Nephrolithiasis and Chronic Kidney Disease

C H A P T E R

59 Nephrolithiasis and Chronic Kidney Disease Anirban Bose and David A. Bushinsky Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

INTRODUCTION Although kidney stones have a propensity to afflict people in industrialized nations, they cause significant morbidity worldwide.1 Their annual incidence is more than 1 per 1000 persons,2 resulting in nearly two million physician office visits in 2000, with estimated annual costs totaling $2 to 5.5 billion.1–3 The incidence of nephrolithiasis is increasing in the US, paralleling the rising rates of obesity, type 2 diabetes and insulin resistance.4 Kidney stones affect men more frequently than women, peaking amongst patients in their 30 s and 40 s before declining in frequency in the sixth to seventh decade of life.5,6 In addition to age and gender, race and geographic location influence the prevalence of stones. Caucasians are more likely to develop stones compared to African-Americans, Hispanics and Asian Americans, and the disease affects more people in warmer climates.7 In the Middle East, more than 70% of kidney stones are composed of uric acid, while a similar percentage of patients in the US have calciumbased stones.7,8 In 2008 melamine adulterated milk in China led to a large number of Chinese babies developing kidney stones and, in some cases, renal failure due to obstructive nephropathy.9

TYPES OF STONES In the US, calcium-based stones account for more than 75% of all stones passed. Uric acid and struvite stones account for approximately 10 to 20% of cases, while cystine stones are seen in 1 to 2% of all stone P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00059-7

formers (Figure 59.1). The recurrence rate of calcium oxalate nephrolithiasis is about 50% at 5 to 10 years, and higher for cystine, uric acid and struvite stones.10

Pathogenesis of Kidney Stone Formation The final common pathway of stone formation is the supersaturation of the urine with the ionic constituents of the specific stone. Saturation refers to the driving force for formation of the solid phase, and takes into account the ambient conditions, concentrations and free ion activities of stone components that influence their solubility. Thus saturation is not just a simple function of ionic molar concentrations. Using calcium oxalate as an example, even if the concentration of these free ions is increased in urine, other substances like citrate, potassium and magnesium act as inhibitors and prevent crystallization. The interaction with these other solutes decreases the free ion activity and allows the lithogenic constituents to increase in concentration to levels that would otherwise cause crystal formation in water. Thus lithogenicity could result from increased excretion of poorly soluble substances or decreased excretion of inhibitors of stone formation. Other factors such as urine pH influence supersaturation by affecting the solubility of these ions. When urine becomes supersaturated, free ions have a greater propensity to join together to form the more stable, solid phase. This process is called nucleation. and can happen from similar ions (homogeneous nucleation), or around dissimilar crystals or sloughed epithelial cells (heterogeneous nucleation). If several small crystals bond together and grow in size (aggregation), this crystal complex can cause obstruction.

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Types of kidney stones Struvite, 22%

Uric acid, 5%

Calcium phosphate, 7%

Cystine, 2%

Calcium oxalate, 26%

Calcium oxalate and calcium phosphate, 37%

FIGURE 59.1  Distribution of the different types of kidney stones.

is a crucial risk factor for stone formation because a low urine volume increases urinary supersaturation of the ionic constituents of all stone types.18–22 Prior history of nephrolithiasis,23,24 family history of nephrolithiasis,25 recent gastric bypass procedures, bariatric surgery or short bowel syndrome are all associated with increased risk of stone formation.26,27 Recurrent urinary tract infections with urease-producing organism such as Proteus or Klebsiella predispose to the formation of struvite stones. Medications such as Indinavir, acyclovir, sulfadiazine, ceftriaxone and triamterene can crystallize and form stones in urine.28–30 The risk of nephrolithiasis is higher in patients with hypertension, diabetes, obesity, metabolic syndrome and gout.4,31,32

CLINICAL PRESENTATION Clinical presentation depends on the size, type and location of the stone. Commonly, stones present with pain or hematuria, but the range of symptoms can vary from asymptomatic small stones discovered on incidental imaging to large calculi that cause obstruction and renal failure. Large obstructing staghorn calculi may be asymptomatic, and thus nephrolithiasis should be in the differential diagnosis of unexplained CKD.33

Pain FIGURE 59.2  An attached stone (double arrow) is seen resting on a region of white plaque (single arrows) and intermixed with small areas of white (single arrow) and yellow plaques (arrowheads). From Reference11, reproduced with permission.

