Autosomal dominant polycystic kidney disease (PCKD) is a genetic disorder resulting in the progressive formation of multiple renal cysts that adversely affect renal function.1 Two genes, PKD1 and PKD2, have been implicated in the development of the disease which comprises approximately 10% of end-stage renal disease (ESRD) diagnoses.2,3 It occurs without sex or racial predilection and is the most common cause of inherited renal failure. Despite optimal medical management, up to 50% of patients progress to ESRD and require renal replacement therapy by 70 years of age.4
PCKD leads to many systemic manifestations and symptoms. Dysregulation of the renin-angiotensin-aldosterone system can lead to severe hypertension,5 whereas compression of surrounding viscera may result in early satiety and abdominal pain. Cysts may rupture leading to painful crises or, sometimes severe, hemorrhage. Infected cysts can also lead to recurrent urinary tract infections or urosepsis. A correlation has also been established between PCKD and renal cancer; however, this may be due to increased screening in this population and not a pathogenic link.6,7 Although medical therapy can halt the progression of kidney growth,8 the only cure for these symptoms is nephrectomy.
The timing of native nephrectomy in relation to renal transplantation has been scrutinized.9-12 Some consider the anephric state rendered with pretransplant nephrectomy to be hazardous especially in the preuremic patient undergoing a preemptive kidney transplant.13 Others remain concerned that the prolonged anesthesia time, fluid shifts, and potential transfusion requirement of bilateral native nephrectomy at the time of transplant may have deleterious effects on the renal allograft. Despite this, recent studies have demonstrated that bilateral native nephrectomy can be performed safely. These studies however have had small sample sizes, or only examined a living donor population.9,11 We sought to evaluate graft function and the postsurgical complication rates in 2 large treatment groups, those undergoing native nephrectomies well in advance of renal transplantation or simultaneous bilateral nephrectomies, and compare them with a control group of PCKD transplant recipients not undergoing native nephrectomy. In addition, we assessed the risks of nontransplantation after transplant candidates undergo pretransplant bilateral native nephrectomy.
MATERIALS AND METHODS
We performed a retrospective review of all PCKD patients at the University of Wisconsin, over a 20-year period, between 1994 and 2014. Patients were included if they had a primary diagnosis of PCKD leading to their first kidney transplant. Patients who had unilateral nephrectomy were excluded. The patients were stratified into 3 groups. Two study groups consisted of patients who had bilateral nephrectomies before transplant (pre) or at the time of renal transplant (simultaneous). A control group consisted of transplanted patients with a diagnosis of PCKD who did not undergo nephrectomy (tx-alone).
The University of Wisconsin’s Division of Transplantation maintains a robust outcomes database cataloging data obtained from the paper chart and subsequently the electronic medical record. The database was first queried to assess demographic data for the 3 groups including patient age, sex, donor type, donor age, cold ischemic time, and body mass index. Operative details including estimated blood loss, number of packed red blood cells transfused, and native kidney weights were assessed among the study groups, where data were available.
We determined actuarial patient and graft survival rates, death-censored graft survival rates, and the cumulative incidence of the various postsurgical complication rates. Actuarial patient and graft survival rates were calculated beginning at the time of transplantation. Kidney graft failure was defined as removal or loss of function requiring return to dialysis. Actuarial survival estimates were calculated using Kaplan Meier life-table analysis (9), and the series was followed through August 15, 2015. A univariate analysis was performed comparing the groups with regard to graft survival, patient survival, and postoperative complications. The latter included renal vascular thromboses, hernias, urine leaks, ureteral strictures, deep vein thrombi, lymphoceles, ileus, and small-bowel obstructions. Univariate analyses of categorical variables were performed using the χ2 test. Subsequently, multiple factors were examined using Cox proportional hazards models. All statistical tests were 2-tailed; P less than 0.05 was considered significant.
There were 565 patients with PCKD who had renal transplants during the study period. Of these, 16 patients had unilateral nephrectomy. Fifty-eight patients had previous transplants. These patients were excluded leaving a total of 520 patients evaluated. There were 303 patients in the tx-alone cohort, 27 patients in the precohort, and 161 patients in the simultaneous cohort (Figure 1). The groups were well matched with regard to donor age, cold ischemic time, and sex. Statistically significant differences were noted in patient age at transplant; however, the mean ages were similar (age, 53.8, 49.9, 50.6 years in the tx-alone, pre, and simultaneous groups, respectively). The groups also significantly differed in BMI, though the mean weights were similar between groups (27.2, 28.9, and 28.3 kg/m2 in the tx-alone, pre, and simultaneous groups, respectively). Patients in the simultaneous bilateral nephrectomy cohort were more likely to have a living donor renal transplant (59% vs 38% tx-alone, 37% pre) and were more likely to be male (Table 1).
