- Email: [email protected]
Living Renal Donor Allograft Lithiasis: A Review of Stone Related Morbidity in Donors and Recipients
Living Renal Donor Allograft Lithiasis: A Review of Stone Related Morbidity in Donors and Recipients Andrew M. Strang,* Mark E. Lockhart, Christopher L. Amling, Peter N. Kolettis and John R. Burns From the Division of Urology and Department of Radiology (MEL), University of Alabama at Birmingham, Birmingham, Alabama
Purpose: The use of screening computerized tomography angiography has resulted in the increased detection of incidental nephrolithiasis in potential living renal donor candidates. We reviewed current acceptance guidelines for donors with stone disease as well as data on stone related outcomes in donors with stone disease and recipients who received a kidney with a stone left in situ. Materials and Methods: We performed a medical literature search in English using MEDLINE®/PubMed® that addressed renal donor allograft lithiasis. We then analyzed the literature with respect to the historical evolution of this concept, current guidelines regarding the acceptance of donors with stones and stone related morbidity in recipients and donors. Results: The prevalence of asymptomatic solitary nephrolithiasis has increased with the widespread use of screening computerized tomography angiography during renal donor evaluation. Few studies have addressed the risk of stone related morbidity in donors and recipients. Short-term studies have shown little stone related morbidity in patients who donate or receive an allograft with a stone left in situ. Consensus statements from transplant societies around the world offer guidance for determining donor eligibility. Conclusions: The available literature on stone related morbidity in donors and recipients is extremely limited. It would appear that the risk of recurrence and subsequent morbidity in renal donors with a solitary kidney is low but not insignificant. Rare stone related adverse events are reported for recipients of an allograft with a stone left in situ. Renal donors and recipients should be educated regarding their unique risk perspectives. Long-term followup is mandatory. Key Words: kidney; kidney transplantation; living donors; kidney calculi; angiography, digital subtraction
Urolithiasis in allograft kidneys is acknowledged to be an uncommon complication in the literature with an incidence of less than 1%.3,4 The term donor gifted nephrolithiasis is uncommonly used and it refers to renal calculi left in situ at living donor transplantation. In past experience with less sensitive radiographic screening donor gifted lithiasis undoubtedly occurred unknowingly. Currently with highly sensitive CT screening of kidney donors the acceptance of donor candidates with incidental stones merits the analysis of stone related complications in donors and recipients. We performed a medical literature search in English using MEDLINE/PubMed that addressed renal donor allograft lithiasis. We then analyzed the literature with respect to the historical evolution of this concept and stone related morbidity in both recipients and donors. We present a concise review of data on to stone related outcomes in recipients who received and renal donors who donated an allograft with a solitary, unilateral asymptomatic stone.
enal transplantation remains the optimal treatment for patients with end stage renal disease. According to statistics provided by the United Network for Organ Sharing 6,564 patients underwent living donor nephrectomy in 2005.1 Despite the increasing use of live donors many patients with end stage renal failure remain on the waiting list for kidney transplantation due to organ shortage. We recently reported the increased incidence of exclusionary radiographic findings in renal transplant donors with the use of screening CT angiography.2 Asymptomatic nephrolithiasis was one of the most common causes for this increased exclusion rate. The increased prevalence of asymptomatic solitary stones on multisection CT and the development of multiple minimally invasive strategies for treating patients with transplant nephrolithiasis have prompted groups at many transplant programs to no longer consider renal calculi an absolute contraindication to donation. As such, many patients without a history of nephrolithiasis but with an incidental solitary stone on screening donor evaluation are accepted for kidney donation.
R
MATERIALS AND METHODS A systematic review in the English language was performed of the MEDLINE and PubMed databases from January 1966
Submitted for publication April 17, 2007. Nothing to disclose. * Correspondence: Division of Urology, University of Alabama at Birmingham, 1530 Third Ave. South, FOT 1105, Birmingham, Alabama 35294-3411 (telephone: 205-996-8765; FAX: 205-934-1470; e-mail: [email protected]).
Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1208 and 1209.
For other articles on a related topic see pages 1184 and 1190.
0022-5347/08/1793-0832/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
832
Vol. 179, 832-836, March 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.10.022
LIVING RENAL DONOR ALLOGRAFT LITHIASIS to January 2007 using the key words transplant nephrolithiasis, donor gifted nephrolithiasis, calculi and renal donors. All relevant articles were studied in full with particular emphasis on donor and recipient stone related morbidity. Editorials and comments were excluded from analysis.
EMERGENCE OF DONOR GIFTED ALLOGRAFT CONCEPT In 1979 a case report entitled “Case Profile: Donor-Graft Lithiasis—Unusual Complication of Renal Transplantation” was published.5 The investigators described the postoperative course in a young female who underwent cadaveric renal transplantation and was found to have a renal allograft stone after radiographic evaluation was performed for delayed graft function. The patient subsequently required pyelolithotomy for stone removal. The group recommended routine conventional radiography of the renal allograft as well as palpation and inspection of the donor kidney renal pelvis to exclude the presence of stones. Despite multiple predisposing factors for stone formation, including higher rates of renal tubular acidosis, urinary tract infection, hyperparathyroidism, hyperuricuria, reflux, hypocitruria and obstruction, the incidence of de novo urolithiasis in renal transplant recipients is low. In 1985 Van Gansbeke et al reported on 2 patients who received donor allografts with stones left in situ, as identified by ultrasound.6 Stone migration into the ureter caused acute postoperative renal allograft failure in 1 patient. The other patient was able to pass the stone uneventfully. Because transplanted kidneys are denervated during procurement, urinary obstruction with classic renal colic symptoms typically does not occur. Discovery of the obstructing calculus usually occurs during evaluation for graft failure. In most cases there is a delay in the diagnosis of obstructive uropathy in transplanted vs native kidneys. The unintentional transplantation of renal allografts with stones and the development of stones in situ have led to various interventional techniques for treating allograft lithiasis. Virtually every modality used to treat stones in native kidneys has been applied with varying degrees of success to allograft stones.7–9 The natural history of allograft stones is somewhat clouded by the immediate intraoperative and in some cases the planned postoperative treatment of stones. Rashid et al recently reported ex vivo ureteroscopic treatment of calculi in 10 donor kidneys with small, unilateral, nonobstructing (1 to 8 mm) calculi.10 At a mean followup of 36.4 and 33.2 months in donors and recipients, respectively, no new stones formed. The intervention was successful but the question of treatment necessity remains unanswered.
