Stesura Seveso 257Archivio Italiano di Urologia e Andrologia 2014; 86, 4 ORIGINAL PAPER Urolithiasis in renal transplantation: Diagnosis and management Elisa Cicerello, Franco Merlo, Mario Mangano, Giandavide Cova, Luigi Maccatrozzo Unità Complessa di Urologia, Ospedale Ca’ Foncello, Treviso, Italy Obiectives: To report our experience of diagnosis and multimodal management of urolithiasis in renal transplantation. Patients and Methods: From January 1995 to December 2012, 953 patients underwent renal transplantation in the Kidney Transplant Unit of Treviso General Hospital. Ten (10%) of them developed urinary calculi and were referred at our institution. Their mode of presentation, investigation and treatment were recorded. Results: Seven had renal and 3 ureteral calculi. Urolithiasis was incidentally discovered on routine ultra- sound in 6 patients, 1 presented with oliguria, 1 with anuria and acute renal failure and in 2 urolithiasis was found at removal of the ureteral stent. Nephrostomy tube was placed in 5 patients. Hypercalcemia with hyper- parathyroidism (HPT) was present in 5 patients and hyperuricemia in 3. Two patients were primary treated by shock wave lithotripsy (SWL) and one of them was stone-free after two sessions. Two patients, one with multiple pielocaliceal calculi and the other with staghorn calculus in the lower calyx, were treated with percuta- neous nephrolitothotomy (PCNL). Three patients were treated by ureteroscopy (URS) and in one of them two treatments were carried out. One patient had calculus impacted in the uretero-vesical anastomosis and surgical ureterolithotomy with re-do ureterocystoneostomy was performed after failure of URS. Two patients with calculi discovered at removal of the ureteral stent were treated by URS. Conclusions: The incidence of urolithiasis in renal transplantation is uncommon. In the most of patients the condition occurs without pain. Metabolic anomalies and medical treatment after renal transplan- tation may cause stone formation. Advancements in endourology and interventional radiology have influ- enced the management of urolithiasis that can be actual- ly treated with a minimal incidence of risk for the renal allograft. KEY WORDS: Urolithiasis management, Renal transplantation. Submitted 15 March 2014; Accepted 30 June 2014 Summary No conflict of interest declared. In the most of cases stone formation appears to form “de novo” after renal transplantation, although some studies suggest that the calculi are more often transplanted with the graft to the recipient (1, 5, 6). Theremore, metabolic anomalies causing stone formation could be present in allograft rather than native kidneys (7). Urolithiasis is often asymptomatic and the clinicians are not able to diag- nose urinary calculi in renal transplant at an earlier stage. Neverthless, the prompt diagnosis and the subsequently stone removal is necessary to prevent adverse effects on a solitary kidney whose renal function is often borderline. Today the development of endourological tecniques for calculi management and interventional radiology for the emergency management of acute obstruction have mini- mized the potential risk for renal graft. However, such minimally invasive procedures could be performed only in centers that are well equipped and have expertise to offer the appropriate treatment. We evaluated our experience of renal transplant patients with urolithiasis, regarding the risk factors associated with the condition and the management by endourolog- ical and open procedures. PATIENTS AND METHODS From January 1995 to December 2012, 953 patiens underwent renal transplantation in the Kidney Transplant Unit of Treviso General Hospital. The transplant were per- formed in the right or left iliac fossa with vascular anas- tomosis to the iliac artery and vein. Ureteral implantation (ureterocistoneostomy) was performed using the extrav- esical tecnique of Lich-Gregoir, with routine use of ureteral catheter that was removed 4-6 weeks later by flexible cystoscopy. Immunosoppression varied with the transplantation era. Ten (10%) of them developed urinary calculi and referred to our institution. For the diagnosis of urolithi- asis one or more of the following investigations were required: ultrasonography (US), plain abdominal X-ray, intravenous urography (IVP), nephrostography and com- puted tomography (CT). Chemistry profile including serum analysis for urea, creatinine, calcium, phosphate, urate, sodium, potassium, phosphate, alkaline phos- phatase and parathyroid hormon and urine analysis (routine and culture) were performed. Management of DOI: 10.4081/aiua.2014.4.257 INTRODUCTION Urolithiasis in renal transplantation is uncommon, with reported prevalence rates between 0.2% and 6.3% (1-4). Cicerello_Stesura Seveso 15/01/15 12:58 Pagina 257 Archivio Italiano di Urologia e Andrologia 2014; 