KHA-CARI Autosomal Dominant Polycystic Kidney Disease Guideline: Management of Renal Stone Disease Andrew Mallett, MB BS, MMed, AFRACMA, FRACP,*,† Manish Patel, MB BS, MMed, PhD, FRACS,‡ David J. Tunnicliffe, MIPH,§,II and Gopala K. Rangan, MB BS, PhD, FRACP¶,#
GUIDELINE RECOMMENDATIONS* a. We recommend that unenhanced computed tomography is the preferred imaging modality for the diagnosis of suspected nephrolithiasis in autosomal dominant polycystic kidney disease (1B). b. We recommend that patients with autosomaldominant polycystic kidney disease complicated by nephrolithiasis should be investigated for predisposing urinary metabolic abnormalities (1C) and we suggest receive corrective therapy if an abnormality is identified (2D).
*Criteria used for recommendations and levels of evidence (1,2;A-D) are described in more detail in Tables 1 and 2 of Rangan G, Savige J. Introduction to the KHACARI Guidelines on ADPKD. Semin Nephrol.2015;35:521-3 in this issue.
UNGRADED SUGGESTIONS FOR CLINICAL CARE
We suggest that in the patients with autosomaldominant polycystic kidney disease (ADPKD) in whom a diagnosis of nephrolithiasis is considered, that the diagnostic performance of the imaging modality needs to be balanced against the relative risks of these different diagnostic tests, as does whether or not a contrast-enhanced computed *
Kidney Health Service and Conjoint Kidney Research Laboratory, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia. † Centre for Kidney Disease Research, Centre for Chronic Disease and CKD, School of Medicine and Centre for Rare Diseases Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. ‡ Discipline of Surgery, University of Sydney and Department of Urology, Westmead Hospital, Western Sydney Local Health District, Westmead, Sydney, Australia. § KHA-CARI Guidelines, Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, Sydney, Australia. II Sydney School of Public Health, University of Sydney, Sydney, Australia. ¶ Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney, Australia. # Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, Sydney, Australia. Seminars in Nephrology, Vol 35, No 6, November 2015, pp 603–606
tomography scan is required for other differential diagnoses or clinical indications. We suggest that in the early stages of cystic renal disease, screening for nephrolithiasis with ultrasound may be more useful. We suggest that the medical management of an acute presentation with suspected nephrolithiasis in a patient with ADPKD as well as the prevention of recurrent stone formation should follow general principles recommended for the general population, with the exception that: ○ A superimposed urinary tract infection should be considered in the acute presentation. ○ The differential diagnosis of the acute presentation should include ruling out other causes of acute loin pain (eg, cyst infection or hemorrhage); and ○ Screening for underlying urinary metabolic abnormalities should be considered in ADPKD patients presenting with their ﬁrst stone. We suggest that the indications for urological intervention for stone removal in ADPKD depend on the clinical circumstances. If required, percutaneous nephrolithotomy, extracorporeal shockwave lithotripsy, or ureteroscopy with laser lithotripsy may be considered.
Financial support: KHA-CARI Guidelines is supported by Kidney Health Australia, the Australian and New Zealand Society of Nephrology, Amgen Australia, and Shire Australia Pty Ltd. Guideline members were not remunerated for their work. Manish Patel received an honorarium from GSK, Janssen, Astellas, Sanoﬁ and Abbvie as an advisory board member. Conﬂict of interest statement: Gopala Rangan is a member of the Advisory Committee on the Safety of Medical Devices, Therapeutic Goods Administration and received ﬁnancial support from KDIGO to attend the KDIGO Controversies Conference on ADPKD in January 2014. Manish Patel received an honorarium from GSK, Janssen, Astellas, Sanoﬁ and Abbvie as an advisory board member. Address reprint requests to Andrew Mallett, MB BS, MMed, AFRACMA, FRACP, Kidney Health Service, Level 9, Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Butterﬁeld St, Herston, Brisbane, QLD, 4029 Australia. E-mail: Andrew. [email protected]
0270-9295/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2015.10.012 603
IMPLEMENTATION AND AUDIT Patients with ADPKD with nephrolithiasis should be referred to urology services to receive further assessment and management. This might be considered for implementation as part of a multidisciplinary clinic service. Further study and clinical audit is required of those with ADPKD complicated by nephrolithiasis, speciﬁcally with regards to interventions utilized, complications and adverse events, and clinical outcomes.
