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Background: Most partial nephrectomies (PNs) are performed with hilar occlusion to reduce blood loss and optimize visualization. However, the histologic status of the preserved renal parenchyma years after PN is unknown., Objective: To compare the histologic chronic kidney disease (CKD) score of renal parenchyma before and years after PN, and to explore factors associated with CKD-score increase and glomerular filtration rate (GFR) decline., Design, Setting, and Participants: A retrospective review of 147 renal cell carcinoma patients who underwent PN and subsequent radical nephrectomy (RN) due to tumor recurrence was performed in 19 Chinese centers and Cleveland Clinic. Macroscopic normal renal parenchyma was evaluated at least 5 mm away from the tumor in PN specimens and at remote sites in RN specimens., Intervention: PN/RN and ischemia., Outcome Measurements and Statistical Analysis: Histologic CKD score (0-12) represents a summary of glomerular/tubular/interstitial/vascular status. Predictive factors for a substantial increase of CKD score (≥3) were evaluated by logistic regression., Results and Limitations: Sixty-five patients with all necessary data were analyzed. The median interval between PN and RN was 2.4 yr. Median durations of warm ischemia (n = 42) and hypothermia (n = 23) were both 23 min. The histologic CKD score was increased after RN in 47 (72%) patients, with 29 (45%) experiencing more substantial increase (≥3). There was no significant difference in the change of CKD score related to the type and duration of ischemia (p = 0.7 and p = 0.4, respectively) or interval from PN to RN (p > 0.9). However, patients with comorbidities of hypertension, diabetes, and/or pre-existing CKD (hypertension [HTN]/diabetes mellitus [DM]/CKD) demonstrated increased rate and extent of CKD-score increase. On univariate analysis, HTN/DM/CKD was the only predictor of a substantial CKD-score increase (odds ratio: 3.53 [1.12-11.1]). Decline of GFR was modest and similar between patients with/without a substantial CKD-score increase., Conclusions: Within the context of conventional, limited durations of ischemia, histologic deterioration of preserved parenchyma after PN appears to be primarily due to pre-existing medical comorbidities rather than ischemia. A subsequent decline in renal function was mild and independent of histologic changes., Patient Summary: After clamped PN, the preserved renal parenchyma demonstrated histologic deterioration in many cases, which correlated with the presence of comorbidities such as hypertension, diabetes mellitus, or chronic kidney disease. In contrast, the type and duration of ischemia did not correlate with histologic changes after PN, suggesting that ischemia insult had only limited impact on parenchyma deterioration., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

XMT-1522, an antibody-drug conjugate (ADC) currently in Phase I clinical development, represents the first Dolaflexin®-based, cleavable ADC with a high drug-antibody ratio (DAR). In this work, a novel immunocapture LC-MS/MS method was successfully developed for the simultaneous quantification of both total antibody and cleavable antibody-conjugated drug auristatin F-hydroxypropylamide (AF-HPA) in human plasma. This method utilized microwave-assisted enzymatic digestion for the total antibody and chemical release of the drug from ADC on a 96-well based immunocapture sample preparation platform. The total antibody and the conjugated drug AF-HPA were separated and subsequently quantified concurrently by LC-MS/MS. The linear range of the standard curve for total antibody was from 50 to 5000 ng/mL and for AF-HPA was from 3.3 to 330 ng/mL. The linearities showed R 2 ≥ 0.993 for total antibody and R 2 ≥ 0.996 for AF-HPA, respectively. The intra- and inter-day precision and accuracy were well within 15%. The validated method, with the characteristics of high efficiency, great selectivity, free of carryover, short LC-MS/MS time (˜3.5 min) and low sample volume (20 μl), was successfully applied for analyzing Phase 1 cancer patient samples., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To evaluate whether excised parenchymal mass (EPM) during partial nephrectomy (PN) correlates with functional decline and can serve as a surrogate for functional outcomes., Materials and Methods: All 215 patients managed with PN for unifocal renal mass with necessary studies to determine EPM and percent glomerular filtration rate (GFR) and parenchymal mass preserved (both global and specific to the operated kidney) were analyzed. EPM was estimated from the pathologic specimen by subtracting the tumor mass from the specimen mass, with both calculated using the elliptical