We Can Rebuild It: Reconstructive Solutions for Structural Urologic Diseases Newaj M. Abdullah and Yegappan Lakshmanan Bladder augmentation and urinary diversion have become standard of care as surgical treatments for structural and functional disorders affecting the bladder, both in children and adults. With improved medical care, long-term survival of these patients is expected. Common medical problems that can occur such as metabolic side effects including acid-base imbalances and nutritional issues need to be anticipated and addressed. In addition, surgical problems caused by impaired urinary drainage, namely stones and urinary tract infections, and mechanical factors related to catheterizable channels and continence also may compound postoperative management. The risk of malignancy after bladder augmentation and substitution, and appropriate surveillance for this, remains to be clearly defined. Q 2015 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Bladder, Augmentation, Urinary diversion, Metabolic complications
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econstructive surgery is needed after bladder extirpation for either congenital conditions or acquired bladder abnormalities. Pediatric conditions such as myelomeningocele or exstrophy affect the structure and function of the bladder, threatening kidney function. This requires pre-emptive medical management from birth, and often these children require surgical remedies including bladder rehabilitation with augmentation or complete replacement. In adults, oncologic indications for removal of the bladder include both muscle invasive bladder cancer and recurrent nonmuscle invasive bladder cancer refractory to conservative treatment.1 Children may also need radical cystectomy for malignancies, such as rhabdomyosarcoma. In addition, other nononcologic causes may occasionally result in the removal of the bladder and, consequently, a urinary diversion, such as severe neuropathic bladder, treatment refractory overactive bladder, interstitial cystitis, radiation cystitis, and tuberculosis.1 SURGICAL APPROACHES Broadly, reconstruction of the bladder includes augmentation and urinary diversions. In benign conditions with at least part of the bladder available, its capacity can be enlarged (augmentation enterocystoplasty) using a bowel segment. If the bladder is unsuitable for use or has to be removed, as in malignancies, urinary diversion is necessary, which can be either an incontinent or a continent type. In incontinent urinary diversions, urine is diverted to a reservoir constructed from a bowel segment, and the bowel segment is then attached to the body wall for the urine to drain into an external collecting system. In contrast, in continent urinary diversions, urine is collected into a reservoir (neobladder) created from intestine. From Department of Pediatric Urology, Children’s Hospital of Michigan, Detroit, MI. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Yegappan Lakshmanan, MD, FAAP, FRCSEd, Department of Pediatric Urology, Children’s Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201-2119. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.04.007
320
Both bladder augmentation and continent diversion require a channel to empty the bladder at periodic intervals and a continence mechanism. If the native urethra is available and usable, the augmented bladder or continent diversion can be emptied through the urethra by intermittent catheterization or rarely by volitional voiding. A bladder made entirely of bowel and attached to the native urethra is termed an “orthotopic neobladder.” When the urethra is unavailable or has been removed, a catheterizable channel can be created using a tubular structure such as the appendix (Mitrofanoff principle).2 Alternatives to the appendix include ureter, fallopian tube, or tubularized segments of small or large bowel.3 The latter procedure involves isolating a 2-cm segment of bowel, opening it on its antimesenteric border and reconfiguring it lengthwise over a catheter, thus creating an “appendix” (Monti technique).3 These catheterizable channels connect the augmented or neobladder to the abdominal wall, where they are hidden in the umbilicus or a fold of skin in the lower abdominal wall. To prevent urinary leak through the channel, an antireflux mechanism is also created by plicating it within the bowel or bladder wall. The above principles can be used in various combinations, and several excellent surgical techniques have evolved over the years, allowing the urological surgeon to choose the appropriate bladder reconstruction to suit the individual needs of any patient. There is an ongoing debate concerning the optimal type of urinary diversion after bladder removal. Various factors including disease stage; patient age, gender, and socioeconomic status; kidney and hepatic function; availability of healthy bowel; adequate sphincter function; and even surgeons’ experience all play an important role in the clinical decision making.4 With advancement of surgical technique, improved safety profile, and increased number of skilled surgeons, urinary diversion has become the standard treatment for many structural and functional bladder disorders.4 Despite widespread utilization in the past years, urinary diversions are not a benign reconstructive effort. Depending on the bowel segment used to construct the diversion, patients may confront long-term metabolic complications including acid-base and electrolyte abnormalities, bone demineralization, increased urolithiasis, altered
Advances in Chronic Kidney Disease, Vol 22, No 4 (July), 2015: pp 320-324
Reconstructive Solutions for Structural Urologic Diseases
absorptive capacity, and deterioration of kidney function.5 With increased utilization and survival after urinary diversion, it is likely that such long-term complications will be more frequently encountered.4-6 Keeping this in mind, the goal of this review is to provide an overview of metabolic abnormalities, their causes, evaluation, and management. The focus of the discussion is from the perspective of nephrologists and internists who will often be faced with managing these patients chronically in the outpatient setting and acutely during hospitalization for this or unrelated issues.