All native nephrectomies were performed through a midline laparotomy incision. In the simultaneous group, the allograft was placed on the iliac vessels through the same incision. In the pregroup, 25 patients had subsequent retroperitoneally placed renal transplants through a Gibson incision in the right or left lower quadrant. Two patients had intraperitoneal kidney transplants through their prior midline incision. The prepatients had a mean of 552 anephric days before receiving a renal transplant allograft. Tx-alone and simultaneous bilateral nephrectomy patients had similar rates of preemptive transplantation (57% and 56%, respectively). The operative details, including blood loss and transfusion requirements, as well as pathology reports were reviewed in all cases where data was available. The average estimated blood loss in the pregroup was 338.6 mL during the nephrectomy and 247.8 mL during the transplant. Meanwhile, the simultaneous group had an estimated blood loss of 510.4 mL and received an average of 0.4 units. The combined total average weight of the 2 native kidneys was 4526.1 g in the pregroup and 4654.8 g in the simultaneous group (Table 2). Although this was statistically significant, 2 patients in the simultaneous group had kidneys with a combined weight of over 14 kg. If removing these outlier weights from the analysis, the statistical significance was lost.
The average postoperative follow-up time was 9.2, 11.7, and 9.4 years in the tx-alone, pre, and simultaneous groups, respectively. There were no significant differences in patient or graft survival. When stratifying the groups by deceased or living donor renal allograft, again, there were no statistically significant differences in the actuarial 1-, 5-, and 10-year graft survival or 5- and 10-year patient survival (Figure 2).
Of the 334 patients in the tx-alone group, 16.3% went on to require unilateral or bilateral nephrectomy at 10 years follow-up (Figure 3). There were statistically more renal vascular thromboses in the simultaneous group (4.4%) versus the pre and tx-alone groups (1.3% and 0%, respectively). In the simultaneous group, there were 2 postoperative thromboses presenting acutely, at 7.6 and 35 months after transplantation. The remaining thromboses occurred at a mean of 5.8 days posttransplant. These specific cases are summarized in Table 3. Just over 25% of the patients in the pregroup had wound complications, which comprised wound infections, skin, and fascial dehiscences. There were no statistical differences in hernia, urine leak, urinary stricture, DVT, ileus, or small-bowel obstruction rates. Patients who had simultaneous bilateral nephrectomies were less likely to have lymphoceles (1.3% vs 10.2% tx-alone, 11.1% pre) (Table 4). There was no difference in the rates of delayed graft function, defined as the requirement of dialysis within the first week posttransplant.
During the study period, an additional 29 PCKD patients were referred for transplant evaluation, having had nephrectomies already performed, who were not ultimately transplanted. Four remain active on our transplant waiting list, 2 of them with high panel-reactive antibody (PRA) levels. An additional 4 patients were highly sensitized and unable to get transplanted before being deemed not a transplant candidate secondary to worsening comorbidities. Of the 29 patients, 6 had their nephrectomies performed at the University of Wisconsin with an average estimated blood loss of 358 mL and an average of 1.3 units of red blood cells transfused. PRA information was available on 4 of these patients. The average PRA increased significantly, 16.5 percentage points, before and after nephrectomy (P < 0.001).
A multivariable analysis was performed to assess the controlled effect of nephrectomy performance and timing on all measured outcomes. Table 5 displays the results, comparing the exposed (pre or simultaneous) to control (tx-alone). Importantly, in the simultaneous cohort, there was a 215% increase in the risk of vascular thrombosis compared with the tx-alone cohort after adjusting for recipient age, race, and BMI as well as surgeon (hazard ratio, 3.15; 95% confidence interval, 1.03-9.71; P = 0.045). The simultaneous cohort had fewer lymphoceles (P = 0.005), whereas the precohort had more frequent wound complications (P = 0.009).
PCKD is a common etiology of renal failure for patients on the transplant waiting list. As such, PCKD patients frequently rely on renal transplantation as a cure for their ESRD.14 During transplant evaluation, clinicians frequently must decide if a patient's symptom burden necessitates nephrectomy. The most frequent of these symptoms include recurrent urinary tract infection and pyelonephritis, cyst hemorrhage, and pain. More infrequently, nephrectomy has been performed when native kidneys are too big to allow successful implantation of a renal allograft. Despite initial enthusiasm to remove polycystic kidneys, the incidence of bilateral nephrectomy for PCKD has decreased over time.10,15,16 If bilateral nephrectomy is deemed necessary, however, clinicians must consider the timing of the operations. There has been increasing scrutiny over outcomes in recipients who had simultaneous bilateral nephrectomies at the time of transplantation. Ahmad et al9 retrospectively analyzed 118 patients with PCKD who had living donor renal transplants with or without concurrent bilateral nephrectomies. They found significantly more frequent major surgery-related intraoperative complications in the nephrectomy group. Importantly though, there were no differences in graft survival at 12 months. Fuller et al11 have examined 32 PCKD patients who had bilateral nephrectomies either before, simultaneously, or posttransplant. They reported no differences in postoperative morbidity or creatinine at 3 months posttransplant.
