Objectives: We report on the long-term follow-up of managing allograft stones at a single tertiary referral institution and review the relevant literature.

Materials and Methods: A retrospective analysis of renal allograft recipient charts was performed to identify patients who developed allograft lithiasis between 1974 and 2009. Patient and stone characteristics, diagnoses, treatments, and outcomes were described.

Results: Sixteen patients developed 22 stones after a median follow-up of 170 months (range, 51-351 mo). The mean (standard deviation) and median diameter of the stones were 13.8 (8.5) mm and 11 mm. Among these, 3 stones were treated conservatively, 3 by shock-wave lithotripsy, and 7 by cystolitholapaxy. Seven patients underwent percutaneous treatment in the form of percutaneous nephrostomy tube fixation and spontaneous passage of stone (1 stone), shock-wave lithotripsy (1 stone), antegrade stenting (1 stone), and percutaneous nephrolithotomy (6 stones). All patients were stone free after treatment, except for 2 patients whose stones were stable and peripheral on long-term follow-up.

Conclusions: Allograft lithiasis requires a multimodal treatment tailored according to stone and graft characteristics. Protocols regarding spontaneous pas­sage can be adopted if there is no harm to the graft and the patient is compliant. Careful attention to the anatomy during percutaneous nephrostomy tube placement is mandatory to avoid intestinal loop injury. A more attentive follow-up is required for early stone management.

Key words : Kidney transplantation, Percutaneous nephrolithotomy, Treatment

Introduction

Renal transplant is the optimal treatment option for patients with end-stage renal disease offering better physical, socioeconomic, and psychologic outcomes.¹ Urolithiasis is an uncommon sequela after renal transplant with a varying incidence of up to 3%.^2-9 Stones in the allograft may be donor gifted or de novo, which develop after transplant. A donor with a stone-bearing kidney is no longer a contrain­dication for donation provided that certain criteria are met,¹⁰ a term called “donor-gifted nephrolithiasis.” These stones could be managed conservatively, by ex vivo stone extraction, or by shock-wave lithotripsy (SWL).^11,12

Many risk factors have been identified for de novo stone development in the recipient side, including urologic and metabolic factors.^13-15 Furthermore, multimodal management options have been reported in the literature, particularly the use of percutaneous nephrolithotomy (PNL) in clearing allograft lithiasis.^13-17 Nevertheless, because the incidence is relatively low, data are still lacking and further investigations are warranted. In addition, there is a paucity of data about the long-term outcomes regarding the effects of PNL on graft outcomes and stone recurrence.

The objective of this study was to report on our long-term experience of treating non-donor-gifted stones in renal allograft patients seen at a single institution. In addition, a literature review of the current diagnostic and treatment modalities of de novo allograft stones was performed.

Materials and Methods

After we received institutional review board approval, a retrospective review of our renal transplant database from 1976 until 2009 was performed to identify recipients who developed stone disease. Recipients who received stones from their donors were excluded. Patient demographics, stone characteristics, treatment types, operative findings, and complications were included for analyses.

For stone recurrence, stone follow-up was calculated as the interval between the time of stone treatment and the date of last imaging. Imaging included ultrasonography and noncontrast computerized tomography (NCCT) of the urinary tract. From imaging, stone status was determined as recurrent, not recurrent, or the same as the last intervention. Graft and patient outcomes were determined. For deceased patients, we used the data available at last visit. Follow-up period was calculated as the interval between the date of last visit and date of stone treatment. In addition, creatinine level at last follow-up was retrieved.

For statistical analyses, we used the commercially available software SPSS Software (SPSS: An IBM Company, version 15.0, IBM Corporation, Armonk, NY, USA). Mann-Whitney U test was used to calculate differences in medians between nonparametric variables, and P < .05 was considered significant.

Results

Patient demographics and stone characteristics
Of the 1208 allotransplant recipients seen at our center during the period of analyses, 16 patients (1.3%) developed de novo graft stones. Mean (SD) recipient age at time of stone presentation was 41 (12) years. Among these patients with de novo stone formation, all but 2 were males and all their donors but 3 were females. All 16 patients received kidneys from living-related donors, except for 1 patient who received a kidney from an emotionally related donor (spouse). All recipients received a first renal allotransplant. Original kidney disease is presented in Table 1.

Twenty-two stones developed in these 16 recipients. Of these, 18 stones (81.8%) were radio-opaque and 4 stones (18.2%) were radiolucent. The mean (SD) and medium stone size at maximum diameter were 13.8 (8.5) mm and 11 mm (range, 5-40 mm). Stones were renal in 13 cases (59.1%), ureteral in 3 cases (13.6%), and vesical in 6 cases (27.3%). Table 2 presents the various stone characteristics.

Treatment modalities
Twenty-two procedures were performed for the 16 renal allograft recipients. In 1 patient, one SWL and 3 separate PNLs were carried out.

Conservative management
A watchful waiting policy was adopted for a 10-mm radiolucent stone in a peripheral middle calyx of the allograft with no change in size until the time of last follow-up despite attempts of chemolysis. However, conservative treatment was successful in 2 patients with the stones in the lower calyx and ureter as the stones passed spontaneously without further intervention.