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believed that the acid-base and electrolyte abnormalities are because of leaky intercellular junctions in the jejunum.6 Patients who have had urinary reconstruction with a segment of jejunum may develop the “jejunal conduit syndrome.” In this setting, patients are acutely ill with evidence of volume depletion likely from urinary losses of sodium, chloride, and bicarbonate. Laboratory data are often notable for hyponatremia, a nonanion gap acidosis, hyperkalemia, and evidence of acute kidney injury. The hyponatremia occurs from volume depletion, oral fluid intake, and appropriate ADH release. In the urologic literature, a “hypochloremic” metabolic acidosis is often described; however, the hypochloremia METABOLIC ABNORMALITIES is seen in concert with hyponatremia and does not repreMetabolic abnormalities are common in both continent sent an anion gap acidosis. Hyperkalemia is also and incontinent type of diversions. The extent of metabolic commonly seen, particularly in patients with reduced abnormalities depends on a number of factors including kidney function at baseline. The constellation of abnortype and length of bowel segment used and the length of malities seen in the jejunal conduit syndrome improve time that urine is in contact with bowel.6 Virtually, all types with administration of saline and are subsequently of bowel segments can be used in urinary diversions, with managed with oral sodium chloride or sodium bicarbonileum and colon being the most commonly used ate supplements often indefinitely.6,9-11 segments.6 The most commonly used bowel segments for urinary diAcid-Base and Electrolyte Abnormalities versions are terminal ileum and colon, both of which may lead to a nonanion gap metabolic acidosis.6,12 In elegant Acid-base and electrolyte abnormalities after urinary studies first using dogs diversion depend on the with interposition of bowel segment used. StomCLINICAL SUMMARY ileum in 1 ureter and then ach and jejunum can be kinetic studies using used for bladder augmenta Use of bowel segments in bladder replacement or sheets of enterocytes, tion or urinary diversion,4,6 augmentation are accompanied by a variety of metabolic yet both these bowel McDougal and others and acid-base side-effects. have clarified the segments are considered secondary options because pathophysiology of the The metabolic problems are specific to the type of bowel they tend to produce more metabolic acidosis that segment used in reconstruction. may occur in the setting severe acid-base and electro These abnormalities are well recognized, and can be lyte disorders.4,6 Indications of urinary diversion to an effectively treated when diagnosed early. for using stomach or intestinal segment.13,14 Ammonium produced by jejunum include radiation the kidney, which has a exposure to the bowel, similar ionic radius to Na1, competitively inhibits the presence of adhesions limiting surgical exposure, and Na1/H1 antiporter, sodium-hydrogen exchanger 3, that inflammatory bowel disease.4,6 is expressed on the apical membrane of the enterocytes. Use of stomach segments has some advantages because the gastric mucosa produces less mucus than more distal In addition, bicarbonate is lost in the urine in exchange bowel segments and is less permeable to urinary solutes, for chloride through the Cl2/HCO3– antiporter.13,14 The net result is an increase in ammonium chloride but severe dysuria and hematuria may occur. This complireabsorption, and this leads to a nonanion gap metabolic cation has led to a significant decrease in use of stomach for acidosis.12,14,15 lower urinary tract reconstruction in recent years. Urinary Most individuals with urinary diversion will not have diversion with stomach can produce a metabolic alkalosis significant metabolic abnormalities, and current series from secretion of HCl into the urine by the parietal cells suggest that only approximately 10% of patients exhibit through the H1/K1 ATPase antiporter, which leads to acid-base and metabolic abnormalities.6,11 In general, renal wasting of potassium and hypokalemia.6,7 continent urinary diversions lead to a greater degree of Treatment with H2 blockers and proton pump inhibitors has considerably improved outcomes for patients who metabolic derangement than incontinent urinary have had gastrocystoplasty or reconstruction of the diversions. For example, ileal and colonic incontinent diversions have a 10% to 15% risk of acid-base abnormalurinary tract using stomach such that use of this tissue remains an option if other surgical strategies cannot ities, whereas continent diversions may produce these abbe used.8 normalities in up to 45% of patients.11 This is primarily because of the increased contact time between urine and Jejunum can also be used in incontinent urinary diversion although this segment is very rarely used because of the bowel reservoir in continent diversions.6,11 4,6 Medical practitioners caring for this special population severe metabolic complications that may ensue. The must recognize that the signs and symptoms of acid-base exact mechanism of electrolyte abnormalities from and electrolyte abnormalities are nonspecific and can be jejunal segments is not well understood; however, it is
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Ileum, colon
Jejunum
Abbreviations: cAMP, cyclic adenosine monophosphate; NHE3, sodium-hydrogen exchanger 3. *Transporters noted are on luminal membrane of bowel segment. †Hyponatremia, volume depletion, hyperkalemia and acute kidney injury reported as part of jejunal conduit syndrome.