NATURAL HISTORY AND RISK OF RECURRENCE IN PATIENTS WITH ASYMPTOMATIC UROLITHIASIS Recent data suggest that the prevalence of stone disease may be increasing in the United States.11 The prevalence of stone disease increased from 3.8% to 5.2% according to the National Health and Nutrition Examination Survey.11 Regional variation in the prevalence of stone disease has also been reported. Curhan et al reported the highest prevalence of stone disease in the southeastern United States.12
833
To make an informed decision regarding donor eligibility one must understand the natural history and risk of recurrence in first time stone formers with an asymptomatic, solitary renal stone. Trinchieri et al prospectively evaluated the recurrence rate and risk factors for recurrence in 195 patients after a first renal stone.13 At a mean followup of 7.5 years 27% of patients experienced symptomatic recurrence. Interestingly a cohort of 36 symptom-free patients without a history of recurrence during followup included 5 with asymptomatic renal calculi greater than 3 mm. Trinchieri et al found no difference in patients with and without recurrence with regard to the male-to-female ratio, family history of stones, age at onset or the incidence of various metabolic disorders. However, age at disease onset was lower in patients who had 2 or more stones during followup than in those who had only 1 stone or no recurrence. Lee et al evaluated the stone recurrence rate and long-term renal function in 50 patients with a solitary kidney.14 These patients had undergone unilateral nephrectomy for urolithiasis. At a mean followup of 70.6 months the mean interval until stone recurrence was 31.1 months. Function in the remaining kidney was unchanged. Two patients in the study experienced anuria with stone recurrence, necessitating emergent nephrostomy tube placement. Stone recurrence rates and subsequent morbidity in patients with a history of nephrolithiasis and a solitary kidney are essential to quantify the risk in renal transplant donors. However, extrapolating risk from patients in the series by Lee14 and Trinchieri13 et al is problematic. The indication for unilateral nephrectomy in all 50 patients reported by Lee et al was urinary tract stone disease.14 A third of these patients had a staghorn calculus with stones of infectious etiology in 30%. These patients differed significantly from renal donor candidates found to have a single, asymptomatic stone. However, even in this high risk group followed by Lee et al only 1 of 50 patients (2%) showed signs of progressive chronic renal insufficiency as a result of stone recurrence. The population followed for the stone recurrence rate in the study by Trinchieri et al13 more closely approximates patients seen during renal donor evaluation. However, these patients were followed after the first symptomatic stone episode and initial stone size was not included in the analysis. Of these patients 26% underwent aggressive intervention, including nephrectomy in 9, nephrolithotomy in 6 and pyelolithotomy in 37. Again, because of the initial presentation with symptoms and level of intervention that this study population required, this patient population may represent a fundamentally higher risk group than renal donor candidates with a single, asymptomatic renal stone. Burgher et al performed a retrospective review of the records of 300 male patients with an asymptomatic renal calculus to evaluate the risk of progression requiring intervention.15 At presentation the mean cumulative stone diameter was 10.8 mm. At a mean followup of 3.2 years 77% of patients experienced disease progression with 26% requiring surgical intervention. Burgher et al found a positive association with stone size and progression. When stratified by stone size, patients with an isolated stone of 4 mm or greater at presentation were 26% more likely to experience failed observation than patients with a smaller solitary calculus. Patients with isolated upper pole calculi measuring less than 4 mm had a lower rate of observation failure. At a followup of 3.7 years none of these patients required inter-
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vention. This population of patients is probably most similar to those evaluated during kidney donor evaluation. Considering the available literature, the study population evaluated by Burgher et al appears to more closely resemble patients routinely evaluated during renal donor evaluation and found to have a solitary, asymptomatic stone.15 It would appear that the risk of recurrence and subsequent morbidity in renal donors with a solitary kidney is low but not insignificant. DONOR SCREENING: THE CT ERA We recently reported an increase in the rate of radiographic exclusion with the use of CT angiography vs conventional imaging modalities during renal donor screening.2 In the group that was radiographically screened with excretory urography, renal arteriography and renal scan 20 of the 270 patients (7%) were excluded from donation due to radiographic findings vs 53 of the 333 (16%) screened with CT angiography and renal scan. Urolithiasis was the reason that 42% of patients were excluded for radiographic reasons in the CT angiography group vs 20% in the conventional imaging group. During this period we identified 10 living renal donors with a solitary, asymptomatic calculus who were accepted as donors. Mean stone size was 2.1 mm (range 1 to 5). Stone related morbidity in donors and recipients was assessed. Donors were contacted and a questionnaire related to recurrent stone disease was administered by telephone. Of the donors 90% could be contacted. The table lists donor characteristics. Recipients underwent a retrospective chart review. Mean followup in donors and recipients was 11.2 and 9.8 months, respectively. No donors or recipients experienced stone related morbidity during this period. In a similar study by Martin et al 5 recipients who received living donor allografts with stones left in situ (all less than 4 mm) were followed for stone related complications.16 At a mean followup of 508 days none of the recipients experienced stone related complications. Nevertheless, 2 patients showed persistent nephrolithiasis on CT. No followup information was provided about the donors. Ho and Chow report the largest series of patients followed with donor gifted lithiasis.17 In a 4-year period 710 donor kidneys were evaluated with nephrolithiasis identified in 44 (6%). Of the kidneys 86% had 1 to 2 mm stones and 6 (14%) had stones that were 3 to 6 mm. CT was performed an average of 10.5 months postoperatively in 13 recipients,