Calcium oxalate crystals often initially adhere to calcium phosphate deposits, so-called Randall’s plaques, which are located on the renal papillae (Figure 59.2). This adherence and subsequent growth occurs only in urine that is supersaturated with respect to calcium oxalate. With continued urinary supersaturation, the stone increases in size. If it breaks off from the Randall’s plaque, it may be large enough to obstruct the ureter, causing clinically significant stone disease.12

Risk Factors for Stone Formation Various clinical conditions and dietary habits increase the risk of nephrolithiasis. Diets high in sodium and animal protein increase urinary calcium excretion and increase the risk of stone formation.13–16 High oxalate or high purine diets also lead to increased risk of stone formation by increasing urinary supersaturation of calcium oxalate and uric acid, respectively.13,17 Low fluid intake

The passage of stones often results in ureteric colic that is abrupt in onset, excruciatingly painful, and frequently accompanied by hematuria, nausea, and vomiting. The pain generally migrates from the flank towards the abdomen and into the groin as the stone moves towards the uretero-vesicular junction. The probability of passage without intervention is 97% for stones smaller than 2 mm, 50% for stones 4 to 6 mm in size and less than 1% for stones larger than 6 mm. A urologic intervention will almost certainly be required for these large stones.34,35 Nephrolithiasis can also produce a dull, poorly localizing pain, or be an incidentally discovered radiologic finding unrelated to the actual cause of flank pain.

Hematuria Hematuria occurs in 90 to 95% of patients with acute unilateral flank pain caused by stones. Hematuria may be microscopic or macroscopic.36,37 Large calculi generally cause macroscopic hematuria and, expectedly, are often associated with bouts of colic. In patients with hematuria, it is always important to consider diagnoses other than kidney stones including tumor, infection, glomerular and interstitial disease and hypercalciuria in children.38

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Diagnosis

Rarer Presentations Less common presentations of nephrolithiasis include urinary tract infections and AKI, if the stone obstructs a single functioning kidney or if both kidneys are obstructed simultaneously. Staghorn calculi often do not produce symptoms unless the stone results in obstruction, leading to decrement in GFR which may occur in more than a quarter of patients.39

DIFFERENTIAL DIAGNOSIS FIGURE 59.3  Renal stones on abdominal X-ray and CT scan.

Pyelonephritis

From www.gehealthcare.com/usen/ct/products/urologyimagegallery.html.

Fever is an uncommon finding in patients with simple stones. Thus, fever should trigger work-up for pyelonephritis that can complicate stones. Struvite stones are often associated with infections by urease producing organisms. Xanthogranulomatous pyelonephritis is a form of chronic pyelonephritis often associated with kidney stones that can produce significant destruction of the renal parenchyma and may mimic a tumor radiologically.40

Ectopic Pregnancy, Rupture or Torsion of Ovarian Cysts, Dysmenorrhea Flank pain associated with these conditions can mimic stones closely. Hematuria is unusual but is frequently misdiagnosed to have occurred if urine is contaminated with vaginal blood.41

Acute Appendicitis, Diverticulitis, Intestinal Obstruction, Mesenteric Ischemia and Biliary Colic These conditions can mimic the pain seen with kidney stones and the accompanying nausea and vomiting. However, hematuria is unusual in these cases and the abdominal signs are more prominent than with renal colic.42

Loin Pain Hematuria Syndrome Typically a disease of young or middle-aged women, this poorly understood condition can cause both microscopic and macroscopic hematuria, and must be in the differential diagnosis of all conditions that cause flank pain and hematuria.43 This diagnosis is made radiographically, and by excluding other conditions like small stones, tumors, urinary infections and glomerular disease.44

FIGURE 59.4  Crystals seen in urine of stone formers. a. Calcium oxalate; b. Urate; c. Cystine; d. Struvite. From Reference 48. Courtesy of Dr. Patrick Fleet, University of Washington, Seattle, Washington, USA.

Clot-Colic, Debris-Colic Bleeding into the renal pelvis from tumors or after a kidney biopsy can produce clots that obstruct the ureter and cause pain.45 Papillary necrosis secondary to diabetes, analgesic abuse or infections can also present similarly.46,47

DIAGNOSIS Suspicion for nephrolithiasis, or work-up of other causes of abdominal pain with or without hematuria, typically involves performing a urinalysis examining for radiological testing (Figure 59.3) and crystals (Figure 59.4) to help differentiate the disorders. The tests that

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can be performed in such a situation include a kidney ureter bladder radiograph (KUB), an ultrasound, a computed tomographic (CT) scan, an intravenous pyelogram (IVP) or magnetic resonance imaging (MRI).

by a contrasted study. This practice should be avoided unless absolutely necessary, as the radiation exposure is doubled and the patient is exposed to the risks of the contrast medium.

Abdominal X-Ray/Kidney Ureter Bladder Radiograph

MRI

Although 90% of urinary calculi (calcium, struvite and cystine) are radio-opaque, the sensitivity of a KUB is 45 to 59% and specificity is 71–77%.49 In addition to uric acid stones being radiolucent, such a low diagnostic yield is likely because of problems with stones being obscured by stool, bowel gas, or overlying vertebrae.