BACKGROUND Nephrolithiasis does commonly complicate ADPKD. When it occurs in ADPKD it poses additional clinical challenges that are not present in the non-ADPKD population. These include the superimposition of complicated urinary tract infection, difﬁculties with the diagnosis (eg, differentiating acute ﬂank pain due to stone formation from acute cyst infection or hemorrhage), and choice of the surgical intervention.1 Accordingly, heightened awareness and potential modiﬁcation of the standard clinical approach is required compared to patients presenting with nephrolithiasis who do not have ADPKD.2,3 The prevalence of nephrolithiasis in ADPKD may be 5 to 10 times higher compared to the general population.4 This increased risk is probably due to reduced urinary ﬂow (and stasis) in renal tubules and calyces due to compression from expanding renal cysts as well as underlying urinary metabolic abnormalities.5 In a large cohort of 751 patients with ADPKD, renal stone disease occurred in 20.1% of subjects over a 10year period.6 However, only a minority of patients with ADPKD with nephrolithiasis report clinical symptoms (ie, either recall having passed a renal stone or required surgical intervention) and the vast majority are asymptomatic with abnormalities (renal stones or calciﬁcations) noted on imaging.7 Patients with ADPKD with nephrolithiasis have greater morbidity burden including ﬂank pain and urinary tract infections compared to those that have not developed stones.7 There may also be a relationship between nephrolithiasis and an increased number and size of renal cysts in ADPKD patients.8 Further, such patients have been observed to have lower levels of renal function, suggesting that progression of ADPKD with resultant intrarenal anatomic obstruction is associated with a predisposition to nephrolithiasis.8 In contrast to the general population (where calcium-containing stones are most prevalent), renal stones in ADPKD are most commonly composed of urate (56%-47%), and to a lesser degree, calcium oxalate.6,9 The most common urine metabolic abnormalities predisposing to stone formation in ADPKD
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are hypocitraturia, aciduria and hypomagesuria, as well as low urine volume.6,8 In the ADPKD subgroup with preserved renal function, other risk factors predisposing to nephrolithiasis include hyperuricosuria, hyperoxaluria, and hypercalcuria.6 Given the latter, emphasis should be placed not just on treating nephrolithiasis, but also its predisposing metabolic and structural factors.10 This presents challenges and opportunities among those affected by both ADPKD and nephrolithiasis, with heightened emphasis on metabolic evaluation and resultant correction.11 The surgical management of nephrolithiasis in ADPKD is not thought to differ from that utilized in those without ADPKD,2 apart from additional considerations required due to the presence of multiple renal cysts, such as extracorporeal shockwave therapy (ESWL) beam targeting (or avoidance of this technique) to minimize the risk of cyst hemorrhage.
SEARCH STRATEGY Databases Searched Medical subject headings and text words for ADPKD were combined with medical subject headings terms and text words relating to the assessment and management of nephrolithiasis and renal stone disease. The search was carried out in Ovid MEDLINE (1946 to June 2014), Embase (1974 to May 23, 2014), PsycINFO (1806 to June 2014), and the Cochrane Database of Systematic Reviews and the Cochrane Registry of Clinical Trials (inception to June 2014). Date of search: June 2014.
WHAT IS THE EVIDENCE? Supplementary evidence Tables are available online. Imaging There are few studies speciﬁcally examining the optimal imaging modality for renal stone disease among those with ADPKD. Nishiura et al12 compared ultrasound and unenhanced computed tomography (CT), which were both performed in all members of a cohort of 125 patients with ADPKD. They found that CT detected the presence of renal stone disease in 32 patients whereas ultrasound only did so in 20. This is not unexpected given the predilection of ADPKD patients especially to urate stones, in which ultrasound may not offer optimal diagnostic performance. The diagnostic performance of ultrasound may be further degraded by the presence of renal cysts within the sonographic ﬁeld.
KHA-CARI ADPKD management
Urinary Metabolic Therapy While evaluation and treatment for predisposing urinary metabolic circumstances is frequently recommended given their increased prevalence in patients with ADPKD complicated by nephrolithiasis,1,6,8 there is no clearly reported evidence of the clinical outcomes when such urinary metabolic predisposition is corrected.
patients (intraoperative bleeding, ureteral perforation, pyelonephritis), the majority of which (7.8%) were uncomplicated urinary tract infections.