Kidney donor characteristics Mean age No. sex: M F No. white race No. side: Rt Lt Mean effective renal plasma flow (ml/min) Mean creatinine clearance (ml/min) Mean stone size (mm) No. donor nephrectomy: Lt hand assisted laparoscopic Rt hand assisted laparoscopic Rt open Mean followup (mos)
44.3 3 6 9 4 5 517 113 2.1 5 3 1 11.2
of whom 5 showed no stones, 4 showed stable stone size and 4 had an increase in stone size. Average stone growth was 2.9 mm (range 1 to 7). Mean followup was 21 months. One patient had a 1 mm stone that showed interval growth to 8 mm. This patient was treated with attempted ureteroscopy, percutaneous nephrolithotomy and shock wave lithotripsy for recurrent urinary tract infections related to the stone. No morbidity or graft loss was related to obstruction from nephrolithiasis. One-year graft survival was 97%. No followup information was provided on renal donors. Ho and Chow suggested following donor gifted stones with CT 12 months after transplantation. To date most of the reported literature on donor gifted nephrolithiasis related morbidity is limited by small patient numbers and short followup. In the absence of long-term outcomes data showing acceptable morbidity in donors and recipients with donor gifted nephrolithiasis those determining eligibility must remain current with transplant guidelines around the world. CURRENT OPINION: SELECTION CRITERIA OF RENAL TRANSPLANT DONORS WITH STONES In 1996 Kasiske et al reported guidelines on the selection of renal transplant donors.18 These guidelines stated that nephrolithiasis was at least a relative contraindication to donation because of the known risk of recurrent stones in the donor. They made reference to a 50% risk of renal colic symptoms in patients with asymptomatic stones in a 5-year period. These guidelines recommended that all patients with a history of stones should undergo metabolic evaluation. Based on these guidelines a patient was allowed to donate, provided that this evaluation was normal and the patient had passed only 1 stone in the past, currently had inactive disease for at least 10 years and no stones were found on donor radiographic studies. In 2005 Davis and Delmonico reviewed these guidelines and relaxed the restrictions on potential donors and nephrolithiasis.19 It was suggested that an asymptomatic potential kidney donor with a current single stone may be suitable if the donor is not at high risk for recurrence and the current stone is less than 15 mm and potentially removable during transplantation. Davis and Delmonico noted the inherent problem with determining which donors are at risk for recurrence. Those with cystine/struvite stones or systemic disorders that lead to high recurrence rates, such as primary or enteric hyperoxaluria, distal renal tubular acidosis, sarcoidosis, inflammatory bowel disease or other conditions that cause nephrocalcinosis, should not donate. Davis and Delmonico recommended evaluation of an asymptomatic donor with a single previous episode of nephrolithiasis using serum calcium, creatinine, albumin, parathyroid hormone, spot urine for cystine, urinalysis and culture, helical CT, analysis of previous stone, if known, and 24-hour urine for oxalate and creatinine. As highly sensitive multisection CT came to the forefront of renal donor imaging, radiologists were among the first to anticipate the growing dilemma of donor selection, given the prevalence of asymptomatic urolithiasis. In a review of multisection CT imaging techniques in renal donors Rydberg et al discussed how stones had changed from an absolute to a relative contraindication.20 They noted that at several centers donation was allowed, provided that certain criteria
LIVING RENAL DONOR ALLOGRAFT LITHIASIS were met, including 1) the donor was older than 40 years and 2) 1 stone was smaller than 8 mm and, if multiple, there were no more than 3 stones, all were unilateral and each was smaller than 3 mm. The Amsterdam Forum on the Care of the Live Kidney Donor outlined certain acceptance criteria for an asymptomatic potential donor with a history of a single stone, including 1) no hypercalciuria, hyperuricemia or metabolic acidosis, 2) no cystinuria or hyperoxaluria, 3) no urinary tract infection and 4) multiple stones or nephrocalcinosis not evident on CT.21 In an asymptomatic potential donor with a current single stone the Amsterdam Forum judged the patient acceptable for donation provided that the described criteria were met and the current stone was less than 15 mm or potentially removable during transplantation.21 The position statement of the forum acknowledged the importance of donor age, specifically highlighting the longer exposure to the risk of recurrence in younger donors (ages 25 to 35 years). By forum guidelines stone formers should not donate if any of certain criteria were present, including 1) nephrocalcinosis evident on imaging or the presence of bilateral stone disease and 2) the presence of stone types with a high recurrence rate that are difficult to prevent, such as 1) cystine stones, 2) struvite stones, 3) stones associated with inherited or systemic disorders such as primary or enteric hyperoxaluria, distal renal tubular acidosis and sarcoidosis, 4) stones in the setting of inflammatory bowel diseases and 5) recurrences while on appropriate therapy.21 At our institution patients with an asymptomatic, solitary renal calculus are accepted, provided that certain criteria are met, including 1) age older than 40 years, 2) no history of stone disease and 3) absent contralateral stone disease. Donors with a solitary stone larger than 5 mm are not accepted, although this particular criterion is largely empirical but based on the known association between the risk of progression and stone size. At our institution donors with a current solitary stone and no history of stones do not undergo urinary metabolic studies because routine donor laboratory assessment, a comprehensive medical evaluation and compliance with the first 3 criteria described effectively screen out potential donors meeting Amsterdam Forum criteria for high risk stone formers.21 Perhaps the most important factor to consider when evaluating potential donors with nephrolithiasis is patient education. Before acceptance donors must understand the importance of careful monitoring and express a commitment to practicing avoidance measures for stone recurrence in the future. Likewise kidney recipients must be educated by physicians determining eligibility regarding their unique risk perspective. Recipients must be informed of the potential for stone related complications in an allograft with a stone left in situ. The recipient must weigh the risk of an obstructing stone that might result in delayed recognition of graft failure against the risk of a shorter life span and increased cardiovascular morbidity due to renal failure without transplantation.