Intravenous Pyelography IVP is more sensitive (64 to 87%) and specific (92 to 94%) than a KUB for the detection of renal calculi.50 IVP can also identify structural abnormalities of the urinary tract that predispose to stone formation and during acute colic may even help move the stone along the ureter by creating a strong osmotic diuretic effect. However, IVPs can miss non-obstructing radiolucent stones that do not generate a “filling defect,” carry the risk of contrast exposure in patients with compromised renal function, carry the risk of radiation exposure and sometimes need re-imaging at 12 to 24 hours in patients with high-grade obstruction because of inadequate concentration of the contrast medium.50

Ultrasonography Ultrasonography is easily performed and very sensitive at detecting obstruction. Although ultrasonography can detect clinically significant renal calculi, it has a sensitivity of only 19% in detecting ureteral stones that are the cause of acute symptoms in a majority of the patients.51 Ultrasound is the imaging modality of choice when radiation exposure must be minimized, such as in young women (especially if they are pregnant).

Non-Contrast Helical CT Non-contrast helical CT can detect most stones with a sensitivity of 95 to 98% and specificity of 98%.52 Noncontrast helical CT is superior to IVP as a diagnostic modality.53 Based on the Hounsfield density of the identified stone, cystine and uric acid stones can be differentiated from calcium-bearing stones.54 A helical CT is also useful to detect other causes of abdominal pain, and thus is the imaging modality of choice in most cases.55 However, a CT is more expensive than an IVP. CT has the added disadvantage of increased exposure to radiation. Often a non-contrast helical CT is followed

MRI is rarely used as a diagnostic test except in situations where it is important to avoid radiation. Although most stones are detected using one or a combination of the above radiological techniques, HIV protease inhibitor-induced stones are not radio-opaque and often do not manifest signs of obstruction, leading to the diagnosis being missed on IVP, ultrasound or noncontrast CT scan.28,29 In such patients, contrast-enhanced CT scanning may be required to establish the diagnosis.56

NEPHROLITHIASIS AND CKD Nephrolithiasis is associated with a two-fold increase in CKD that is independent of other risk factors such as diabetes and hypertension found in stone formers.57–59 A French study estimated the incidence rate of ESRD because of nephrolithiasis to be about 3.1 cases per million population per year.60 A Canadian study demonstrated that although only 0.8% of patients with ESRD had nephrolithiasis, any stone episode previously was associated with an increased risk of ESRD (hazard ratio 2.16).61 This risk was stronger in women than in men. Approximately 40% of stone formers who develop ESRD have a solitary functioning kidney.62 The most common reason for loss of a single kidney in stone formers were staghorn calculi, high stone burden, infection and ureteral obstruction.63 The mechanism of development of renal damage with stone disease probably arises from ureteral obstruction causing parenchymal damage.57 Most of these data come from animal models, suggesting unilateral ureteral obstruction causes intense renal vasoconstriction, and reduces renal blood flow and GFR.64 Other injury-producing events during the same process include increased interstitial volume, matrix deposition, monocyte infiltration and fibroblast differentiation, leading to up-regulation of transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α, and progression to tubulointerstitial inflammation and fibrosis.65,66 The incidence of stone formation varies by the type of stone. Brushite stone formers have an increased risk of cortical fibrosis.67 The formation of Randall’s plaques in brushite stone formers was associated with duct plugging, collecting duct cell death and inflammation.68 In patients with staghorn calculi, renal biopsy demonstrates extensive inflammation and macrophage infiltration.69 Other stone forming diseases like

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Management

primary hyperoxaluria, cystinuria, and Dent’s disease have all been associated with crystal formation in the renal parenchyma that presumably triggers subsequent inflammation and CKD.70 With declining GFR, the calcium excretion decreases.71 Stone recurrence rates may be lower in stone formers with reduced GFR.72 Thus there may be significant under-recognition of the contribution of kidney stones to the development of CKD.

MANAGEMENT Management of Acute Renal Colic Management of acute renal colic is centered on pain control with adequate analgesia, assessment of the stone size/location to determine likelihood of passing, and evaluation of co-existent conditions or complications that might necessitate urgent urologic intervention. Analgesia is achieved by use of either non-steroidal anti-inflammatory drugs (NSAIDs) or opiates. A systematic review found both were equally effective in achieving analgesia.73 A combination may be superior to either one alone.74 NSAID administration avoids the nausea and vomiting common to opiates but carries the risk of worsening AKI in an obstructed kidney. Also, administration of NSAIDs must be stopped 3 days before planned lithotripsy, to avoid excessive bleeding.75 The more distal the stone is in the ureter, the more likely it is to pass spontaneously. In the kidney, stones in the lower pole are associated with poor clearance after lithotripsy. Percutaneous lithotomy may be necessary for removal of stones if they are more than 1 cm in size.76 Stones greater than 6 mm have a less than 1% chance of spontaneous passage, and will likely need urologic intervention.77,78 Eighty percent of patients will pass a stone less than 5 mm in size spontaneously within 4 weeks. However patients must have repeat KUBs to document the stone’s passage and they should be followed weekly for any signs of sepsis or worsening renal function.79 A stone’s passage can be facilitated by the use of alpha blockers such as tamsulosin or calcium channel blockers such as nifedipine. These agents appear to reduce the need for surgical intervention.80 For patients presenting with acute renal colic and signs of sepsis, anuria, acute renal failure, intractable vomiting or intractable pain or with a stone larger than 5 mm, an urgent urologic consultation is essential to relieve the obstruction.81,82

