Urolithiasis after Kidney Transplantation in Pediatric Recipients: A Single Center Report

Abstract

Background. 

Urolithiasis occurs in approximately 6% of adult kidney transplant (KTx) recipients. Limited data are available on urolithiasis after pediatric KTx. We report the incidence, management of, and risk factors for stone development in children after KTx.

Methods. 

We reviewed the medical records of 399 children who received KTx at our center between September 1986 and January 2003. Transplant outcomes were compared in stone formers and controls.

Results. 

Twenty (5%) patients, age 9±5 ( ± SD) years, developed stones over the follow-up period (74±53 months). Time to stone presentation was 19±22 months post-KTx. Presenting features were urinary tract infection (UTI), 8; gross hematuria, 5; microscopic hematuria, 2; dysuria without infection, 6; difficulty voiding, 3; and silent stones, 2. Stones were removed by cystoscopy in 11 (55%) patients. Stone composition was determined in 11 patients: calcium phosphate (55%), calcium oxalate (18%), mixed calcium phosphate and oxalate (9%), and struvite (18%). Factors predisposing to stones in study patients included suture retention (n=4), elevated urinary calcium excretion (n=2), recurrent UTI (n=2), and urinary stasis (n=2). The incidence of UTI was higher (P=0.003) and of acute rejection was lower (P=0.02) in stone patients compared with controls. Patient and graft survival rates and the incidence of chronic rejection did not significantly differ between study patients and controls (P=NS).

Conclusions. 

Urolithiasis is not uncommon in pediatric KTx patients. Factors associated with post-KTx urolithiasis include retention of suture material, recurrent UTI, hypercalciuria, and urinary stasis. Treatment is associated with excellent outcome and low recurrence rate.

The incidence of urolithiasis in adult kidney transplant (KTx) patients ranges between 0.2% and 6.3% and has been associated with metabolic disturbances, urinary tract obstruction, infection, and retention of suture material (^1–5). Limited data are available on urolithiasis incidence post-KTx in pediatric patients but, reported incidence ranges from 0.6% to 2.5% (^6–8). The aims of this study are to review the incidence, clinical features, stone composition, management, and risk factors for stone formation post-KTx and to compare Tx outcomes in stone formers with controls.

PATIENTS AND METHODS

Using our database and medical records, we retrospectively reviewed the records of pediatric patients (0–18 years, n=399) undergoing KTx at the University of Minnesota between September 1986 and January 2003. Of the 399 patients, 20 (5%) were diagnosed with urolithiasis post-KTx. The mean (±SD) age at Tx was 9±5 years (1 year old, n=1; 2–5 years, n=4; 6–12 years, n=10; 13–18 years, n=5), 85% (n=17) were male, and 90% (n=18) received living donor (LD) grafts. Transplant outcomes were compared with 20 asymptomatic controls matched for Tx date, Tx number, donor type, immunosuppression, and age at Tx (within 2 years). In the cases where there were several potential matches, the control with the primary disease most similar to the study patient was selected. The controls were not assessed for stones. Mean period of follow-up was 74±53 months (range 5–198 months). Patient characteristics are listed in (Table 1). This study was approved by the Institutional Review Board of the University of Minnesota.