more accepted. Most of the reported literature on donor gifted nephrolithiasis related morbidity is limited by small patient numbers and short followup. In the absence of longterm outcomes data showing acceptable morbidity in donors and recipients with donor gifted nephrolithiasis those determining eligibility must remain current with ongoing changes in transplant guidelines around the world. Long-term studies at major transplantation centers are needed to further assess donor and recipient stone related morbidity.
Abbreviations and Acronyms CT ⫽ computerized tomography
REFERENCES 1. 2.
3.
4.
5.
6.
7. 8.
9.
10.
11.
12.
13.
14.
CONCLUSIONS Urologists who participate in kidney donor selection should remain the advocate for the donor. However, with increasing organ shortages the use of suboptimal donors is becoming
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15.
OPTN/SRTR Annual Report 2005. Available at www.optn.org/ latestData/rptData.asp. Accessed April 17, 2007. Strang AM, Lockhart ME, Kenney PJ, Amling CL, Urban DA, El-Galley R et al: Computed tomographic angiography for renal donor evaluation leads to higher exclusion rate. J Urol 2007; 177: 1826. Hayes JM, Streem SB, Graneto D, Hodge EE, Steinmuller DR and Novick AC: Renal transplant calculi: a re-evaluation of risks and management. Transplantation 1989; 47: 949. Shoskes DA, Hanbury D, Cranston D and Morris PJ: Urological complications in 1,000 consecutive renal transplant recipients. J Urol 1995; 153: 18. Lerut J, Lerut T, Gruwez JA and Michielsen P: Case profile: donor graft lithiasis— unusual complication of renal transplantation. Urology 1979; 14: 627. Van Gansbeke D, Zalcman M, Matos C, Simon J, Kinnaert P and Stuyven J: Lithiasis complications of renal transplantation: the donor graft lithiasis concept. Urol Radiol 1985; 7: 157. Crook TJ and Keoghane SR: Renal transplant lithiasis: rare but time-consuming. BJU Int 2005; 95: 931. Challacombe B, Dasgupta P, Tiptaft R, Glass J, Koffman G, Goldsmith D et al: Multimodal management of urolithiasis in renal transplantation. BJU Int 2005; 96: 385. Lu H, Shekarriz B and Stoller M: Donor-gifted allograft urolithiasis: early percutaneous management. Urology 2002; 59: 25. Rashid MG, Konnak JW, Wolf JS, Punch JD, Magee JC, Arenas JD et al: Ex vivo ureteroscopic treatment of calculi in donor kidneys at renal transplantation. J Urol 2004; 171: 58. Stamatelou KK, Francis ME, Jones CA, Nyberg LM and Curhan GC: Time trends in reported prevalence of kidney stones in the United States: 1976 –1994. Kidney Int 2003; 63: 1817. Curhan GC, Rimm EB, Willett WC and Stampfer MJ: Regional variation in nephrolithiasis incidence and prevalence among United States men. J Urol 1994; 151: 838. Trinchieri A, Ostini F, Nespoli R, Rovera F, Montanari E and Zanetti G: A prospective study of recurrence rate and risk factors for recurrence after a first renal stone. J Urol 1999; 162: 27. Lee YH, Huang WC, Chang LS, Chen MT, Yang YF and Huang JK: The long-term stone recurrence rate and renal function change in unilateral nephrectomy urolithiasis patients. J Urol 1994; 152: 1386. Burgher A, Beman M, Holtzman JL and Monga M: Progression of nephrolithiasis: long-term outcomes with observation of asymptomatic calculi. J Endourol 2004; 18: 534.
836 16.
17.
18.
LIVING RENAL DONOR ALLOGRAFT LITHIASIS Martin G, Lipke MC, Sharfuddin A, Govani M and Sundaram CP: Asymptomatic unilateral urolithiasis in living donor transplant kidneys. JSLS, suppl., 2006; 10: 3. Ho KLV and Chow G: Prevalence and early outcome of donor graft lithiasis in living renal transplants at the Mayo Clinic. J Urol, suppl., 2005; 173: 439, abstract 1622. Kasiske BL, Ravenscraft M, Ramos EL, Gaston RS, Bia MJ and Danovitch GM: The evaluation of living renal transplant donors: clinical practice guidelines. Ad Hoc Clinical Practice Guidelines Subcommittee of the Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol 1996; 7: 2288.
19.
Davis CL and Delmonico FL: Living-donor kidney transplantation: a review of the current practices for the live donor. J Am Soc Nephrol 2005; 16: 2098. 20. Rydberg J, Kopecky KK, Tann M, Persohn SA, Leapman SB, Filo RS et al: Evaluation of prospective renal donors for laparoscopic nephrectomy with multisection CT: the marriage of minimally invasive imaging with minimally invasive surgery. Radiographics 2001; 21: S223. 21. Delmonico F: A report of the Amsterdam Forum on the Care of the Live Kidney Donor: data and medical guidelines. Council of the Transplantation Society. Transplantation 2005; 79: S53.
