Right and left living donor kidneys harvested laparoscopically offer comparable post-transplant donor and recipient outcomes, researchers concluded in a presentation at the Canadian Urological Association annual meeting in Ottawa.

Clare E. Gardiner, MD, a urology resident, and colleagues at the University of Manitoba in Winnipeg reviewed 72 donor-recipient pairs in which a living donor underwent a laparoscopic nephrectomy. Of the 72 nephrectomies, 56 were left sided and 16 were right sided. The investigators found no significant differences between the right and left nephrectomy groups in donor demographics, donor estimated blood loss, warm ischemic time, complications, hospital length of stay, and rejection and delayed graft function rates. Recipient mean serum creatinine levels were equivalent between the groups at 0, 1, and 6 weeks post-transplant.

Dr. Gardiner's team noted in their study abstract that surgeons are reluctant to harvest the right kidney laparoscopically because of concerns about shorter right renal vein length, greater complexity of the dissection, and potentially worse renal allograft outcomes and complication rates.

“Harvesting the right kidney laparoscopically is safe and does not have a negative impact on donor recovery or long term graft function in the recipient,” the authors concluded.

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Local tumor ablation (LTA) for small renal masses offers a significant advantage over expectant management (EM) in terms of cancer-specific mortality, data presented at the Canadian Urological Association annual meeting in Ottawa suggest.

The 5-year cancer-specific mortality (CSM) rates were 3.5% for LTA and 9.1% for EM, investigator Vincent Trudeau, MD, a urology resident at the University of Montreal Health Centre reported. In multivariate competing risks analyses, LTA was associated with a significant 53% decreased risk of CSM compared with EM.

The study included 1,860 patients with cT1a kidney cancer treated with either LTA or expectant management from 2000 to 2009. Compared with EM patients, LTA patients were significantly younger (median age 77 vs. 78 years). The LTA group had a significantly greater proportion of Caucasians than the EM group (84% vs. 78%) and a significantly greater proportion of patients with high socio-economic status (54% vs. 45%).

The investigators used propensity score matching to decrease potential measured differences between LTA and EM patients. After propensity score matching, 553 patients in each group remained for analyses.

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Literature search and included trials

The results of the literature search are illustrated in Fig. 1. Twenty-one reports from 11 trials were identified [12]–[22], with a total of 4930 randomized participants.

Fig. 1. Flowchart showing the process of identification of randomized controlled trials for inclusion in the meta-analysis

All of the included reports were published in English. Seven randomized controlled trials were multicenter trials [12]–[15], [17], [21], [22]. Seven trials compared sirolimus to MMF [13], [15]–[20], while 3 trials compared everolimus to MMF [12], [14], [22], and 1 trial compared everolimus to EC-MPS [21]. Five trials had two arms [12], [17], [18], [20], [22], and 5 trials had three arms [13]–[15], [19], [21]: four of these examined the effects of two different doses of mTOR-I compared with MPA, and the other one compared mTOR-I combined with different CNI to MMF combined with CsA. One trial had four arms that investigated sirolimus versus MMF when combined with different CNI [16]. Two trials used a rapid steroid withdrawal immunosuppression protocol, all recipients received no more than 3 doses of methylprednisolone, then steroid therapy was discontinued [16], [20]. Five trials used basiliximab induction [12], [16], [20]–[22], while 1 trial used daclizumab induction [19], and 5 trials received no induction therapy [13]–[15], [17], [18]. The basic characteristics of the included trials are summarized in Table 1.

Table 1. Characteristics of the included trials

Risk of bias

Overall, the quality of the included trials was moderate. The overall assessment of the risk of included trials is displayed in Fig. 2. Ten trials reported adequate sequence generation and for 1 trial this was unclear [13]. Nine trials had low risk of allocation concealment. Only one trial reported blinding of participants and personnel [14]. Eight trials had low risk of bias for reporting incomplete outcome data and for the remaining three trials this was unclear [16]–[18]. All trials were funded or partially sponsored by a pharmaceutical industry company. Withdraw rates for all studies were?<?20 %. All the studies used appropriate statistical tests within their analysis.