TABLE 1: Patient characteristics

Immunosuppression

Our immunosuppression protocol has been previously described (⁹). Briefly, all patients received quadruple therapy including: prophylactic antibody, prednisone (P), azathioprine (Aza), or mycophenolate mofetil (MMF) at the time of Tx and delayed introduction of cyclosporine A (CsA). Prophylactic antibody consisted of Minnesota antilymphocyte globulin (20 mg/kg per day for 14 doses, n=15), antithymocyte globulin (20 mg/kg per day for 14 doses, n=11), Thymoglobulin (1.5 mg/kg per day for 10 doses, n=13), or Daclizumab (1 mg/kg/dose for 5 doses, n=1). All patients received P (2 mg/kg per day tapered to 0.45 mg/kg per day at 1 month and 0.25 mg/kg per day at 1 year post-Tx) and Aza (5 mg/kg per day tapered over 1 week to a maintenance dose of 2.5 mg/kg per day) or MMF (600 mg/m² body surface area twice a day). On post-Tx days 10–12 CsA (Sandimmune; Sandoz/Novartis, Switzerland) was started at 5 mg/kg per day orally and then reduced by 1 mg/kg per month to a maintenance dose of 3 mg/kg per day. Since June 1993, CsA is started (at 6–10 mg/kg/day in divided doses) on post-KTx days 1–5. The dosage is adjusted to maintain a trough level of 150–200 ng/mL by high-pressure liquid chromatography for the first 3 months post-KTx. Since August 1995, we have used the microemulsion formulation of CsA (Neoral; Novartis Pharmaceuticals, East Hanover, NJ). Two patients received tacrolimus (FK506, Fujisawa) at 0.15 mg/kg per day.

Antimicrobial and Antifungal Prophylaxis

Generally, trimethoprim-sulfamethoxazole orally was given daily as prophylaxis against urinary tract (UTI) and Pneumocystis carinii infection (⁹). Fungal prophylaxis was provided with oral nystatin for 6 months after transplantation.

Ureteroneocystostomy

Ureteroneocystostomy was done using the Leadbetter-Politano method in 18 patients (90%) and the anterior single-stitch method in 2 patients (10%) (¹⁰). The following absorbable suture materials were used: polydioxanone suture (PDS, n=17), polyglycolic acid suture (Dexon, n=2), and polyglyconate (Maxon, n=1). The bladder wall was closed in three layers in an interrupted fashion with absorbable suture materials (¹⁰). All grafts were negative for stones at the time of KTx.

Patient Evaluation

A urinary calcium/creatinine ratio was measured in nine patients. Hypercalciuria was defined as a urinary calcium excretion >4 mg/kg per day or a spot urine calcium/creatinine ratio above the normal value for age (¹¹). Twenty-four-hour urines were evaluated for calcium (n=3), oxalate (n=3), uric acid (n=3), citrate (n=1), and phosphorus (n=1) at the University of Minnesota hospital laboratories. Our normal laboratory values for urinary excretion are: oxalate (13–38 mg/day, age 0–12 years; 7–44 mg/day, male ≥13 years, 4–31 mg/day, female ≥13 years); phosphorus (0.4–1.3 g/day); uric acid (0.25–0.75 g/day); and citrate (320–1240 mg/day). Stones were analyzed in 11 patients by Fourier transform-infrared spectrophotometry at the laboratories of the Louis C. Herring Co, Orlando, Florida (¹²). UTI was diagnosed by urine culture.

Rejection

All rejection episodes were confirmed by percutaneous biopsy. Patients underwent biopsy if there was a ≥25% increase in the baseline serum creatinine (sCr), persistent fever, graft tenderness, or new onset or worsening of hypertension. Rejection was characterized as either acute or chronic, tubulointerstitial, and/or vascular by established criteria (⁹). Briefly, acute tubulointerstitial (Ti) rejection was defined by the presence of tubular mononuclear infiltrates, interstitial mononuclear infiltrates and edema, erythrocyte extravasation, and tubular damage. Acute vascular rejection was defined by subendothelial mononuclear infiltrates and endothelial sloughing. Chronic Ti rejection was characterized by interstitial fibrosis and tubular atrophy. Chronic vascular rejection was characterized by fibrointimal thickening and obliteration of arteries and arterioles (⁹).

Statistical Analyses

Data are expressed as mean ± standard deviation (SD) and range. Statistical analyses were performed using the Wilcoxon rank sum test, chi-square test, Fisher exact test, and Kruskal-Wallis test. Actuarial graft and patient survival rates were calculated using Kaplan-Meier survival methods. Graft loss was defined as a return to chronic dialysis, Tx nephrectomy, reTx, or pt death. A P value ≤0.05 was considered statistically significant.