Metabolic Evaluation of Kidney Stone Formers A history and physical examination should focus on issues pertinent to nephrolithiasis, including a thorough

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review of the patient’s diet, fluid intake, medications, history of gastrointestinal surgery and family history. Of these, an estimation of the dietary content of the patient’s consumption of calcium, oxalate, sodium, acid (animal protein), citrus fruits, purine-rich foods and exogenous vitamin C or D can offer clues to the risk factors predicting stone formation. Patients passing stones should be encouraged to strain their urine. If a stone is obtained, its analysis can provide important diagnostic and prognostic information.83 However, most patients need a metabolic evaluation to identify their lithogenic risk. It is recommended this be performed 4 to 6 weeks after an acute episode.84 After the initial episode of nephrolithiasis, observational studies estimate that the likelihood of recurrence, in the absence of specific treatment to prevent recurrence, ranges from about 5% per year for the first 5 years22 to 50% at 5 years.85 Given the success of the general measures to prevent recurrent stone formation, such as ample fluid intake, reduction in dietary sodium intake, age and gender appropriate calcium intake and reduction of dietary protein, some have recommended that a comprehensive evaluation be reserved for patients with multiple stones, a strong family history of stones, those passing gravel, metabolically active stones (stones that grow in size or number on follow-up), in children, in demographic groups not prone to forming stones and in those in whom the stones are not made of calcium. Whether first-time stone formers undergo a complete metabolic evolution is controversial, as studies have shown that first-time stone formers have the same underlying metabolic risk factors and severity of stone disease as recurrent stone formers.86 The basic evaluation includes measurement of serum sodium, potassium, chloride, bicarbonate, creatinine, calcium, phosphate and uric acid levels, urine analysis and culture (Table 59.1). A parathyroid hormone level should be measured if S[Ca] is elevated or even at the upper limit of normal, and if S[P] is decreased or even at the lower limit of normal. The presence of hypokalemia and metabolic acidosis may suggest the presence of renal tubular acidosis. Urinalysis might reveal crystals of uric acid, cystine, calcium oxalate, calcium phosphate or magnesium ammonium phosphate. The comprehensive evaluation includes all of the above and a 24-hour urine collection for assessment of urinary volume and ion excretion with the supersaturation calculated for the calcium oxalate, calcium phosphate and uric acid solid phases. Supersaturation of urine correlates well with stone composition87 and involves the measurement of urinary volume, pH, calcium, oxalate, citrate, uric acid, creatinine, sodium, potassium, magnesium, sulfate, phosphate, chloride and urine urea nitrogen (Table 59.2). Patients should

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TABLE 59.1  Basic Evaluation of Nephrolithiasis

Fluid Intake

Stone History Number of stones formed Frequency of stones formed Age at first onset Size of stones passed or still present Stone type, if known Side of kidney involved Need for urologic intervention Response to surgical procedures History and presence of urinary tract infections Medical History Medications Family History Occupation, Lifestyle Fluid Intake, Diet Physical Examination Laboratory Data Urine analysis Urine culture Stone analysis Blood Chemistry Sodium, Potassium, Chloride, Bicarbonate, Creatinine, Calcium, Phosphate, Uric Acid, iPTH Radiologic Evaluation KUB Helical CT IVU Ultrasound

Fluid intake resulting in a urine volume of more than 2 to 2.5 liters per day reduces the incidence of stone formation22,88 and is a mainstay of therapy for nephrolithiasis. Since the risk of stones is maximal at night when urine concentration is increased, patients should be encouraged to drink enough water to provoke nocturia and drink more fluid before returning to bed.2

TABLE 59.2  The Comprehensive Evaluation and Urinary Supersaturation OPTIMAL 24-HOUR URINE VALUES IN RECURRENT NEPHROLITHIASIS Urine volume >2.5 L Calcium <4 mg/kg or <300 mg in men and <250 mg in women ● Oxalate <40 mg ● Uric acid <800 mg in men and <750 mg in women ● Citrate >320 mg ● Sodium <3000 mg ● Phosphate <1100 mg

Dietary Salt Intake Urine calcium excretion parallels urinary sodium excretion.14 Patients limiting dietary salt intake to less than 2 g/day will reduce urinary supersaturation for calcium-containing stones.89

Dietary Protein Intake Consumption of animal protein is a risk factor for calcium as well as uric acid formation.90 The acid generated from this diet causes efflux of calcium from bone91 and increases filtered load of calcium. Reduced urinary citrate excretion92 and lowered calcium solubility because of the presence of sulfates from the acidic amino acids are the other lithogenic effects of such a diet.91 Reducing the protein content of the diet to 0.8 to 1.0 g/kg/day can reduce the risk of stone formation.24

● ●

URINE SUPERSATURATION VALUES Calcium oxalate supersaturation <5 Calcium phosphate supersaturation 0.5–2 ● Uric acid supersaturation 0–1 ● ●

collect urine on a typical day while eating a typical diet, and should be instructed appropriately to avoid overor under-collections.

