Toshio Takagi

Decline in Renal Function after Partial Nephrectomy: Etiology and Prevention

PURPOSE Partial nephrectomy is the reference standard for the management of small renal tumors and is commonly used for localized kidney cancer. A primary goal of partial nephrectomy is to preserve as much renal function as possible. New baseline glomerular filtration rate after partial nephrectomy can have prognostic significance with respect to long-term outcomes. Recent studies provide an increased understanding of the factors that determine functional outcomes after partial nephrectomy as well as preventive measures to minimize functional decline. We review these advances, highlight ongoing controversies and stimulate further research. MATERIALS AND METHODS A comprehensive literature review consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria was performed from January 2006 to April 2014 using PubMed®, Cochrane and Ovid Medline. Key words included partial nephrectomy, renal function, warm ischemia, hypothermia, nephron mass, parenchymal volume, surgical approaches to partial nephrectomy, preoperative and intraoperative imaging, enucleation, hemostatic agents and energy based resection. Relevant reviews were also examined as well as their cited references. An additional Google Scholar search was conducted to broaden the scope of the review. Only English language articles were included in the analysis. The primary outcomes of interest were the new baseline level of function after early postoperative recovery, percent decline in function, potential etiologies and preventive measures. RESULTS Decline in function after partial nephrectomy averages approximately 20% in the operated kidney, and can be due to incomplete recovery from the ischemic insult or loss of nephron mass related to parenchymal excision or collateral damage during reconstruction. Compensatory hypertrophy in the contralateral kidney after partial nephrectomy in adults is marginal and decline in global renal function for patients with 2 kidneys averages about 10%, although there is some variance based on tumor size and location. Irreversible ischemic injury can be minimized by pharmacological intervention or surgical approaches such as hypothermia, limited warm ischemia, or zero or segmental ischemia. Excessive loss of nephron mass can be minimized by improved preoperative or intraoperative imaging, use of a bloodless field, enucleation and vascular microdissection. Hemostatic agents or energy based resection that minimizes the need for parenchymal and capsular suturing can also optimize preservation of the vascularized nephron mass. CONCLUSIONS Our understanding of the decline in renal function after partial nephrectomy has advanced considerably, including better appreciation of its magnitude and impact in various settings, possible etiologies and potential preventive measures. Many controversies persist and this remains an important area of investigation.

Survival and Functional Stability in Chronic Kidney Disease Due to Surgical Removal of Nephrons: Importance of the New Baseline Glomerular Filtration Rate.

BACKGROUND Chronic kidney disease (CKD) can be associated with a higher risk of progression to end-stage renal disease and mortality, but the etiology of nephron loss may modify this. Previous studies suggested that CKD primarily due to surgical removal of nephrons (CKD-S) may be more stable and associated with better survival than CKD due to medical causes (CKD-M). OBJECTIVE We addressed limitations of our previous work with comprehensive control for confounding factors, differentiation of non-renal cancer-related mortality, and longer follow-up for more discriminatory assessment of the impact of CKD-S. DESIGN, SETTING, AND PARTICIPANTS From 1999 to 2008, 4299 patients underwent surgery for renal cancer at a single institution. The median follow-up was 9.4 yr (7.3-11.0). The new baseline glomerular filtration rate (GFR) was defined as the highest GFR between the nadir and 42 d after surgery. Three cohorts were retrospectively evaluated: no CKD (new baseline GFR >60 ml/min/1.73 m(2)); CKD-S (new baseline GFR<60 but preoperative >60 ml/min/1.73 m(2)); and CKD-M/S (new baseline and preoperative GFR both <60 ml/min/1.73 m(2)). Cohort status was permanently set at 42 d after surgery. INTERVENTION Renal surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Decline in renal function (50% reduction in GFR or dialysis), all-cause mortality, and non-renal cancer mortality were examined using a multivariable Cox proportional hazards model. RESULTS AND LIMITATIONS CKD-M/S had a higher incidence of relevant comorbidities and the new baseline GFR was lower. On multivariable analysis (controlling for age, gender, race, diabetes, hypertension, and cardiac disease), CKD-M/S had higher rates of progressive decline in renal function, all-cause mortality, and non-renal cancer mortality when compared to CKD-S and no CKD (hazard ratio [HR] 1.69-2.33, all p<0.05). All-cause mortality was modestly higher for CKD-S than for no CKD (HR 1.19, p=0.030), but renal stability and non-renal cancer mortality were similar for these groups. New baseline GFR of <45 ml/min/1.73 m(2) significantly predicted adverse outcomes. The main limitation is the retrospective design. CONCLUSIONS CKD-S is more stable than CKD-M/S and has better survival, approximating that for no CKD. However, if the new baseline GFR is <45 ml/min/1.73 m(2), the risks of functional decline and mortality increase. These findings may influence counseling for patients with localized renal cell carcinoma and higher oncologic potential when a normal contralateral kidney is present. PATIENT SUMMARY Survival is better for surgically induced chronic kidney disease (CKD) than for medically induced CKD, particularly if the postoperative glomerular filtration rate is ≥45 ml/min/1.73 m(2). Patients with preexisting CKD are at risk of a significant decline in kidney function after surgery, and kidney-preserving treatment should be strongly considered in such cases.

