Molecular methods Direct detection and identi \201 cation, e.g. peptide nucleic acid \202 uorescence in situ hybridization (PNA FISH) for Candida spp. Polymerase chain reaction , although promis- ing for the diagnosis of IFI, has not been widely used. Fungal infections following renal transplantation Fungal infections remain a signi \201 ca nt challenge after trans- plantation. Their incidence varies according to the organ transpl anted. In renal transplant recipients an incidence of 1 \200\22314% has been reported and t hese infections are associated with a very high mortality. This is related to environmental expo- sure and the degree of immunosuppression. In an analysis of 850 renal transplant rec ipients from a terti- ary care center in North India, Gupta (2001) described fungal infecti ons in 83 patients (9.8%). These were candidia- sis in 25 (2.8%), cryptococcosis in 16 (1.9 %), aspergillosis in 20 (2.3%), zygomycosis in 17 (2.0%) and rare fungal infec- tions in \201 ve others including pheohyphomycosis in three and disseminated histoplasmosis in two p atients. The role of prophylaxis or pre-emptive therapy in subsets of solid organ transplan t patients is still being de \201 ned, but evidence supports the use of \202 uconazole p rophylaxis in liver transplant recipients. Emerging fungal pathogens may be resistant to co nven- tional antifungal agents, and speci \201 c microbiological diag- nosis is important. Combination therapy With the availability of antifungal agents acting on different targets in the fungal cell, the possibility of combination therapy exists. In vitro testing suggest s combination therapy (e.g. caspofun- gin + \202 uconazole or \202 ucytosine + amphoter icin) produces synergy which is particularly useful in dif \201 cult-to-treat infections s uch as scedosporiosis and aspergillosis as well as candidiasis and cryptococcosis. The drug management of various renal mycoses is described in Table 7.5.2. Surgery Surgical measures may also be necessary to treat the fungal balls as well as to rem ove infected tissue. Debulking of bezoars in patients with candidiasis and aspergillosis ma y be carried out by percutaneous nephros- tomy, endoscopic removal, or open pyelotomy. In a ddition, it may be combined with local irrigation with amphotericin B. CHAPTER 7.5 Fungal infections and the kidney 267 Immune therapy Adjunctive immune therapy with interferon- , granulocyte- macrophage colony -stimulating factor and granulocyte colony-stimulating factor can be considered for severe IFI refractory to conventional antifungal treatment. Table 7.5.2 Treatment of invasive fungal infections Infection Drugs and dosage Candiduriaa Fluconazole 200 mg/day (loading 400 mg) for 14 days Amphotericin B 0.3 \200\2230.7 mg/kg/day for 1 \200\2237 days Further reading Almyroudis NG, Sutton DA, Linden P, et al. Zygomycosis in solid organ trans plant recipients in a tertiary transplant center and review of the literature. Am J Transpl ant 2006; 6: 2365 \200\2232374. Candidemiaa/ invasive candidiasis Fluconazole 200 \200\223400 mg/day or Chayakulkeeree M, Ghannoum M, Perfect J. Zygomycosis: the re- emerging fungal infection. Eu r J Clin Microbiol Infect Dis 2006; 25: 215 \200\223229. Caspofungin 70 mg on day 1, 50 mg/day thereafter or Amphotericin B 0.5 \200\2231 mg/kg/day or Lipid- AmB 5 mg/kg/day Comments C. krusei, C. glabrata are \202 uconazole resistant; t reat with an echinocandin, voriconazole or posaconazole Chugh KS, Sakhuja V, Gupta KL, et al. Renal mucormycosis: compu- terized tomographic \201 ndings and their diagnostic signi \201 cance. Am J Kidney Dis 1993; 22: 393 \200\223397. Gabardi S, Kubiak DW, Chandraker AK, et al. Invasive fungal infec- tions and antifungal the rapies in solid organ transplant recipients. Transpl Int 2007; 20: 993 \200\2231015. Gupta KL. Fungal infectons and the kidney. Ind J Nephrol 2001; 11: Invasive aspergillosis Voriconazole 6 mg/kg IV \2272 doses, then 147 \200\223154. 4 mg/kg/day twice daily IV, can convert to 200 mg twice daily orally. Caspofungin 70 mg on day 1, 50 mg/day thereafter Amphotericin B 1 \200\2231.5 mg/kg/day or Lipid- AmB 5 mg/kg/da y Itraconazole 400 mg/day Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit. Clin Infect Dis 2007; 45: 205 \200\223216. Pappas PG, Rex JH, Sobel JD, et al. Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38: 161 \200\223189 [Revised in 2008: see j ournal website.] Pappu LD, Purohit DM, Bradford BF, et al. Primary renal candidiasis in two preterm neonates . Report of cases and review of literature on renal candidiasis in infancy. Am J Dis Child1 984; 138: 923 \200\223-926. Scheinfeld NA. Review of the new antifungals: posaconazole, mic afun- Fluconazole 200 \200\223400 mg/day or itraconazole 200 \200\223400 mg/day; or Lipid-AmB 5 m g/kg/day with \202 ucytosine 100 mg/kg/day for 2 weeks followed by \202 uconazole 400 m g/day Cryptococcosis gin, and anidulafungin. J Drugs Dermatol 2007; 6: 1249 \200\2231251. Internet resources Infectious Diseases Society of America. Guidelines for treatment of cand idiasis. 