of renal colic in patients who have not received prophylactic treatment is ~15% within a year, up to 40% within 5 years, and 50% within 10 years. Early diagnosis of the underlying conditions along with the introduction of targeted treatment improves prognosis, in particular in patients with recurrent nephrolithiasis or with nephrolithiasis developing at a young age. In rare cases nephrolithiasis may lead to end-stage renal failure (2%-4% of patients require renal replacement therapy; 40% of these have struvite nephrolithiasis associated with the formation of staghorn stones).

PreventionTop

General Measures

1. Increased fluid intake (maintain daily urine output ≥2.5 L).Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity. Fink HA, Akornor JW, Garimella PS, et al. Diet, fluid, or supplements for secondary prevention of nephrolithiasis: a systematic review and meta-analysis of randomized trials. Eur Urol. 2009 Jul;56(1):72-80. doi: 10.1016/j.eururo.2009.03.031. Epub 2009 Mar 13. Review. PMID: 19321253; PMCID: PMC2925677.

2. Moderation of animal protein intake and avoidance of purine-rich foods such as fish, red meats, and shellfish (particularly in patients with recurrent calcium oxalate and uric acid stones).

3. Salt intake restricted if possible to 1500 mg (65 mmol) daily and not exceeding 2300 mg (100 mmol) due to the calciuretic effects of sodium.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision (small number of events). 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 Jan 10;346(2):77-84. PMID: 11784873.

4. The goal of dietary calcium intake should be 1000 to 1200 mg/d.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993 Mar 25;328(12):833-8. PMID: 8441427.

5. For patients receiving vitamin C supplementation, the daily dose should not be >1000 mg because of the associated risk of hyperoxaluria and stone formation, although robust studies are lacking.

6. Vitamin D supplementation may be considered in patients with calcium oxalate stone formation and vitamin D deficiency, with urinary monitoring over the subsequent 24 hours for hypercalciuria, although robust studies are lacking.

7. A high-fiber diet may protect against kidney stone formation.

8. Specific measures will depend on the underlying etiology of the stone.

Details on treatment and prevention strategies: Table 2.

TablesTop