Template-based lymphadenectomy in urothelial carcinoma of the renal pelvis: A prospective study

Recent studies showed the therapeutic benefit of lymphadenectomy in advanced stage urothelial carcinoma of the upper urinary tract, but there is still a lack of prospective studies and standardization of the extent of lymphadenectomy. The aim of this multi‐institutional study was to examine the role of lymphadenectomy in urothelial carcinoma of the upper urinary tract.

Predictors of precision of excision and reconstruction in partial nephrectomy.

PURPOSE The precision of excision and reconstruction to optimize vascularized parenchymal preservation is a major determinant of renal function after partial nephrectomy. We assessed partial nephrectomy surgical precision using volumetric computerized tomography and analyzed predictive factors. MATERIALS AND METHODS We analyzed the records of 122 patients treated with partial nephrectomy in whom detailed analysis of the precision of excision and reconstruction specific to the operated kidney could be performed. We used volumetric computerized tomography to measure functional parenchymal volume before and after partial nephrectomy in the operated kidney. The glomerular filtration rate in the operated kidney was determined by the MDRD2 (Modification of Diet in Renal Disease 2) equation along with renal scan in patients with a contralateral kidney. Surgical precision was defined as actual postoperative parenchymal volume/predicted postoperative parenchymal volume, presuming loss of a 5 mm rim of normal parenchyma related to excision and reconstruction. RESULTS Median patient age was 61 years and 64 patients (52%) underwent an open procedure. Cold ischemia was used in 50 patients (median 26 minutes) and limited warm ischemia (median 20 minutes) was used in 72. The R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior and location relative to polar line) nephrometry score indicated low, intermediate and high complexity in 43 (35%), 55 (45%) and 24 patients (20%), respectively. A total of 45 patients (37%) with a solitary kidney were included in analysis. The median precision of excision and reconstruction was 93%. The median preserved glomerular filtration rate was 80% in the operated kidney. A solitary kidney was the only significant predictor of excision and reconstruction precision on univariable and multivariable analysis. CONCLUSIONS A solitary kidney significantly impacted partial nephrectomy surgical precision. This was likely related to the recognized need to preserve as much renal parenchyma as possible to optimize renal function in the absence of a contralateral kidney.

Superior Tolerability of Altered Dosing Schedule of Sunitinib with 2-Weeks-on and 1-Week-off in Patients with Metastatic Renal Cell Carcinoma—Comparison to Standard Dosing Schedule of 4-Weeks-on and 2-Weeks-off

OBJECTIVE Poor tolerability to sunitinib with the standard dosing schedule has become an issue. We retrospectively analyzed the treatment efficacy and the profile of adverse events of 2 weeks of sunitinib treatment followed by 1-week-off (Schedule 2/1) and compared the results with the standard dosing schedule with 4 weeks of treatment followed by 2-weeks-off (Schedule 4/2). METHODS From January 2010 until December 2012, 48 patients with metastatic renal cell carcinoma who received at least two cycles of sunitinib as first-line therapy were the subjects of this study. After 2011, we switched to Schedule 2/1 for most patients. RESULTS Schedule 2/1 included 26 patients and Schedule 4/2 had 22. The incidence of most adverse events was not significantly different between the two groups except for hand-foot syndrome and diarrhoea, which were observed more frequently in Schedule 4/2 and reached statistical significance. A dose interruption due to adverse events in the first three cycles was significantly lower in Schedule 2/1 patients than in those on Schedule 4/2 (27 versus 53% P = 0.04). With respect to treatment efficacy, the objective response rate tended to be higher in Schedule 4/2 than in Schedule 2/1 (50 versus 32%), and median progression-free survival was longer in patients on Schedule 2/1 than those on Schedule 4/2 (18.4 versus 9.1 months). These differences, however, did not reach statistical significance (P = 0.14, P = 0.13). CONCLUSIONS Alteration in dosing schedule of sunitinib with 2-weeks-on and 1-week-off showed a lower incidence of dose interruption and a similar oncological outcome compared with the standard dosing schedule of 4-weeks-on and 2-weeks-off.

