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Paediatric urolithiasis in emerging economies
Accepted Manuscript Paediatric urolithiasis in emerging economies S. Adibul Hasan Rizvi, Sajid Sultan, Mirza Naqi Zafar, Sadaf Aba Umar, Bashir Ahmed, S.A. Anwar Naqvi PII:
S1743-9191(16)31094-9
DOI:
10.1016/j.ijsu.2016.11.085
Reference:
IJSU 3239
To appear in:
International Journal of Surgery
Received Date: 10 November 2016 Accepted Date: 10 November 2016
Please cite this article as: Rizvi SAH, Sultan S, Zafar MN, Aba Umar S, Ahmed B, Naqvi SAA, Paediatric urolithiasis in emerging economies, International Journal of Surgery (2016), doi: 10.1016/ j.ijsu.2016.11.085. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
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PAEDIATRIC UROLITHIASIS IN EMERGING ECONOMIES
Author names:
S Adibul Hasan Rizvi1, Sajid Sultan2, Mirza Naqi Zafar3, Sadaf Aba Umar2, Bashir
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Affiliations
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Ahmed2, S A Anwar Naqvi1
1. Department of Urology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
2. Department of Paediatric Urology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
Karachi, Pakistan
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Corresponding Author:
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3. Department of Pathology, Sindh Institute of Urology and Transplantation,
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Dr S Adibul Hasan Rizvi Professor and Director Sindh Institute of Urology and Transplantation, Civil Hospital Karachi - 7420, Pakistan Tel: +9221 32730351 Fax: 9221 99215469 Email: [email protected], [email protected]
Running title: Paediatric urolithiasis in …….
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Abstract Background Paediatric urolithiasis remains endemic in low resource countries. This review highlights
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the epidemiology, causation and management of urolithiasis in an Asian country in the context of emerging economies. Methods
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A literature review of recent articles with key words paediatric urolithiasis, developing countries, endemic stone disease, stone composition, metabolic risk factors,
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management of paediatric urolithiasis was undertaken and 51 relevant articles were selected with the main focus on experience of this centre in managing stone disease in the last two decades. Results
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Prevalence of paediatric urolithiasis is high upto 15% affecting children under 15 years with male predominance. Bladder stones still constitutes 10-70% of the burden. Etiology remains unknown where 55% are considered idiopathic, 25% metabolic, 7% infection
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and 12% due to anatomical abnormalities. Hot climate, poor nutrition, diarrheal diseases are the major causative factors. Chemical composition of stones showed CaOX in 30-
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63%, AAU in 17-55%, struvite in 8-9%, uric acid in 3-6% and cystine in 1%. Important metabolic risk factors are hypocitruaturia in 63-87%, hyperoxaluria in 40-43%, hypocalciuria in 20%, hyperuricosuria in 27%, hyperammonuria in 11-51% and hypovolumia in 31%.
Minimally invasive surgery is the mainstay of surgical management. ESWL provides excellent free rates of 84% for smaller stones. PCNL is the option for majority of renal
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stones with success rates of 89% for simple and 71.5% for complex stones. For bladder stones PUCL and PCCL success rates were 100%. URS for ureteric stones showed clearance rate of 90%. Open surgery is required in 12% of patients with large stone
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burden. Conclusion
Paediatric urolithiasis remains a devastating health problem in low resource settings.
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MIS offers relief to majority of patients with excellent stone free rates and short hospital stay. Preventable strategies have to be put in place by improving nutrition and
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eliminating risk factors by diet and medical intervention.
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Key words: Paediatric, urolithiasis, emerging, economies
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Introduction Paediatric urolithiasis remains endemic in low resource countries, mostly situated in the geographical region of the world, dubbed “The Afro-Asian Stone Belt”.1 The prevalence
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rates are high, with up to 15% of children under 15 years of age being affected, as compared to the 1 - 5% affected in developed countries.2-4 Endemic bladder calculi continue to contribute a major proportion of stones in the developing world from 10% in
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Nepal,5 and 21% in Tunisia,6 to 18% in Pakistan7 and 70% in Cameroon.8 However, in recent years a number of countries (namely Afghanistan, Iraq, Iran, Turkey and Egypt)
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have reported reductions in bladder stones ranging between 2 and 10%.9-13 In contrast to this bladder stones are rarely reported from the developed countries.14 Paediatric urolithiasis remains a significant urological problem in this region contributing upto 60% of the urological work load in our center.2 Furthermore, due to neglect 4 - 8% of cases with
end
stage
renal
disease.7
Most
of
the
studies
report
male
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present
predominance.2,7,15-17 The spectrum of paediatric urological workload from 1998 to 2015 recorded 21,390 patients where urolithiasis workload increased to 62% (Figure 1)
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This review presents the epidemiology of paediatric stones in emerging economies and focuses on the experience of our unit over the last 2 decades which indicates the
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spectrum of the disease, its devastating effects and the special issues in management of paediatric patients with stones in the context of a poor resource Asian country where the capita income is US$2535, expenditure on health is 1.3% of GNP and 60% of the people live below the poverty line on less than a dollar a day.18
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Epidemiology The overall risk of forming a stone depends upon several factors-geographical region, race, gender, climate and dietary habits.1 Etiologies remains largely unknown in
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emerging economies where 55% are considered idiopathic, 25% metabolic, 7% infection and 12% associated with anatomical abnormalities.2 In Korea, urinary tract abnormalities were identified in 9.5% and infection in 10%,17 and in Turkey infection
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was reported in 20%.16
In low resources countries, hot climate (with average temperature > 280C)19 and poor
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nutrition are the major causes of urolithiasis. Acidogenic diets high in cereal, low in protein, calcium and phosphate; with high urinary ammonium and urate ions result in ammonium acid urate (AAU) stones. In other situations high intake of oxalate from leaves and vegetable increases oxalate excretion, resulting in a mixture of (AAU) and
Stone Composition
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calcium oxalate (CaOX) stones.5,8,10-13,20,21
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Recent reports of stone analysis show continuing presence of AAU and CaOX in both renal and bladder stones.2,16,22 In our study where core and surface of stones were