Shock-wave lithotripsy
Shock-wave lithotripsy was successful for 3 radio-opaque caliceal stones, which had complete disintegration and passage of gravels without complications.

Percutaneous nephrostomy tube and auxiliary procedure
Percutaneous management of the stones was required for 9 stones in 7 patients. Percutaneous nephrostomy tube (PCN) was fixed in 1 patient diagnosed with a middle caliceal radio-opaque stone; however, the stone was mobile and obstructed the upper ureter. After PCN fixation, the stone spontaneously passed 7 days later. In 1 patient with a radio-opaque ureteral stone, a PCN was fixed and SWL was attempted for the stone, resulting in complete disintegration and complete passage of the fragments. In another patient, a PCN with antegrade double J stent was fixed without intervention of a stone in the upper calyx. This patient was diagnosed with chronic allograft nephropathy; therefore, there was no attempt for stone removal and the patient was kept under close observation.

Percutaneous nephrolithotomy
Six PNL pro­cedures were conducted in 4 patients. An ultraso­nography-guided puncture of the graft pelvicaliceal system to place the PCN tube was conducted by an interventional radiologist in a well-equipped angiography room. In 1 patient, the stone was directly punctured by a biplanar fluoroscopy into the upper calyx. In 2 patients, the PCN site was not suitable for extraction of the stone and a second intraoperative puncture to extract the stones was carried out. In 3 patients, an antegrade double J stent fixation was performed and removed 2 weeks later.

All procedures were completed successfully with complete stone clearance, as evidenced by postoperative NCCT and confirmed by antegrade pyelography. Postoperative complications were reported in 3 patients, which included 2 with grade I and 1 with grade IIIb modified Clavien-Dindo classification.¹⁸ One patient developed hematuria necessitating clamping of the PCN and postponing its removal for 2 days. No blood transfusion or any additional procedures were needed. In another patient, excessive urine leakage developed but resolved spontaneously. In the third patient, abdominal distention and recurrent vomiting occurred secondary to intestinal obstruction, as confirmed by a plain radiographic scan done in both the erect and supine positions. The cause was PCN-induced injury to the intestinal loops. The patient required surgical treatment; under fluoroscopy guidance, the PCN was readjusted and the patient received another operation 2 weeks later by PNL that ended successfully.

Cystolitholapaxy
Seven vesical stones were managed by cystolitholapaxy. One of these stones was initially diagnosed in the distal ureter and passed spontaneously to the bladder.

Follow-up
After a median follow-up of 63 months (range, 12-184 mo), 14 patients were free of stones and 2 patients had the same stone burden as the previous treatment time. The median serum creatinine level was 1.9 mg/dL (interquartile range = 3.98; range, 0.7-9 mg/dL) at last follow-up. Table 3 presents patient status at last follow-up.

Discussion

De novo allograft stones continue to be a rare oc­currence after renal transplant despite identification of multiple risk factors for development.^19,20 A metabolic change in the serum and urine of the renal transplant recipient may be a favoring factor for stone development. Hyperparathyroidism, lower citraturia,⁹ higher oxaluria,²¹ excessive alkaline urine pH,¹⁹ and cyclosporine-induced hyperuricosuria²² are contributing factors to different types of stone development, namely, calcium oxalate, calcium phosphate, and uric acid stones. In addition, various urologic risk factors have been identified, including infection by urea-splitting microorganisms, voiding dysfunction, retained double J stents, infravesical obstruction, and ureteral obstruction.^14,16,23,24

The reported incidence of 1.3% in our series is comparable to the rates reported in the literature.^19,21,24 Recently, a decline in the rate of urolithiasis was reported by Verrier and associates until it had stabilized around 0.6%.²⁴ Different hypotheses have been proposed to explain this relatively low incidence of allograft urolithiasis. Dumoulin and associates demonstrated that there is a lack of increased urinary calcium oxalate supersaturation in long-term kidney transplant recipients.²¹ In addition, Rhee and associates reported increases in urinary interleukin 6 levels in patients with urolithiasis and its usefulness as a potential marker for stone disease,¹⁹ suggesting a role of cyclosporine, as an interleukin 2 inhibitor, in the development of stones. Furthermore, the graft recipients were found to have lower calciuria, lower uricosuria, and larger urine volume than the healthy control patients, suggesting a combination of these factors in preventing lithiasis development.²¹

Allograft lithiasis management is variable and multimodal according to stone characteristics and influence on graft and patient outcomes. To date, no definite criteria have been specified for adopting conservative treatment. Dalgic and associates reported no surgical intervention for 2 stones developed in their series.³ Similarly, this policy has been reported in many series, although this was judged only by surgeon opinion with no specified characteristics.^14,19