Fig. 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

Biopsy-proven acute rejection (BPAR)

Eight trials reported the incidence of BPAR [12]–[16], [19]–[21], 3 trials reported both clinically defined AR and BPAR [17], [18], [22]. However, only the BPAR was included in the meta-analysis. There was no significant difference in the risk of BPAR when mTOR-I was compared with MPA at 6 months, 1 year, 2 years, and at the end of the follow-up period (6 months: 5 studies, 2710 patients, RR?=?0.98, 95 % CI 0.83–1.16, P?=?0.81; 1 year: 8 studies, 3210 patients, RR?=?0.91, 95 % CI 0.78–1.07, P?=?0.25; 2 years: 4 studies, 1977 patients, RR?=?0.86, 95 % CI 0.66–1.11, P?=?0.24; overall: 11 studies; 4630 patients, RR?=?0.99, 95 % CI 0.83–1.19, P?=?0.94; Fig. 3). Significant heterogeneity was found in the overall risk of BPAR outcome (P?=?0.06, I ² ?=?43 %) without evidence of publication bias (P?=?0.39). Subgroup analysis and meta-regression were performed to explore the sources of heterogeneity and to examine whether key trial design features modified the overall BPAR results. The results are summarized in Table 2. There was no evidence that the effects of BPAR differed among subgroups defined according to the key trial design features examined (P?>?0.05 for all comparisons).

Fig. 3. Forest plot showing the relative risk of biopsy-proven acute rejection at 6 months, 1 year, 2 years and at the end of the follow-up period

Table 2. Meta-regression analysis of potential sources of heterogeneity for the outcome of biopsy-proven acute rejection and graft loss

Graft and patient survival

Patient survival was reported in all trials. There was no significant difference in mortality (11 studies, 4630 patients, RR?=?1.17, 95 % CI 0.89–1.53, P?=?0.27), with no evidence of heterogeneity (P?=?0.80, I ² ?=?0 %) or publication bias (P?=?0.97).

Overall graft loss (including death with a functioning graft) was reported in all trials. The use of a mTOR-I led to a significantly higher risk of overall graft loss (11 studies, 4630 patients, RR?=?1.20, 95 % CI 1.02–1.40, P?=?0.03) (Fig. 4a). No evident heterogeneity (P?=?0.50, I ² ?=?0 %) or publication bias (P?=?0.60) were observed. Death-censored graft loss was reported in 9 trials [12]–[14], [17]–[22]. Similarly, patients treated with a mTOR-I showed a significantly increased risk of death-censored graft loss (9 studies, 3453 patients, RR?=?1.31, 95 % CI 1.02–1.69, P?=?0.03) (Fig. 4b). The results of subgroup analysis and meta-regression for overall graft loss are shown in Table 2. No evident difference was observed on the effects of overall graft loss among any subgroups (P?>?0.05 for all comparisons).

Fig. 4. Forest plot showing the relative risk of graft loss (a) and death-censored graft loss (b)

Graft function

Serum creatinine and creatinine clearance (Cockcroft-Gault Formula) was reported in 8 trials [12]–[15], [17]–[19], [21]; however, only 6 of them had enough data for meta-analysis (the other 2 trials only described median serum creatinine and a standard deviation could not be calculated). There was no significant difference in serum creatinine between the mTOR-I and MPA groups (6 trials, 2427 patients, WMD?=?7.79 ?mol/L, 95 % CI ?2.18–17.76, P?=?0.13, I ² ?=?51 %). Patients treated with a mTOR-I demonstrated a lower creatinine clearance (6 trials, 2177 patients, WMD?=??2.41 ?mol/L, 95 % CI ?4.55 to ?0.26, P?=?0.03, I ² ?=?24 %). We performed subgroup analysis for these two outcomes. Serum creatinine was significantly higher and creatinine clearance was significantly lower in the mTOR-I group when combined with equal doses of CNI, as compared with the MPA group (serum creatinine: WMD?=?17.31 ?mol/L, 95 % CI 7.90–26.72, P?=?0.0003; creatinine clearance: WMD?=??4.78 ml/min, 95 % CI, ?7.61 to ?1.95, P?=?0.0009). However, when a mTOR-I was combined with a lower dose of CNI than the MPA group, no significant difference was observed between these two treatment groups (serum creatinine: WMD?=??3.11 ?mol/L, 95 % CI ?11.87–5.64, P?=?0.49; creatinine clearance: WMD?=?0.76 ml/min, 95 % CI ?2.51–4.03; P?=?0.65). No heterogeneity was observed in either subgroup (I ² ?=?0 %) (Fig. 5a and b).

