Epidemiology

A review of 2045 renal transplants from a single center found an allograft lithiasis incidence of 0.44% [8]. Mean time to presentation was 3.1 years following transplantation. A similar series of 1525 recipients reported an incidence of 0.46% [9]. A review of 42 096 transplant patients from the United States Renal Data System found a nephrolithiasis‐associated hospitalization rate of 0.11% for men and 0.15% for women [10]. Female recipients were noted to be at increased risk of hospitalization for stone‐related events compared to women within the general population.

Stones may be passed from the donor to the recipient at the time of transplantation (donor‐gifted nephrolithiasis), or develop de novo after surgery. Donor‐gifted nephrolithiasis is more common following deceased donor transplants as compared to living‐donor transplants [11–13]. One explanation for this finding has been the traditionally low rate of imaging done prior to procurement. In a series of deceased donor renal transplants that underwent ex vivo ultrasound screening, the incidence of donor‐gifted urolithiasis was found to be 0.64% [14].

In contrast, imaging is a fundamental component of the living donor screening process. Institutional variation exists but the following modalities have been utilized: renal ultrasound, computed tomography (CT) angiography, and magnetic resonance angiography. A consequence of this rigorous screening process has been the identification of nephrolithiasis in potential donors. A review of 377 individuals undergoing donor evaluation with CT angiography found a 5% prevalence of asymptomatic renal stones [15].

Taking into account the increased utilization of CT to screen potential living donors, Kasiske and colleagues published guidelines in 1996 outlining selection criteria [16]. Nephrolithiasis was considered a relative contraindication to donation given the high risk of stone recurrence. However, the discrepancy between available donors and individuals suffering from ESRD has continued to widen over the past decade [17]. In an effort to address this shortage, some transplant organizations have developed less stringent guidelines to allow for “expanded criteria” deceased and “complex living” donors.

In 2004 more than 100 kidney transplant experts from over 40 countries met in Amsterdam to develop consensus‐based guidelines meant to protect potential living donors [18]. Per the Amsterdam Forum, a potential donor with a single stone should undergo a metabolic workup including a 24 hour urine collection. In the absence of hypercalciuria, hyperoxaluria, hyperuricemia, cystinuria, or metabolic acidosis, donation may be considered. Contraindications to donation include infected stones and systemic disorders associated with increased recurrence rates such as inflammatory bowel disease, distal renal tubular acidosis (RTA), and sarcoidosis. The presence of multiple stones or nephrocalcinosis also preclude donation.

Pathophysiology

A variety of surgical, pharmacologic, and physiologic factors promote de novo stone formation following transplantation. Technical factors include vesicoureteral reflux and ureteroneocystostomy stricture. Both complications promote stone formation by increasing the risk of urinary stasis and urinary tract infection (UTI). Foreign bodies such as persistent suture material or a retained ureteral stent also increase the risk of both infectious and noninfectious stones.

Immunosuppressive medications may also play a key role in de novo stone formation. Corticosteroids cause bone resorption, which has been associated with increased urinary calcium excretion [19]. Besides being nephrotoxic, calcineurin inhibitors (cyclosporine and tacrolimus) have been shown to induce hypocitraturia and hyperoxaluria [20]. In addition, cyclosporine has been demonstrated to cause hyperuricemia and gout [21].

ESRD is associated with a number of metabolic changes that promote stone formation. These may persist even after renal transplantation. Increased phosphorus levels along with parathyroid hormone resistance result in secondary hyperparathyroidism, which is associated with hypercalcemia, hypercalciuria, and hypocitraturia [22]. Up to 50% of individuals will continue to have persistently elevated parathyroid hormone levels (tertiary hyperparathyroidism) after transplantation [23]. This was confirmed in a series of 15 patients with allograft lithiasis who underwent a metabolic workup [24]. The authors found a 53% incidence of tertiary hyperparathyroidism.

Renal failure results in hyperuricemia because nearly 70% of uric acid is eliminated by the kidneys. Hyperuricemia may not resolve following transplantation for a number of reasons. As previously mentioned, cyclosporine is associated with hyperuricemia. Regardless, up to 55% of recipients not being managed with cyclosporine will have elevated uric acid levels [25]. The cause is not completely understood but graft dysfunction, diuretic use, male gender, diabetes mellitus, and obesity have been implicated [26]. The resulting hyperuricuria is not only a risk factor for uric acid stones but also calcium oxalate urolithiasis by heterogeneous nucleation.

Renal tubular acidosis following renal transplantation is common, with one study finding an incidence of 33% [27]. Type 1 RTA is most common, but type 2 and 4 RTA have also been reported [28]. Poor allograft function, calcineurin inhibitor nephrotoxicity, acute rejection, and ischemic tubular dysfunction have all been reported as causative factors [27]. Other potential etiologies include tertiary hyperparathyroidism, postoperative urinary obstruction, and UTI [29]. Type 1 RTA is associated with hypercalciuria and urinary alkalinization, which promote calcium phosphate stone formation.

Presentation

Diagnosing an obstructive ureteral stone is relatively straightforward in the general population due to the classic signs and symptoms of renal colic. However, it is notoriously difficult in renal transplant patients due to denervation of the allograft during the harvesting process. Recipients rarely present with renal colic. In fact, more than half of recipients do not have any discomfort at the time of diagnosis [8, 30]. When present, patients usually report mild lower abdominal pain, which is believed to be due to peritoneal irritation from the hydronephrotic allograft. Collecting system dilation may be palpable on physical exam.

Most patients present with less specific signs and symptoms including decreased urine output, gross hematuria, recurrent UTIs, or urosepsis [11, 31, 32]. Acute renal insufficiency may be the only sign in some patients [33]. As a result, recipients with an obstructive stone may be misdiagnosed with acute rejection delaying appropriate treatment [34]. Fortunately, transplant nephrolithiasis does not appear to be associated with graft loss in the majority of those afflicted [35].

Time to presentation and subsequent diagnosis has been reported anywhere from 3 months to 18 years after transplantation [36]. However, a postoperative range of 1–4 years is more commonly cited [9, 11, 24].

Workup

A high index of suspicion for allograft lithiasis must exist in recipients presenting with vague abdominal discomfort, hematuria, recurrent UTIs, or worsening renal function. Evaluation should begin with a detailed history and physical exam. The presenting complaint should be fully characterized along with a review of the recipient’s immunosuppression regimen and other medical comorbidities. On exam the abdomen should be palpated to assess for evidence of allograft obstruction. Men with obstructive voiding symptoms should have a post‐void residual performed to ensure adequate bladder emptying.

Laboratory testing should include a urinalysis (with microscopic exam and culture if indicated), complete blood count, and metabolic panel. Imaging should include either an ultrasound or CT. Ultrasonography may visualize a stone or show indirect signs such as hydroureteronephrosis (Figure 69.1). If obstruction is noted without an apparent cause, then a noncontrast CT scan should be obtained. CT should be the initial imaging study in patients presenting with severe signs and symptoms due to its higher sensitivity for urolithiasis and other urologic complications such as urine leak, lymphocele, or stricture (Figure 69.2).

Plain films should not be used as a primary diagnostic modality due to their low sensitivity for urolithiasis and inability to detect other surgical complications. If ultrasound or CT demonstrate an allograft stone, then consideration for obtaining an abdominal X‐ray may be warranted to determine if the recipient is a potential candidate for shock‐wave lithotripsy (SWL).