Our study looked to clarify the postoperative outcomes and long-term patient and graft survivals of patients who had bilateral nephrectomies either before or at transplant versus patients who retained their native kidneys. We were able to do this by evaluating the largest reported cohort over the longest reported follow-up. The patients were similarly matched, although significantly more simultaneous patients were recipients of living donor allografts. When comparing outcomes among the living donor and deceased donor recipients, there were no significant differences. Overall graft and patient survival did not differ among the 3 groups.
Previous studies have criticized performing nephrectomies before transplantation.17,18 The anephric state rendered by pretransplant nephrectomy may subject patients to renal osteodystrophy, anemia, uremia, fluid overload, congestive cardiac failure, and hyperkalemia. Further, preexisting anemia, surgical blood loss, and postoperative hypotension can all trigger a blood transfusion. In this study, among the prepatients, there were few who received blood transfusions during nephrectomy. Twenty-nine patients were referred having had nephrectomies, who were ultimately not transplanted. Six of the patients had their nephrectomies at University of Wisconsin, and 4 patients had PRA information available before and after transplant. Importantly, there were significant increases in sensitization as measured by PRA before and after nephrectomy, rendering recipients difficult to match. This represents a significant risk in performing nephrectomy in the pretransplant setting.
Somewhat alarmingly, we noted that patients in the simultaneous group also had a higher rate of early renal vascular thromboses. Though the significance of multiple arteries on thrombosis risk is unclear, it is important to note that of the 13 vascular thrombosis patients in this study, 7 patients had transplants complicated by multiple renal arteries. Four of them were in the simultaneous group and 3 had back-table arterial reconstructions (Table 3).19-22 Indeed, these reconstructions may have been thrombogenic and partially responsible for postoperative thrombosis. The episodes were well distributed over the study period. Though we were not able to capture central venous pressures and blood pressures in the studied patients, the thrombosis risk in the simultaneous group may be higher because of postoperative hemodynamic lability. The removal of massive polycystic kidneys is associated with large intravascular and extravascular volume shifts, especially if excessive blood loss occurs. Further, a sudden loss of the intrarenal renin-angiotensin system immediately after nephrectomy may exacerbate hypotension.5,23,24 Though not the standard practice at our institution, perhaps all simultaneous nephrectomy and transplant patients should have advanced hemodynamic monitoring (through either invasive or noninvasive techniques) to closely monitor intravascular volume. This way, patients can be adequately resuscitated to specific hemodynamic targets to prevent blood pressure lability and possibly secondary thrombosis. Without further study into the etiology of these thromboses, the simultaneous approach should be attempted with caution.
Other postoperative complications should be considered, as well. Patients receiving pretransplant nephrectomies were more likely to have wound complications after transplant, perhaps due to an abdominal wall rendered ischemic by multiple incisions. A laparoscopic approach may obviate this risk, and according to a recent meta-analysis, may do so with a lower complication rate.25,26 Though operator-dependent, laparoscopic donor nephrectomy is safe and feasible in patients with large polycystic kidneys. The simultaneous group had a significantly lower rate of lymphoceles, certainly secondary to the intra-abdominal placement of these kidneys.
Our study aims to inform clinicians about the risks and benefits of simultaneous bilateral nephrectomy and renal transplantation in both living and deceased donor recipients. It is limited by its retrospective nature; however, a prospective randomized study evaluating these approaches would be impractical and require quite a large sample size. We show that although simultaneous bilateral nephrectomy and renal transplantation can be performed safely with acceptable graft and patient survival, it may not be as risk-free as previous literature suggests.9-12 Clearly, there was a significantly higher incidence of renal vascular thrombosis in the simultaneous group. The threshold to remove bilateral native kidneys at the time of transplant should reflect this risk. Only patients with significant pain, recurrent infections, severe hemorrhage, or true inability to place a renal allograft should have simultaneous bilateral nephrectomies at the time of transplant. A patient who has large kidneys but is minimally symptomatic may be better served with his native kidneys left in place. Caution should also be rendered in performing elective pretransplant nephrectomy because there is a risk of transfusion and concomitant sensitization. Surgeons should carefully evaluate PCKD patients' symptoms and selectively choose whether and when to perform nephrectomies.
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