Fig. 5. Subgroup analysis for creatinine clearance (a) and serum creatinine (b), stratified by calcineurin inhibitor dose

Glomerular filtration rate (GFR) estimated by the Modification of Diet in Renal Disease (MDRD) study equation [23] was also reported in 4 trials. Guerra et al. [19] and Chhabra et al. [20] showed a significantly lower mean GFR in the mTOR-I group compared with the MMF group throughout the entire long-term follow-up period (beyond 8 years). In contrast, Takahashi et al. [22] and Crbrik et al. [21] reported no significant difference in GFR between the two treatments with 1 and 2 years follow-up, respectively.

New-onset diabetes mellitus (NODM)

New-onset diabetes mellitus (NODM) was reported in 10 trials [13]–[22]. Patients treated with mTOR-I showed a significantly increased risk of NODM (10 studies, 3550 patients, RR?=?1.32, 95 % CI 1.07–1.62, P?=?0.008). No significant heterogeneity (I ² ?=?4 %) or publication bias (P?=?0.15) were observed.

Vitko et al. [14] and Cibrik et al. [21] reported that patients treated with a high dose of everolimus (3 mg/d) had a significantly increased risk of NODM when compared with those treated with a low dose of everolimus (1.5 mg/d) or MPA. Similar results were also reported in a Sirolimus study (0.5 mg/d versus 2 mg/d) published by Vitko et al. in 2006 [15].

Infections

CMV infection was reported in all trials. Patients treated with mTOR-I showed a significantly reduced risk of CMV infection (11 studies, 4622 patients, RR?=?0.43, 95 % CI 0.29–0.63, P?<?0.0001). Heterogeneity was significant (P?=?0.02, I ² ?=?54 %), but no publication bias was observed (P?=?0.66). Subgroup analysis and meta-regression also demonstrated that the heterogeneity observed between the studies could not be explained by the type of mTOR-I and MPA used, steroid withdrawal or not, the use of antibody induction or the length of follow-up. No significant difference in the RR of CMV infection was observed for any subgroups examined (P?>?0.05 for all comparisons).

Urinary tract infection (UTI) was reported in 7 trials [12], [14], [17]–[21]. There was no significant difference in the incidence of UTI when a mTOR-I was compared with MPA (7 studies, 2962 patients, RR?=?1.00, 95 % CI 0.87–1.15, P?=?0.96), with no significant heterogeneity (P?=?0.32, I ² ?=?15 %) or publication bias (P?=?0.94).

Only 2 trials [19], [21] reported the incidence of polyoma virus infection. No significant difference was observed between the two treatment groups (2 studies, 975 patients, RR?=?1.05, 95 % CI 0.03–40.89, P?=?0.98). Heterogeneity was significant and evident (P?=?0.01, I ² ?=?84 %). Because of the small number of included trials, no subgroup analysis was performed to explore the source of heterogeneity.

Dyslipidemia

Serum cholesterol and triglyceride levels were also reported in 6 trials [13], [14], [17]–[19], [21]. Meta-analysis showed that patients treated with mTOR-I had significantly higher cholesterol and triglyceride levels (cholesterol: 6 studies, 1932 patients, WMD?=?33.02 mg/dl, 95 % CI 1.11–64.93, P?=?0.04; triglyceride: 6 studies, 1932 patients, WMD?=?36.15 mg/d, 95 % CI 23.65–48.64, P?<?0.00001). Patients treated with mTOR-I were more likely to require statin therapy (8 studies; 2950 patients; RR?=?1.35; 95 % CI 1.18–1.54; P?<?0.0001). Heterogeneity was evident in all three analyses (Table 3). Subgroup analysis failed to demonstrate a cause for this heterogeneity (data not shown).

Table 3. Meta-analysis for secondary outcomes

Hematologic adverse events

Hematologic adverse events, including thrombocytopenia, leucopenia and anemia were reported in several trials. The use of a mTOR-I showed a significantly increased risk of thrombocytopenia (3 studies, 1774 patients, RR?=?1.97, 95 % CI 1.19–3.35, P?=?0.008, I ² ?=?37 %) [13], [14], [21] and a significantly reduced risk of leucopenia (7 studies, 3954 patients, RR?=?0.43, 95 % CI 0.29–0.64, P?<?0.0001, I ² ?=?59 %) [13]–[15], [18], [20]–[22]. However, no significant difference in the risk of anemia was observed (6 studies, 2734 patients, RR?=?1.21, 95 % CI 0.88–1.68, P?=?0.21, I ² ?=?81 %) [12], [14], [18], [20]–[22]. The heterogeneity could not be explained by subgroup analysis.