SUMMARY OF THE EVIDENCE
In a case series of 19 patients with ADPKD and uppertract nephrolithiasis greater than 2 cm in largest diameter, including one with bilateral renal stone disease, percutaneous nephrolithotomy (PCNL) achieved stone clearance in 89.4%, with a mean hospital stay of 3 days, no patient deaths, improvement in renal function in all who had acute kidney injury, and three complications.13 Another case series of 25 such patients achieved stone clearance in 88%, improvement in renal function, and seven complications, although the mean hospital stay was not known and two and one patient, respectively, required a repeat PCNL and ESWL.14 A third case series of nine ADPKD patients with upper-tract nephrolithiasis greater than 2 cm in largest diameter achieved 82% stone clearance without any postoperative complications and no recurrence at 2.7 years of follow-up.15
Nephrolithiasis is more common among those with ADPKD, and commonly has an underlying urinary metabolic predisposition. Given a predilection to forming urate stones, unenhanced CT has a better diagnostic performance in comparison to ultrasound. There is no speciﬁc evidence that the standard medical management to prevent recurrent stone formation should differ from the general population.19 In the setting that urological intervention is required, PCNL for upper renal tract stones greater than 2 cm in maximal diameter among those with ADPKD is effective and safe in limited published case series. Similarly, ESWL is effective in the same circumstances for stones that generally are smaller, although up to a 3.5-cm maximal diameter. The choice of intervention (and its urgency) depends on the location of the renal stone within the urinary tract, the clinical presentation, other complicating co-existing or intercurrent factors, the renal stone composition, the degree of renal cyst burden, and the clinical opinion of the treating urologist. However, current urological practice is evolving and ULL is being increasingly utilized and favored.
Extracorporeal Shockwave Lithotripsy
WHAT DO THE OTHER GUIDELINES SAY?
There is only one case series exclusively reporting on the use of ESWL for nephrolithiasis in patients with ADPKD. In 13 patients a stone-free rate of 85% was achieved at 3 months, with two patients requiring repeated treatments in this time.16 The mean stone size was 15.2 mm (range, 7-35 mm). Complete stone fragmentation was achieved for 69% of patients with one session. No complications were reported. Another case series of 15 patients with nephrolithiasis in the setting of renal cysts demonstrated a 60% stone-free rate at 1 month.17 One of four patients with ADPKD in the cohort was stone-free at 1 month; however, complete stone fragmentation was achieved in all patients in the cohort.
Kidney Disease Outcomes Quality Initiative: No recommendation. UK Renal Association: No recommendation. Canadian Society of Nephrology: No recommendation. European Best Practice Guidelines: No recommendation. International Guidelines: No recommendation.
Ureteroscopy With Laser Lithotripsy
There was one case series that reported on the use of ureteroscopy with laser lithotripsy (ULL) among patients with ADPKD complicated by nephrolithiasis.18 Among 51 such patients with a mean stone size of 6.6 ⫾ 3 mm per patient, stone-free rates of 64.7% and 92.2% were achieved with one and two procedures, respectively. Complications occurred in 13.6% of
Spanish Guidelines20: Diagnosis i) CT scanning should be used in uncertain cases or in those with suspicion of associated renal disease such as stones or tumor (D).
i) Renal lithiasis may beneﬁt from potassium citrate when hypocitraturia is present, as well as from urine alkalinization (D). ii) Percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy can be used in an individualized setting (D).
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SUGGESTIONS FOR FUTURE RESEARCH Further research is required into the outcomes of correcting predisposing urinary metabolic circumstances for nephrolithiasis in those with ADPKD. Audit, comparison, and description of the treatment (PCNL, ESWL, ULL) and clinical outcomes in cohorts with ADPKD complicated by nephrolithiasis is required to further delineate and inform future clinical decision making.
APPENDIX A. SUPPLEMENTARY INFORMATION
Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10. 1016/j.semnephrol.2015.10.012.