GENERAL MEASURES TO PREVENT STONE RECURRENCE The goal of treatment is to lower urinary supersaturation as an undersaturated urine reliably predicts freedom from recurrence.2,5

Dietary Calcium Intake In the intestine dietary calcium binds dietary oxalate which leads to decreased oxalate absorption and a reduction in oxaluria.93 Thus patients on a low calcium diet have a significantly increased incidence of stone formation compared to patients on a normal calcium diet.24,94 This beneficial effect of dietary calcium is abrogated in women taking calcium supplements, likely because the supplement is often taken between meals and it generally rapidly dissolves, resulting in a bolus of calcium that is quickly absorbed, leading to increased urinary supersaturation.93,95 Although a low calcium, low oxalate diet can also reduce urine supersaturation with respect to calcium oxalate,13 given the risk of bone demineralization with this approach it should be avoided. It is currently recommended that most patients consume an age-appropriate calcium diet.95,96 The current recommendations regarding daily elemental calcium intake are 1000 mg for men aged 19 to 70 years and 1200 mg after age 71. For women it is 1000 mg from ages 19 to 50 years and 1200 mg after age 51.97

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Treatment of Specific Stone Types

TREATMENT OF SPECIFIC STONE TYPES Calcium Stones and Hypercalciuria Most calcium-based kidney stones are composed of calcium oxalate, but can amalgamate with calcium phosphate or uric acid. In addition to the increased risk associated with low fluid, high or low calcium intake, high sodium and high animal protein intake, the specific metabolic risk factors for development of calcium stones include hypercalciuria, hyperoxaluria, hyperuricosuria and renal tubular acidosis. Most causes of hypercalcemia (such as hyperparathyroidism, vitamin D intoxication, for example) can cause hypercalciuria because of the increased filtered load of calcium which is incompletely reabsorbed. Idiopathic hypercalciuria is defined as daily urinary calcium excretion exceeding 4 mg/kg or 250 mg in women and 275–300 mg in men, in the absence of a known cause. Although we set arbitrary levels for defining hypercalciuria, it is clear that stone formation is a continuous function of urine calcium excretion – the higher the urinary calcium, the greater the supersaturation of the urine and the greater the risk for stone formation. Idiopathic hypercalciuria results from a combination of excessive intestinal calcium absorption, decreased bone mineralization and/or reduced renal tubular calcium reabsorption.98,99 Idiopathic hypercalciuria is considered to be caused by a dysregulation of calcium transport at the major calcium transporting sites which include the intestine, the kidney and the bone. At least in a genetic strain of hypercalciuric stone-forming rats, it appears to be due to an excessive number of vitamin D receptors.98–101 At least one human study has shown an increased number of vitamin D receptors in the circulating monocytes of hypercalciuric stone-forming humans.102 Thiazide diuretics such as hydrochlorthiazide, chlorthalidone and indapamide can significantly decrease urinary calcium excretion and reduce the incidence of stone formation.103,104 Thiazides also may improve bone mineralization and reduce the risk of fractures.105 A S[K] should be checked within 7–10 days of starting thiazides. If the patient develops hypokalemia, supplementation with potassium citrate is appropriate. Alternatively, a potassium-sparing diuretic such as amiloride can be added to further reduce hypercalciuria.106

Hyperoxaluria Hyperoxaluria results from excessive dietary intake (dietary oxaluria), gastrointestinal disorders or surgery that leads to excess oxalate absorption (enteric oxaluria), or an enzyme deficiency that results in excessive

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TABLE 59.3 Foods High in Oxalate Vegetables Green beans Beets Green onions Leeks Leafy greens (spinach, Swiss chard, rhubarb, kale, collard greens, escarole, dandelion greens) Okra Peppers Rutabagas Fruits Elderberry Figs Strawberries Blueberries Raspberries Grains and starches

Buckwheat Wheat bran Rye or wheat crispbread Beverages Beer: dark, robust Cocoa Black tea Coffee: instant Legumes and nuts Almonds Peanuts Pistachios Pecans Hazelnuts Miscellaneous Chocolate Orange peel Lemon peel