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analyzed. AAU was found in the core of 43% of renal and 38% of bladder stones.2 These findings suggest a common cause of malnutrition, dehydration and recurrent diarrhea episodes for both renal and bladder stones. Of the different components CaOX was present in 30-63%, AAU in 17-58%, Calcium Phosphate (CaP) in 11-12%, Struvite in 8-9%, Uric Acid in 3-6% and Cystine in 1%.7,22 This contrasts from developed countries where calcium oxalate constitute 63% and the rest CaOX + CaP in 30%,
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struvite in 4% and cystine in 2%.23 In our study of 2039 stones, 726 (36%) were composed purely of a single compound and the rest 64% were mixtures. Composition of pure 570 renal stones showed variation in different age groups. In age group < 5 years
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AAU was found in 65% and CaOX in 18%, in age group 6-10 years, AAU in 19% and CaOX in 61% while in > 10 years CaOX was found in 70%, AAU in 10%.7
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Metabolic Risk Factors
Evaluation of urinary risk factors are important in the treatment and prevention of
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urolithiasis, especially in children where risk factors are identified in majority and can be corrected by dietary and medical intervention.7 In our center, two separate studies evaluating urinary risk factors in stone formers hypocitraturia was found in 63-87%, hyperoxaluria
in
40-43%,
hypercalciuria
in
11-26%,
hypocalciuria
in
20%,
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hyperuricosuria in 26-27%, hyperammonuria in 11-51% and low urinary volume in 931% of the children.2,7 A study from Turkey showed hypercalcuria in 41%, hypocitraturia in 40%, hyperoxaluria in 22% and hyperuricosuria in 9% and cystinuria in 4%.16 A
risk
factors
in
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recent study identified risk factors in genders and different age groups showed similar males
and
females
except
higher
rates
of
hyponatriuria,
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hypophosphatruria and hypocalciuria in females. Hyperuricosuria, hyponatriuria and hypovolemia were highest in children aged 1-5 years, 52%, 49% and 49% respectively as compared to 18%, 21% and 12% in children aged 11-15 years old.24 Another study from Korea, an economically advanced country showed that common risk factors in preschool age children, were hypercalcuria in 64% and hyperuricosuria in 36% and in school age children hypercalcuria in 47%, hyperuricosuria in 21% and hypomagnesuria
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in 16%.17 These findings differ from developed countries where hypocitraturia was reported in 7%, hyperoxaluria in 21% and hypercalciuria in 32%.25 These findings suggest that risk factors are different in age groups and while hypocitruria is a major
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finding in the low resource settings, hypercalciuria is more prevalent in developed countries leading to AAU stones in the former and CaOX in the later areas.
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Clinical Presentation
There have been reports of prenatal diagnosis of fetal urolithiasis. In our clinic the
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youngest patient presented at the age of 53 days and some may present in infancy (Figure 2) however the mean age is 6.5+ 3.6 years.26
The commonest presentation is abdominal pain, vague in young children and more localized flank pain in older children or ureteric colic. Other features include haematuria,
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dysuria, urgency, frequency, fever, strangury and/or urinary retention in case of vesical calculus, oligo-anuric in cases of acute or chronic renal failure. Some of them are associated with anatomical abnormalities including pelviureteric junction obstruction
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(PUJO), megaureter, bladder outlet obstruction, ectopia abnormalities of fusion like horseshoe kidney (Figure 3). Patients may present with large stone burden, atrophic
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renal cortex (Figure 4), pyonephrosis or even with xanthogranulomatous pyelonephritis (Figure 5). Those with extremes of diseases are anaemic, with stunted growth and osteodystrophy (Figure 6).26
Medical Management
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The goals of conservative treatment are to relieve pain and to prevent factors interfering with spontaneous stone expulsion such as oedema, spasm and infection.27,28 Medical expulsive therapy with alpha blockers is prescribed especially for lower ureteric stones
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5- 10 mm and post ESWL residual fragments. In paediatric age group inadequate data are available where in some studies beneficial outcomes have been attained, while in others expected benefits could not be gained.29-31
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The other indication for medical management is to prevent recurrence. Adequate hydration over the entire 24 hours and alkalinization of urine is recommended for
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patients with calcium oxalate, cystine, xanthine and urate stones. Specific medical therapy is advised on individual basis.
Surgical Management
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Historically all patients were managed by open surgery. Advances in technology and invention of paediatric size endoscopic instruments has created a paradigm shift from open surgical procedures to minimally invasive surgery (MIS).32 These include
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Extracorporeal Shock Wave Lithotripsy (ESWL), Percutaneous Nephrolithotomy (PCNL), Retrograde IntrarenalSurgery (RIRS), Ureterorenoscopy (URS), Laparoscopy
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and Robotics for renal and ureteric stones and per urethral and Percutaneous Cystolithoclast (PUCL/PCCL) for vesical calculi.33 In developed countries more than 95% of the patients are managed by MIS. Our experience from 2009 to 2012 showed 29.4% open surgery which has gradually reduced to 12% between 2013 and 2015 (Table). The main reason for this, besides anatomical abnormalities is complex and
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large stones with atrophic cortices neglected stones with renal failure and/or sepsis
Minimally invasive surgery Extracorporeal Shock Wave Lithotripsy (ESWL)
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overburdened by socioeconomic and geographical dynamics of the patient (Figure 7).34
Large size stones and even staghorn calculi have been treated with ESWL.35,36 A
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review of ESWL by Jeong et al showed that stone free rates range from 37% to 97% in different series but these data are difficult to interpret for comparison of the outcome
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because of the discrepancies in the available data with regards to number of shock waves administered, retreatment rates, stone free status and size of residual fragments. The conclusion was that ESWL outcome depends on type of lithotripter, operator skills, ESWL protocol used, stone characteristics including location, size, multiplicity and
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composition.37
Our initial experience with paediatric ESWL published in 2003 showed a stone free rate of 84% with a mean of 1.4 sessions given to a stone size ranging from 0.5 to 2.5 cms.26
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In a recent audit we analyzed clearance with different stone burdens, locations and densities. These results showed that there is increase in mean ESWL session with the
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increase in stone burden, lower calyceal location and higher density stones.26 Therefore to avoid repeated anesthesia and renal damage, we recommend ESWL where complete clearance is expected in single session.
