Urological consequences following renal transplantation: a review of the literature

Post-RT surgical urological complications

The most common surgical urological complications include ureteral stricture and urinary leakage.

Ureteral strictures are generally classified as early (<3 months from RT) and late-onset (>3 months). The former may be caused by kinking, temporary oedema of the ureteral wall, narrow anastomosis or extrinsic compression by haematoma or lymphocele (3, 4). The latter are usually related to bad ureteral vascularisation resulting in ischemia and subsequent fibrosis and three risk factors have been identified: donor age more than 65 years, kidneys with more than two arteries and delayed graft function (5). Another cause of late-onset ureteral stenosis but with different pathogenesis is represented by BK virus (BKV) infection. This DNA virus acts as a pathogen only in immunocompromised population. Urothelial cells are natural reservoirs for BKV replication and ureteral stenosis associated with this virus accounts for 2-6% of all cases. Histologically, the stenotic tract appears ischaemic and fibrotic, resembling the lack of vascularisation encountered in bad vascular supply cases (6). Ureteral strictures may be treated with an endourologic (usually percutaneous) or a surgical approach. Balloon dilation and temporary ureteral stenting are the most common endourologic procedures. Generally, percutaneous approach is considered as the first option, as it is simpler and has both a diagnostic and therapeutic value (7). In the short term, endourologic procedures have a high success rate (from 73 to 100%), dropping to 40-55% in the long-term due to a high recurrence rate (8-9-10-11). In 2005, Juaneda et al identified early obstruction and the presence of previous acute rejection as factors associated with better success rates (7). In the algorithm proposed by Helfand, a stricture less than 3 cm in length was considered as a good prognostic factor (12). Recently, He et al proposed a new classification on the basis of the entity and nature of the stricture. Specific treatments correspond to different grades of strictures: temporary stent placement for G1 (increased creatinine and hydronephrosis without evidence of significant stricture), balloon dilation or endoscopic incision for G2 (stricture <1 cm), and immediate surgery for G3 (stricture >1 cm) (13). Ho:YAG laser endoureterotomy of the stenotic tract has a high success rate (>80%) in case of strictures less than 0.5-1 cm (14, 15). Surgery provides the highest success rate (>75%) (12, 16, 17). According to algorithms proposed by Helfand and He, surgery might be indicated after failure of endourologic treatment or as immediate treatment in case of late-onset strictures more than 3 cm (12, 13). The feasibility of a so-called extra-anatomic stent has been recently described as a salvage procedure when surgery is not indicated or ineffective (18).

Urinary leakage occurring within 15 days from RT is usually due to anastomosis dehiscence, whereas ureteral necrosis owing to vascular insufficiency is the main cause of later events (19, 20). Donor age and delayed graft function have been identified as independent risk factors for ureteral leakage (5). To avoid this complication, a careful preservation of ureteral vascularisation both during organ procurement and transplantation is mandatory (19). The endourologic management consists in temporary ureteral stenting or nephrostomy, even though it is not as effective as in strictures. Specific factors have been related to better treatment outcome, such as the occurrence of leakage more than 3 days after RT and a small entity of leakage, allowing the passage of contrast into the bladder at the first pyelography. According to recent studies, success rate of ureteral stenting for leakage ranges between 36 and 85% (21-22-23). In case of failure of endourologic treatment and in proximal or massive leakage, surgery is the only option (24, 25).

When surgical intervention is indicated, two options are available to manage leakages or stenosis: ureteral reimplantation or reconstruction with native urinary tract. Ureteral reimplantation is indicated in case of anastomotic or distal defects. The most used surgical techniques reported in literature are Lich-Gregoire, Taguchi, and Politano-Ledbetter reimplantation. Tagichi reimplantation, therefore, is associated with more haematuria episodes, while Lich–Gregoire technique is the preferred one, as it is a relatively easy procedure, it does not require a second cistotomy such as Politano-Ledbetter reimplantation, and it requires less ureteral length compared with other techniques (26, 27). Pike et al described 18 strictures corrected with direct reimplantation (occasionally requiring mobilisation of the urinary bladder) and 19 with reimplantation on a Boari flap, with a graft survival of 72.5% at 5 years (28). In a large series by Karam et al, reimplantation had no impact on graft survival as compared with non-stenotic grafts (10-year graft survival, 64 vs. 63%, p = 0.36) (5). Native urinary tract can be used to perform uretero-ureterostomy (UU), pyelo-ureterostomy (PU) and, less frequently, pyelo-pyelostomy (PP), with acceptable success rates (76-100%) considering that only small series have been reported (24, 29-30-31).