Most commonly used segments Ileum may reabsorb K1 and offset losses, colon less likely to do so B12 deficiency may occur if significant terminal ileum removed Oral NaHCO3 Sodium or potassium citrate Chlorpromazine and nicotinic acid (inhibition of cAMP activity of NHE3) Hyperchloremic (nonanion gap) metabolic acidosis 1/2 Hypokalemia
Hypovolemia† Hyponatremia Nonanion gap metabolic acidosis Hyperkalemia (more common in CKD or volume depletion)
Stomach is impermeable to solutes and produces less mucus; but acid can also cause hematuria, severe dysuria Rarely used because of volume and electrolyte complications in large percentage of patients Proton pump inhibitor H2 blockers KCl repletion Repletion of NaCl Correction of metabolic acidosis Metabolic alkalosis Renal potassium wasting
Secretion of HCl by parietal cells H1/K1 ATPase antiporter and luminal Cl2 channel Secretion of Na1 and Cl2 and HCO2 3 Transporters responsible for these changes have not been characterized in this setting Absorption of NH41 and Cl2 Secretion of K1 and HCO2 3 Absorption of NH41 in lieu of 1 1 1 Na via Na /H ATPase 2 And HCO2 3 loss/Cl gain via Cl2/HCO2 antiporter 3 Secretion of K1 (mechanism unclear) Stomach
Treatment Strategies Metabolic Complication Pathogenesis* Bowel Segment
Table 1. Metabolic Complications Associated With Urinary Diversion
Additional Notes
Abdullah and Lakshmanan
missed if caregivers are not aware of these potential complications (Table 1). Metabolic acidosis may manifest as easy fatigability, anorexia, polydipsia, and lethargy.6,7,11 Treatment of metabolic acidosis is important, both to relieve symptoms and to limit resultant complications including stunted growth in children, altered bone metabolism, and potential progression of CKD. Alkalinization is usually achieved with sodium bicarbonate, sodium citrate, citric acid, or combined potassium and sodium citrate.6,7,11 The latter option can also help address a concomitant potassium deficit. Alternative options for the treatment of the metabolic acidosis include chlorpromazine and nicotinic acid. These agents have been used successfully in some patients in whom sodium or potassium supplements cannot be tolerated or are undesirable.11 Both agents are known to inhibit the production of cyclic adenosine monophosphate, and by doing so, it is thought that these agents can block the activity of sodium-hydrogen exchanger 3 and, therefore, blunt the absorption of ammonium.11,16 It is also worth noting that the removal of significant lengths of bowel segments may decrease absorption of dietary magnesium and result in hypomagnesemia. This can lead to cardiac arrhythmias, tremor, tetany, and seizures and can be treated with magnesium replacement.11 Bone Demineralization A worrisome potential long-term effect of urinary diversion to intestinal segments is bone demineralization. Historically, this presented as rickets in children, but fortunately, this severe form of bone demineralization is rare in the current era. Nevertheless, attention to growth and normal bone development is still an important aspect of care. In adults, osteomalacia can occur as bone mineral is lost and replaced by osteoid, resulting in decreased bone strength.6,17 The pathophysiology is complex, but longstanding metabolic acidosis is likely the major contributory factor.11 In the setting of chronic acidosis, bone carbonate and phosphate buffer excess hydrogen ions and release calcium into the circulation, which is then cleared by the kidney, thus decreasing skeletal calcium content.11,17 Chronic acidosis may also activate osteoclasts, resulting in bone resorption.11 Finally, poor intestinal absorption of calcium and vitamin D may occur after ileal resection further affecting healthy bone formation.11 A recent population-based study showed that patients with urinary diversion are at 21% greater risk of fracture compared with normal healthy counterparts.18 Because urinary diversions are more common in older individuals, who may already have decreased bone density, it is important for their physicians pay careful attention to this issue.6,11 Patients who present with osteomalacia and have evidence of a metabolic acidosis should have taken sufficient alkali to improve their serum bicarbonate to limit further demineralization. In addition, patients should have sufficient vitamin D levels and ageappropriate dietary calcium or calcium supplements.6 Vitamin B12 Deficiency Vitamin B12 is absorbed in the terminal ileum.6,11 Thus, the use of ileum and, to a lesser degree, the ileocecal segment,
Reconstructive Solutions for Structural Urologic Diseases
for urinary diversion, may lead to chronic vitamin B12 deficiency in some patients.11 Chronic vitamin B12 deficiency is insidious and may result in irreversible neurologic and hematologic sequelae.6,11 The absolute prevalence and clinical significance of this entity in urinary diversion are undetermined.19,20 Some investigators report that routine administration of vitamin B12 every 6 months prevents vitamin B12 deficiency in all patients at 10-year follow-up.19 It is also worth noting that laboratory measurement of B12 levels is unreliable, although very low levels usually do reflect B12 deficiency. Instead, measurement of homocysteine levels and methylmalonic acid is more reliable. These levels are typically high in B12 deficiency and return to normal promptly with treatment.21 The merits of monitoring vitamin B12 levels versus routine long-term supplementation may be debated from a cost and practical standpoint.6,11 However, as survival after treatment for bladder disorders steadily improves and the number of patients with continent urinary diversion increases, this issue may assume greater importance.1,20,22 Disorders of Hepatic Metabolism When intestine is used in urinary diversion, absorption of ammonia into the portal circulation increases because of the increased load of ammonia from the urine.6,11,23 Under normal circumstance, the liver clears the increased ammonia load without significant alteration in serum ammonia levels. This hepatic reserve for ammonia clearance is great, and it is unlikely that acute changes in ammonia loads result in significant alteration in serum ammonia level when hepatic function is normal.11,23 However, advanced liver disease or small amount of endotoxin can significantly limit hepatic metabolism and transport.11,23 Hyperammonemic encephalopathy has been reported most commonly in patients with ureterosigmoidostomy.24 In addition, patients with normal liver function but a urease-producing bacterium can develop encephalopathy from elevated