Percutaneous Nephrolithotomy (PCNL)
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Fernstorm and Johanson in 1976 reported the first case of PCNL done in an adult.38 Woodside and associates in 1985 were the first to present PCNL in paediatric population with adult instruments.39 We also initially started off with adult sized
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nephroscopes (27 and 24 Fr) and gradually reduced it to 20, 18 and 15 Fr. Now we usually use MiniPCNL 12Fr Nephroscope and 14-16Fr working sheath in most situations. Although instruments as small as 4.8 and 8 Fr (MicroPerc.) have also been
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used40 but they go on to the other side of the spectrum and are used only for selected cases. Miniaturization of the PCNL instruments have facilitated its use in all age groups.
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Our indications for PCNL are stone size of 1.5cm or more with favourable anatomy, previous open surgery on the respective side and failed ESWL; or in stones where more than one session of ESWL is expected. From 2009 to 2014 we had successfully performed more than 1600 PCNL in children with mean age group of 7.4+3.41 years,
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35% of which were upto 5 years of age and 10% were less than 2 years of age.26 Micro PERC has been performed in selected cases.41,42 It allows direct puncture into relevant calyx via all seeing needle, no need for tract dilatation after puncture, with less
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radiation exposure, direct fragmentation/powdering of the stone in situ, thus requiring less operation time and lower complication rates. There are certain limitations of
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microperc, firstly that the vision is not as good as in mini PCNL because the irrigation fluid is intermittently pushed, there is no regular outflow passage, the stone or its fragments might migrate into a calyx where it becomes impossible or difficult to access. At the same time microperc instruments are costly and meant to be disposable making their universal use in emerging economies difficult. As an alternate we also use semirigid miniscope of 4-9 Fr.
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Tubeless PCNLs have been performed in cases where there is no significant bleeding, pelvicalyceal breach or residual fragments. However, we prefer to place 10 to 16 Fr nephrostomy tube postoperatively in all cases with supracostal approach.
calyceal stone to partial or complete staghorn stone.26
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The variety of stones managed at our centre with PCNL ranged from single pelvic or
For the purpose of evaluating our results of PCNL we divided our stone burden into
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simple (81%) and complex (19%) stones. The success rate of PCNL as monotherapy is higher in simple stones (89%) as compared to the complex stones (71.5%).26
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We evaluated our data of PCNL in 1135 renal units on the basis of age groups (Group A <3years, B= 3-5 years, C= 5 -10 years and D= 10 -15 years). Data revealed increase in stone volume (cm2) with increasing age i.e. 1.47± 0.9, 1.59±0.8, 2.17±1.6 and 2.69±1.8 respectively (p=<0.0001) with stone clearance of 94%, 89.2%, 87.4% and 81%
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respectively which revealed good stone clearance in all age groups, however there is some consistent decrease in stone clearance with increasing stone burden. Blood transfusion requirement and operative time were more in the complex stone
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cases. It was also observed that blood transfusion requirement was significantly less in older age group (Group D) where preoperaive hemoglobin (11.9±1.4) and hematocrit
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(35.3±4.2) was higher as compared to smaller children (Group A) with low preoperative hemoglobin (10.2±1.3), hematocrit (30.9±3.4) and low allowable blood loss. Blood transfusion requirement was consistently lower in all age groups with smaller sheath (<20 Fr) as compared to larger sheath (>20 Fr.) . The age group, stone volume and sheath size does not significantly affect the operative time.
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Our mean hospital stay is 4.1 + 3 days. Our patients tend to over stay in hospital as they come from far off areas where follow up facilities are not present. Majority of post-operative complications were in Clavien group I and II. Post operative
peri renal collections are seen in 1.5% of cases.
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complications included hydrothorax in 2%, urosepsis in 1.6% while intraperitoneal and
The effect on renal functions has been evaluated by creatinine levels in all cases and by
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DMSA scan in selected cases. We did not find any significant deterioration in renal function post operatively even in compromised kidneys or in patients with renal failure.
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To conclude PCNL is safe and effective method of renal stone management in all age group with acceptable complication rate.
Endoscopic combined intrarenal surgery (ECIRS) and Retrograde intrarenal surgery
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(RIRS)
With the advent of newer instruments, better visualization and increased experience, the use of Flexible ureterorenoscopy and laser-tripsy (FURSL) for renal stone removal
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in paediatric population is being attempted more often.42-44 We have performed RIRS and ECIRS in selected cases of older age children. However RIRS is an unfavorable
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modality in smaller children as placing a 9/11 Fr size ureteric access sheath may not be possible, and requires ureteric dilatation in most situations, with either ureteric prestenting under GA for at least 3 weeks to ensure passive dilation of the ureter, or active balloon dilation, which risks vesicoureteric reflux. Most cases need post-intervention stenting as well; therefore opting for RIRS entails a minimum of two or more GA sessions. Apart from many other limitations of FURSL, the endoscope is also very
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costly and fragile. A review by Ishii et al42 showed the incidence of preoperative stenting in FURSL, ranged from 26 to 96% with postoperative stenting requiring extraction in 67 - 98%. Ishii et al42 also compared the safety and efficacy of FURSL with ESWL and
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PCNL and recommended that large, multicentre trials would be required and that, at present, FURSL should be undertaken by experienced surgeons who are familiar with
Ureterorenoscopy (URS) for ureteric stones
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the difficulties encountered in the paediatric population.
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For ureteric stone management, mostly semi-rigid Ureterorenoscopes of size 4.5/6, 6/7.5 and 8/9.8 Fr are used, depending on the age and anatomy of the patient, which are more efficient and durable.
We evaluated our results of ureterorenoscopy for ureteric stone comparing pneumatic
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lithoclast (PL) v/s low power 30 watts Holmium:YAG laser (LL) in 266 RU and 406 RU respectively. The stone volume [(cm2) 0.7±0.5 vs 0.73±0.56], age [6.4±3.6 vs 6.4±3.8 yrs], stone location [71.8% vs 68.7% in the distal ureter] and prestenting [50% vs 58%]
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were all comparable. Both technologies were found to be safe, effective and with comparable outcome, having an overall clearance rate 91% v/s 89% with mean
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sessions of 1.2±0.5 vs 1.3±0.7 and complication rate (Clavien I and II) of 37% v/s 25%. However 100% required prestenting in the less than 1 year age in the PL group requiring minimum of 7 Fr. Ureterorenoscope. PL is found to be more cost effective than LL.45
Perurethral cystolithotripsy (PUCL)
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Bladder stones up to 3 cms can be fragmented with 100% success and minor complications.46 Pneumatic (Mechanical) lithoclast is the most cost effective technology and can safely be used through a 7 or 8 Fr. Ureterorenoscope.47 Lasers are costly, take
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longer time to disintegrate a similar sized stone; however it can be used through the fine caliber miniscope, and thus can be very safely used in babies less than one year of age.48
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A 10 -12 Fr. urethral foley is retained up to 24 hours to recover from the effects of general or caudal anesthesia. Postoperatively relief of symptoms, attainment of normal
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voiding and a normal pre and post void ultrasound bladder confirms a successful outcome.