Allograft nephrectomy

Nowadays, graft failure rates are declining due to an improvement in immnosuppressive regimens. Nevertheless, acute or chronic rejection of allograft still happens and represents an indication to AN. Other indications are represented by vascular complications, including thrombosis, infectious complications and neoplastic diseases (32). AN is considered as early if performed within 12 months from RT and late if performed afterwards (33). Late AN represents a challenging procedure due to the desmoplastic reaction of the graft on chronic rejection that makes it adherent to the abdominal wall. As a consequence, late AN might harbour more peri-operative complications than early ones, such as major bleedings and death (32). When performing an AN, two major techniques are possible: intracapsular AN (ICAN) and extracapsular AN (ECAN). ICAN is performed by means of previous skin incision, graft identification, subsequent capsulotomy and finding of the plane between kidney parenchyma and renal capsule that is subsequently developed digitally until identification of the hilum that is closed with a vascular clamp and sutured with a two-line running suture. On the contrary, ECAN considers the complete and precise identification of vascular structures: artery and vein, and ureteral dissection until the bladder anastomosis. Subsequently, the structures are all ligated separately and AN is performed. As a matter of fact, the main difference between the two techniques is that ICAN leaves more donor tissues inside the recipient than ECAN, this possibly being a cause for allosensitisation and a reduced success of further transplantations. Literature findings on this topic are inhomogeneous. Touma et al in a recent study comparing ICAN with ECAN demonstrated a higher complication rate in the ECAN group in terms of perioperative bleeding and mortality (34). On the contrary, Mazzucchi et al did not find any statistically significant difference between the two techniques (32). Despite that, the only pathology that makes ECAN mandatory is graft neoplasia that forces surgeons to remove the entire graft for oncologic reasons. Independently from kidney neoplasm, further studies are needed to compare the two techniques to establish which is the less morbid.

Urologic de-novo malignancies following RT

RT patients have an increased risk of developing neoplastic diseases (35), mainly due to immunosuppressive treatment. This is the main risk factor for both short and long-term neoplasms, even though not every cancer type has the same etiopathogenetic association with immunosuppression (36). Among the mechanisms by which immunosuppressive treatment may favour malignancies are impaired immune surveillance and infections by oncogenic viruses. Irrespective of the causes, malignancy is the third cause of death in RT recipients following cardiovascular diseases and infections.

De-novo cancer is a major complication of RT that causes significant short and long-term mortality. It accounts for 20% of RT patient deaths every year and 30% of deaths among RT recipients with a follow-up greater than 20 years (37). According to the main registries on this topic, which are the Cincinnati Transplant Tumor Registry (CTTR), the Nordic Renal Transplant Registry (NRTR) and the Australian and New Zeland Transplant Registry (ANTR), the most frequent de-novo neoplasms following RT are skin cancer and posttransplant lymphoproliferative disease (PTLD). De-novo cancer incidence in patients followed-up more than 20 years is between 34 and 50% and, of these, 75% are skin cancers (38).

Focusing on urological malignancies, renal cell carcinoma (RCC) is the most frequent neoplasm accounting for almost 31% of all urologic malignancies and for 3.3% of post-RT overall malignancies. RCC most frequently arises in native kidneys. A well-known risk factor is represented by developing acquired cystic kidney disease (ACKD), a condition that progressively increases with the duration of chronic kidney disease and time on dialysis. Moreover, data also suggest that an unexpected underlying nephropathy, a uremic state, dialysis time and transplantation itself might have a role in malignant transformation of native kidneys (39). Nine cases have been reported in one of the largest series reported in literature, showing a 15-fold increased risk of developing RCC compared with general population (40).

According to Penn et al, the majority of kidney cancer is diagnosed early after RT, maybe due to more intense immunosuppression, while graft involvement is a rare event that requires every effort to spare the graft itself. Breda et al recently performed a retrospective study comparing pathologic characteristics of RCC arising in ESRD patients (under dialysis or after transplantation) with general population. Their results highlighted how RCC arising in ESRD patients harbour less aggressive characteristics, being much smaller, lower grade and lower stage tumours, thus leading to a 5-year cancer-specific survival of 90% compared with 69% of general population (41).