86, 4 E. Cicerello, F. Merlo, M. Mangano, G. Cova, L. Maccatrozzo 258 these calculi involved shock wave lithotripsy (SWL), ureteroscopy (URS), percutaneous nephrolithotomy (PCNL) and ureterolithotomy with re-do ureterocistoneostomy. RESULTS Six patients were females and 4 males. Ages ranged from 31 to 59 years (mean 43 years). Seven had renal and 3 ureteral calculi. The overall diameter range was 0.7-3 cm (mean 1.2 cm). Urolithiasis was incidentally discovered on routine ultrasound in 6 patients with calculi located in the calices. One patient with multiple pielocaliceal cal- culi presented with oliguria and 1 with calculus impact- ed in the vesico-ureteral anastomosis with anuria and acute renal failure. In 2 patients urolithiasis was found at removal of the ureteral stent. Nephrostomy tube was quickly placed in the following cases: calculi causing oliguria, anuria or hydronephrosis and in 2 patients with calculi discovered removing ureteral stent. Hypercalcemia with hyperparathiroidism was present in 5 patients and hyperuricemia in 3. Four patients had uri- nary tract infections (UTIs), in 3 infecting organism was E. Coli and in 1 Proteus mirabilis (Table 1). Two patients were primary treated by SWL (Lithostar plus Siemens) in prone position and one of them with calculus in the upper calyx was stone free after two ses- sions, while in the other with calculus in the lower calyx URS was performed after failure of SWL. Two patients, one with multiple calculi and the other with staghorn in the lower calyx, were treated with PCNL. Three patients were treated with ureteroscopy and in one of them two treatments were carried out. One patient had calculus impacted in the uretero-vesical anastomosis and ureterolithotomy with re-do ureterocistoneostomy was performed after the failure of URS (Table 2). DISCUSSION Urolithiasis in patients with kidney transplantation is often asymptomatic. A possible explanation for this observation is denervation of the transplanted graft (1, 2, 5, 8). In some cases, concomitant increase of serum cre- atinine should be considered with caution to avoid a misdiagnosis of episode of acute rejection (9). In our experience urolithiasis was incidentally discovered on routine ultrasound in one-half of them. The presence of uncomplicated calculus is not a contraindication to uro- logical procedures. In fact, as it has previously been reported, calculus in the kidney transplantation, such as in patients with solitary kidney, must be removed in every case because it may cause urinary infection or pass in the ureter causing anuria with acute renal failure (10). Previous studies have shown that SWL is the treatment of choice for unobstructive calculi with diameter less than 1.5 cm (11). However, there are potential difficul- ties in locating transplant calculi because of the overlying bony pelvis which may limit visualization of stones on fluoroscopy as well mitigate the propagation of shock waves energy. Prone position with ultrasound targeting may counter these disadvantages (12). An additional dis- advantage of SWL is the need for multiple sessions. Challacombe et al. have reported stone free rate in 13 patients with kidney transplantation and urolithiasis who underwent SWL, but in 8 of them multiple proce- dures were required. In our study two patients with asymptomatic calculi were primarily treated by SWL and Pts Ex Age Clinics Metabolic anomalies UTIs 1 F 31 oliguria HPT no 2 F 41 anuria HPT yes 3 M 45 renal US hyperuricemia yes 4 M 47 renal US no no 5 F 48 hydronephrosis hyperuricemia no 6 M 51 renal US no no 7 F 59 renal US HPT no 8 F 34 failure to remove DJ HPT yes 9 F 42 failure to remove DJ HPT yes 10 M 35 renal US hyperuricemia no Table 1. Characteristic of patients with renal transplantation and urolithiasis. Diameter Location Nephrostomy SWL URS PCN Ureterolithotomy (cm) with re-do ureterocystoneostomy 1 3 pielocaliceal yes yes 2 1.3 ureteral-vesical anastomosis yes failure yes 3 0.8 lower calix no failure yes 4 0.7 upper calix no yes 5 1.2 UPJ yes yes 6 1.1 upper calix no yes 7 1.0 middle calix no yes 8 1.4 distal ureter yes yes 9 1.5 distal ureter yes yes 10 1.2 lower calix no yes Table 2. Characteristic of calculi and urologic treatments. Cicerello_Stesura Seveso 15/01/15 12:58 Pagina 258 only one of them was stone-free. In both cases not more than 2 treatments were performed and URS was carried out in 1 patient after failure of SWL. Actually URS is the treatment of choice emerging as for small renal and ureteral calculi within kidneys transplan- tation (13). Access to these kidneys may be difficult because of their position in the pelvis and the location of the neo-ureteric orifice. Using both retrograde and antero- grade approaches, stone-free rate of the calculi in kidney transplantion could be obtained with minor complica- tions. We used both approaches