Percutaneous (Suprapubic) Cystolithotripsy (PCCL)
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PCCL is performed for large stones between 2 – 5 cms to avoid risks of uretheral injury, long surgical and anesthesia time or where there is no urethral access.49 PCCL has a low morbidity, low complication rate, better cosmetic outcome, short hospital stay and
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post operative urethral catheterization compared to open cystolithotomy.50
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Stones with renal failure
About 15 % of our paediatric stone patients present with renal dysfunction.7 There are two major groups of patients who present with renal dysfunction. In the calculus oligo anuric group, children are younger (mean age 4.3+2.9 years). In the chronic calculus renal failure group, children are older (mean age of 6.9+3.4 years) and have been harboring renal dysfunction for an extended period.
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The initial management in many of these patients requires multidisciplinary intensive care management with resuscitation, ventilator support, immediate imaging, renal decompression and / or renal replacement therapy. Unfortunately many end up in renal
(ESRD) in 16% of the transplanted children are stones.51
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failure and require renal transplantation. In fact etiology of end stage renal disease
Majority of the patients in the calculus anuria group are managed by placement of JJ
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stent under general anaesthesia within few hours of their presentation leading to immediate urine formation. There are 24 hours services of multidisciplinary team
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including anaesthesia, paediatric nephrology and urology are available under one roof.
Conclusion
Pediatric Urolithiasis remains a significant health problem in low resource settings. Hot
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climate diarrheal diseases, diet poor in protein and calcium and rich in oxalates leads to formation of AAU and CaOX stones. Although the burden of bladder stones has reduced, upper tract stones remain highly prevalent. MIS is the mainstay of
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management since it offers excellent stone free rates in more than third of the patients. Open surgery is now limited to large stone burden in about 12% of the patients.
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Management of children who present in calculus renal failure continues to present a challenge and remains a major cause of morbidity and mortality from stone disease. The future holds promise only if preventable strategies are put in place by improving nutrition and dietary modification to eliminate risk factors causing these devastating stones.
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Declaration of interest None
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Funding Source
This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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removal in children. J Urol 1985 134(6):1166-7.
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39. Woodside JR, Stevens GF, Stark GL, Borden TA, Ball WS. Percutaneous stone
40. Desai MR, Sharma R, Mishra S, Sabnis RB, Stief C, Bader M. Single-step percutaneous nephrolithotomy (microperc): the initial clinical report. J Urol 2011
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186(1):140-5.
41. Sabnis RB, Chhabra JS, Ganpule AP, Abrol S, Desai MR. Current role of PCNL
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in pediatric urolithiasis. Curr Urol Reports 2014 15(7):1-8.
42. Ishii H, Griffin S, Somani BK. Flexible ureteroscopy and lasertripsy (FURSL) for paediatric renal calculi: results from a systematic review. J Pediatr Urol 2014 10(6):1020-5.
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43. Resorlu B, Unsal A, Tepeler A, et al. Comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in children with moderate-size kidney stones: results of multi-institutional analysis. Urology 2012 80(3):519-23.
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44. Bas O, Dede O, Aydogmus Y, et al. Comparison of retrograde intrarenal surgery and micro-percutaneous nephrolithotomy in moderately size pediatric kidney
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stones. J Endourol 2016
45. Sultan S. Abstract ESPU 2016, Harrogate UK 46. Khosa AS, Hussain M, Hussain M. Safety and efficacy of transurethral pneumatic lithotripsy for bladder calculi in children. J Pak Med Assoc 2012 62(12):1297.
47. Isen K, Em S, Vehbi K. et al. Management of bladder stones with pneumatic lithotripsy by using a ureteroscope in children: J Endourol 2008 22(5):1037-40.
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48. Prem RA, Mohammed M, Younis ABH et al, Holmium laser cystolithotripsy in children: initial experience. Canadian J Urol 2005 12(6):2880 -6. 49. Ahmadnia H, Kamalati A, Younesi M. Percutaneous treatment of bladder stone in
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children: 10 years experience, is blind access safe? Pediatr Surg Int 2013 29:725-8.
50. Holman E, Khan AM, Flasko T, et al. Endoscopic management of pediatric
51. Rizvi SA, Sultan S, Zafar MN, et al.
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urolithiasis in a developing country. Urology 2004 63:159-162.
Pediatric kidney transplantation in the
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developing world: challenges and solutions. Am J Transplant 2013 13:2441-
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2449.
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Era 1 (2009 – 2012)
%
983
28.6
n = 2955
No
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Open surgery
No
Era 2 (2013 – 2015)
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n = 3434
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Table: Management of paediatric urolithiasis in two eras
%
353
11.9
Pyelolithotomy
735
21.4
228
7.7
Nephrectomy
82
2.4
30
1.0
90
2.6
59
2.0
76
2.2
36
1.2
2451
71.4
2602
88.1
568
16.5
510
17.2
733
21.3
1047
35.4
Lap nephrectomy
25
0.7
25
0.85
URS + Laser
529
15.4
407
13.8
596
17.3
613
20.7
Ureterolithotomy
Minimally Invasive ESWL
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PCNL
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Cystolithotomy
PUCL + PCCL
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n = 21,390 Figure 2: Stone disease in infancy Figure 3: Stone in anatomically abnormal kidney
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Figure 4: Large stone burden at multiple sites
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Figure 1: Paediatric Urological Workload (1998 – 2015)
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Legends to Figures
Figure 5: Stones leading to perinephric abscess
Figure 6: Neglected stone with extreme disabilities
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Figure 7: Open surgery for large stone burden with renal dysfunction and sepsis
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Highlights Paediatric stone disease remains endemic in emerging economies
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Hot climate, poor nutrition and diarrheal disease are the main causative factors
•
Ammonium hydrogen urate and calcium oxalate stones remain highly prevalent
•
Hypocitraturia is a major risk factor
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MIS is now the mainstay of management of paediatric urolithiasis
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International Journal of Surgery Author Disclosure Form The following additional information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.