When feasible, conservative surgery represents the first choice in this case. There are also a few case reports of graft RCC treated with cryoablation or other minimally invasive techniques (42). Radical nephrectomy is indicated for RCC affecting native kidney irrespectively of its stage and grade. Concerning immunosuppressive regimen, the introduction of mammalian target of Rapamicin (mTOR) inhibitors, because of their well-known anti-proliferative activity, is highly suggested even if not already standardised (43).

As for bladder tumours, the most frequent pathological pattern is transitional cell carcinoma (TCC), with a three-fold risk compared with the general population. Overall incidence of TCC in RT population is 0.4%. The relative risk (RR) of TCC in RT recipients is very high in China, as compared with western countries (RR 14 vs. 2), probably due to the consumption of aristolochic acid and rhubarb, which are known TCC risk factors and are widely used in Chinese traditional medicine (44). Moreover, in the Asian population, there is a trend towards higher incidence of upper urinary tract involvement associated with higher-grade initial presentation in RT patients compared with dialysed ones. Zhang et al, in a single-centre retrospective study, confirm these data but no statistically significant differences in overall and cancer-specific survival are reported from the authors between the two populations (45). Recognised risk factors are represented by age, time from transplantation, female sex and smoking history (46, 47).

Generally, TCC treatment does not differ from normal clinical practice. Concerns about the use of intravesical BCG are related to the risk of sepsis and the possible reduced efficacy in immunocompromised patients. However, a recent study evaluating BCG use in RT patients with high-risk TCC did not report any side effect or a decrease in its efficacy. Further studies are needed to confirm these data (46). Another difference in treating TCC is radical cystectomy. Pelvic lymph node dissection is a mandatory step of the procedure that is not usually performed in RT patients on the graft side, mainly due to the fibrosis that surrounds the graft and the risk of vascular damages to the graft itself.

Prostate cancer (Pca) is the most frequent urologic malignancy in RT population with a two to five-fold greater risk than normal population (48). As far as immunosuppressive treatment alters host response to oncogenic stimuli, it is worldwide accepted that active surveillance is not a considerable option for RT patients who develop de-novo PCa. These patients are therefore treated with radical prostatectomy (RP) or radiation therapy. Concerning surgical strategy, no difference has been found between different approaches in terms of oncologic or functional outcomes: open retropubic, laparoscopic/robotic transperitoneal and transperineal RP (49). In a cohort study on retropubic RP, Lechevallier et al evidenced some surgical difficulties that might be encountered in RT recipients. First of all, caution is needed when placing the retractors in order to avoid ureteral or graft damage. Furthermore, it is almost always impossible to perform lymph node dissection on the side of the graft, as previously described for cystectomy. Finally, careful identification and dissection of the ureter of the graft is needed to avoid injuries (50).

Lower urinary tract dysfunction related to RT

Assessment of lower urinary tract function in future RT recipients is mandatory. This population can be divided into two groups: patients with a conserved diuresis and patients with disused bladders due to oliguria or complete anuria. The former needs to be evaluated with standard LUTS questionnaires, uroflowmetry and ultrasound with assessment of post-void residual volume, in order to rule out any bladder outlet obstruction or other less frequent conditions that could lead to graft damage (51). The latter needs careful evaluation because of an increased risk of developing filling phase LUTS after RT. Progressive reduction in bladder capacity and compliance is normally found in patients with ESRD due to an oliguric and then a progressively anuric state. Profound anatomic changes occur in disused bladder that leads to the development of a small and relatively poorly compliant bladder wall. In a comparative study, Chun et al analysed a population of 340 patients with ESRD demonstrating a linear and progressive relation between total dialysis years and both bladder capacity and compliance (52). Reduced bladder capacity and compliance may be responsible for the development of posttransplant LUTS, high-pressure bladder contraction and possibly graft damage. Careful evaluation of bladder function with urodynamic exam is therefore advisable before RT. The same authors showed that patients with bladder capacity inferior to 100 ml had a higher risk of developing LUTS because bladder function most likely will not recover completely. Lefrancois et al (53), on the contrary, demonstrated that the majority of patients recover bladder capacity, contractility and function after RT. These findings were confirmed by Serrano et al, who performed urodynamic examination in previously anuric patients and demonstrated that bladder capacity reached normal values (300 ml) after RT even in patients with a bladder capacity inferior to 100 ml before RT (54). Other authors confirmed a progressive improvement of LUTS even at 6 years after RT (55). These findings question the need to perform a bladder augmentation before RT with the aim of obtaining a low bladder filling pressure and an adequate cistometric capacity. Morales et al evaluated the possibility of performing RT in patients with augmented bladder, showing that urinary tract infections (UTIs) due to excessive postvoid residue represented the principal complication. They concluded that RT in an augmented bladder is feasible both before and after RT, but there might be the need of a period of clean intermittent catheterisation to minimise the risk of UTIs (56).