Martin and associates acknowledged conser­vative treatment for stones of < 4 mm in the presence of good diuresis.²⁵ Although the stones reported in their study were from the donor graft, this principle can be applied to de novo allograft stones. For example, in our study, a 7-mm stone passed spontaneously. However, not every stone below 4 mm can pass, which was exemplified in one of our patients who had a 3-mm stone that failed to pass spontaneously and was retrieved by ureteroscopy (PCN fixation and SWL).¹³ The cut-off value of 4 mm has not been the standard, as long as the stone is peripheral, diuresis is good, and the patient is highly compliant. Similarly, Klingler and associates reported conservative treatment for 3 stones, in which 2 measured 4 mm and the other measured 9 mm.²⁶

Various factors might contribute to a less successful outcome with SWL in clearing allograft stones. A pelvic location of the transplanted kidney in the iliac fossa makes it in close proximity to the pelvic bones, with difficult localization. In addition, an abnormal location of the transplanted ureteral orifice adds to the difficulty of retrograde access to manage “steinstrasse” if the latter obstructs the ureter. Rifaioglu and associates described 2 transplant patients who underwent PNL after SWL failure.¹⁴ Nevertheless, we reported successful outcomes after SWL for 3 patients with calyceal stones and 1 patient with PCN coverage. All stones were completely cleared with free passage of fragments through the urethra. In general, a radio-opaque nonobstructing calculus of less than 15 mm is suitable for SWL.^5,26 Even in cases of graft obstruction, a rapid relief with PCN followed by SWL appears to be optimal for stone clearance.⁵

Retrograde access to the transplanted ureter is technically demanding because of the domal location of ureteral orifice. However, a successful report of retrograde ureteroscopy has been published.²⁷ In our series, none of our patients required a retrograde intervention.

Percutaneous nephrolithotomy continues to be the optimal option for clearing allograft calculi measuring more than 1.5 mm because of its ability to clear all stone fragments.5 In addition, the superficial location of a renal allograft to the abdominal wall might contribute to an easier procedure. Furthermore, PNL has been performed in the early postoperative period with minimal morbidity.²⁸ Nevertheless, certain precautions have to be addressed. Ultrasonography guidance is mandatory, as fluoroscopy alone might be insufficient because of difficult retrograde access. Therefore, some authors recommended scheduling a NCCT before PCN placement.¹³

During the track dilatation, difficulty is expected because of the dense perinephric scarring. There is also the possibility for iliac vessel injury because of the abnormally located pelvic graft. Fortunately, during PCN procedures reported in our study, no significant difficulty was noted during track dilation. This might be because of the already well-developed track, as usually the PNL is performed in a second stage after PCN placement by the radiologist. We encountered a case of postoperative bleeding. Although blood transfusion was not required, a gentle manipulation should be conducted so that no vigorous change to the axis of the graft occurs, which would predispose to bleeding. The bleeding risk can also be increased by platelet dysfunction in the early transplant period from preexisting renal failure.¹⁴ We reported excessive urinary leakage after PCN removal. This could have been prevented by antegrade double J stent fixation during the procedure. Nevertheless, antegrade stenting remains an option tailored according to operative details and surgeon preference.

The question remains regarding why stones can develop in renal transplant recipients and which patients need a more invasive intervention. In our institution, recipients are extensively followed for the first year after transplant, and thereafter they are followed-up at relatively longer intervals. Therefore, theoretically speaking, a stone can be detected as soon as it develops and becomes visualized by ultrasonography. Meanwhile, later after transplant, the absence of the renal colic sensation because of denervated allograft may contribute to silent stone development and late presentation, unless the stone obstructs the graft ureter and causes anuria or hematuria. Although this observation has to be confirmed, a regular and strict follow-up is mandatory, with the transplant surgeon keeping in mind the possibility of stone development.

In the present study, complete clearance of stones with no significant morbidity was shown, a finding that is comparable to previously published cases.^13,14,16,24 Similarly, the rare incidence of stone recurrence after treatment in the present study is in concordance with other reports.^13,14 In addition, in our study as well as in others, no graft loss because of stone disease or its treatment was shown.^13,14

Several limitations in our study should be mentioned. The inherent criteria of a retrospective analysis are the main drawbacks. In addition, our sample size (number of patients) was relatively low. However, as with all previous reports, the rarity of this finding results in the lack of a large enough study population for performing adequate statistical analyses and drawing solid conclusions. In this report, we were not able to identify risk factors for stone development except for 2 cases, where the stones developed in the bladder secondary to nylon sutures. In previous reports, the risk factors for stone disease may not be known.¹³

Conclusions

De novo allograft lithiasis is a rare occasion and requires a multimodal management tailored according to stone, graft, and patient characteristics. Conservative treatment can be adopted in stones up to 10 mm in diameter, especially if there is good diuresis, patient compliance, and no obstruction. Shock-wave lithotripsy achieves satisfactory out­comes in stones of less than 15 mm, and PNL is optimal for stones that are more than 15 mm. Fixation of PCN should be performed under ultrasonographic guidance with preoperative NCCT to avoid bowel injury. Patients should be carefully followed, keeping in mind the possibility of stone disease development even when no risk factors are present.

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