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Please state any conflicts of interest
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None
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Please state any sources of funding for your research
None
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Not Applicable
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Please state whether Ethical Approval was given, by whom and the relevant Judgement’s reference number
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Research Registration Unique Identifying Number (UIN) Please enter the name of the registry and the unique identifying number of the study. You can register your research at http://www.researchregistry.com to obtain your UIN if you have not already registered your study. This is mandatory for human studies only.
N/A
1
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors.
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S Adibul Hasan Rizvi - Study Design, Data Analysis, Writing
Sajid Sultan - Study Design, Data Collection, Data Analysis, Writing
Mirza Naqi Zafar - Study Design, Data Collection, Data Analysis, Writing
Sadaf Aba Umer - Study Design, Data Collection, Data Analysis, Writing
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Bashir Ahmed - Study Design, Data Collection, Data Analysis
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Anwar Naqvi - Study Design, Data Collection, Writing
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Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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Dr S Adibul Hasan Rizvi Professor and Director Sindh Institute of Urology and Transplantation Civil Hospital Karachi, Pakistan
2
S1743-9191(16)31094-9
DOI:
10.1016/j.ijsu.2016.11.085
Reference:
IJSU 3239
To appear in:
International Journal of Surgery
Received Date: 10 November 2016 Accepted Date: 10 November 2016
Please cite this article as: Rizvi SAH, Sultan S, Zafar MN, Aba Umar S, Ahmed B, Naqvi SAA, Paediatric urolithiasis in emerging economies, International Journal of Surgery (2016), doi: 10.1016/ j.ijsu.2016.11.085. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
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PAEDIATRIC UROLITHIASIS IN EMERGING ECONOMIES
Author names:
S Adibul Hasan Rizvi1, Sajid Sultan2, Mirza Naqi Zafar3, Sadaf Aba Umar2, Bashir
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Affiliations
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Ahmed2, S A Anwar Naqvi1
1. Department of Urology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
2. Department of Paediatric Urology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
Karachi, Pakistan
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Corresponding Author:
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3. Department of Pathology, Sindh Institute of Urology and Transplantation,
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Dr S Adibul Hasan Rizvi Professor and Director Sindh Institute of Urology and Transplantation, Civil Hospital Karachi - 7420, Pakistan Tel: +9221 32730351 Fax: 9221 99215469 Email: [email protected], [email protected]
Running title: Paediatric urolithiasis in …….
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Abstract Background Paediatric urolithiasis remains endemic in low resource countries. This review highlights
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the epidemiology, causation and management of urolithiasis in an Asian country in the context of emerging economies. Methods
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A literature review of recent articles with key words paediatric urolithiasis, developing countries, endemic stone disease, stone composition, metabolic risk factors,
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management of paediatric urolithiasis was undertaken and 51 relevant articles were selected with the main focus on experience of this centre in managing stone disease in the last two decades. Results
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Prevalence of paediatric urolithiasis is high upto 15% affecting children under 15 years with male predominance. Bladder stones still constitutes 10-70% of the burden. Etiology remains unknown where 55% are considered idiopathic, 25% metabolic, 7% infection
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and 12% due to anatomical abnormalities. Hot climate, poor nutrition, diarrheal diseases are the major causative factors. Chemical composition of stones showed CaOX in 30-
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63%, AAU in 17-55%, struvite in 8-9%, uric acid in 3-6% and cystine in 1%. Important metabolic risk factors are hypocitruaturia in 63-87%, hyperoxaluria in 40-43%, hypocalciuria in 20%, hyperuricosuria in 27%, hyperammonuria in 11-51% and hypovolumia in 31%.
Minimally invasive surgery is the mainstay of surgical management. ESWL provides excellent free rates of 84% for smaller stones. PCNL is the option for majority of renal
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stones with success rates of 89% for simple and 71.5% for complex stones. For bladder stones PUCL and PCCL success rates were 100%. URS for ureteric stones showed clearance rate of 90%. Open surgery is required in 12% of patients with large stone
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burden. Conclusion
Paediatric urolithiasis remains a devastating health problem in low resource settings.
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MIS offers relief to majority of patients with excellent stone free rates and short hospital stay. Preventable strategies have to be put in place by improving nutrition and
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eliminating risk factors by diet and medical intervention.