RESULTS

Of the 399 pediatric KTx recipients, 20 (5%) were diagnosed with urolithiasis post-Tx. The patient characteristics, immunosuppression used, and ureteroneocystostomy methods did not significantly differ between the stone formers and the control patients (P=NS, (Table 1). The mean doses of prednisone and furosemide at 3 months and 1-year post-Tx did not significantly differ between the two groups (P=NS, (Table 2).

TABLE 2: Mean furosemide and prednisone doses

The mean time to stone presentation was 19±22 months (range 2–72). Stones occurred within the first year post-Tx in 12 patients (60%) and at 6 years post-Tx in 2 (10%). The most common presenting feature was UTI (40%) and 40% of stones were localized to the orifice of the transplanted ureter (Table 3). Stones were diagnosed by renal ultrasound (55%), cystoscopy (20%), plain x-ray (10%), computed tomography (10%), and clinical passage (10%). Factors predisposing to stone formation in study patients included suture retention (20%), recurrent UTI (10%), elevated urinary calcium excretion (10%), and urinary stasis secondary to urethral stricture (10%). Twelve patients had no known predisposing factors. The majority of stones were removed by cystoscopy (55%). (Table 4) shows clinical outcomes in the stone patients. The most common complication of stone formation was UTI (40%) (Table 5). The mean number of UTI episodes was six (range 1–13). No patient developed bladder outlet obstruction or required nephrostomy tube placement.

TABLE 3: Clinical presentation in stone patients

TABLE 4: Stone removal and analysis in study patients

TABLE 5: Clinical outcomes

Serum creatinine, calcium, phosphorus magnesium, and bicarbonate levels were normal in patients and controls (only sCr data shown, (Table 5). Urinary calcium/creatinine ratios were elevated in two consecutive samples in two patients: 0.65 and 0.71 (1.5-year-old male) and 0.40 and 0.30 (11-year-old male). All 24-hour urine samples had normal values for measured substances.

Crystallographic examination of stones was performed in 11 patients (Table 4). Most stones were calcium phosphate (55%, Fig. 1). Five (25%) patients had recurrent stones (mean 3 episodes, range 2–3). Two recurrent stones formers had hypercalciuria and were treated with a thiazide diuretic (3 months in 1, 1 year in 1). Cause of recurrence was unexplained in three patients. At follow-up, 19 (95%) patients remained stone free. One patient with a small, asymptomatic, nonobstructive bladder stone continues to be monitored.

FIGURE 1.: Calcium phosphate stones in the bladder of an 11-year-old boy at 4 months post-KTx.

Although one stone former had oxalosis as the primary cause of ESRD, the patient had also received a liver Tx and had normal urinary oxalate excretion at the time of stone formation. Unfortunately, the stones were not analyzed in this patient.

Four of the stone formers had bladder dysfunction pre- and post-KTx including a large irregular bladder with high postvoid residual volumes (n=1), a small trabeculated bladder (n=1), bladder sphincter dysynergia (n=1), and a bladder augmented with ileum (n=1). The incidence of urological complications post-Tx did not differ significantly between the stone formers and controls (P=NS, (Table 5).

The incidence of UTI was increased in the stone formers compared with controls (40% vs. 0%, P=0.003, (Table 5). The incidence of acute rejection was lower in the stone formers than in controls (28% vs. 58%, P=0.02). Graft and patient survival rates, the incidence of chronic rejection, and sCr levels did not differ significantly between stone formers and controls (Table 5).

DISCUSSION

Our 5% incidence of urolithiasis is higher than that of 0.6% to 2.5% from previous reports in pediatric KTx recipients (^6–8). Possible explanations include a longer follow-up period (information not stated in other studies), the type of suture material used for ureteroneocystostomy and bladder wall closure, and a higher incidence of UTI in our patients. As in our study, the studies by Zaontz et al. and Nuininga et al. found retention of suture material to be associated with stone formation post-KTx (^6,8). However, catgut, a more rapidly absorbing suture material, was used in their patients compared with the more slowly absorbing suture materials used in ours. Animal studies have shown that the length of time it takes for suture material to dissolve is a risk factor for stone formation (¹³). The incidence of stone formation in the sterile bladders of rabbits studied over a period of 90 days varies by the type of suture material used: polypropylene (very slowly absorbed) 74%, polydioxanone (slowly absorbed) 46%, and chromic catgut (fast absorption) 14% (¹³). Polydioxanone suture was used in the majority of our Tx patients; it has been shown to have improved tensile strength for wound closure compared with catgut (¹⁴).