Purpose: The use of screening computerized tomography angiography has resulted in the increased detection of incidental nephrolithiasis in potential living renal donor candidates. We reviewed current acceptance guidelines for donors with stone disease as well as data on stone related outcomes in donors with stone disease and recipients who received a kidney with a stone left in situ. Materials and Methods: We performed a medical literature search in English using MEDLINE®/PubMed® that addressed renal donor allograft lithiasis. We then analyzed the literature with respect to the historical evolution of this concept, current guidelines regarding the acceptance of donors with stones and stone related morbidity in recipients and donors. Results: The prevalence of asymptomatic solitary nephrolithiasis has increased with the widespread use of screening computerized tomography angiography during renal donor evaluation. Few studies have addressed the risk of stone related morbidity in donors and recipients. Short-term studies have shown little stone related morbidity in patients who donate or receive an allograft with a stone left in situ. Consensus statements from transplant societies around the world offer guidance for determining donor eligibility. Conclusions: The available literature on stone related morbidity in donors and recipients is extremely limited. It would appear that the risk of recurrence and subsequent morbidity in renal donors with a solitary kidney is low but not insignificant. Rare stone related adverse events are reported for recipients of an allograft with a stone left in situ. Renal donors and recipients should be educated regarding their unique risk perspectives. Long-term followup is mandatory. Key Words: kidney; kidney transplantation; living donors; kidney calculi; angiography, digital subtraction
Urolithiasis in allograft kidneys is acknowledged to be an uncommon complication in the literature with an incidence of less than 1%.3,4 The term donor gifted nephrolithiasis is uncommonly used and it refers to renal calculi left in situ at living donor transplantation. In past experience with less sensitive radiographic screening donor gifted lithiasis undoubtedly occurred unknowingly. Currently with highly sensitive CT screening of kidney donors the acceptance of donor candidates with incidental stones merits the analysis of stone related complications in donors and recipients. We performed a medical literature search in English using MEDLINE/PubMed that addressed renal donor allograft lithiasis. We then analyzed the literature with respect to the historical evolution of this concept and stone related morbidity in both recipients and donors. We present a concise review of data on to stone related outcomes in recipients who received and renal donors who donated an allograft with a solitary, unilateral asymptomatic stone.
enal transplantation remains the optimal treatment for patients with end stage renal disease. According to statistics provided by the United Network for Organ Sharing 6,564 patients underwent living donor nephrectomy in 2005.1 Despite the increasing use of live donors many patients with end stage renal failure remain on the waiting list for kidney transplantation due to organ shortage. We recently reported the increased incidence of exclusionary radiographic findings in renal transplant donors with the use of screening CT angiography.2 Asymptomatic nephrolithiasis was one of the most common causes for this increased exclusion rate. The increased prevalence of asymptomatic solitary stones on multisection CT and the development of multiple minimally invasive strategies for treating patients with transplant nephrolithiasis have prompted groups at many transplant programs to no longer consider renal calculi an absolute contraindication to donation. As such, many patients without a history of nephrolithiasis but with an incidental solitary stone on screening donor evaluation are accepted for kidney donation.
R
MATERIALS AND METHODS A systematic review in the English language was performed of the MEDLINE and PubMed databases from January 1966
Submitted for publication April 17, 2007. Nothing to disclose. * Correspondence: Division of Urology, University of Alabama at Birmingham, 1530 Third Ave. South, FOT 1105, Birmingham, Alabama 35294-3411 (telephone: 205-996-8765; FAX: 205-934-1470; e-mail: [email protected]).
Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1208 and 1209.
For other articles on a related topic see pages 1184 and 1190.
0022-5347/08/1793-0832/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
832
Vol. 179, 832-836, March 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.10.022
LIVING RENAL DONOR ALLOGRAFT LITHIASIS to January 2007 using the key words transplant nephrolithiasis, donor gifted nephrolithiasis, calculi and renal donors. All relevant articles were studied in full with particular emphasis on donor and recipient stone related morbidity. Editorials and comments were excluded from analysis.
EMERGENCE OF DONOR GIFTED ALLOGRAFT CONCEPT In 1979 a case report entitled “Case Profile: Donor-Graft Lithiasis—Unusual Complication of Renal Transplantation” was published.5 The investigators described the postoperative course in a young female who underwent cadaveric renal transplantation and was found to have a renal allograft stone after radiographic evaluation was performed for delayed graft function. The patient subsequently required pyelolithotomy for stone removal. The group recommended routine conventional radiography of the renal allograft as well as palpation and inspection of the donor kidney renal pelvis to exclude the presence of stones. Despite multiple predisposing factors for stone formation, including higher rates of renal tubular acidosis, urinary tract infection, hyperparathyroidism, hyperuricuria, reflux, hypocitruria and obstruction, the incidence of de novo urolithiasis in renal transplant recipients is low. In 1985 Van Gansbeke et al reported on 2 patients who received donor allografts with stones left in situ, as identified by ultrasound.6 Stone migration into the ureter caused acute postoperative renal allograft failure in 1 patient. The other patient was able to pass the stone uneventfully. Because transplanted kidneys are denervated during procurement, urinary obstruction with classic renal colic symptoms typically does not occur. Discovery of the obstructing calculus usually occurs during evaluation for graft failure. In most cases there is a delay in the diagnosis of obstructive uropathy in transplanted vs native kidneys. The unintentional transplantation of renal allografts with stones and the development of stones in situ have led to various interventional techniques for treating allograft lithiasis. Virtually every modality used to treat stones in native kidneys has been applied with varying degrees of success to allograft stones.7–9 The natural history of allograft stones is somewhat clouded by the immediate intraoperative and in some cases the planned postoperative treatment of stones. Rashid et al recently reported ex vivo ureteroscopic treatment of calculi in 10 donor kidneys with small, unilateral, nonobstructing (1 to 8 mm) calculi.10 At a mean followup of 36.4 and 33.2 months in donors and recipients, respectively, no new stones formed. The intervention was successful but the question of treatment necessity remains unanswered.