2008 update: Posaconazole 800 mg/day Lipid-AmB 5 \200\22315 mg/kg/day Zygomycosis www.idsociety.org/WorkArea/downloadasset. aspx?id=7818 Information about aspergillus and ap ergillo-sis: a Infectious Diseases Society of America (IDSA) published guidelines for the treatment of c andidiasis (2004). http://www.aspergillus.org.uk/ Information about human mycoses: For extensively damaged tissues in patients with angioinva- sive infections such as mucormy cosis, debridement and excision of the tissue (which may include nephrectomy) may be necess ary. http://www.doctorfungus.org/ See also Infection-related glomerulonephritis, p. 128 This page intentionally left blank 269 Chapter 8 Renal stone disease Chapter contents Medical management of stone disease 270 Surgical management of stone disease 274 Nephrocalc inosis 278 Renal stone disease in children 282 R. AL JAYYOUSI 270 Medical management of stone disease De \201 nition Nephrolithiasis is the formation of stones in the renal tubules or collecti ng system. Epidemiology and incidence The incidence of nephrolithiasis varies geographicall y. In industrialized nations the incidence is 1 in 1000. The peak age is the third decade and the prevalence is higher in men. A prevalence of 10% occurs in industrialized nations b ut is higher in areas such as the Middle East. The recurrence rate for nephrolithiasis rang es from 50 to 80%. Environmental factors \200 \200 \200 \200 \200 Occupation. Fluid intake. Diet. Exercise intensity. Urine volume. Drug history Drugs that may precipitate into stones \200 \200 \200 Triamterene. Aciclovir. Indinavir. Drugs that increase the risk of stone formation \200 \200 \200 \200 \200 \200 \200 \200 \200 Loop diuretics. Calcium and vitamin D supplements. Glucocorticoids. Antacids. Theophylline. Acetozalamide. Salicylates. Probenecid. Vitamin C. Etiology Stones form when the urinary concentration of the stone constituents rises above t he supersaturation level. The super- saturation level re \202 ects the product of free ion activities. It is not solely dependent on the concentration of consti- tuents but also on the presence of promoters and inhibitors of stone formation such as urine pH and citrate co ncentration. The common types of renal stones are listed in Table 8.1.1. Examination Physical examination should be undertaken to identify other possible causes for pain and hematuria. Table 8.1.1 Types of renal stones (listed in order of decreasing prevalence) Combination of calcium oxalate and calcium phosphate Calcium oxalate Struvite Calcium phosp hate Uric acid Cystine Investigations Following formation of a single stone Stone analysis If the stone is not cap tured ask the patient to sieve the urine to collect any remaining stone fragments. Urine analysis \200 \200 \200 Urine microscopy to identify crystals. Urine culture. Cystine concentration on a \200\230s pot \200\231 urine sample. Clinical presentation Pain is the commonest presenting feature. Stones passing through the renal pelvis or ureter cause colicky loin pain with or without radiation to the groin, test is or labia. Macroscopic or microscopic hematuria is a common \201 nd- ing but its absenc e does not exclude stone disease. Hematuria may occur with or without associated pain. Ston es can be an incidental finding in asymptomatic patients undergoing imaging for other reaso ns. Venous blood analysis \200 \200 \200 \200 \200 \200 Calcium. Parathyroid hormone (if hypercalcemic). Phosphate. Uric acid. Bicarbonate. Sodium, potassium, chloride, urea and creatinine. History Assessing risk factors \200 \200 \200 Table 8.1.2 Imaging techniques for the investigation of renal stones Age. Family history. History of stone disease (age at presentation, frequency, surgical his tory). History of urinary tract infections. History of neoplastic disease, sarcoidosis, end ocrine dis- ease (risk factors for hypercalcemia). Diseases of the gastrointestinal tract. Gout. Obesity. Diabetes mellitus. Noncontrast enhanced helical CT Highest speci \201 city and sensitivity. Investigation of choice at \201 rst presentatio n. \200 Plain KUB radiograph If history of radio-opaque stones. Intravenous urogram Time-consuming. In practice now used only if CT is not available. \200 \200 \200 Ultrasound Poor at detecting ureteric stones. Useful in pregnant patients and in detecting hydronephro sis. Use if cholecystitis or gynecological cause of pain is suspected. CHAPTER 8.1 Medical management of stone disease 271 Imaging The imaging modalities used in the evaluation of patients with suspected stone dise ase are listed in Table 8.1.2 and discussed in Chapter 1.6. Excess excretion of urinary calcium Idiopathic hypercalciuria This is commonly