Previous pediatric reports have not associated UTI with stone formation (^6–8). We found UTI in 40% of stone formers compared with 0% in controls. In experimental studies, infection has been shown to be a risk factor for stone formation. Milroy studied stone formation in rat bladders that had been infected with either Proteus or Escherichia coli bacteria (¹⁵). Bladder stones developed in 23 of 25 (92%) rats infected with Proteus bacteria, 2 of 10 (20%) infected with E. coli, and none of the rats with sterile bladders. Although not studied in our patients, urine pH also likely plays a role as Milroy found that the urine pH was alkaline in rats infected with Proteus bacteria and acid or neutral in rats infected with E. coli (¹⁵). Only two of our patients had struvite stones compared with 22% and 30% of stone formers reported in adult KTx patients (^16,17). In a study of cystic fibrosis patients who developed kidney stones (10 of 96 patients), a greater ingestion of cotrimoxazole and ceftazidim, cumulatively, was found in patients with kidney stones than in patients without stones (¹⁸). All stone formers and controls in this study received trimethoprim-sulfamethoxazole prophylaxis and suffered similar antibiotic exposure.

Hypercalciuria is a risk factor for stone formation post-KTx (^{4,16, 17}). The reports by Zaontz and Nuininga did not comment on this factor in their pediatric patients (^6,8). We documented hypercalciuria in two of our stone formers. Both responded to a course of therapy with a thiazide diuretic (¹⁹). Steroids and furosemide can induce hypercalciuria, but we found no significant difference in steroid dosage or the use of furosemide between stone formers and controls (^20,21). We also did not find abnormalities in urinary uric acid, oxalate, and citrate excretion in our patients; urinary concentrations of these substances have been found to be abnormal in some patients with stone formation post-KTx (^16,17). A limitation of our study was the fact that we did not perform urinary calcium, oxalate, uric acid, phosphorus, citrate measurement, and stone analysis in every patient that developed stones. Although stone formation has been reported in the setting of secondary hyperparathyroidism post-Tx, a limitation of this study is that we did not routinely measure parathyroid hormone levels in our patients and cannot comment on its role in the development of stones in our patients (^3,17). Serum calcium levels were normal in both stone formers and controls in our study.

An increased incidence of urolithiasis has been reported in pediatric KTx patients with lower urinary tract dysfunction ranging from 3.3% to 9.5% although total numbers of patients with stones in these studies ranged from 1 to 2 (^22–25). In these patients urinary diversion, bladder augmentation, and/or hypercalciuria in an immobilized patient may have played a role. One of the four stone formers in our study with lower urinary tract dysfunction post-Tx also had an augmented bladder.

Allograft outcome was excellent in our patients despite the development of stones. We found a lower incidence of acute rejection and the graft and patient survival rates of 95% and 100%, respectively, at 5 years were comparable with those of 89% and 100% in controls. We believe the lower incidence of acute rejection found in this study was a random association. We found no other studies that compared patient and graft survival rates and rejection incidence between stone formers and controls.

In conclusion, urolithiasis is not uncommon in pediatric KTx recipients and should be considered in patients presenting with dysuria, hematuria, recurrent UTI, and difficulty voiding. Factors associated with post-KTx urolithiasis include retention of suture material, recurrent UTI, hypercalciuria, and urinary stasis. Diagnosis and treatment of urolithiasis post-KTx are associated with excellent graft outcome and low rate of recurrence in pediatric KTx recipients.

Acknowledgments

We gratefully thank Sandy Cragg for her assistance in the preparation of this manuscript and Sue Kupcho and Kerri Sawyer for their assistance with data retrieval.