NATURAL HISTORY AND RISK OF RECURRENCE IN PATIENTS WITH ASYMPTOMATIC UROLITHIASIS Recent data suggest that the prevalence of stone disease may be increasing in the United States.11 The prevalence of stone disease increased from 3.8% to 5.2% according to the National Health and Nutrition Examination Survey.11 Regional variation in the prevalence of stone disease has also been reported. Curhan et al reported the highest prevalence of stone disease in the southeastern United States.12
833
To make an informed decision regarding donor eligibility one must understand the natural history and risk of recurrence in first time stone formers with an asymptomatic, solitary renal stone. Trinchieri et al prospectively evaluated the recurrence rate and risk factors for recurrence in 195 patients after a first renal stone.13 At a mean followup of 7.5 years 27% of patients experienced symptomatic recurrence. Interestingly a cohort of 36 symptom-free patients without a history of recurrence during followup included 5 with asymptomatic renal calculi greater than 3 mm. Trinchieri et al found no difference in patients with and without recurrence with regard to the male-to-female ratio, family history of stones, age at onset or the incidence of various metabolic disorders. However, age at disease onset was lower in patients who had 2 or more stones during followup than in those who had only 1 stone or no recurrence. Lee et al evaluated the stone recurrence rate and long-term renal function in 50 patients with a solitary kidney.14 These patients had undergone unilateral nephrectomy for urolithiasis. At a mean followup of 70.6 months the mean interval until stone recurrence was 31.1 months. Function in the remaining kidney was unchanged. Two patients in the study experienced anuria with stone recurrence, necessitating emergent nephrostomy tube placement. Stone recurrence rates and subsequent morbidity in patients with a history of nephrolithiasis and a solitary kidney are essential to quantify the risk in renal transplant donors. However, extrapolating risk from patients in the series by Lee14 and Trinchieri13 et al is problematic. The indication for unilateral nephrectomy in all 50 patients reported by Lee et al was urinary tract stone disease.14 A third of these patients had a staghorn calculus with stones of infectious etiology in 30%. These patients differed significantly from renal donor candidates found to have a single, asymptomatic stone. However, even in this high risk group followed by Lee et al only 1 of 50 patients (2%) showed signs of progressive chronic renal insufficiency as a result of stone recurrence. The population followed for the stone recurrence rate in the study by Trinchieri et al13 more closely approximates patients seen during renal donor evaluation. However, these patients were followed after the first symptomatic stone episode and initial stone size was not included in the analysis. Of these patients 26% underwent aggressive intervention, including nephrectomy in 9, nephrolithotomy in 6 and pyelolithotomy in 37. Again, because of the initial presentation with symptoms and level of intervention that this study population required, this patient population may represent a fundamentally higher risk group than renal donor candidates with a single, asymptomatic renal stone. Burgher et al performed a retrospective review of the records of 300 male patients with an asymptomatic renal calculus to evaluate the risk of progression requiring intervention.15 At presentation the mean cumulative stone diameter was 10.8 mm. At a mean followup of 3.2 years 77% of patients experienced disease progression with 26% requiring surgical intervention. Burgher et al found a positive association with stone size and progression. When stratified by stone size, patients with an isolated stone of 4 mm or greater at presentation were 26% more likely to experience failed observation than patients with a smaller solitary calculus. Patients with isolated upper pole calculi measuring less than 4 mm had a lower rate of observation failure. At a followup of 3.7 years none of these patients required inter-
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vention. This population of patients is probably most similar to those evaluated during kidney donor evaluation. Considering the available literature, the study population evaluated by Burgher et al appears to more closely resemble patients routinely evaluated during renal donor evaluation and found to have a solitary, asymptomatic stone.15 It would appear that the risk of recurrence and subsequent morbidity in renal donors with a solitary kidney is low but not insignificant. DONOR SCREENING: THE CT ERA We recently reported an increase in the rate of radiographic exclusion with the use of CT angiography vs conventional imaging modalities during renal donor screening.2 In the group that was radiographically screened with excretory urography, renal arteriography and renal scan 20 of the 270 patients (7%) were excluded from donation due to radiographic findings vs 53 of the 333 (16%) screened with CT angiography and renal scan. Urolithiasis was the reason that 42% of patients were excluded for radiographic reasons in the CT angiography group vs 20% in the conventional imaging group. During this period we identified 10 living renal donors with a solitary, asymptomatic calculus who were accepted as donors. Mean stone size was 2.1 mm (range 1 to 5). Stone related morbidity in donors and recipients was assessed. Donors were contacted and a questionnaire related to recurrent stone disease was administered by telephone. Of the donors 90% could be contacted. The table lists donor characteristics. Recipients underwent a retrospective chart review. Mean followup in donors and recipients was 11.2 and 9.8 months, respectively. No donors or recipients experienced stone related morbidity during this period. In a similar study by Martin et al 5 recipients who received living donor allografts with stones left in situ (all less than 4 mm) were followed for stone related complications.16 At a mean followup of 508 days none of the recipients experienced stone related complications. Nevertheless, 2 patients showed persistent nephrolithiasis on CT. No followup information was provided about the donors. Ho and Chow report the largest series of patients followed with donor gifted lithiasis.17 In a 4-year period 710 donor kidneys were evaluated with nephrolithiasis identified in 44 (6%). Of the kidneys 86% had 1 to 2 mm stones and 6 (14%) had stones that were 3 to 6 mm. CT was performed an average of 10.5 months postoperatively in 13 recipients,