familial, af fects males more than females, and typically presents in the third decade of life. The mech anism of hypercalciuria is unclear but is likely to be a combination of increased intestina l absorption and abnormal handling of calcium by the kidney. Management: Advise the general management measures (Table 8.1.4) plus: Dietary: \200 Following the formation of second or multiple stones In addition to the above investigation s at least two 24 h urine collections \200\230on a normal day, on a normal diet \200\231 s hould be made to allow measurement of the items listed in Table 8.1.3. Table 8.1.3 Components to be measured in a 24 h urine collection in recurrent stone disease Restrict sodium intake to reduce renal calcium excre- tion. Maintain a normal calcium diet, but avoid additional cal- cium supplementation. There is no bene \201 t to restricting di etary calcium and this may lead to bone demineraliza- tion and reduce oxalate binding in th e gut leading to hyperoxaluria (see below). Pharmacological (Table 8.1.7): \200 Volume Calcium Usually requires an acid preservative Phosphate Oxalate Usually requires an acid preservative Uric acid Usually a plain or alkaline solution Long-acting thiazide (e.g. chlorthalidone 25 \200\22350 mg/day) to reduce urinary calcium e xcretion. Potassium supplements, potassium-sparing diuretic or potassium citrate to maintai n serum potassium at nor- mal levels and increase urinary citrate (use potassium citrate li quid or urocit-K wax tablet 20 \200\22340 mmol/day). Hypokalemia leads to intracellular aci dosis resulting in hypocitraturia. Oral potassium supplementation and a diet rich in fruit has been shown to increase urinary citrate excretion. Sodium Citrate Creatinine To ensure complete collection pH General management of stone disease The general principles of management that apply to all types of stone disease are listed in Table 8.1.4. The manage- ment of speci \201 c risk fa ctors and individual stone types is described in the remainder of this chapter. Hypercalcemic hypercalciuria The common causes are: \200 hyperparathyroidism; \200 gran ulomatous disease, e.g. sarcoidosis; \200 neoplastic disease; \200 lithium therapy. Management of calcium stone disease Several risk factors for calcium stone formation are dis- cussed in this section (Table 8.1 .5). Management: \200 \200 treat underlying cause; general stone prevention advice. Table 8.1.4 General advice for prevention of recurrent stone formation of all stone types Distal renal tubular acidosis This causes mainly calcium phosphate stone formation. Hyperca lciuria, hyperphosphaturia and high urinary pH leads to urinary calcium phosphate supersatu ration, and the metabolic acidosis causes hypocitraturia. Management: \200 Maintain sodium intake of <100 meq/day (5 g). Maintain urine output >2 L/day with drinking at bedtime to induce nocturia. Reduce animal protein intake. Encourage potassium intake. Re view medication use and where possible avoid drugs that increase risk of stone formation. Alkalinize the serum and when possible treat the under- lying cause of RTA. Avoid a urine p H >6.5 as this encourages calcium phos- phate precipitation. Table 8.1.5 Summary of risk factors for calcium stone formation Dent \200\231s disease (see Chapter 8.3) Hypercalciuria Renal tubular acidosis Hypocitraturia Hyperoxaluria Hyperuricosuria Decreased citrate excretion Citrate binds with urinary calcium forming a soluble com- plex which inhibits its crystallization. Metabolic acidosis results in an increase in citrate re ab- sorbtion and therefore hypocitraturia. Other causes include hypokalemia, hypomagnesemia , uri- nary tract infection, and acetozalamide therapy. In one study urinary potassium leve ls were the strongest predic- tor of urinary citrate levels. Most laboratories will not mea sure urinary citrate. However, in some patients no risk factors can be identi \201 ed. Management of these patie nts relies upon general stone prevention advice (Table 8.1.4). R. AL JAYYOUSI 272 Management \200 \200 reductase (GRHPR) respectively) which lead to increa- sed oxalate formation. Treatment is w ith pyridoxine and liver transplantation if multiple organ involvement occurs. Alkalinizati on of the urine and use of orthophos- phate (if GFR is well preserved) may reduce stone for mation. Ethylene glycol (EG) intoxication. EG is metabolized to glycolate, glyoxylate and o xalate. Its metabolism is cata- lyzed by alcohol dehydrogenase (AD) and other enzymes. Mana gement consists of urinary alkalinization to reduce the risk of stone formation, and preven tion of formation of EG metabolites by inhibition of AD using ethanol or fomepizol. Excessi ve intake of ascorbic acid which is oxidized to form oxalate. Reduce animal protein content of diet. Supplement with oral potassium citrate or bicarbonat e (Table 8.1.7). Hyperoxaluria Urinary oxalate