Evaluation of Low-Dose Rituximab Induction Therapy in Living Related Kidney Transplantation

Background. Rrituximab has been used for desensitization of anti-blood type antibody and anti-human leukocyte antigen (HLA) antibody as an induction immunosuppressant in our hospital. After having used rituximab for more than 2 years, we performed a retrospective study to clarify the effectiveness and safety of rituximab. Materials and Methods. We performed 144 kidney transplants between January 2005 and December 2007 at our hospital. Low-dose rituximab was administered to 78 of these transplant recipients as an induction immunosuppressant. A comparison of viral infection, leucopenia, and rejection incidence between patients administered (Rit group) and not administered (Non-Rit group) rituximab before kidney transplantation was performed. Result. A comparison of Rit group and Non-Rit group revealed no significant difference in the incidence of cytomegalovirus infections (Rit: 26%, Non-Rit: 29%; P=1.00), BK virus infections (Rit: 2.6%, Non-Rit: 0%; P=0.53), or leukopenia (Rit:23%, Non-Rit: 14%; P=0.25) between the two groups of patients. The incidence of acute antibody-mediated rejection was also not significantly different between the two groups (Rit: 6.8%, Non-Rit: 8.3%; P=0.75). On the other hand, the incidence of acute T-cell-mediated rejection was significantly lower in the Rit group (Rit: 8.2%, Non-Rit: 23.3%; P<0.05). Anti-HLA antibodies belonging to HLA class 1 and class 2 were depleted by 70% and 83%, respectively, for more than 2 years after rituximab administration. Conclusions. We could confirm the effectiveness and safety of rituximab more than 2-year follow-up period.

A Phase II Study of Pazopanib in Patients with Localized Renal Cell Carcinoma to Optimize Preservation of Renal Parenchyma

PURPOSE Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy. MATERIALS AND METHODS Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m(2), or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery. RESULTS A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization. CONCLUSIONS Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy in a select subset of patients who would otherwise require radical nephrectomy.

Enhanced computed tomography after partial nephrectomy in early postoperative period to detect asymptomatic renal artery pseudoaneurysm

We systematically examined the incidence and potential implications of renal artery pseudoaneurysm occurring after partial nephrectomy detected by computed tomography screening in the early postoperative period.

Clinical Results and Pharmacokinetics of Sorafenib in Chronic Hemodialysis Patients with Metastatic Renal Cell Carcinoma in a Single Center

OBJECTIVE We investigated the safety and feasibility of sorafenib in patients with end-stage renal disease undergoing hemodialysis by examining the influence of pharmacokinetic parameters to their benefit and also the occurrence of drug-related adverse events of sorafenib. METHODS Ten patients with metastatic renal cell carcinoma undergoing hemodialysis received sorafenib. Initial dose was 200 mg once daily, and the dose was increased up to the maintenance dose of 200 mg twice daily. The pharmacokinetic study was performed after a steady state was reached with 200 mg twice daily in six patients. RESULTS Complete response occurred in one patient, partial response in three, stable disease in four and progressive disease in two. Median progression-free survival was 6.3 months. Serious adverse events were found in nine patients, including a Grade 5 subarachnoid hemorrhage and a Grade 4 cerebellar hemorrhage. In the pharmacokinetic study, the geometric mean of maximum concentration and area under the curve from 0 to 10 h of plasma concentration were similar on the day of hemodialysis and the day off hemodialysis. These data were lower than those from Japanese people with healthy kidneys and normal kidney function. There was no association between objective response or the occurrence of serious adverse events and pharmacokinetic parameters. CONCLUSIONS Treatment with sorafenib of patients with metastatic renal cell carcinoma undergoing hemodialysis appears to be feasible, but we express some concern about the higher incidence of serious adverse events even with the reduced dose. However, clinical efficacy was not compromised.

Early unclamping might reduce the risk of renal artery pseudoaneurysm after robot-assisted laparoscopic partial nephrectomy.

To determine the influence of the early unclamping technique on the risk of renal artery pseudoaneurysm during robot‐assisted laparoscopic partial nephrectomy.