production of oxalate (primary hyperoxaluria). Dietary oxaluria from oxalate-rich foods (Table 59.3) generally does not raise urinary oxalate above 60 to 80 mg/ day.107 Although most dietary oxalate is of plant origin, a high protein diet stimulates endogenous oxalate production. Dietary oxalate becomes even more important in patients on a low calcium diet, where the unbound oxalate is absorbed instead of precipitating with calcium in the intestine. Complex formation of intestinal oxalate with calcium supports the recommendation that patients with oxalate stones consume a normal calcium diet in addition to restricting high oxalate foods. Enteric oxaluria is a feature of patients with gastrointestinal disorders such as celiac disease, Crohn’s colitis, chronic pancreatitis, short bowel syndrome and following bariatric surgery, where the shortened bowel length allows excessive oxalate absorption. The urinary oxalate excretion in enteric hyperoxaluria is often greater than 60 mg/day (often more than 100 mg/day), which imparts a higher risk of nephrolithiasis.108 Enteric oxaluria is persistent and needs aggressive and lifelong therapy for the hyperoxaluria, acidosis, hypokalemia and hypocitraturia in this condition, not only to prevent nephrolithiasis but also to prevent the development and progression of CKD.109,110 Primary hyperoxaluria (PHO) results in excessive oxalate production that deposits in different tissues and causes cardiomyopathy, bone marrow suppression and renal failure at an early age. PHO arises from various genetic mutations of oxalate production by the liver.111 PHO type 1 (80% of the cases) is due to the defect in the gene encoding the hepatic enzyme alanine glyoxylate aminotransferase (AGT) involved in the conversion of glyoxylate to glycine. PHO type 2 (10% of cases) is due to a defect in the gene encoding the hepatic enzyme

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glyoxylate reductase/hydroxypyruvate reductase (GRHPR), involved in the conversion of glyoxylate to glycolate. PHO type 3 is due to a defect in the HOGA1 gene that encodes for the mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme, accounting for the remaining cases of PHO. In all these types, urinary oxalate is increased, often to more than 300 mg/day.112 Patients can present in childhood with nephrocalcinosis. Systemic deposition of oxalate in organs leads to renal failure, cardiac defects, joint immobility, gangrene and bone marrow suppression.111,112 Treatment of hyperoxaluria consists of restricting dietary oxalate intake, and using calcium carbonate with meals to bind oxalate in the intestine. To prevent the sequestration of calcium by fatty acids, the diet should also be low in fat. Cholestyramine is effective in binding oxalate, but its unpleasant taste limits its use.2 In patients with enteric oxaluria, treatment of the underlying malabsorption syndrome leads to reduced urinary oxalate secretion. The chronic diarrhea often associated with such colonic conditions leads to bicarbonate loss, hypokalemia, hypocitraturia, and hypomagnesemia, as well as low urine volumes and worsens the risk of nephrolithiasis. In such situations, treatment should also include increased fluid intake, potassium citrate and magnesium supplementation. The treatment of primary hyperoxaluria involves administration of high doses of pyridoxine and orthophosphate to reduce oxalate levels and inhibit urinary calcium oxalate precipitation.113 Treatment with both pyridoxine and orthophosphate improved renal survival from 20% to 74% at 20 years in patients with PHO type I and II.113 Liver transplantation to treat the enzyme deficiency is the definitive therapy for this condition,114 but combined kidney–liver transplant may be necessary if nephrocalcinosis has developed.115

Hypocitraturia Citrate is the most important inhibitor of calcium crystallization in the urine.116 Conditions that acidify the proximal tubule cell (such as renal tubular acidosis, chronic diarrhea, and hypokalemia) cause hypocitraturia. Other causes of hypocitraturia include high protein diets, exercise, infections, therapy with androgens, starvation and acetazolamide therapy. Although citrate excretion below a level of 320 mg/day/L of urine is defined as hypocitraturia, the risk of nephrolithiasis is a continuous function of urinary citrate concentration.117 Therapy involves dietary modification in the case of excessive protein intake, and treatment with potassium citrate118 or potassium-magnesium citrate.119 Both citrate formulations are efficacious in prevention of calcium stone formation, even in patients who do not have hypocitraturia.119 Patients with CKD should have S[K] monitored while on therapy.

Distal Renal Tubular Acidosis Patients with distal RTA have impaired excretion of hydrogen in the distal tubule, leading to a persistently high urine pH, metabolic acidosis, hypokalemia and hypocitraturia. The alkaline urine pH and the low citrate lead to a high likelihood for calcium phosphate precipitation. Nephrocalcinosis is common in this setting. Therapy involves administration of large doses of sodium and potassium citrate to treat the acidemia and hypokalemia.

Hyperuricosuria Hyperuricosuria is a risk factor for calcium stones in 10 to 15% of cases.120 The details of its causes, risk factors and therapy are discussed under uric acid stones.

Oxalobacter Formingenes Oxalobacter formingenes is an enteric bacterium that uses oxalate for energy. Patients colonized with the bacterium have lower urinary oxalate compared to those not colonized.121,122 Studies to show probiotic supplementation to increase colonization with O. formingenes would lead to reduction in urinary oxalate excretion are lacking.123 An interesting study suggests that the increased incidence of stones in industrialized nations may be explained by the reduced enteric O. formingenes colonization from substantial antibiotic use.124