formula. Vascularized parenchymal mass preserved was measured from computed tomography scans obtained <2 months prior and 3-12 months after surgery. All functional analyses were required to be within the same time frames, and patients with a contralateral kidney were also required to have nuclear renal scans., Results: The median tumor size was 3.5 cm and the median R.E.N.A.L. was 7. Warm and cold ischemia were utilized in 123 and 92 patients, respectively (median ischemia time = 23 minutes). The median global GFR preserved was 89%, the median total parenchymal mass preserved was 93%, and the median estimated EPM was 16 cm 3 . Whereas percent parenchymal mass preserved correlated strongly with global and ipsilateral GFR preserved (both P < .001), EPM failed to correlate with functional outcomes on both univariable and multivariable analyses., Conclusion: Our data suggest that parenchymal mass preserved with standard PN by experienced surgeons associates strongly with function preserved, whereas EPM fails to correlate with functional outcomes. Further study of the functional impact of EPM in other circumstances will be required, such as enucleation or PN performed by less-experienced surgeons., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Many mechanisms contribute to the secondary injury cascades following traumatic spinal cord injury (SCI). However, most current treatment strategies only target one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline hydrochloride (MH) is a clinically available antibiotic and anti-inflammatory drug that has been shown to target a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations. The inability to translate the high doses of MH used in experimental animals to tolerable doses in human patients limits its clinical efficacy. In addition, the duration of MH treatment is limited because long-term systemic administration of high doses of MH has been shown to cause liver toxicity and even death. We have developed a drug delivery system in the form of hydrogel loaded with polysaccharide-MH complexes self-assembled by metal ions for controlled release of MH. This drug delivery system can be injected into the intrathecal space for local delivery of MH with sufficient dose and duration, without causing any additional tissue damage. We show that local delivery of MH at a dose that is lower than the standard human dose (3 mg/kg) was more effective in reducing secondary injury and promoting locomotor functional recovery than systemic injection of MH with the highest dose and duration reported in experimental animal SCI (90-135 mg/kg)., Competing Interests: The authors declare no competing financial interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To compare the surgical precision for optimizing nephron-mass preservation of tumor enucleation (TE) vs standard partial nephrectomy (SPN), with primary focus on functional outcomes. TE is presumed to optimize preservation of parenchymal mass and function but this has not yet been rigorously studied and quantified., Materials and Methods: Robotic partial nephrectomy patients who had appropriate pre- and postoperative studies for analysis of parenchymal mass preservation specific to the operated kidney were included. Computed tomography or magnetic resonance imaging and estimated glomerular filtration rate were required to be <2 months prior and 4-12 months after surgery. Parenchymal mass preservation and surgical precision were estimated for each technique, with precision defined as actual postoperative parenchymal volume or predicted postoperative parenchymal volume, presuming loss of a 5 mm rim of parenchyma associated with tumor excision and reconstruction., Results: Analysis included 57 TE and 53 SPN. Median age, body mass index, and tumor size were comparable. Percent parenchymal mass preserved in the operated kidney with TE was 96% (interquartile range [IQR] = 90-100) vs 89% (IQR = 83-96) for SPN (P = .003). Precision of excision or reconstruction was 101% (IQR = 96-105) for TE vs 94% (IQR = 88-100) for SPN (P < .001). On multivariable analysis, only TE correlated with improved surgical precision (coefficient = 6.7, 95% confidence interval = 1.6-11.8, P = .01). Although preservation of global renal function also favored TE, the differences were marginal (96% vs 93%), and statistical significance was not observed (P = .2)., Conclusion: Our analysis, which specifically focuses on the functional implications of TE, demonstrates that TE maximally spares normal parenchyma compared to SPN. Thus far, functional differences remain marginal and not statistically significant. Clinical significance of these findings in various clinical settings will require further investigation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Acute