excretion is normally 20% that of calcium excretion. Hyperox aluria increases the risk of calcium oxalate stone formation. However, these stones can for m and precipitate even in the absence of hyperoxaluria. Causes of hyperoxaluria Three causes of hyperoxaluria have been described. Dietary hyperoxaluria Management involves restricting dietary oxalate (Table 8.1.6) while m aintaining the balance between calcium and oxalate ultimately to reduce the urinary supersa turation of calcium oxalate. Restriction of dietary oxalate may reduce calcium binding in t he gut, leading to increased calcium absorption and hypercalciuria. Dietary oxalate should not therefore be restricted in the presence of a high calcium diet or calcium supplementati on. Restriction of dietary calcium is not recommended for the reasons discussed above. Ther e is some evidence to sug- gest that a high calcium diet in the absence of calcium sup- ple ments may reduce oxalate absorption from the gut, thereby reducing the risk of hyperoxaluri a. Usually, a nor- mal calcium diet is recommended. Hyperuricosuria Calcium stone formers are more likely to have increased urinary uric acid e xcretion. Furthermore, uric acid crystals can form a nidus for cal- cium oxalate crystal ag gregation. A reduction of the intake of dietary animal protein and the use of allopurinol r educes uric acid excretion and may reduce the risk of calcium stone formation. Uric acid stones Uric acid stones are radiolucent and therefore not detect- able on a plain KUB X-ray. Risk factors for stone formation are low urine volume, low urine pH, and a high urine uric acid concentration. Low urine volumes can be a feature of gastrointestinal dis- ease, for example in patients with a high output ileostomy. Uric acid solubility increases with rising pH. Increased levels of urinary uric acid can result from: \200 \200 \200 Table 8.1.6 Oxalate-rich foods High bioavailability of oxalate Moderate bioavailability of oxalate Spinach Peanuts gout; tumor lysis syndrome; inherited disorders of metabolism such as Lesch \200\223Nyhan s yndrome; high dietary purine intake from animal protein; drugs that increase urinary uric a cid excretion, e.g. sali- cylates. Rhubarb Instant tea Almonds Chocolate \200 Pecans Management \200 Enteric hyperoxaluria This is caused by excessive colonic absorption of oxalate. It is seen in disorders that result in fat malabsorption such as Crohn \200\231s disease, chronic pan creatitis and short bowel syndrome. Increased fatty acid delivery to the colon increases ox alate absorption. Malabsorption may also lead to reduced urine volume, hypokalemia and hypo citraturia, which will all promote stone formation. Management includes treating the underl ying cause, increasing dietary calcium (as part of the diet and not with additional supplem ents) to enhance oxalate bind- ing in the gut and reduce its absorption, and using pharmaco logical agents such as cholestyramine to bind fatty acids. Increase the fluid intake to increase urine volumes (>3 L/day). Reduce dietary animal prote in intake. Alkalinize the urine with bicarbonate or citrate aiming for a pH between 6 and 7 . Sodium salts should be avoided as the volume expansion will enhance sodium urinary excret ion and with it passive calcium excretion from the proximal tubule. Encourage patients to t est the urine pH at home. Allopurinol may be of bene \201 t (Table 8.1.7). \200 \200 Struvite stones (magnesium ammonium phosphate) These occur in patients with urine infection due to urea- splitting organisms (e.g. Proteus). The breakdown of urea generates excess am monium lead- ing to a rise in urinary pH. The excess ammonium and the reduction in phosphat e solubility caused by the increased urinary pH lead to an increase in the concentration of insoluble magnesium ammonium phosphate and stone formation. Increased systemic production of oxalate This can occur in several situations: \200 Primary hyperoxaluria I and II. These are inherited liver enzyme deficiencies (alanine-glyo xalate amino- transferase and glyoxylate reductase/hydroxypyruvate CHAPTER 8.1 Medical management of stone disease 273 Complications of nephrolithiasis \200 These stones can increase to a large size forming a staghorn calculus. Risk factors include female gender, indwelling urinary catheters, neurogenic bladder and alkaline urine. Occasi onally special culture medium is required to isolate urea-splitting organisms such as Mycop lasma and the lab will need to be alerted if this is suspected. Stones can lead to obstruction at the level of the pelviu- reteric junction (PUJ) or ureter causing hydronephrosis or pyonephrosis. Staghorn calculi increase the risk of urinary infe ction. Progressive renal failure may occur. A report from France suggests that 2.2% of pati ents on an end-stage renal dis- ease program had nephrolithiasis as the underlying cause. \200 