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Key words: Paediatric, urolithiasis, emerging, economies
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Introduction Paediatric urolithiasis remains endemic in low resource countries, mostly situated in the geographical region of the world, dubbed “The Afro-Asian Stone Belt”.1 The prevalence
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rates are high, with up to 15% of children under 15 years of age being affected, as compared to the 1 - 5% affected in developed countries.2-4 Endemic bladder calculi continue to contribute a major proportion of stones in the developing world from 10% in
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Nepal,5 and 21% in Tunisia,6 to 18% in Pakistan7 and 70% in Cameroon.8 However, in recent years a number of countries (namely Afghanistan, Iraq, Iran, Turkey and Egypt)
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have reported reductions in bladder stones ranging between 2 and 10%.9-13 In contrast to this bladder stones are rarely reported from the developed countries.14 Paediatric urolithiasis remains a significant urological problem in this region contributing upto 60% of the urological work load in our center.2 Furthermore, due to neglect 4 - 8% of cases with
end
stage
renal
disease.7
Most
of
the
studies
report
male
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present
predominance.2,7,15-17 The spectrum of paediatric urological workload from 1998 to 2015 recorded 21,390 patients where urolithiasis workload increased to 62% (Figure 1)
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This review presents the epidemiology of paediatric stones in emerging economies and focuses on the experience of our unit over the last 2 decades which indicates the
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spectrum of the disease, its devastating effects and the special issues in management of paediatric patients with stones in the context of a poor resource Asian country where the capita income is US$2535, expenditure on health is 1.3% of GNP and 60% of the people live below the poverty line on less than a dollar a day.18
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Epidemiology The overall risk of forming a stone depends upon several factors-geographical region, race, gender, climate and dietary habits.1 Etiologies remains largely unknown in
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emerging economies where 55% are considered idiopathic, 25% metabolic, 7% infection and 12% associated with anatomical abnormalities.2 In Korea, urinary tract abnormalities were identified in 9.5% and infection in 10%,17 and in Turkey infection
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was reported in 20%.16
In low resources countries, hot climate (with average temperature > 280C)19 and poor
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nutrition are the major causes of urolithiasis. Acidogenic diets high in cereal, low in protein, calcium and phosphate; with high urinary ammonium and urate ions result in ammonium acid urate (AAU) stones. In other situations high intake of oxalate from leaves and vegetable increases oxalate excretion, resulting in a mixture of (AAU) and
Stone Composition
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calcium oxalate (CaOX) stones.5,8,10-13,20,21
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Recent reports of stone analysis show continuing presence of AAU and CaOX in both renal and bladder stones.2,16,22 In our study where core and surface of stones were
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analyzed. AAU was found in the core of 43% of renal and 38% of bladder stones.2 These findings suggest a common cause of malnutrition, dehydration and recurrent diarrhea episodes for both renal and bladder stones. Of the different components CaOX was present in 30-63%, AAU in 17-58%, Calcium Phosphate (CaP) in 11-12%, Struvite in 8-9%, Uric Acid in 3-6% and Cystine in 1%.7,22 This contrasts from developed countries where calcium oxalate constitute 63% and the rest CaOX + CaP in 30%,
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struvite in 4% and cystine in 2%.23 In our study of 2039 stones, 726 (36%) were composed purely of a single compound and the rest 64% were mixtures. Composition of pure 570 renal stones showed variation in different age groups. In age group < 5 years
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AAU was found in 65% and CaOX in 18%, in age group 6-10 years, AAU in 19% and CaOX in 61% while in > 10 years CaOX was found in 70%, AAU in 10%.7
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Metabolic Risk Factors
Evaluation of urinary risk factors are important in the treatment and prevention of
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urolithiasis, especially in children where risk factors are identified in majority and can be corrected by dietary and medical intervention.7 In our center, two separate studies evaluating urinary risk factors in stone formers hypocitraturia was found in 63-87%, hyperoxaluria
in
40-43%,
hypercalciuria
in
11-26%,
hypocalciuria
in
20%,
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hyperuricosuria in 26-27%, hyperammonuria in 11-51% and low urinary volume in 931% of the children.2,7 A study from Turkey showed hypercalcuria in 41%, hypocitraturia in 40%, hyperoxaluria in 22% and hyperuricosuria in 9% and cystinuria in 4%.16 A
risk
factors
in
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recent study identified risk factors in genders and different age groups showed similar males
and
females
except
higher
rates
of
hyponatriuria,
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hypophosphatruria and hypocalciuria in females. Hyperuricosuria, hyponatriuria and hypovolemia were highest in children aged 1-5 years, 52%, 49% and 49% respectively as compared to 18%, 21% and 12% in children aged 11-15 years old.24 Another study from Korea, an economically advanced country showed that common risk factors in preschool age children, were hypercalcuria in 64% and hyperuricosuria in 36% and in school age children hypercalcuria in 47%, hyperuricosuria in 21% and hypomagnesuria
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in 16%.17 These findings differ from developed countries where hypocitraturia was reported in 7%, hyperoxaluria in 21% and hypercalciuria in 32%.25 These findings suggest that risk factors are different in age groups and while hypocitruria is a major
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finding in the low resource settings, hypercalciuria is more prevalent in developed countries leading to AAU stones in the former and CaOX in the later areas.
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Clinical Presentation
There have been reports of prenatal diagnosis of fetal urolithiasis. In our clinic the
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youngest patient presented at the age of 53 days and some may present in infancy (Figure 2) however the mean age is 6.5+ 3.6 years.26
The commonest presentation is abdominal pain, vague in young children and more localized flank pain in older children or ureteric colic. Other features include haematuria,
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dysuria, urgency, frequency, fever, strangury and/or urinary retention in case of vesical calculus, oligo-anuric in cases of acute or chronic renal failure. Some of them are associated with anatomical abnormalities including pelviureteric junction obstruction
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(PUJO), megaureter, bladder outlet obstruction, ectopia abnormalities of fusion like horseshoe kidney (Figure 3). Patients may present with large stone burden, atrophic
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renal cortex (Figure 4), pyonephrosis or even with xanthogranulomatous pyelonephritis (Figure 5). Those with extremes of diseases are anaemic, with stunted growth and osteodystrophy (Figure 6).26
Medical Management
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The goals of conservative treatment are to relieve pain and to prevent factors interfering with spontaneous stone expulsion such as oedema, spasm and infection.27,28 Medical expulsive therapy with alpha blockers is prescribed especially for lower ureteric stones
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5- 10 mm and post ESWL residual fragments. In paediatric age group inadequate data are available where in some studies beneficial outcomes have been attained, while in others expected benefits could not be gained.29-31
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The other indication for medical management is to prevent recurrence. Adequate hydration over the entire 24 hours and alkalinization of urine is recommended for
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patients with calcium oxalate, cystine, xanthine and urate stones. Specific medical therapy is advised on individual basis.
Surgical Management
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Historically all patients were managed by open surgery. Advances in technology and invention of paediatric size endoscopic instruments has created a paradigm shift from open surgical procedures to minimally invasive surgery (MIS).32 These include
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Extracorporeal Shock Wave Lithotripsy (ESWL), Percutaneous Nephrolithotomy (PCNL), Retrograde IntrarenalSurgery (RIRS), Ureterorenoscopy (URS), Laparoscopy
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and Robotics for renal and ureteric stones and per urethral and Percutaneous Cystolithoclast (PUCL/PCCL) for vesical calculi.33 In developed countries more than 95% of the patients are managed by MIS. Our experience from 2009 to 2012 showed 29.4% open surgery which has gradually reduced to 12% between 2013 and 2015 (Table). The main reason for this, besides anatomical abnormalities is complex and
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large stones with atrophic cortices neglected stones with renal failure and/or sepsis
Minimally invasive surgery Extracorporeal Shock Wave Lithotripsy (ESWL)
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overburdened by socioeconomic and geographical dynamics of the patient (Figure 7).34
Large size stones and even staghorn calculi have been treated with ESWL.35,36 A
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review of ESWL by Jeong et al showed that stone free rates range from 37% to 97% in different series but these data are difficult to interpret for comparison of the outcome
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because of the discrepancies in the available data with regards to number of shock waves administered, retreatment rates, stone free status and size of residual fragments. The conclusion was that ESWL outcome depends on type of lithotripter, operator skills, ESWL protocol used, stone characteristics including location, size, multiplicity and
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composition.37
Our initial experience with paediatric ESWL published in 2003 showed a stone free rate of 84% with a mean of 1.4 sessions given to a stone size ranging from 0.5 to 2.5 cms.26
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In a recent audit we analyzed clearance with different stone burdens, locations and densities. These results showed that there is increase in mean ESWL session with the
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increase in stone burden, lower calyceal location and higher density stones.26 Therefore to avoid repeated anesthesia and renal damage, we recommend ESWL where complete clearance is expected in single session.