ischemic injury in the operated kidney after partial nephrectomy (PN) is often masked by a functional contralateral kidney; however, there is no practical method to assess this and its prognostic significance has not been defined., Objective: We propose a spectrum score to reflect the degree of ischemic insult in the ipsilateral kidney and study its relationship to subsequent functional recovery., Design, Setting, and Participants: From 2007 to 2014, 243 patients with a functional contralateral kidney underwent PN with necessary studies for detailed analysis of function and parenchymal mass before and after surgery in the ipsilateral kidney. Based on split function and percent parenchymal mass preserved in the ipsilateral kidney, we determined: serum creatinine (SCr) ideal-peak : expected peak SCr presuming no ischemic injury; and SCr worstcase-peak : expected peak SCr presuming temporary complete nonfunction of the ipsilateral kidney. The acute ipsilateral renal dysfunction spectrum score was defined: (observed peak SCr - SCr ideal-peak )/(SCr worstcase-peak - SCr ideal-peak ). Subsequent functional recovery was defined: (percent function preserved)/(percent mass saved)., Intervention: PN., Outcome Measurements and Statistical Analysis: Factors associated with spectrum score and relationship between spectrum score and subsequent functional recovery were evaluated by linear regression., Results and Limitations: Median duration of warm ischemia (n=152) was 21min (interquartile range [IQR] = 15-27) and hypothermia (n=91) 26min (IQR=23-30). Median parenchymal mass preservation was 83% (IQR=74-91%). Warm ischemia and longer ischemia duration associated with higher spectrum score (both p<0.05). Increased spectrum score (<25%, 25-50%, 50-75%, and >75% quartiles) had decreased functional recovery (98%, 94%, 90%, and 89%, respectively, p<0.001). However, this trend was not observed in the hypothermia cohort. On multivariable analysis spectrum score and ischemia type significantly associated with functional recovery (both p<0.01), while age and comorbidities failed to associate (p=0.3-0.7)., Conclusions: Acute ipsilateral renal dysfunction spectrum score unmasks the degree of ischemic insult in the operated kidney after PN and associates with functional recovery. While increased spectrum score associates with suboptimal recovery, even patients with a high spectrum score reached 89-90% recovery., Patient Summary: Acute functional decline after partial nephrectomy is difficult to evaluate in patients with two kidneys, but a proposed spectrum score can be used to evaluate this. Increased spectrum score reflects increased ischemia and may impact the functional recovery of the kidney., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate whether surgeons can predict the percent parenchymal mass that will be preserved by partial nephrectomy (PN) based on preoperative imaging, which could have potential utility for preoperative surgical planning and patient counseling. The proportion of preserved viable parenchyma following PN is the primary determinant of functional recovery. However, direct measurement of parenchymal volume preservation (VP) can be complex and time consuming., Materials and Methods: For patients managed with PN at our institution (2007-2014), we randomly selected 45 with a third in each of low, intermediate, or high R.E.N.A.L. complexity groups. All patients had recorded postoperative surgeon assessment of volume preservation (SAVP) and measured VP based on preoperative or postoperative computed tomography. Nine clinical providers predicted VP based solely on review of preoperative imaging while blinded to SAVP and measured VP. Clinical experience of the providers ranged from medical students to experienced urologic surgeons., Results: Median age was 66 years, median tumor size was 4.0 cm, and median R.E.N.A.L. was 8. Median measured VP was 81% (interquartile range of 74-89%). Preoperative prediction of VP correlated poorly with measured VP among the different surgeons (mean correlation coefficient, R = 0.34, range = 0.24-0.40). Surgeon experience provided minimal incremental improvement. Correlation between R.E.N.A.L. and measured VP was also marginal (R = 0.43). In contrast, correlation between postoperative SAVP and measured VP was much more robust (R = 0.75, P <.001)., Conclusion: Preoperative prediction of VP and R.E.N.A.L. score correlated poorly with measured VP for patients managed with PN. In contrast, postoperative SAVP provided a relatively reliable estimate of VP, and should be considered an acceptable substitute in most clinical circumstances., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Acute increase of serum creatinine (SCr) after partial nephrectomy (PN) is primarily due to parenchymal mass reduction or ischemia; however, only ischemia can impact subsequent functional recovery., Objective: We evaluate etiologies of acute kidney injury (AKI) after PN and their prognostic significance., Design, Setting, and Participants: From 2007-2014, 83 solitary kidneys managed with PN had necessary studies for detailed analysis of function and parenchymal mass before/after surgery. AKI was classified by Risk/Injury/Failure/Loss/Endstage classification and defined by either standard criteria (comparison to preoperative SCr) or proposed criteria (comparison to projected postoperative SCr based on parenchymal mass reduction). Subsequent recovery was defined as percent function preserved/percent mass saved., Intervention: PN., Outcome Measurements and Statistical Analysis: Predictive factors for AKI were evaluated by logistic regression. Relationship between AKI grade and subsequent functional recovery was assessed by linear regression., Results and Limitations: Median duration warm ischemia (n=39) was 20 min and hypothermia (n=44) was 29 min. Median parenchymal mass reduction was 11%. AKI occurred in 45 patients based on standard criteria and 38 based on proposed criteria, and reflected injury/failure (grade = 2/3) in 23 and 16 patients, respectively. On multivariable analysis, only ischemia time associated with AKI occurrence (p=0.016). Based on the proposed criteria, median recovery from ischemia was 99% in patients without AKI and 95%/90%/88% for patients with grades 1/2/3 AKI, respectively. The coefficient for association between AKI grade based on proposed criteria and subsequent functional recovery was -4.168 (p=0.018). Main limitation is limited patient cohort., Conclusions: Parenchymal mass reduction and ischemia both contribute to acute changes in SCr after PN. Classification of AKI by proposed criteria significantly associates with subsequent functional recovery. However, more robust numbers will be needed to further assess the merits of the proposed criteria. While AKI is associated with suboptimal recovery, even patients with grade 2/3 AKI reached 88-90% of recovery expected., Patient Summary: Acute decline in function after partial nephrectomy associates with more prolonged ischemia time, and appears to impact subsequent functional recovery. However, most kidneys eventually recover strongly, even if their function is sluggish in the first few days after surgery., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the impact of extended warm ischemia on incidence of acute kidney injury (AKI) and ultimate functional recovery after partial nephrectomy (PN), incorporating rigorous control for loss of parenchymal mass, and embedded within comparison to cohorts of patients managed with hypothermia or limited warm ischemia., Materials and Methods: From 2007 to 2014, 277 patients managed with PN had appropriate studies to evaluate changes in function/mass specifically within the operated kidney. Recovery from ischemia was defined as %function saved/%parenchymal mass saved. AKI was based on global renal function and defined as a ≥1.5-fold increase in serum creatinine above the preoperative level., Results: Hypothermia was utilized in 112 patients (median = 27 minutes) and warm ischemia in 165 (median = 21 minutes). AKI strongly correlated with solitary kidney (P < .001) and duration (P < .001) but not type (P = .49) of ischemia. Median recovery from ischemia in the operated kidney was 100% (interquartile range [IQR] = 88%-109%) for cold ischemia, with 6 (5%) noted to have <80% recovery from ischemia. For the warm ischemia group, median recovery from ischemia was 91% (IQR = 82%-101%, P < .001 compared with hypothermia), and 34 (21%) had recovery from ischemia <80% (P < .001). For warm ischemia subgrouped by duration <25 minutes (n = 114), 25-35 minutes (n = 35), and >35 minutes (n = 16), median recovery from ischemia was 92% (IQR = 86%-100%), 90% (IQR = 78%-104%), and 91% (IQR = 80%-96%), respectively (P = .77)., Conclusion: Our results suggest that AKI after PN correlates with duration but not with type of ischemia. However, subsequent recovery, which ultimately defines the new baseline glomerular filtration rate, is most reliable with hypothermia. However, most patients undergoing PN with warm ischemia still recover relatively strongly from ischemia, even if extended to 35-45 minutes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To compare freehand scripting and semiautomated renal parenchymal volume measurements on preoperative or postoperative computed tomography scans and assess relationships between parenchymal volume loss and functional changes within the operated kidney after partial nephrectomy (PN)., Materials and Methods: Fifty patients (16 