Management \200 Struvite stones are dif \201 cult to eradicate. Any residual fragments form a nidus for ne w stone formation and make eradication of infection dif \201 cult. Surgical or percutaneou s nephrolithotomy may be required to remove the stones. Continuous cyclical antibiotic ther apy may be bene \201 cial. Urease inhibitors have not been useful clinically due to a high side-effect pro \201 le. Further reading Bushinsky D. Nephrolithiasis. J Am Soc Nephrol 1998; 9: 917 \200\223924. Do mprongkitchaiporn S, Sticharntrakul W, Kochakarn W. Causes of hypocitraturia in recurrent c alcium stone formers: focusing on urinary potassium excretion. Am J Kidney Dis 2006; 48: 54 6 \200\223554. \200 Goldfarb DS, Coe FL. The medical mangement of stone disease. 2005. In: Davison AM, Cameron JS, Grunfeld J-P, Kerr DNS, Ritz E, Winearls CG (eds), The Oxford textbook of nephrology, 3 rd edn. Oxford: Oxford University Press; 2005. pp. 1225 \200\2231242. Cystine stones Cystine stone disease presents typically in the fourth dec- ade in patients with cystinuria. This is a rare hereditary dis- order in which dibasic amino acid transport ation is impaired. The diagnosis is made by measuring the urine cystine con- centration on a \200\230spot \200\231 urine sample and then quantifying cystine excretion in a 24 h urin e collection. Heilberg I. Update on dietary recommendations and medical treatment of renal stone disease. Nephrol Dial Transplant 2000;15:117 \200\223123. Jungers P, Joly D, Barbey F, et al. ESRD caused by nephrolithiasis: prevalence, mechanisms, and prevention. Am J Kidney Dis 2004; 44: 799 \200\223805. Monk R, Bushinsky D. Nephrolithiasis and nephrocalcinosis. In: Johnson RJ, Feehally J (eds) , Comprehensive clinical nephrology, 3rd edn. Amsterdam: Elsevier; 2003. pp. 641 \200\22365 5. Management To keep cystine in solution the urine must be very dilute and alkaline. The trea tment therefore includes: \200 \200 \200 Pak C. Medical management of urinary stone disease. Nephron Clin Pract 2004; 98: c49 \200\223c53. maintaining very large urine volumes (>3 L/day); alkalinization of the urine; D-penicillami ne 250 mg to 2 g/day, or tiopronin (10- 40 mg/kg/day, max. 2 g/day) to reduce the urinary s uper- saturation of cystine (Table 8.1.7). Pak CY, Poindexter JR, Adams-Huet B, et al. Predictive value of kid- ney stone composition in the detection of metabolic abnormali- ties. Am J Med 2003; 115: 26 \200\22332. Tiselius H-G. Aetiological factors in stone formation. In: Davison AM, Cameron JS, Grunfeld J-P, Kerr DNS, Ritz E, Winearls CG (eds), The Oxford textbook of nephrology, 3rd edn. Oxfo rd: Oxford University Press; 2005. pp. 1199 \200\2231224. Table 8.1.7 Pharmacological agents used in the management of stone disease See also Imaging in renal disease, p. 20 Hypo-/hypercalcemia, p. 52 Renal tubular acidosis, p. 208 Uric acid and the kidney, p. 232 Surgical management of stone disease, p. 274 Nephr ocalcinosis, p. 278 Inherited disorders of purine metabolism and transportation, p. 636 Iso lated defects of tubular function, p. 200 Drug Indication/mode of action Thiazides or indapamide Reduce urinary calcium excretion. Potassium citrate Increase urinary citrate and urinary pH. Not advisable in the presence of urinary tract inf ection. Allopurinol Reduce uric acid formation. D-Penicillamine or tiopronin Bind cystine. P. BUTTERWORTH 274 Surgical management of stone disease Demographics and incidence Symptoms caused by urinary tract stone disease are com- mon. The estimated lifetime risk of a stone episode is 1 in 10 for men and 1 in 25 for women. The c osts associated with stones are considerable and in the USA in 1993 were estimated at $1.7 billion. Much of the cost is due to the fact that stone episodes tend to af \202 ict the m ost \201 nancially productive age groups with the peak incidence occurring in the 20s to 40s. There is no clear relationship between stone incidence and geography, but there is a r elationship between environ- mental temperature and stone episodes: the highest inci- dence of stone-related episodes occurs 2 months after the maximum mean annual temperature. Clinically, the risk factors for stone formation may be con- sidered as: \200 \200 congenital: cystinuria, medullary sponge kidney. malignant: hyperuricosuria following treat ment of malig- nancy, particularly myeloproliferative disorders. idiopathic: calcium oxalat e stones. metabolic: the hypercalciuria of hyperparathyroidism, hyperuricosuria. social: in adequate \202 uid intake, excess \202 uid losses partic- ularly bakers and foundry work ers. \200 Stone composition subtypes The common types of renal stones are listed in Table 8.2.1. Table 8.2.1 Stone composition subtypes Pathophysiology of stone formation Stone production and composition is dictated by environm ental factors, the anatomy of the urinary tract, and the constituents of