Percutaneous Nephrolithotomy (PCNL)
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Fernstorm and Johanson in 1976 reported the first case of PCNL done in an adult.38 Woodside and associates in 1985 were the first to present PCNL in paediatric population with adult instruments.39 We also initially started off with adult sized
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nephroscopes (27 and 24 Fr) and gradually reduced it to 20, 18 and 15 Fr. Now we usually use MiniPCNL 12Fr Nephroscope and 14-16Fr working sheath in most situations. Although instruments as small as 4.8 and 8 Fr (MicroPerc.) have also been
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used40 but they go on to the other side of the spectrum and are used only for selected cases. Miniaturization of the PCNL instruments have facilitated its use in all age groups.
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Our indications for PCNL are stone size of 1.5cm or more with favourable anatomy, previous open surgery on the respective side and failed ESWL; or in stones where more than one session of ESWL is expected. From 2009 to 2014 we had successfully performed more than 1600 PCNL in children with mean age group of 7.4+3.41 years,
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35% of which were upto 5 years of age and 10% were less than 2 years of age.26 Micro PERC has been performed in selected cases.41,42 It allows direct puncture into relevant calyx via all seeing needle, no need for tract dilatation after puncture, with less
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radiation exposure, direct fragmentation/powdering of the stone in situ, thus requiring less operation time and lower complication rates. There are certain limitations of
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microperc, firstly that the vision is not as good as in mini PCNL because the irrigation fluid is intermittently pushed, there is no regular outflow passage, the stone or its fragments might migrate into a calyx where it becomes impossible or difficult to access. At the same time microperc instruments are costly and meant to be disposable making their universal use in emerging economies difficult. As an alternate we also use semirigid miniscope of 4-9 Fr.
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Tubeless PCNLs have been performed in cases where there is no significant bleeding, pelvicalyceal breach or residual fragments. However, we prefer to place 10 to 16 Fr nephrostomy tube postoperatively in all cases with supracostal approach.
calyceal stone to partial or complete staghorn stone.26
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The variety of stones managed at our centre with PCNL ranged from single pelvic or
For the purpose of evaluating our results of PCNL we divided our stone burden into
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simple (81%) and complex (19%) stones. The success rate of PCNL as monotherapy is higher in simple stones (89%) as compared to the complex stones (71.5%).26
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We evaluated our data of PCNL in 1135 renal units on the basis of age groups (Group A <3years, B= 3-5 years, C= 5 -10 years and D= 10 -15 years). Data revealed increase in stone volume (cm2) with increasing age i.e. 1.47± 0.9, 1.59±0.8, 2.17±1.6 and 2.69±1.8 respectively (p=<0.0001) with stone clearance of 94%, 89.2%, 87.4% and 81%
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respectively which revealed good stone clearance in all age groups, however there is some consistent decrease in stone clearance with increasing stone burden. Blood transfusion requirement and operative time were more in the complex stone
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cases. It was also observed that blood transfusion requirement was significantly less in older age group (Group D) where preoperaive hemoglobin (11.9±1.4) and hematocrit
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(35.3±4.2) was higher as compared to smaller children (Group A) with low preoperative hemoglobin (10.2±1.3), hematocrit (30.9±3.4) and low allowable blood loss. Blood transfusion requirement was consistently lower in all age groups with smaller sheath (<20 Fr) as compared to larger sheath (>20 Fr.) . The age group, stone volume and sheath size does not significantly affect the operative time.
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Our mean hospital stay is 4.1 + 3 days. Our patients tend to over stay in hospital as they come from far off areas where follow up facilities are not present. Majority of post-operative complications were in Clavien group I and II. Post operative
peri renal collections are seen in 1.5% of cases.
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complications included hydrothorax in 2%, urosepsis in 1.6% while intraperitoneal and
The effect on renal functions has been evaluated by creatinine levels in all cases and by
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DMSA scan in selected cases. We did not find any significant deterioration in renal function post operatively even in compromised kidneys or in patients with renal failure.
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To conclude PCNL is safe and effective method of renal stone management in all age group with acceptable complication rate.
Endoscopic combined intrarenal surgery (ECIRS) and Retrograde intrarenal surgery
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(RIRS)
With the advent of newer instruments, better visualization and increased experience, the use of Flexible ureterorenoscopy and laser-tripsy (FURSL) for renal stone removal
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in paediatric population is being attempted more often.42-44 We have performed RIRS and ECIRS in selected cases of older age children. However RIRS is an unfavorable
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modality in smaller children as placing a 9/11 Fr size ureteric access sheath may not be possible, and requires ureteric dilatation in most situations, with either ureteric prestenting under GA for at least 3 weeks to ensure passive dilation of the ureter, or active balloon dilation, which risks vesicoureteric reflux. Most cases need post-intervention stenting as well; therefore opting for RIRS entails a minimum of two or more GA sessions. Apart from many other limitations of FURSL, the endoscope is also very
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costly and fragile. A review by Ishii et al42 showed the incidence of preoperative stenting in FURSL, ranged from 26 to 96% with postoperative stenting requiring extraction in 67 - 98%. Ishii et al42 also compared the safety and efficacy of FURSL with ESWL and
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PCNL and recommended that large, multicentre trials would be required and that, at present, FURSL should be undertaken by experienced surgeons who are familiar with
Ureterorenoscopy (URS) for ureteric stones
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the difficulties encountered in the paediatric population.