ammonia levels when the filtered urea is converted to ammonium, and this is reabsorbed, as outlined earlier.11 Often, the infection is associated with obstruction of the urinary tract.11,25 In patients with bowel augmentation, urinary infection provides direct access of bacteria and endotoxin to the liver through the portal circulation leading to altered hepatic metabolism without significant alterations in hepatic enzyme concentrations.11,24,25 Abnormal Drug Metabolism Drugs secreted unchanged in the urine and absorbed by the intestinal tract may cause additional issues.6,11 Chemotherapeutic agents are of particular interest as these are commonly used in the treatment of bladder cancer.11 Methotrexate toxicity in patients with ileal conduit is well recognized.26,27 Patients with continent diversion who are receiving chemotherapy should be monitored closely and should stay well hydrated.6,11 Additionally, the reservoir should be drained during treatment to reduce contact time between the therapeutic agent and the reservoir wall. Other drugs reported to be
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absorbed from intestinal segment in the urinary tract include phenytoin, theophylline, and antibiotics.11,27 Individuals with diabetes mellitus appear to have an enhanced ability to absorb glucose from the intestinal reservoir; therefore, screening with urine test may be inaccurate in this population.28 Surveillance of patients with diabetes should rely on blood test results. Bladder Stones Incorporation of bowel in the bladder predisposes patients to a high risk of stone formation because of mucus production, altered urinary pH, stasis, and infection.6,11,29 The stones are predominantly struvite, and the incidence varies from 3% to 50%, depending on the bowel segments used and the type of drainage mechanism.29 Stones rarely form in the acid milieu in gastrocystoplasty, except uric acid calculi, but are more frequent after ileocystoplasty.11 Stones are also much less frequent in those voiding per urethra, compared with those catheterizing through a channel in the umbilicus (against gravity), or when a bladder neck procedure has been performed.30 Recurrent urinary tract infections with urea-splitting bacteria, such as Proteus mirabilis, have been implicated, with the risk compounded by stasis of mucus.6 Therefore, daily bladder irrigation is used to reduce the incidence of stones.11 In addition, the use of bladder instillation with acetylcysteine has been reported to decrease mucus and stones.11,31 The risk is highest in the first 2 years after the reconstructive surgery, and regular follow-up with ultrasound studies is indicated. Risk for Malignancy The high incidence of malignancy after ureterosigmoidostomy is well recognized. This occurs after a long latency and is thought to be because of mixing of the urinary and fecal streams and production of N-nitroso compounds.32 These compounds are also noted in urine after augmentation and diversion.32 In addition, animal models have shown hyperplasia, particularly in the transitional zones after augmentation. In humans, the risk of malignancy varies with the type of intestinal segment used.32 Although gastrocystoplasty seems to carry a higher risk of malignancy, the incidence of tumors with ileum or colon appears to be no higher than those occurring in congenitally abnormal bladders.32 For this reason, some have recommended surveillance with periodic cystoscopy and urinary cytology starting 10 to 15 years after bladder reconstruction.32 Nevertheless, no demonstrable benefit for this approach has been forthcoming with mediumterm follow-up.33 CONCLUSIONS With advancement in surgical technique and safety profile, urinary diversions are commonly used for reconstruction of the urinary system. Additionally, as survival after treatment for bladder cancer steadily improves, the number of patients with urinary diversions is increasing. As a result, the next generation of health care providers will encounter more patients with urinary diversions and need to be familiar with the long-term metabolic complications to appropriately manage them.
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REFERENCES 1. Cody JD, Nabi G, Dublin N, et al. Urinary diversion and bladder reconstruction/replacement using intestinal segments for intractable incontinence or after cystectomy. Cochrane Database Syst Rev. 2012;2:CD003306. 2. Mitrofanoff P. Trans-appendicular continent cystostomy in the management of the neurogenic bladder. Chir Pediatr. 1980;21(4):297-305. 3. Monti PR, Lara RC, Dutra MA, Carvalho JR. New techniques for construction of efferent conduits based on the Mitrofanoff principle. Urology. 1997;49(1):112-115. 4. Parekh DJ, Donat SM. Urinary diversion: options, patient selection and outcomes. Semin Oncol. 2007;34(2):98-109. 5. Cruz DN, Huot SJ. Metabolic complications of urinary diversions: an overview. Am J Med. 1997;102(5):477-483. 6. Jacobsen NB, Koch M. Metabolic complications of urologic surgery. In: Taneja S, ed. Complications of Urologic Surgery. Philedelphia, PA: Saunders Elsevier; 2010:45-56. 7. Gosalbez R Jr, Woodward JR, Broecker BH, Warshaw B. Metabolic complications of the use of stomach for urinary reconstruction. J Urol. 1993;150(2 Pt 2):710-712. 8. DeFoor W, Minevich E, Reeves D, Tackett L, Wacksman J, Sheldon C. Gastrocystoplasty: long-term follow-up. J Urol. 2003;170(2):1647-1650. 9. Golimbu M, Morales P. Electrolyte disturbances in jejunal urinary diversion. J Urol. 1993;1(5):432-438. 10. Fontaine E, Barthelemy Y, Houlgatte A, Chartier E, Beurton D. Twenty-year experience with jejunal conduits. Urology. 1997;50(2):207-213. 11. Hautmann RE, Abol-Enein H, Hafez K, et al. Urinary diversion. Urology. 2007;69(1A):17-49. 12. Mills RD, Studer UE. Metabolic consequences of continent urinary diversion. J Urol. 1999;161(4):1057-1066. 13. Koch MO, McDougal WS. The pathophysiology of hyperchloremic metabolic acidosis after urinary diversion through intestinal segments. Surgery. 1985;98(3):561-570. 14. Stampfer DS, McDougal WS. Inhibition of the sodium/hydrogen antiport by ammonium ion. J Urol. 1997;157(1):362-365. 15. McDougal WS, Stampfer DS, Kirley S, Bennett PM, Lin CW. Intestinal ammonium transport by ammonium and hydrogen exchange. J Am Coll Surg. 1995;181(3):241-248. 16. Koch MO, McDougal WS. Nicotinic acid: treatment for the hyperchloremic acidosis following urinary diversion through intestinal segments. J Urol. 1985;134(1):162-164. 17. Siklos P, Davie M, Jung RT, Chalmers TM. Osteomalacia in ureterosigmoidostomy: healing by correction of acidosis. Br J Urol. 1980;52(1):61-62.