Kidney donor characteristics Mean age No. sex: M F No. white race No. side: Rt Lt Mean effective renal plasma flow (ml/min) Mean creatinine clearance (ml/min) Mean stone size (mm) No. donor nephrectomy: Lt hand assisted laparoscopic Rt hand assisted laparoscopic Rt open Mean followup (mos)
44.3 3 6 9 4 5 517 113 2.1 5 3 1 11.2
of whom 5 showed no stones, 4 showed stable stone size and 4 had an increase in stone size. Average stone growth was 2.9 mm (range 1 to 7). Mean followup was 21 months. One patient had a 1 mm stone that showed interval growth to 8 mm. This patient was treated with attempted ureteroscopy, percutaneous nephrolithotomy and shock wave lithotripsy for recurrent urinary tract infections related to the stone. No morbidity or graft loss was related to obstruction from nephrolithiasis. One-year graft survival was 97%. No followup information was provided on renal donors. Ho and Chow suggested following donor gifted stones with CT 12 months after transplantation. To date most of the reported literature on donor gifted nephrolithiasis related morbidity is limited by small patient numbers and short followup. In the absence of long-term outcomes data showing acceptable morbidity in donors and recipients with donor gifted nephrolithiasis those determining eligibility must remain current with transplant guidelines around the world. CURRENT OPINION: SELECTION CRITERIA OF RENAL TRANSPLANT DONORS WITH STONES In 1996 Kasiske et al reported guidelines on the selection of renal transplant donors.18 These guidelines stated that nephrolithiasis was at least a relative contraindication to donation because of the known risk of recurrent stones in the donor. They made reference to a 50% risk of renal colic symptoms in patients with asymptomatic stones in a 5-year period. These guidelines recommended that all patients with a history of stones should undergo metabolic evaluation. Based on these guidelines a patient was allowed to donate, provided that this evaluation was normal and the patient had passed only 1 stone in the past, currently had inactive disease for at least 10 years and no stones were found on donor radiographic studies. In 2005 Davis and Delmonico reviewed these guidelines and relaxed the restrictions on potential donors and nephrolithiasis.19 It was suggested that an asymptomatic potential kidney donor with a current single stone may be suitable if the donor is not at high risk for recurrence and the current stone is less than 15 mm and potentially removable during transplantation. Davis and Delmonico noted the inherent problem with determining which donors are at risk for recurrence. Those with cystine/struvite stones or systemic disorders that lead to high recurrence rates, such as primary or enteric hyperoxaluria, distal renal tubular acidosis, sarcoidosis, inflammatory bowel disease or other conditions that cause nephrocalcinosis, should not donate. Davis and Delmonico recommended evaluation of an asymptomatic donor with a single previous episode of nephrolithiasis using serum calcium, creatinine, albumin, parathyroid hormone, spot urine for cystine, urinalysis and culture, helical CT, analysis of previous stone, if known, and 24-hour urine for oxalate and creatinine. As highly sensitive multisection CT came to the forefront of renal donor imaging, radiologists were among the first to anticipate the growing dilemma of donor selection, given the prevalence of asymptomatic urolithiasis. In a review of multisection CT imaging techniques in renal donors Rydberg et al discussed how stones had changed from an absolute to a relative contraindication.20 They noted that at several centers donation was allowed, provided that certain criteria
LIVING RENAL DONOR ALLOGRAFT LITHIASIS were met, including 1) the donor was older than 40 years and 2) 1 stone was smaller than 8 mm and, if multiple, there were no more than 3 stones, all were unilateral and each was smaller than 3 mm. The Amsterdam Forum on the Care of the Live Kidney Donor outlined certain acceptance criteria for an asymptomatic potential donor with a history of a single stone, including 1) no hypercalciuria, hyperuricemia or metabolic acidosis, 2) no cystinuria or hyperoxaluria, 3) no urinary tract infection and 4) multiple stones or nephrocalcinosis not evident on CT.21 In an asymptomatic potential donor with a current single stone the Amsterdam Forum judged the patient acceptable for donation provided that the described criteria were met and the current stone was less than 15 mm or potentially removable during transplantation.21 The position statement of the forum acknowledged the importance of donor age, specifically highlighting the longer exposure to the risk of recurrence in younger donors (ages 25 to 35 years). By forum guidelines stone formers should not donate if any of certain criteria were present, including 1) nephrocalcinosis evident on imaging or the presence of bilateral stone disease and 2) the presence of stone types with a high recurrence rate that are difficult to prevent, such as 1) cystine stones, 2) struvite stones, 3) stones associated with inherited or systemic disorders such as primary or enteric hyperoxaluria, distal renal tubular acidosis and sarcoidosis, 4) stones in the setting of inflammatory bowel diseases and 5) recurrences while on appropriate therapy.21 At our institution patients with an asymptomatic, solitary renal calculus are accepted, provided that certain criteria are met, including 1) age older than 40 years, 2) no history of stone disease and 3) absent contralateral stone disease. Donors with a solitary stone larger than 5 mm are not accepted, although this particular criterion is largely empirical but based on the known association between the risk of progression and stone size. At our institution donors with a current solitary stone and no history of stones do not undergo urinary metabolic studies because routine donor laboratory assessment, a comprehensive medical evaluation and compliance with the first 3 criteria described effectively screen out potential donors meeting Amsterdam Forum criteria for high risk stone formers.21 Perhaps the most important factor to consider when evaluating potential donors with nephrolithiasis is patient education. Before acceptance donors must understand the importance of careful monitoring and express a commitment to practicing avoidance measures for stone recurrence in the future. Likewise kidney recipients must be educated by physicians determining eligibility regarding their unique risk perspective. Recipients must be informed of the potential for stone related complications in an allograft with a stone left in situ. The recipient must weigh the risk of an obstructing stone that might result in delayed recognition of graft failure against the risk of a shorter life span and increased cardiovascular morbidity due to renal failure without transplantation.