the urine, and not by cellular processes. Three basic phenomena are critical to stone formation, irrespective of the composition of the stone: \200 Calcium oxalate ( calcium phosphate) 80% Struvite 6 \200\22314% Uric acid 5 \200\22310% Calcium phosphate and others 5% Cystine 1 \200\2232% Supersaturation of the urine In this situation urine has in solution the maxi- mum amount of dissolved solute. This is a re \202 ection of the product of free ion activities rather than the absolute molar conce ntrations, and the supersatura- tion level can be altered by stone promoters and inhibitors . Particle formation Calcium oxalate stones These are common stones and are radio-opaque. They form in associati on with: \200 \200 \200 hypercalciuria (idiopathic or with hypercalcemia); primary or secondary hyperoxaluria; hype ruricosuria and hypocitraturia. The addition of extra solute to the urine or changes in the contents of the urine may cause solute to pre- cipitate as crystals, a process known as nucleation. In urine, crystal nucl ei usually form on a surface, such as cell debris, casts or red blood cells. Struvite stones These are composed of a mixture of magnesium ammo- nium phosphate and calci um carbonate \200\223apatite. These almost always \201 ll the pelvicalyceal system to for m a staghorn stone. Urine infection with a urease-producing bacterium (e.g. Proteus, Klebie lla, Pseudomonas spp.) results in ammonia production and a urine pH of >7.2. This promotes the pre- cipitation of struvite. They can be potentially life-threatening because of septi- cemia if left untreated. Particle retention Individual crystals are small and cannot grow large enough to occlude tubules in the 5 \200 \2237 min it takes to pass into the renal pelvis. Aggregation of many indi- vidual crystals into a clump is required to produce a large enough particle to be retained by obstruction of a collecting duct. Promoters of stone formation include: \200 excess urinary solute caused by cystinuria, oxaluria, hypercalciuria, uricosuria; slow tubu lar transit for example in chronic volume depletion and medullary sponge kidney. Uric acid stones These are radiolucent stones. They have a strong geographical distribution . They are par- ticularly common in Israel. They are associated with the production of an a cidic urine (pH 5) and low urine volumes over prolonged periods. There is an association wi th the presence and therapy of myeloproliferative disorders in which nucleic acid conver- s ion to uric acid is increased. They may be dissolved in situ by alkalinizing the urine to a pH of 6.5 \200\2237.0. Inhibitors of stone formation include: \200 water diuresis which speeds tubular transit and prevents particle formation; citrate which binds with calcium to form a soluble com- pound which inhibits nucleation; magnesium which also inhibits crystal aggregation. Aggregated crystals/early stones may be seen during endo- scopic procedures in the pelvical yceal system. These aggre- gates develop beneath the epithelium on the tips of renal papill ae and are called Randall \200\231s plaques. Ulceration through the mucosa releases the sto ne into the pelvicalyc- eal system. Cystine stones Cystinuria is an autosomal recessive disease characterized by defective transportation of d ibasic amino acids (cystine, orni- thine, arginine and lysine). CHAPTER 8.2 Surgical management of stone disease 275 This defect leads to decreased cystine absorption from the intestine and reabsorption from the proximal tubule. Only homozygotes form cystine stones. Cystine is poorly soluble at nor mal urinary pH, but much more soluble at pH 7 \200\2238. Cystine stones are very hard and d o not respond to shock wave lithotripsy. are radiolucent and are not detected on plain \201 lms; radio-opaque stones in the middle third of the ureter may not be detectable against the background of the sacroiliac joint. Intravenous urogram (IVU). Historically this was the first-line investigation, but there ar e concerns about the nephrotoxic effects of the contrast and the potential for rare but fat al anaphylaxis in 0.9 per 100 000 cases. Noncontrast enhanced spiral CT scan. This is now t he standard of care. All stones (except indinavir stones) are detected by CT. Stones as sma ll as 1 mm dia- meter may be identi \201 ed. The presence of ureteric dilata- tion and/or perinephric stranding indicates ureteric obstruction. Clinical presentations Acute ureteric colic This presents with loin-to-groin colic with ass ociated nausea and vomiting. Dipstick urinalysis usually reveals evidence of nonvisible hem aturia. Urinary frequency and penile tip or clitoral pain may develop with stones impacted at the vesicoureteric junction. Principles of management Relief of pain The pain of acute ureteric colic is described by ma ny patients as the worst pain imaginable. NSAIDs work well. Administration by suppository