18. Gupta A, Atoria CL, Ehdaie B, et al. Risk of fracture after radical cystectomy and urinary diversion for bladder cancer. J Clin Oncol. 2014;32(29):3291-3298. 19. McDougal WS. Metabolic complications of urinary intestinal diversion. J Urol. 1992;147(5):1199-1208. 20. Alcini E, D’Addessi A, Racioppi M, et al. Results of 4 years of experience with bladder replacement using an ileocecal segment with multiple transverse teniamyotomies. J Urol. 1993;149(4):735-738. 21. Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368(2): 149-160. 22. Lee KS, Montie JE, Dunn RL, Lee CT. Hautmann and Studer orthotopic neobladders: a contemporary experience. J Urol. 2003;169(6): 2188-2191. 23. Sagalowsky AI, Frenkel EP. Cobalamin profiles in patients after urinary diversion. J Urol. 2002;167(4):1696-1700. 24. Edwards RH. Hyperammonemic encephalopathy related to ureterosigmoidostomy. Arch Neurol. 1984;41(11):1211-1212. 25. McDougal WS, Heimburger S, Wilmore DW, Pruitt BA Jr. The effect of exogenous substrate on hepatic metabolism and membrane transport during endotoxemia. Surgery. 1978;84(1):55-61. 26. Bowyer GW, Davies TW. Methotrextate toxicity associated with an ileal conduit. Br J Urol. 1987;60(6):592-593. 27. Fossa SD, Heilo A, Bormer O. Unexpectedly high serum methotrexate level in cystectomized bladder cancer patients with an ileal conduit treated with intermediate doses of the drug. J Urol. 1990;143(3):498-501. 28. Sridhar KN, Samuell CT, Woodhouse CR. Absorption of glucose from urinary conduits in diabetics and non-diabetics. BMJ. 1983;287(6402):1327-1329. 29. Woodhouse CR, Lennon GN. Management and aetiology of stones in intestinal urinary reservoirs in adolescents. Eur Urol. 2001;39(3): 253-259. 30. Berkowitz J, North AC, Tripp R, Gearhart JP, Lakshmanan Y. Mitrofanoff continent catheterizable conduits: top down or bottom up? J Peadiatr Urol. 2009;5(2):122-125. 31. van den Heijkant M, Haider N, Taylor C, Subramaniam R. Efficacy of bladder irrigation and surveillance program in prevention of urinary tract infections and bladder calculi in children with ileocystoplasty and bladder neck repair. Pediatr Surg Int. 2011;27(7):781-785. 32. Higuchi TT, Granberg CF, Fox JA, Husmann DA. Augmentation cystoplasty and risk of neoplasia: fact, fiction and controversy. J Urol. 2010;184(6):2492-2496. 33. Higuchi TT, Fox JA, Husmann DA. Annual endoscopy and urine cytology for the surveillance of bladder tumors after enterocystoplasty for congenital bladder anomalies. J Urol. 2011;186(5):17911795.
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econstructive surgery is needed after bladder extirpation for either congenital conditions or acquired bladder abnormalities. Pediatric conditions such as myelomeningocele or exstrophy affect the structure and function of the bladder, threatening kidney function. This requires pre-emptive medical management from birth, and often these children require surgical remedies including bladder rehabilitation with augmentation or complete replacement. In adults, oncologic indications for removal of the bladder include both muscle invasive bladder cancer and recurrent nonmuscle invasive bladder cancer refractory to conservative treatment.1 Children may also need radical cystectomy for malignancies, such as rhabdomyosarcoma. In addition, other nononcologic causes may occasionally result in the removal of the bladder and, consequently, a urinary diversion, such as severe neuropathic bladder, treatment refractory overactive bladder, interstitial cystitis, radiation cystitis, and tuberculosis.1 SURGICAL APPROACHES Broadly, reconstruction of the bladder includes augmentation and urinary diversions. In benign conditions with at least part of the bladder available, its capacity can be enlarged (augmentation enterocystoplasty) using a bowel segment. If the bladder is unsuitable for use or has to be removed, as in malignancies, urinary diversion is necessary, which can be either an incontinent or a continent type. In incontinent urinary diversions, urine is diverted to a reservoir constructed from a bowel segment, and the bowel segment is then attached to the body wall for the urine to drain into an external collecting system. In contrast, in continent urinary diversions, urine is collected into a reservoir (neobladder) created from intestine. From Department of Pediatric Urology, Children’s Hospital of Michigan, Detroit, MI. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Yegappan Lakshmanan, MD, FAAP, FRCSEd, Department of Pediatric Urology, Children’s Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201-2119. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.04.007
320
Both bladder augmentation and continent diversion require a channel to empty the bladder at periodic intervals and a continence mechanism. If the native urethra is available and usable, the augmented bladder or continent diversion can be emptied through the urethra by intermittent catheterization or rarely by volitional voiding. A bladder made entirely of bowel and attached to the native urethra is termed an “orthotopic neobladder.” When the urethra is unavailable or has been removed, a catheterizable channel can be created using a tubular structure such as the appendix (Mitrofanoff principle).2 Alternatives to the appendix include ureter, fallopian tube, or tubularized segments of small or large bowel.3 The latter procedure involves isolating a 2-cm segment of bowel, opening it on its antimesenteric border and reconfiguring it lengthwise over a catheter, thus creating an “appendix” (Monti technique).3 These catheterizable channels connect the augmented or neobladder to the abdominal wall, where they are hidden in the umbilicus or a fold of skin in the lower abdominal wall. To prevent urinary leak through the channel, an antireflux mechanism is also created by plicating it within the bowel or bladder wall. The above principles can be used in various combinations, and several excellent surgical techniques have evolved over the years, allowing the urological surgeon to choose the appropriate bladder reconstruction to suit the individual needs of any patient. There is an ongoing debate concerning the optimal type of urinary diversion after bladder removal. Various factors including disease stage; patient age, gender, and socioeconomic status; kidney and hepatic function; availability of healthy bowel; adequate sphincter function; and even surgeons’ experience all play an important role in the clinical decision making.4 With advancement of surgical technique, improved safety profile, and increased number of skilled surgeons, urinary diversion has become the standard treatment for many structural and functional bladder disorders.4 Despite widespread utilization in the past years, urinary diversions are not a benign reconstructive effort. Depending on the bowel segment used to construct the diversion, patients may confront long-term metabolic complications including acid-base and electrolyte abnormalities, bone demineralization, increased urolithiasis, altered