in those patients with nephrostomy tube placed because urinary tract obstruc- tion and after failure to remove ureteral stent, while in the other cases only a retrograde approach was performed. However, as endoscopes have become increasingly minia- turized and deflectable, ureteral dilation has become unnecessary and all urinary collecting system can be accessed in a straightforward manner. In our experience semirigid retrograde URS was performed over a decade ago and the access to the ureter was facilitated with angled catheters and hydrophilic wires and ureteral orifice was balloon dilated with a high-pressure balloon dilator. Nowday, URS has carried out by flexible ureteroscopy. This method and disintegration of calculi with holmium laser is an effective method for the treatment of urolithia- sis in kidney transplantion and the access to the neo- ureteric orifice and to the pelvis may be achieved by intro- ducing the ureteroscope over a guide wire. Instruments with “active” secondary deflection are particularly useful in reaching calculi in transplanted kidney. In our experience, according to Hymas et al., we could suggest that URS is a viable treatment modality as well. For renal calculi with diameter greater then 1.5 cm, PCNL has been effective to remove all stone fragments in one procedure. The superficial position of transplanted kidney makes straightforward percutaneous procedure so that may be justified by maximal stone clearance and carried out in special centers because of the greater risk in patients with solitary kidney (14). In fact, due to the proximity of the bowels to the renal graft, the risk of perforation is high. Furthemore, there have been reports of allograft renal artery injury and arte- riovenous fistulae after trans abdominal access. Theremore, tract dilatation can become difficult to per- form because of the presence of a fibrous sheath and lim- ited mobility of the kidney during rigid nephroscopy (15). In our experience percutaneous nephrolithotomy was only carried out in two patients, one with staghorn calculus located in the lower calyx and the other with multiple pielocaliceal calculi. Previous reports have reported that calculi occurring in transplanted kidney are composed of calcium oxalate and calcium phosphate (5, 7). Infected stone consisting of struvite or mixed form of struvite and calcium phos- phate are also relatively common (4, 16). Lithogenic fac- tors include hyperparathyroidsm, hypercalciuria, hypoc- itraturia, hyperuricosuria, chronic urinary tract infection (UTIs), urinary stasis, incrusted double J stent and nidus such as nonabsorbable suture (7). Hyperparathyroidism has been reported the most important factor in calculus formation in kidney transplantion (16, 17). Medical treatments, such as cinecalcet hydrochloride, have been shown to be efficacious in treating hyperparathyroidism by soppression of the action of parathyroid hormone. However, if the hyperparathiroidism persist after 1 or 2 years, a parathyroidectomy must be carried out (2). Furthemore, immunosoppressive agents may have a con- tributory role in the cause of calculi in transplant. Ciclosporin, a calcineurin inhibitor used more common- ly in the past, is associated with hypeuricemia (18). However, this has not been necessarily associated to an an increase in uric acid calculi risk (16, 19). Ciclosporin has been superseded by tacrolimus, another calcineurin inhibitor which has not been shown to affect uric acid levels (20). Stapenhorst et al. have reported that cal- cineurin inhibitor, treatment can lead to hypocitraturia, whereas hyperoxaluria can be primarily the result of a removal of significant body oxalate stores deposited dur- ing the dialysis (21). These authors have suggested to treat these patients with alkaline citrate to increase their urinary citrate excretion and urinary solubility index decreasing the risk for cal- culi formation. In our experience hyperparathiroidism was present in 5 patients and hyperuricemia in 3, but complete metabolic assessment was not carried out in all patients. 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Hyperuricemia in adult renal allograft recipients: prevalence and predictors. Transplant Proc. 2012; 44:2369-72. 21.Stapenhorst L, Sassen R, Beck B, et al. Hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation. Pediatr Nephrol 2005; 20:652-656. 22.Cicerello E, Merlo F, Fandella A, Maccatrozzo L. Metabolic eval- uation of infected urolithiasis. Eur Urol. suppl 2009; 8:2005. Correspondence Elisa Cicerello, MD elisa.cicerello@tin.it Franco Merlo, MD f.merlo@ulss.tv.it Mario Mangano, MD m.mangano@ulss.tv.it Giandavide Cova, MD gd.cova@ulss.tv.it Luigi Maccatrozzo, MD l.maccatrozzo@ulss.tv.it Unità Complessa di Urologia, Ospedale Cà Foncello Piazza Ospedale - 31100 Treviso, Italy Cicerello_Stesura Seveso 15/01/15 12:58 Pagina 260