Uric Acid Stones and Hyperuricosuria Hyperuricosuria refers to the increased excretion of both uric acid as well as sodium urate. Like citrate excretion in urine, hyperuricosuria is a continuous variable, and in addition to excess uric acid/urate production, the key factors influencing solubility of these substances in the urine are urine pH and urine volume. The most common cause of hyperuricosuria in patients with kidney stones is excessive dietary purine intake from animal proteins.125,126 Other causes include gout, uricosuric medications such as atorvastatin, amlodipine and losartan, and, less commonly, disorders of excess production such as myeloproliferative disorders, tumor lysis syndrome, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency or phosphoribosyl pyrophosphate (PRPP) excess. Urine pH is the major determinant of uric acid nephropathy. The solubility of uric acid increases sixfold with an increase in urine pH from 5.3 to 6.5.127 In a compilation of four studies, every patient with uric acid stones had a urine pH less than 6.128–131 Even when the total amount of uric acid being excreted is not above normal, a low urinary pH leads to the formation of uric acid which is poorly soluble as opposed to the

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Treatment of Specific Stone Types

TABLE 59.4 Foods High in Purines Organ meats: Sweetbreads, liver, kidney, brains, heart Shellfish Meat: Beef, pork, lamb, poultry Fish: Anchovies, sardines, herring, mackerel, cod, halibut, tuna, carp Meat extracts: Bouillon, broth, consommé, stock Gravies Vegetables: Asparagus, cauliflower, peas, spinach, mushrooms, lima beans, lentils

urate anion which is more soluble.127 A similar mechanism, where decreased ammoniagenesis leads to a lowered urine pH, is postulated to be the cause of uric acid stones in patients with type 2 diabetes, metabolic syndrome and chronic diarrhea.31,132 Uric acid stones are not radio-opaque and an ultrasound or an IVP may be needed to diagnose their presence. Treatment of uric acid stones involves alkalizing the urine, switching to a low animal protein diet, avoiding high purine foods (Table 59.4), increasing urine volume, and lowering uric acid production. Increasing urine volume by increasing consumption of water reduces recurrence of uric acid stones.22 Sufficient alkali should be prescribed to raise the urine pH above 6.5.133 Since there is no added benefit to raising the urine pH beyond 7.0, and there is a potential risk of forming calcium phosphate stones in alkaline urine, patients should be instructed to check their urine pH once a day and titrate their consumption of alkali to aim for a urine pH between 6.3 and 7.134 Increasing urine pH with potassium citrate or potassium bicarbonate can dissolve uric acid stones.135 In patients at risk for hyperkalemia, acetazolamide can be used instead of increasing potassium citrate therapy, to increase urinary bicarbonate excretion, urine pH and reduce the risk of uric acid stones.136 If patients continue to form uric acid stones, or excrete uric acid in excess of 1000 mg/day, allopurinol is recommended to decrease uric acid stone formation.137 Allopurinol reduces the incidence of calcium stones in hyperuricosuric patients.138 Allopurinol must be used with caution in patients of Han Chinese descent, who carry the HLA-B*5801 gene and have a high risk of cutaneous drug reactions.139,140

Calcium Phosphate Stones and Nephrocalcinosis Some calcium stones are predominantly composed of calcium phosphate. Typically these patients are hypercalciuric and their urine volumes and urine pH are higher than observed in calcium oxalate stone formers.141 The precise pathogenesis of such calcium phosphate stones is unclear, but the inciting event is thought to be renal tubular acidosis that can be incomplete (no evidence of acidemia on serum chemistry but patients

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TABLE 59.5 Infections Associated with Struvite Stone Formation (Urease-Producing Bacteria) Proteus Haemophilus Yersinia Staphylococcus epidermidis Pseudomonas Klebsiella Serratia Citrobacter Ureaplasma

cannot acidify urine if challenged with acid). In such cases, the urine pH stays above 6.1 and supersaturation of calcium phosphate is increased. Type 1 RTA is a dramatic example of this clinical scenario. Type 1 RTA can manifest as nephrocalcinosis, where there is extensive deposition of calcium phosphate within the renal parenchyma. Drugs such as acetazolamide or topiramate also produce a similar urinary chemical milieu that is conducive to calcium phosphate stone formation. Hyperphosphaturia is another risk factor that can lead to the development of calcium phosphate stones or nephrocalcinosis. Hyperphosphaturia contributes to stone formation in patients with hyperparathyroidism, vitamin D intoxication, tumor lysis syndrome, acute phosphate nephropathy after oral sodium phosphate bowel preparation, and inherited phosphate wasting disorders. Treatment consists of general measures as outlined above and therapy to lower urinary calcium with thiazides. Alkali supplementation may be beneficial if there is acidemia. However, care must be taken to ensure that the urine pH does not increase beyond 7.0, as that may worsen the supersaturation for calcium phosphate.