Advances in Chronic Kidney Disease, Vol 22, No 4 (July), 2015: pp 320-324
Reconstructive Solutions for Structural Urologic Diseases
absorptive capacity, and deterioration of kidney function.5 With increased utilization and survival after urinary diversion, it is likely that such long-term complications will be more frequently encountered.4-6 Keeping this in mind, the goal of this review is to provide an overview of metabolic abnormalities, their causes, evaluation, and management. The focus of the discussion is from the perspective of nephrologists and internists who will often be faced with managing these patients chronically in the outpatient setting and acutely during hospitalization for this or unrelated issues.
321
believed that the acid-base and electrolyte abnormalities are because of leaky intercellular junctions in the jejunum.6 Patients who have had urinary reconstruction with a segment of jejunum may develop the “jejunal conduit syndrome.” In this setting, patients are acutely ill with evidence of volume depletion likely from urinary losses of sodium, chloride, and bicarbonate. Laboratory data are often notable for hyponatremia, a nonanion gap acidosis, hyperkalemia, and evidence of acute kidney injury. The hyponatremia occurs from volume depletion, oral fluid intake, and appropriate ADH release. In the urologic literature, a “hypochloremic” metabolic acidosis is often described; however, the hypochloremia METABOLIC ABNORMALITIES is seen in concert with hyponatremia and does not repreMetabolic abnormalities are common in both continent sent an anion gap acidosis. Hyperkalemia is also and incontinent type of diversions. The extent of metabolic commonly seen, particularly in patients with reduced abnormalities depends on a number of factors including kidney function at baseline. The constellation of abnortype and length of bowel segment used and the length of malities seen in the jejunal conduit syndrome improve time that urine is in contact with bowel.6 Virtually, all types with administration of saline and are subsequently of bowel segments can be used in urinary diversions, with managed with oral sodium chloride or sodium bicarbonileum and colon being the most commonly used ate supplements often indefinitely.6,9-11 segments.6 The most commonly used bowel segments for urinary diAcid-Base and Electrolyte Abnormalities versions are terminal ileum and colon, both of which may lead to a nonanion gap metabolic acidosis.6,12 In elegant Acid-base and electrolyte abnormalities after urinary studies first using dogs diversion depend on the with interposition of bowel segment used. StomCLINICAL SUMMARY ileum in 1 ureter and then ach and jejunum can be kinetic studies using used for bladder augmenta Use of bowel segments in bladder replacement or sheets of enterocytes, tion or urinary diversion,4,6 augmentation are accompanied by a variety of metabolic yet both these bowel McDougal and others and acid-base side-effects. have clarified the segments are considered secondary options because pathophysiology of the The metabolic problems are specific to the type of bowel they tend to produce more metabolic acidosis that segment used in reconstruction. may occur in the setting severe acid-base and electro These abnormalities are well recognized, and can be lyte disorders.4,6 Indications of urinary diversion to an effectively treated when diagnosed early. for using stomach or intestinal segment.13,14 Ammonium produced by jejunum include radiation the kidney, which has a exposure to the bowel, similar ionic radius to Na1, competitively inhibits the presence of adhesions limiting surgical exposure, and Na1/H1 antiporter, sodium-hydrogen exchanger 3, that inflammatory bowel disease.4,6 is expressed on the apical membrane of the enterocytes. Use of stomach segments has some advantages because the gastric mucosa produces less mucus than more distal In addition, bicarbonate is lost in the urine in exchange bowel segments and is less permeable to urinary solutes, for chloride through the Cl2/HCO3– antiporter.13,14 The net result is an increase in ammonium chloride but severe dysuria and hematuria may occur. This complireabsorption, and this leads to a nonanion gap metabolic cation has led to a significant decrease in use of stomach for acidosis.12,14,15 lower urinary tract reconstruction in recent years. Urinary Most individuals with urinary diversion will not have diversion with stomach can produce a metabolic alkalosis significant metabolic abnormalities, and current series from secretion of HCl into the urine by the parietal cells suggest that only approximately 10% of patients exhibit through the H1/K1 ATPase antiporter, which leads to acid-base and metabolic abnormalities.6,11 In general, renal wasting of potassium and hypokalemia.6,7 continent urinary diversions lead to a greater degree of Treatment with H2 blockers and proton pump inhibitors has considerably improved outcomes for patients who metabolic derangement than incontinent urinary have had gastrocystoplasty or reconstruction of the diversions. For example, ileal and colonic incontinent diversions have a 10% to 15% risk of acid-base abnormalurinary tract using stomach such that use of this tissue remains an option if other surgical strategies cannot ities, whereas continent diversions may produce these abbe used.8 normalities in up to 45% of patients.11 This is primarily because of the increased contact time between urine and Jejunum can also be used in incontinent urinary diversion although this segment is very rarely used because of the bowel reservoir in continent diversions.6,11 4,6 Medical practitioners caring for this special population severe metabolic complications that may ensue. The must recognize that the signs and symptoms of acid-base exact mechanism of electrolyte abnormalities from and electrolyte abnormalities are nonspecific and can be jejunal segments is not well understood; however, it is
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Ileum, colon
Jejunum
Abbreviations: cAMP, cyclic adenosine monophosphate; NHE3, sodium-hydrogen exchanger 3. *Transporters noted are on luminal membrane of bowel segment. †Hyponatremia, volume depletion, hyperkalemia and acute kidney injury reported as part of jejunal conduit syndrome.