a voids the dif \201 culty of administering oral drugs to nauseated patients. Parenteral opi ates and antiemetics may also be required. Hematuria Stone disease is a common cause of both visible and nonvisible hematuria. Althoug h usually associated with colicky pain, it may also be painless. Pyonephrosis This is suppuration within an obstructed pelvicaly- ceal system. This combinat ion of infection and obstruc- tion results in septicemia, usually with Gram-negative bacill i. Failure to relieve the obstruction begins to irreversibly damage nephrons within hours a nd a nonfunctioning kid- ney may result. Gram-negative septicemic shock is a life-threateni ng com- plication. Relief of obstruction The diagnostic imaging will indicate if the ureter or renal pelvis is obstructed. In the absence of infection a short period of obstruction (i.e. 2 \200\2234 we eks) probably does not result in permanent renal damage. In the presence of infection and o bstruction (pyonephro- sis) urgent relief of obstruction (within hours) is manda- tory. Ins ertion of a percutaneous nephrostomy under local anesthesia, or a ureteric stent under gene ral anesthesia (although it can be inserted under local anesthesia if neces- sary) are the initial treatment choices. Chronic loin pain Vague loin pain, which may occur in the absence of other urinary symptoms , may also be present. Relapsing urine infections Organisms may be found within the crystalline structure of some stones, especially struvite stones. Antibiotics eradicate the organisms that are free in th e urine, but penetrate the stone structure poorly. Therefore when the antibiotics are stopp ed, the urine is rapidly repopulated from organisms residing within the stone. Treatment of associated sepsis Where there is fever or other evidence of infection, antibi- otics should be used. The selected agent should have excellent activity against Gram-negat ive bacilli, including Pseudomonas spp., and for this reason gentamicin has traditionally b een used. This should, however, be avoided when there is renal impairment. The insertion of a nephrostomy to treat pyonephrosis is commonly followed shortly afterwards by profound se pti- cemia and this should be anticipated. Asymptomatic Stones may be identi \201 ed on imaging studies that are under- taken for oth er indications. Clinical assessment and investigation The evaluation of acute colic and chronic loin pain s hould include: The assessment of vital signs for evidence of fever, septi- cemia, and shock . Dipstick urinalysis for the urine pH, the presence of hema- turia, and evidence of infect ion (leukocyte esterase and nitrite). Measurement of full blood count, renal function, seru m calcium and uric acid. Culture of a midstream urine sample. Diagnostic imaging. The diagn osis of a ureteric stone can only be made by imaging. \200 Treatment of the stone The options available are: \200 conservative management with observation and analgesia; extracorporeal shock wave lithotrip sy; ureteroscopy and in situ fragmentation extraction of fragments usually using holmium laser energy; percutaneous nephrolithotomy for larger renal stones or stones in the proxim al ureter; open surgery; this is now rarely required, but the open techniques may now be re plicated by laparo scopic sur- geons and the future may see a growing role for laparo- scop ic ureterolithotomy and pyeloli thotomy. \200 Plain X-ray of the abdomen. This has little role in establishing the initial diagnosis. Uri c acid stones P. BUTTERWORTH 276 Stones \211 5 mm in diameter will pass in 68% of cases, and stones 5 \200\22310 mm in dia meter will pass in only 47% of cases. Treatment of stones in the pelvicalyceal system Chemical dissolution therapy for uric acid stones This can be achieved noninvasively using a combination of: \200 \200 Medical expulsive therapy -adrenoceptor blockers have recently been shown to increase the proportion of patients with ureteric stones who pass their stone spontaneously. The increa se in stone passage rate is 29%. Some studies also show a decrease in both the number of h ospital readmissions and interventions that are required. Most studies have restricted them selves to distal ureteric stones and it should be noted that the use of -blockers for thi s indication is not licensed. Patients who elect conservative observation or medical expuls ive therapy should have well-controlled pain and no evidence of sepsis. These patients shou ld be monitored with periodic imaging studies to monitor stone position, and to identify de velop- ing hydronephrosis or obstruction. high \202 uid intake (>2 \200\2232.5 L/day); urine alkalinization using potassium citrate 6 \200\22310 mmol 2 \200\2233 times a day to achieve a urine pH of >6.5; allopurinol 300 m g/day (particularly if urinary urate excretion is >1000 mg (6 mmol)/day). Alternatively percutaneous dissolution can