Struvite Stones Also referred to as triple phosphate stones, struvite stones are seen in urine colonized with urea splitting organisms, and are composed of magnesium ammonium phosphate (struvite) and hydrated calcium carbonate (apatite). Struvite stones are formed when urease-producing bacteria (Table 59.5) split urea and generate ammonia in alkaline urine. Under these conditions phosphate combines with ammonium, magnesium and calcium and leads to the formation of struvite. Untreated, struvite stones can grow rapidly and fill the renal collecting system, forming staghorn calculi. Women are more prone to forming such stones because of their increased risk of urinary tract infections.142 Other predisposing factors include patients with urinary catheters, neurogenic bladders, spinal cord lesions and anatomical abnormalities of the genitourinary tract. Infection with a urease-producing bacterium,

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59.  Nephrolithiasis and Chronic Kidney Disease

Cystine Stones About 1 to 2% of all kidney stones are composed of cystine. This genetic disorder of amino acid transport across the tubular membrane leads to reduced proximal tubular re-absorption of cystine from the filtrate and excess urine excretion of this relatively insoluble amino acid.149,150 Normally, the daily volume of urine is adequate to keep the typical urinary cystine excretion (approximately 50 mg/day) in solution. Patients with cystinuria produce 250 to 1000 mg of cystine daily, which is exceedingly difficult to keep in solution, resulting in crystal and stone formation.151 Cystine solubility rises markedly when urine pH is greater than 6.5. Because of their sulfur content, these stones are radioopaque and detected on CT scans. Cystine stones should be suspected in patients with staghorn calculi and visualization of the pathognomonic hexagonal crystals in urine (Figure 59.5) supports this diagnosis. Treatment is directed at increasing urine volume to 4 L/day, lowering urine sodium152 and dietary protein intake,153 urinary alkalinization with potassium bicarbonate or acetazolamide.136 Treatment with d-penicillamine6,154 or tiopronin155–157 forms soluble heterodimers

1400

ic Acid, mg/L

1200 1000 800

400

Ac

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ary

ric

0

1200 1000 800 600 400 200 0

id, m

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To tal U

alkaline urine, and large stones are very suggestive of struvite nephrolithiasis. Colony counts can be low, but speciation and sensitivities are necessary for diagnosis and treatment. If cultures are negative, a specific request should be made for Ureaplasma urealyticum, which exhibits fastidious growth on regular culture medium. Left untreated, struvite stones can cause sepsis or lead to ESRD, and thus require aggressive medical and surgical therapy.62 Early urological intervention is necessary for stone removal. Stones less than 2 cm may respond well to extracorporeal shock wave lithotripsy (ESWL). For larger stones, percutaneous lithotomy, with or without ESWL, is the preferred surgical intervention.143 Stone fragments should be cultured and bacteria-specific antibiotics used until urine cultures remain sterile for 3 consecutive months. Surveillance cultures should be continued for a year.144 Adjunctive medical therapies include urease inhibitors and chemolysis. Urease inhibitors such as acetohydroxamic acid are effective in inhibiting urease and can retard the growth of struvite stones and prevent new stone formation,145,146 but are limited by their side-effects and use in patients with renal failure. Chemolysis – the irrigation of the kidney through a nephrostomy tube or ureter with a solution used to dissolve the stones – is currently rarely used because of the significant severe side-effects.147,148 Chemolysis might only be useful in patients with residual disease that cannot be cleared surgically.

Undissociated Ur

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pH

FIGURE 59.5  Relationship between undissociated uric acid, total uric acid, and urinary pH The limit of solubility of undissociated uric acid is depicted by the dotted line (~100 mg/l). Two hypothetical urine pHs are considered (two arrows). At low urinary pH (e.g. 5.0), even a modest amount of total urinary uric acid will exceed its solubility. At high urine pH (e.g. 6.5), even massive hyperuricosuria is well tolerated. Source: Reproduced from Reference158 with permission.

with cysteine and thereby reduces the cystine available for crystallization. However, both drugs can produce similar side-effects of loss of taste, fever, proteinuria, serum sickness reactions, and even nephrotic syndrome. Thus, these drugs are added if stone formation continues despite use of conservative measures such as increasing fluids, dietary changes, and urinary alkalinization.

CONCLUSION Kidney stones are a cause of significant morbidity worldwide. After the initial stone episode a metabolic evaluation to search for the underlying causes is recommended in patients with risk factors such as a family history of kidney stones, history of bowel surgery or laboratory abnormalities that suggest other diagnoses. Most stones in the US are calcium-based. Kidney stones may lead to CKD, but because the incidence of recurrent stone formation decreases with progressive CKD, they may be under-recognized as a risk factor. Suggested dietary modifications include increasing fluid intake, reducing salt and animal protein intake and encouraging consumption of an age- and genderappropriate amount of calcium, preferably from dairy foods, and not supplements. Restriction of oxalaterich foods is also important to reduce recurrence rates.

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REFERENCES

Determination of urinary supersaturation and analysis of passed stones guide treatment. Measures to reduce urinary supersaturation are highly effective in lowering recurrent stone formation. Reduced urinary pH is found in most patients with uric acid stones and such patients benefit from an increase in urinary pH. Targeted medical therapy can be initiated once a metabolic abnormality is found. Medications used to prevent stone recurrence are well tolerated and highly effective. Thiazide diuretics are a cornerstone of therapy in patients who form calcium-containing kidney stones. Potassium citrate is also highly effective in reducing recurrent stone formation.

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