Most commonly used segments Ileum may reabsorb K1 and offset losses, colon less likely to do so B12 deficiency may occur if significant terminal ileum removed Oral NaHCO3 Sodium or potassium citrate Chlorpromazine and nicotinic acid (inhibition of cAMP activity of NHE3) Hyperchloremic (nonanion gap) metabolic acidosis 1/2 Hypokalemia
Hypovolemia† Hyponatremia Nonanion gap metabolic acidosis Hyperkalemia (more common in CKD or volume depletion)
Stomach is impermeable to solutes and produces less mucus; but acid can also cause hematuria, severe dysuria Rarely used because of volume and electrolyte complications in large percentage of patients Proton pump inhibitor H2 blockers KCl repletion Repletion of NaCl Correction of metabolic acidosis Metabolic alkalosis Renal potassium wasting
Secretion of HCl by parietal cells H1/K1 ATPase antiporter and luminal Cl2 channel Secretion of Na1 and Cl2 and HCO2 3 Transporters responsible for these changes have not been characterized in this setting Absorption of NH41 and Cl2 Secretion of K1 and HCO2 3 Absorption of NH41 in lieu of 1 1 1 Na via Na /H ATPase 2 And HCO2 3 loss/Cl gain via Cl2/HCO2 antiporter 3 Secretion of K1 (mechanism unclear) Stomach
Treatment Strategies Metabolic Complication Pathogenesis* Bowel Segment
Table 1. Metabolic Complications Associated With Urinary Diversion
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Abdullah and Lakshmanan
missed if caregivers are not aware of these potential complications (Table 1). Metabolic acidosis may manifest as easy fatigability, anorexia, polydipsia, and lethargy.6,7,11 Treatment of metabolic acidosis is important, both to relieve symptoms and to limit resultant complications including stunted growth in children, altered bone metabolism, and potential progression of CKD. Alkalinization is usually achieved with sodium bicarbonate, sodium citrate, citric acid, or combined potassium and sodium citrate.6,7,11 The latter option can also help address a concomitant potassium deficit. Alternative options for the treatment of the metabolic acidosis include chlorpromazine and nicotinic acid. These agents have been used successfully in some patients in whom sodium or potassium supplements cannot be tolerated or are undesirable.11 Both agents are known to inhibit the production of cyclic adenosine monophosphate, and by doing so, it is thought that these agents can block the activity of sodium-hydrogen exchanger 3 and, therefore, blunt the absorption of ammonium.11,16 It is also worth noting that the removal of significant lengths of bowel segments may decrease absorption of dietary magnesium and result in hypomagnesemia. This can lead to cardiac arrhythmias, tremor, tetany, and seizures and can be treated with magnesium replacement.11 Bone Demineralization A worrisome potential long-term effect of urinary diversion to intestinal segments is bone demineralization. Historically, this presented as rickets in children, but fortunately, this severe form of bone demineralization is rare in the current era. Nevertheless, attention to growth and normal bone development is still an important aspect of care. In adults, osteomalacia can occur as bone mineral is lost and replaced by osteoid, resulting in decreased bone strength.6,17 The pathophysiology is complex, but longstanding metabolic acidosis is likely the major contributory factor.11 In the setting of chronic acidosis, bone carbonate and phosphate buffer excess hydrogen ions and release calcium into the circulation, which is then cleared by the kidney, thus decreasing skeletal calcium content.11,17 Chronic acidosis may also activate osteoclasts, resulting in bone resorption.11 Finally, poor intestinal absorption of calcium and vitamin D may occur after ileal resection further affecting healthy bone formation.11 A recent population-based study showed that patients with urinary diversion are at 21% greater risk of fracture compared with normal healthy counterparts.18 Because urinary diversions are more common in older individuals, who may already have decreased bone density, it is important for their physicians pay careful attention to this issue.6,11 Patients who present with osteomalacia and have evidence of a metabolic acidosis should have taken sufficient alkali to improve their serum bicarbonate to limit further demineralization. In addition, patients should have sufficient vitamin D levels and ageappropriate dietary calcium or calcium supplements.6 Vitamin B12 Deficiency Vitamin B12 is absorbed in the terminal ileum.6,11 Thus, the use of ileum and, to a lesser degree, the ileocecal segment,
Reconstructive Solutions for Structural Urologic Diseases