be achieved by the infusion of an alkaline solut ion (e.g. trihydroxymethyl aminomethan (THAM)) through a percutaneous nephros- tomy. To pre vent either the chemolysis solution draining into the bladder, or an increase in intrarenal pressure, a second nephrostomy tube is usually required for drainage of the irrigation \202 uid. Extracorporeal shock wave lithotripsy (ESWL) Fragmentation of stones needs to be followed b y clearance of the fragments. The likelihood of fragment clearance is determined by the pel vicalyceal anatomy. A dependent calyx with a long infundibulum may retain fragments which t hen form a nidus for further stone for- mation. The passage of multiple large fragments may obstruct the ureter as a Steinstrasse or \200\230stone street \200\231. For stones >2 cm diameter a ureteric stent should be placed prior to ESWL to prevent this complication. Management of ureteric obstruction Persistent or marked obstruction with gross hydronephro- sis warrants intervention. Obstruction may be relieved by insertion of a percutane- ous ne phrostomy under radiological guidance, or by inser- tion of a ureteric stent. The nephrosto my drains an obstructed system more reli- ably, but necessitates an external drainage bag. Ureteric stents drain internally but give rise to lower uri- nary symptoms of frequency and urgency. Flexible ureterorenoscopy and in situ laser lithotripsy The \202 exible ureteroscope can carry a \202 exible laser \201 ber to a stone in any part of the collecting system. Lit hotripsy by contact with holmium laser energy is very effective but the technique is limite d by the very small size of the instruments (200 m diameter laser \201 ber) and the vie w down the ureteroscope which is obscured by even trivial bleeding. Ureteric stone removal This is indicated in the presence of persistent obstruction, failure of stone progression, or recurrent or uncontrolled pain. ESWL and ureteroscopy are both ac ceptable \201 rst-line treatments for ureteric stones. The success rates for each treatme nt modality are listed in Table 8.2.2. Ureteroscopy is associated with a higher stone-free rate after a single treatment in all cases except for larger stones in the proximal one-thi rd of the ureter. However, this advantage comes at the cost of greater risks of ureteric in jury and sepsis, and the requirement for anesthesia. Use of ESWL for stones in the middle t hird of the ureter may be restricted by the bones of the pelvis which prevent penetration o f the shock wave. Percutaneous nephrolithotomy A sheath is delivered into the pelvicalyceal system through th e skin of the loin via the renal parenchyma. The stone is removed under direct vision using instruments passed down the sheath. The main complications relate to the puncture and incl ude hemorrhage, which rarely requires embolization of the kidney or even emergency nephrect omy, and septicemia. Excellent stone-free rates are achievable, but other less invasive tec hniques may subsequently be required to treat residual fragments ( \200\230sandwich therapy \200\231). Ureterolithotomy Open ureterolithotomy should be required only rarely. A small number of se ries describe good results when laparoscopic ureterolithotomy is used to treat large impact ed stones in the proximal ureter. Treatment of ureteric stones In ureteric colic, encouraging patients to drink plenty of \202 uid to induce a forced diuresis is of no bene \201 t. An increased urine output reduc es the rate of ureteric peristalsis, which is the mechanism by which stones are expelled. A s obstruction of the ureter becomes chronic (>18 h), afferent arteriolar vasoconstriction c auses a decrease in glomerular \201 ltration and effectively diverts urine produc- tion t o the contralateral kidney. Table 8.2.2 Stone-free rate after single treatment for ureteric stone ESWL Ureteroscopy Proximal Mid-ureter Distal ureter 82% 73% 74% 87% 86% 94% Conservative, observational management Many ureteric stones may be safely left to pass spon taneously. CHAPTER 8.2 Surgical management of stone disease 277 Prevention of recurrence In high risk patients or recurrent stone-formers a formal metaboli c screen may be useful. Identi \201 cation of the likely stone composition can facilitate targeted therapy. This involves analysis of a 24 h urine collection for volume, and the qua ntity of calcium, oxalate, phosphate, uric acid and sodium (and citrate if available). A sp ot urine test for the presence of cystine (followed by a 24 h collection for cystine excret ion if the spot urine is positive) should also be undertaken. The composition of the stone should also be analyzed when possible. In all cases and irrespective of the stone subtypes, mainte- nance of a large output of dilute urine (minimum 2 L, ide- ally more) is the most important intervention. This should also include drinking at bed-time to induce nocturia.