solitary kidneys, 34 bilateral kidneys) with renal tumors managed by PN with necessary studies for analysis were included. Freehand scripting and semiautomated threshold-based analysis were performed before and 4-12 months after PN to obtain preoperative normal parenchymal volumes, projected residual parenchymal volumes, and actual postoperative volumes. Glomerular filtration rate was determined by the Modification of Diet in Renal Disease 2 equation along with nuclear renal scan to provide split function for patients with 2 kidneys. Limits of agreement and Bland-Altman analyses were performed. The relationship between the amount of vascularized parenchyma preserved and renal function saved was correlated for each measurement method using Pearson correlation., Results: The semiautomated method yielded estimates that were higher than freehand scripting by a mean of 14 cm(3) for estimation of preoperative normal parenchymal volume, 21 cm(3) for projected residual parenchymal volume, and 9 cm(3) for actual postoperative parenchymal volume. For the semiautomated method, correlation between the amount of normal parenchyma preserved and renal function saved was 0.52 (95% confidence interval [CI], 0.28-0.69; P <.001), and for the scripting method, correlation was 0.60 (95% CI, 0.39-0.76; P <.001)., Conclusion: Semiautomated and freehand scripting measurements of parenchymal volumes were relatively consistent before and after PN, although the semiautomated approach tended to yield volumes that were approximately 5%-10% higher on average. Measurement of parenchymal volume changes by both approaches correlated significantly with functional changes after PN., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Ischemia is a potential contributor to decline of function after partial nephrectomy (PN), although loss of parenchymal mass related to excision and reconstruction appears to be a more significant factor. However, loss of parenchymal mass could also be due to global effects of ischemia leading to parenchymal atrophy. In this study, we evaluated parenchymal volumes in regions away from the operated site to assess for atrophy., Materials and Methods: A total of 164 patients undergoing PN for whom detailed analysis of function and parenchymal mass within the operated kidney could be performed were assessed for opposite pole volume (OPV) before and 4-12 months after surgery. Tumor location was required to be ≥2 cm away from the opposite polar line to exclude local effects related to excision or reconstruction. OPV was estimated by software analysis, and the ratio of the estimates (OPV ratio = postoperative OPV to preoperative OPV) was used to assess for atrophy., Results: Patient demographics and tumor characteristics were representative of conventional PN populations, and warm ischemia (n = 101; median, 21 minutes) and cold ischemia (n = 63; median, 26 minutes) were applied by surgeon discretion. OPVs before and after PN were 63.2 and 62.5 cm(3), respectively (P = .76). The median OPV ratio was 0.99 suggesting that significant atrophy did not occur. OPV ratio was 0.99 for warm ischemia cases and 0.99 for cold ischemia cases (P = .95)., Conclusion: Limited warm ischemia or hypothermia was not associated with significant parenchymal atrophy after PN, which suggests that parenchymal volume loss in this setting is primarily due to excision or reconstruction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In this work, the cellular uptake, elimination and toxicity of CdSe/ZnS QDs in HepG2 cells were comprehensively studied using inductively coupled plasma mass spectrometry (ICP-MS), MTT assay, AO/EB staining, and glutathione level and gene expression analysis. ICP-MS analytical results showed that the uptake efficiency of CdSe QDs by HepG2 cells was lower than that of Cd(II) and Se(IV), and the uptake was dose- and time-dependent. The uptake amount was related to the physicochemical properties of QDs, and NH2-QDs with smaller size were more easily taken up by cells. In combination with various biochemical methodologies, a systematic and thorough quantitative analysis of the in vitro effects of CdSe/ZnS QDs with different coatings was conducted, along with that of Cd (II) and Se (IV). Although Cd(II) above 8.9 μM exhibited obvious toxicity to the cells, no obvious toxicity of four CdSe/ZnS QDs was observed within the tested concentration range (10-100 nM), most likely due to the protection of the ZnS shell and the PEG coating. From the molecular level's point of view, QDs at concentration of 100 nM exhibit obvious impact on the cells, such as increased gene expression (MT1A and CYP1A1), which was positively correlated with the intracellular concentration of QDs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)