for urinary diversion, may lead to chronic vitamin B12 deficiency in some patients.11 Chronic vitamin B12 deficiency is insidious and may result in irreversible neurologic and hematologic sequelae.6,11 The absolute prevalence and clinical significance of this entity in urinary diversion are undetermined.19,20 Some investigators report that routine administration of vitamin B12 every 6 months prevents vitamin B12 deficiency in all patients at 10-year follow-up.19 It is also worth noting that laboratory measurement of B12 levels is unreliable, although very low levels usually do reflect B12 deficiency. Instead, measurement of homocysteine levels and methylmalonic acid is more reliable. These levels are typically high in B12 deficiency and return to normal promptly with treatment.21 The merits of monitoring vitamin B12 levels versus routine long-term supplementation may be debated from a cost and practical standpoint.6,11 However, as survival after treatment for bladder disorders steadily improves and the number of patients with continent urinary diversion increases, this issue may assume greater importance.1,20,22 Disorders of Hepatic Metabolism When intestine is used in urinary diversion, absorption of ammonia into the portal circulation increases because of the increased load of ammonia from the urine.6,11,23 Under normal circumstance, the liver clears the increased ammonia load without significant alteration in serum ammonia levels. This hepatic reserve for ammonia clearance is great, and it is unlikely that acute changes in ammonia loads result in significant alteration in serum ammonia level when hepatic function is normal.11,23 However, advanced liver disease or small amount of endotoxin can significantly limit hepatic metabolism and transport.11,23 Hyperammonemic encephalopathy has been reported most commonly in patients with ureterosigmoidostomy.24 In addition, patients with normal liver function but a urease-producing bacterium can develop encephalopathy from elevated ammonia levels when the filtered urea is converted to ammonium, and this is reabsorbed, as outlined earlier.11 Often, the infection is associated with obstruction of the urinary tract.11,25 In patients with bowel augmentation, urinary infection provides direct access of bacteria and endotoxin to the liver through the portal circulation leading to altered hepatic metabolism without significant alterations in hepatic enzyme concentrations.11,24,25 Abnormal Drug Metabolism Drugs secreted unchanged in the urine and absorbed by the intestinal tract may cause additional issues.6,11 Chemotherapeutic agents are of particular interest as these are commonly used in the treatment of bladder cancer.11 Methotrexate toxicity in patients with ileal conduit is well recognized.26,27 Patients with continent diversion who are receiving chemotherapy should be monitored closely and should stay well hydrated.6,11 Additionally, the reservoir should be drained during treatment to reduce contact time between the therapeutic agent and the reservoir wall. Other drugs reported to be
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absorbed from intestinal segment in the urinary tract include phenytoin, theophylline, and antibiotics.11,27 Individuals with diabetes mellitus appear to have an enhanced ability to absorb glucose from the intestinal reservoir; therefore, screening with urine test may be inaccurate in this population.28 Surveillance of patients with diabetes should rely on blood test results. Bladder Stones Incorporation of bowel in the bladder predisposes patients to a high risk of stone formation because of mucus production, altered urinary pH, stasis, and infection.6,11,29 The stones are predominantly struvite, and the incidence varies from 3% to 50%, depending on the bowel segments used and the type of drainage mechanism.29 Stones rarely form in the acid milieu in gastrocystoplasty, except uric acid calculi, but are more frequent after ileocystoplasty.11 Stones are also much less frequent in those voiding per urethra, compared with those catheterizing through a channel in the umbilicus (against gravity), or when a bladder neck procedure has been performed.30 Recurrent urinary tract infections with urea-splitting bacteria, such as Proteus mirabilis, have been implicated, with the risk compounded by stasis of mucus.6 Therefore, daily bladder irrigation is used to reduce the incidence of stones.11 In addition, the use of bladder instillation with acetylcysteine has been reported to decrease mucus and stones.11,31 The risk is highest in the first 2 years after the reconstructive surgery, and regular follow-up with ultrasound studies is indicated. Risk for Malignancy The high incidence of malignancy after ureterosigmoidostomy is well recognized. This occurs after a long latency and is thought to be because of mixing of the urinary and fecal streams and production of N-nitroso compounds.32 These compounds are also noted in urine after augmentation and diversion.32 In addition, animal models have shown hyperplasia, particularly in the transitional zones after augmentation. In humans, the risk of malignancy varies with the type of intestinal segment used.32 Although gastrocystoplasty seems to carry a higher risk of malignancy, the incidence of tumors with ileum or colon appears to be no higher than those occurring in congenitally abnormal bladders.32 For this reason, some have recommended surveillance with periodic cystoscopy and urinary cytology starting 10 to 15 years after bladder reconstruction.32 Nevertheless, no demonstrable benefit for this approach has been forthcoming with mediumterm follow-up.33 CONCLUSIONS With advancement in surgical technique and safety profile, urinary diversions are commonly used for reconstruction of the urinary system. Additionally, as survival after treatment for bladder cancer steadily improves, the number of patients with urinary diversions is increasing. As a result, the next generation of health care providers will encounter more patients with urinary diversions and need to be familiar with the long-term metabolic complications to appropriately manage them.
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