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For ureteric stone management, mostly semi-rigid Ureterorenoscopes of size 4.5/6, 6/7.5 and 8/9.8 Fr are used, depending on the age and anatomy of the patient, which are more efficient and durable.
We evaluated our results of ureterorenoscopy for ureteric stone comparing pneumatic
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lithoclast (PL) v/s low power 30 watts Holmium:YAG laser (LL) in 266 RU and 406 RU respectively. The stone volume [(cm2) 0.7±0.5 vs 0.73±0.56], age [6.4±3.6 vs 6.4±3.8 yrs], stone location [71.8% vs 68.7% in the distal ureter] and prestenting [50% vs 58%]
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were all comparable. Both technologies were found to be safe, effective and with comparable outcome, having an overall clearance rate 91% v/s 89% with mean
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sessions of 1.2±0.5 vs 1.3±0.7 and complication rate (Clavien I and II) of 37% v/s 25%. However 100% required prestenting in the less than 1 year age in the PL group requiring minimum of 7 Fr. Ureterorenoscope. PL is found to be more cost effective than LL.45
Perurethral cystolithotripsy (PUCL)
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Bladder stones up to 3 cms can be fragmented with 100% success and minor complications.46 Pneumatic (Mechanical) lithoclast is the most cost effective technology and can safely be used through a 7 or 8 Fr. Ureterorenoscope.47 Lasers are costly, take
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longer time to disintegrate a similar sized stone; however it can be used through the fine caliber miniscope, and thus can be very safely used in babies less than one year of age.48
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A 10 -12 Fr. urethral foley is retained up to 24 hours to recover from the effects of general or caudal anesthesia. Postoperatively relief of symptoms, attainment of normal
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voiding and a normal pre and post void ultrasound bladder confirms a successful outcome.
Percutaneous (Suprapubic) Cystolithotripsy (PCCL)
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PCCL is performed for large stones between 2 – 5 cms to avoid risks of uretheral injury, long surgical and anesthesia time or where there is no urethral access.49 PCCL has a low morbidity, low complication rate, better cosmetic outcome, short hospital stay and
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post operative urethral catheterization compared to open cystolithotomy.50
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Stones with renal failure
About 15 % of our paediatric stone patients present with renal dysfunction.7 There are two major groups of patients who present with renal dysfunction. In the calculus oligo anuric group, children are younger (mean age 4.3+2.9 years). In the chronic calculus renal failure group, children are older (mean age of 6.9+3.4 years) and have been harboring renal dysfunction for an extended period.
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The initial management in many of these patients requires multidisciplinary intensive care management with resuscitation, ventilator support, immediate imaging, renal decompression and / or renal replacement therapy. Unfortunately many end up in renal
(ESRD) in 16% of the transplanted children are stones.51
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failure and require renal transplantation. In fact etiology of end stage renal disease
Majority of the patients in the calculus anuria group are managed by placement of JJ
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stent under general anaesthesia within few hours of their presentation leading to immediate urine formation. There are 24 hours services of multidisciplinary team
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including anaesthesia, paediatric nephrology and urology are available under one roof.
Conclusion
Pediatric Urolithiasis remains a significant health problem in low resource settings. Hot
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climate diarrheal diseases, diet poor in protein and calcium and rich in oxalates leads to formation of AAU and CaOX stones. Although the burden of bladder stones has reduced, upper tract stones remain highly prevalent. MIS is the mainstay of
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management since it offers excellent stone free rates in more than third of the patients. Open surgery is now limited to large stone burden in about 12% of the patients.
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Management of children who present in calculus renal failure continues to present a challenge and remains a major cause of morbidity and mortality from stone disease. The future holds promise only if preventable strategies are put in place by improving nutrition and dietary modification to eliminate risk factors causing these devastating stones.
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Declaration of interest None
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Funding Source
This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
References
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48. Prem RA, Mohammed M, Younis ABH et al, Holmium laser cystolithotripsy in children: initial experience. Canadian J Urol 2005 12(6):2880 -6. 49. Ahmadnia H, Kamalati A, Younesi M. Percutaneous treatment of bladder stone in
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Pediatric kidney transplantation in the
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developing world: challenges and solutions. Am J Transplant 2013 13:2441-
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Era 1 (2009 – 2012)
%
983
28.6
n = 2955
No
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Open surgery
No
Era 2 (2013 – 2015)
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n = 3434
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Table: Management of paediatric urolithiasis in two eras
%
353
11.9
Pyelolithotomy
735
21.4
228
7.7
Nephrectomy
82
2.4
30
1.0
90
2.6
59
2.0
76
2.2
36
1.2
2451
71.4
2602
88.1
568
16.5
510
17.2
733
21.3
1047
35.4
Lap nephrectomy
25
0.7
25
0.85
URS + Laser
529
15.4
407
13.8
596
17.3
613
20.7
Ureterolithotomy
Minimally Invasive ESWL
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PCNL
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Cystolithotomy
PUCL + PCCL
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n = 21,390 Figure 2: Stone disease in infancy Figure 3: Stone in anatomically abnormal kidney
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Figure 4: Large stone burden at multiple sites
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Figure 1: Paediatric Urological Workload (1998 – 2015)
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Figure 5: Stones leading to perinephric abscess
Figure 6: Neglected stone with extreme disabilities
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Figure 7: Open surgery for large stone burden with renal dysfunction and sepsis
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Highlights Paediatric stone disease remains endemic in emerging economies
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Hot climate, poor nutrition and diarrheal disease are the main causative factors
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Ammonium hydrogen urate and calcium oxalate stones remain highly prevalent
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Hypocitraturia is a major risk factor
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MIS is now the mainstay of management of paediatric urolithiasis
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International Journal of Surgery Author Disclosure Form The following additional information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors.
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S Adibul Hasan Rizvi - Study Design, Data Analysis, Writing
Sajid Sultan - Study Design, Data Collection, Data Analysis, Writing
Mirza Naqi Zafar - Study Design, Data Collection, Data Analysis, Writing
Sadaf Aba Umer - Study Design, Data Collection, Data Analysis, Writing
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Bashir Ahmed - Study Design, Data Collection, Data Analysis
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Anwar Naqvi - Study Design, Data Collection, Writing
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Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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Dr S Adibul Hasan Rizvi Professor and Director Sindh Institute of Urology and Transplantation Civil Hospital Karachi, Pakistan
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