more accepted. Most of the reported literature on donor gifted nephrolithiasis related morbidity is limited by small patient numbers and short followup. In the absence of longterm outcomes data showing acceptable morbidity in donors and recipients with donor gifted nephrolithiasis those determining eligibility must remain current with ongoing changes in transplant guidelines around the world. Long-term studies at major transplantation centers are needed to further assess donor and recipient stone related morbidity.
Abbreviations and Acronyms CT ⫽ computerized tomography
REFERENCES 1. 2.
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CONCLUSIONS Urologists who participate in kidney donor selection should remain the advocate for the donor. However, with increasing organ shortages the use of suboptimal donors is becoming
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OPTN/SRTR Annual Report 2005. Available at www.optn.org/ latestData/rptData.asp. Accessed April 17, 2007. Strang AM, Lockhart ME, Kenney PJ, Amling CL, Urban DA, El-Galley R et al: Computed tomographic angiography for renal donor evaluation leads to higher exclusion rate. J Urol 2007; 177: 1826. Hayes JM, Streem SB, Graneto D, Hodge EE, Steinmuller DR and Novick AC: Renal transplant calculi: a re-evaluation of risks and management. Transplantation 1989; 47: 949. Shoskes DA, Hanbury D, Cranston D and Morris PJ: Urological complications in 1,000 consecutive renal transplant recipients. J Urol 1995; 153: 18. Lerut J, Lerut T, Gruwez JA and Michielsen P: Case profile: donor graft lithiasis— unusual complication of renal transplantation. Urology 1979; 14: 627. Van Gansbeke D, Zalcman M, Matos C, Simon J, Kinnaert P and Stuyven J: Lithiasis complications of renal transplantation: the donor graft lithiasis concept. Urol Radiol 1985; 7: 157. Crook TJ and Keoghane SR: Renal transplant lithiasis: rare but time-consuming. BJU Int 2005; 95: 931. Challacombe B, Dasgupta P, Tiptaft R, Glass J, Koffman G, Goldsmith D et al: Multimodal management of urolithiasis in renal transplantation. BJU Int 2005; 96: 385. Lu H, Shekarriz B and Stoller M: Donor-gifted allograft urolithiasis: early percutaneous management. Urology 2002; 59: 25. Rashid MG, Konnak JW, Wolf JS, Punch JD, Magee JC, Arenas JD et al: Ex vivo ureteroscopic treatment of calculi in donor kidneys at renal transplantation. J Urol 2004; 171: 58. Stamatelou KK, Francis ME, Jones CA, Nyberg LM and Curhan GC: Time trends in reported prevalence of kidney stones in the United States: 1976 –1994. Kidney Int 2003; 63: 1817. Curhan GC, Rimm EB, Willett WC and Stampfer MJ: Regional variation in nephrolithiasis incidence and prevalence among United States men. J Urol 1994; 151: 838. Trinchieri A, Ostini F, Nespoli R, Rovera F, Montanari E and Zanetti G: A prospective study of recurrence rate and risk factors for recurrence after a first renal stone. J Urol 1999; 162: 27. Lee YH, Huang WC, Chang LS, Chen MT, Yang YF and Huang JK: The long-term stone recurrence rate and renal function change in unilateral nephrectomy urolithiasis patients. J Urol 1994; 152: 1386. Burgher A, Beman M, Holtzman JL and Monga M: Progression of nephrolithiasis: long-term outcomes with observation of asymptomatic calculi. J Endourol 2004; 18: 534.
836 16.
17.
18.
LIVING RENAL DONOR ALLOGRAFT LITHIASIS Martin G, Lipke MC, Sharfuddin A, Govani M and Sundaram CP: Asymptomatic unilateral urolithiasis in living donor transplant kidneys. JSLS, suppl., 2006; 10: 3. Ho KLV and Chow G: Prevalence and early outcome of donor graft lithiasis in living renal transplants at the Mayo Clinic. J Urol, suppl., 2005; 173: 439, abstract 1622. Kasiske BL, Ravenscraft M, Ramos EL, Gaston RS, Bia MJ and Danovitch GM: The evaluation of living renal transplant donors: clinical practice guidelines. Ad Hoc Clinical Practice Guidelines Subcommittee of the Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol 1996; 7: 2288.
19.
Davis CL and Delmonico FL: Living-donor kidney transplantation: a review of the current practices for the live donor. J Am Soc Nephrol 2005; 16: 2098. 20. Rydberg J, Kopecky KK, Tann M, Persohn SA, Leapman SB, Filo RS et al: Evaluation of prospective renal donors for laparoscopic nephrectomy with multisection CT: the marriage of minimally invasive imaging with minimally invasive surgery. Radiographics 2001; 21: S223. 21. Delmonico F: A report of the Amsterdam Forum on the Care of the Live Kidney Donor: data and medical guidelines. Council of the Transplantation Society. Transplantation 2005; 79: S53.