Graft urolithiasis

Urinary stones in RT patients are a rare complication, with a posttransplant incidence inferior to 2% (57-58-59). Only case reports and small series (<35 patients) described this event and its management. Renal stones may also be found already in the graft at procurement (so-called ‘donor-gifted’). Asymptomatic renal stones were found in 19 (5%) cases out of 377 potential living donors evaluated with CT scan by Olsburgh et al (60) and do not represent contraindication to RT but lead to a potential risk of severe postoperative complications. Treatment is indicated and most recent studies support ex-vivo ureterorenoscopy. Schade et al described 18 cases treated on bench by direct basket extraction or laser lithotripsy; all the recipients were stone-free at long-term follow-up (61). Similar results were reported by other studies, without any intra or postoperative complication, also in case of multiple stones (60, 62).

Post-transplant lithiasis can be found occasionally during follow-up. In case of ureteral migration, clinical presentation can be different as compared with general population: patients may report no pain because of graft denervations (57) and may present with urinary infections, haematuria and graft function impairment (57, 59). In other cases, clinical presentation may be dramatic with acute renal injury and sepsis (63), requiring immediate nephrostomy (63, 64). Elective treatments consist in conservative management, extracorporeal shockwave lithotripsy (ESWL), ureteroscopy, percutaneous nephrolithotomy and open surgery. Stones smaller than 4 mm can be safely managed by close surveillance alone, as they tend to remain stable or pass spontaneously without complications (65). ESWL is feasible in RT patients, even if stone targeting can be difficult due to the overlying bony pelvis. Prone position can counter this disadvantage. Challacombe et al successfully performed 13 ESWLs in a prone position (66), while in other series, a success rate more than 70% was reported without any complication (57, 64, 67). Cassini et al concluded that ESWL could be safely performed in case of stones less than 15 mm, while other treatments may be considered in case of failure (57). Ureteroscopy is also effective for stones less than 15 mm, with direct basket extraction or Holmium laser lithotripsy. Both anterograde and retrograde approaches have been described (68). Retrograde ureteroscopy can be challenging due to the location and the mobility of reimplanted ureteral orifice. Most studies reported success rates of 60-80% (58, 65, 69). Hyams et al described seven successful retrograde ureteroscopy and recommended the use of a Kumpe catheter to facilitate the access to ureteral orifice (68). In case of stones larger than 15-20 mm, PCNL is the non-surgical treatment with the highest stone-free rate (66). Krambeck et al presented one of the largest series of PCNL in RT patients, using a standard technique and dilating the existing nephrosotmy tract with Amplatz fascial dilators till 28Fr. Stone-free rate was 76%, but after a second procedure, all patients became stone-free (70). Mini-percutaneous nephrolithotomy using a 8.5/11.5 F nephroscope was successfully described by He in 2007 in seven patients (71). Open surgery is still a valid option in most complex cases, especially when stones coexist with ureteral strictures, or after failure of minimally invasive procedures. Stone surgery in RT patients is challenging due to the high risk of vascular damage and systemic complications (63). In the largest series of renal graft stones reported by Verrier et al, eight out of 31 patients required open surgery to remove the stone and correct a concomitant ureteral stricture (65).

Andrological dysfunctions related to RT

End-stage renal disease affects patients’ sexual and reproductive functions. As a matter of fact, erectile dysfunction (ED), loss of libido and infertility are frequently reported. Even if part of these problems can be restored after RT, sexual and reproductive troubles are common complaints in these patients (72-73-74). Thus urologists dealing with RT have to be familiar with diagnosis and treatment of andrological complaints.