Proteinuria

Proteinuria was reported in 7 trials [12], [15]–[17], [20]–[22]. Patients treated with a mTOR-I showed a significantly increased risk of proteinuria (7 studies, 2861 patients, RR?=?1.79, 95 % CI 1.38–2.31, P?<?0.0001), with no evident heterogeneity (P?=?0.73, I ² ?=?0 %).

Wound related complications

Impaired wound healing (including wound infection and dehiscence) was reported in 6 trials [15]–[17], [19], [21], [22]. No significant difference was observed when mTOR-I were compared with MPA (6 studies, 2374 patients, RR?=?1.55, 95 % CI 0.97–2.47, P?=?0.07), although patients treated with a mTOR-I had a significantly increased risk of lymphocoele (7 studies, 3345 patients, RR?=?1.80, 95 % CI 1.38–2.34, P?<?0.0001) [12], [14], [15], [17], [19], [21], [22]. Both of these meta-analyses showed low heterogeneity (I ² ?=?0 %).

Malignancy

Eight trials reported the incidence of malignancy after transplantation [12]–[16], [18], [20], [21]. The pooled incidence of malignancy was 2.4 % (62 of 2621) in the mTOR-I group and 3.6 % (58 of 1629) in the MPA group. Patients treated with mTOR-I showed a significantly reduced risk of post-transplantation malignancy (8 studies, 4250 patients, RR?=?0.64, 95 % CI 0.45–0.91, P?=?0.01), heterogeneity was not significant (P?=?0.17; I ² ?=?32 %). Among the 8 trials, 4 trials [12], [15], [16], [18] reported the incidence of post-transplantation lymphoproliferative disease (PTLD). There was no significant difference in the risk of PTLD between the two treatment groups (4 studies, 2394 patients, RR?=?0.78, 95 % CI 0.27–2.28, P?=?0.65), with no significant heterogeneity (P?=?0.22, I ² ?=?32 %).

Other adverse events

Diarrhea was reported in 7 trials [12], [15], [16], [18]. No significant difference was observed (7 studies, 3729 patients, RR?=?0.89, 95 % CI 0.64–1.25, P?=?0.50), although heterogeneity was evident (P?<?0.0001, I ² ?=?80 %). Even if we excluded the trial which used EC-MPS [21], no evident change in the RR (RR?=?0.89, 95 % CI 0.58–1.36) was observed and the heterogeneity was still present (I ² ?=?83 %).

Five trials [12], [13], [16], [19], [22] reported the incidence of peripheral edema. Patients treated with mTOR-I showed a significantly higher incidence of peripheral edema (5 studies, 2752 patients, RR?=?1.34, 95 % CI 1.08–1.68, P?=?0.009). Heterogeneity was evident, but not significant (P?=?0.06, I ² ?=?56 %).

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On June 26, 2015, the Centers for Medicare & Medicaid Services (CMS) released its proposed rule to update the Medicare end-stage renal disease (ESRD) prospective payment system (PPS) for calendar year (CY) 2016. CMS anticipates that the proposed rule would increase overall Medicare payments to ESRD facilities by 0.3% ($20 million) compared with CY 2015 payments. The proposed CY 2016 ESRD PPS base rate of $230.20 would be a $9.23 reduction from the CY 2015 base rate of $239.43. The proposed rule would, among other things, modify case mix and low-volume payment adjustments and update outlier Medicare Allowable Payment and fixed dollar loss amounts. CMS also proposes a variety of updates to the ESRD Quality Incentive Program (QIP) for payment years 2017 through 2019, including changes to the reporting measures and revisions to the Small Facility Adjuster. Furthermore, in conformance with the Protecting Access to Medicare Act of 2014 (PAMA), the proposed rule would establish a drug designation process for: (1) determining when a product would no longer be considered an oral-only drug; and (2) including new injectable and intravenous products into the bundled payment under the ESRD PPS (under current statutory provisions, payment for oral-only ESRD drugs cannot be made under the ESRD PPS prior to January 1, 2025). CMS will accept comments on the proposed rule until August 25, 2015. The official version of the rule will be published on July 1, 2015.

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