1. Amar AD, Das S, Egan RM. Management of urinary calculous disease in patients with renal cysts: review of 12 years of experience in 18 patients. J Urol. 1981;125:153-6. 2. Torres VE, Wilson DM, Hattery RR, Segura JW. Renal stone disease in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 1993;22:513-9. 3. Tan YK, Cha DY, Gupta M. Management of stones in abnormal situations. Urol Clin North Am. 2013;40:79-97. 4. Delaney VB, Adler S, Bruns FJ, Licinia M, Segel DP, Fraley DS. Autosomal dominant polycystic kidney disease: presentation, complications, and prognosis. Am J Kidney Dis. 1985;5:104-11. 5. Mufti UB, Nalagatla SK. Nephrolithiasis in autosomal dominant polycystic kidney disease. J Endourol. 2010;24:1557-61. 6. Torres VE, Erickson SB, Smith LH, Wilson DM, Hattery RR, Segura JW. The association of nephrolithiasis and autosomal dominant polycystic kidney disease. Am J Kidney Dis. 1988;11:318-25. 7. Levine E, Grantham JJ. Calciﬁed renal stones and cyst calciﬁcations in autosomal dominant polycystic kidney disease: clinical and CT study in 84 patients. AJR Am J Roentgenol. 1992;159:77-81. 8. Grampsas SA, Chandhoke PS, Fan J, Glass MA, Townsend R, Johnson AM, et al. Anatomic and metabolic risk factors for
nephrolithiasis in patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2000;36:53-7. Idrizi A, Barbullushi M, Petrela E, Kodra S, Koroshi A, Thereska N. The inﬂuence of renal manifestations to the progression of autosomal dominant polycystic kidney disease. Hippokratia. 2009;13:161-4. Muldoon LD, Resnick MI. Secondary urolithiasis. Endocrinol Metab Clin North Am. 1990;19:909-18. Gambaro G, Fabris A, Puliatta D, Lupo A. Lithiasis in cystic kidney disease and malformations of the urinary tract. Urol Res. 2006;34:102-7. Nishiura JL, Neves RFCA, Eloi SRM, Cintra SMLF, Ajzen SA, Heilberg IP. Evaluation of nephrolithiasis in autosomal dominant polycystic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:838-44. Al-Kandari AM, Shoma AM, Eraky I, El-Kenawy MR, Al-Eezi H, El-Kappany HA. Percutaneous nephrolithotomy for management of upper urinary tract calculi in patients with autosomal dominant polycystic kidney disease. Urology. 2009;74: 273-7. Srivastava A, Bansal R, Srivastava A, Chaturvedi S, Ranjan P, Ansari MS, et al. Percutaneous nephrolithotomy in polycystic kidney disease: is it safe and effective? Int Urol Nephrol. 2012;44:725-30. Umbreit EC, Childs MA, Patterson DE, Torres VE, LeRoy AJ, Gettman MT. Percutaneous nephrolithotomy for large or multiple upper tract calculi and autosomal dominant polycystic kidney disease. J Urol. 2010;183:183-7. Delakas D, Daskalopoulos G, Cranidis A. Extracorporeal shockwave lithotripsy for urinary calculi in autosomal dominant polycystic kidney disease. J Endourol. 1997;11:167-70. Deliveliotis C, Argiropoulos V, Varkarakis J, Albanis S, Skolarikos A. Extracorporeal shock wave lithotripsy produces a lower stone-free rate in patients with stones and renal cysts. Int J Urol. 2002;9:11-4. Breda A, Ogunyemi O, Leppert JT, Schulam PG. Flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. Eur Urol. 2009;55:1190-6. Thomas M, Becker G, Kairaitis L, Hughes P, Richmond J. KHA-CARI guidelines kidney stones. Nephrology. 2007;12: S1-36. Ars E, Bernis C, Fraga G, Martínez V, Martins J, Ortiz A, et al. Spanish guidelines for the management of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2014;29 (iv):95-105.
RENAL COMPLICATIONS - STONE DISEASE Date written: Author: Table 1. Study ID
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Table 2. Study ID
Time between tests
Outcome of interest
Table 3. Study ID
Shape of intervention pre-specified
Intervention unlikely to affect data collection
Blind outcome assessment
Other risks of bias
Table 4. Study ID
Flow and timing
Table 5. Study ID
5 Table 6. Study ID
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Table 7. Study ID
Table 8 Study ID