Sudhir Isharwal

Devascularized Parenchymal Mass Associated with Partial Nephrectomy: Predictive Factors and Impact on Functional Recovery

Purpose: Parenchymal mass loss is the predominant factor associated with functional outcomes after partial nephrectomy. It is primarily due to excised and/or devascularized parenchymal mass. We evaluated the importance of excised and devascularized parenchymal mass relative to functional recovery after partial nephrectomy. Materials and Methods: In 168 patients who underwent partial nephrectomy the necessary studies were done to determine excised and devascularized parenchymal mass, and evaluate parenchymal mass changes and functional loss of the operated kidney. Parenchymal mass loss in the ipsilateral kidney was measured on contrast enhanced computerized tomography less than 2 months before and 3 to 12 months after partial nephrectomy. Excised parenchymal mass was estimated by subtracting tumor volume from specimen volume. Devascularized parenchymal mass was defined as total parenchymal mass loss minus excised parenchymal mass. We used the Pearson correlation to evaluate relationships between glomerular filtration rate preservation and parenchymal mass loss. Multivariable analysis was done to assess factors associated with devascularized parenchymal mass. Results: Median tumor size was 3.4 cm and median R.E.N.A.L. (radius, exophytic/endophytic tumor properties, nearness of tumor to collecting system or sinus, anterior/posterior and location relative to polar lines) score was 7. Warm and cold ischemia was used in 100 and 68 patients, respectively. Median excised parenchymal and devascularized parenchymal mass was 9 and 16 cm3, respectively (p <0.001). Total parenchymal mass loss and devascularized parenchymal mass were associated strongly with glomerular filtration rate preservation in the operated kidney (each r ≥0.55, p <0.001). However, excised parenchymal mass was only weakly associated with functional outcomes (r = 0.23). The preoperative glomerular filtration rate and endophytic status were associated with devascularized parenchymal mass on multivariable analysis. Conclusions: To our knowledge we report the first study to specifically evaluate the relative contributions of devascularized and excised parenchymal mass to functional recovery after partial nephrectomy. Our study suggests that devascularized parenchymal mass has more impact, which may have implications regarding surgical technique. Prospective study is required to further evaluate the relative contributions of excised and devascularized parenchymal mass in various settings.

Excised Parenchymal Mass During Partial Nephrectomy: Functional Implications

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 cm3. 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.

Ischemia and Functional Recovery from Partial Nephrectomy: Refined Perspectives

BACKGROUND Nephron mass preservation is a key determinant of functional outcomes after partial nephrectomy (PN), while ischemia plays a secondary role. Analyses focused specifically on recovery of the operated kidney appear to be most informative, yet have only included limited numbers of patients. OBJECTIVE To evaluate the relative impact of parenchymal preservation and ischemia on functional recovery after PN using a more robust cohort allowing for more refined perspectives about ischemia. DESIGN, SETTING, AND PARTICIPANTS A total of 401 patients managed with PN with necessary studies were analyzed for function and nephron mass preserved specifically within the kidney exposed to ischemia. INTERVENTION PN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The nephron mass preserved was measured from computed tomography scans <2 mo before and 3-12 mo after PN. Patients with two kidneys were required to have nuclear renal scans within the same timeframes. Recovery from ischemia was defined as the percent function preserved normalized by the percent nephron mass preserved. Pearson correlation was used to evaluate relationships between functional recovery and nephron mass preservation or ischemia time. Multivariable linear regression assessed predictors for recovery from ischemia. RESULTS AND LIMITATIONS The median tumor size was 3.5cm and the median RENAL score was 8. Cold and warm ischemia were utilized in 151 and 250 patients, and the median ischemia time was 27 and 21min, respectively. The function preserved was strongly correlated with nephron mass preserved(r=0.63; p<0.001). Median recovery from ischemia was significantly higher for hypothermia (99% vs 92%; p<0.001) and remained consistently strong even with longer duration. Multivariable analysis demonstrated that recovery from ischemia, which normalizes for nephron mass preservation, was significantly associated with ischemia type and duration (both p<0.05). However, each additional 10min of warm ischemia was associated with only a 2.5% decline in recovery from ischemia. Limitations include the retrospective design. CONCLUSIONS Our data suggest that functional recovery from clamped PN is most reliable with hypothermia. Longer intervals of warm ischemia are associates with reduced recovery; however, incremental changes are modest and may not be clinically significant in patients with a normal contralateral kidney. PATIENT SUMMARY Functional recovery after clamped partial nephrectomy is primarily dependent on preservation of nephron mass. Recovery is most reliable when hypothermia is applied. Longer intervals of warm ischemia are associated with reduced recovery; however, the incremental changes are modest.

Impact of Comorbidities on Functional Recovery from Partial Nephrectomy

Purpose: Parenchymal mass preservation, and ischemia type and/or duration can influence functional recovery after partial nephrectomy. Some groups have hypothesized that relevant comorbidities may also impact nephron stability and functional recovery but this has not been adequately investigated. Materials and Methods: At our center 405 patients treated with partial nephrectomy from 2007 to 2015 had the necessary data to determine the function and parenchymal mass preserved in the ipsilateral kidney. Comorbidities potentially associated with renal functional status were reviewed, including various degrees of hypertension, diabetes, cardiovascular disease, obesity, smoking status and related medications. Multivariable linear regression was done to assess factors associated with functional recovery, defined as the percent of preserved ipsilateral glomerular filtration rate. Results: Median tumor size was 3.5 cm and the median R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines and tumor touching main renal artery or vein) score was 8. Warm and cold ischemia were done in 264 (65%) and 141 patients for a median duration of 21 and 27 minutes, respectively. The median preserved ipsilateral glomerular filtration rate was 79%. Patient age, comorbidity index, hypertension and proteinuria were each associated with the preoperative glomerular filtration rate (all p <0.01). On univariable and multivariable analyses the preserved parenchymal mass, and ischemia type and duration were significantly associated with functional recovery (all p <0.001). On univariable analysis of comorbidities only hypertension was significantly associated with functional recovery. However, on multivariable analysis none of the analyzed comorbidities were associated with functional recovery. Conclusions: Recovery of function after partial nephrectomy depends primarily on parenchymal mass preservation and ischemia characteristics. Comorbidities failed to be associated with functional outcomes. Comorbidities can impact function, leading to surgery, and may influence long‐term functional stability. However, our data suggest that they do not influence short‐term recovery after partial nephrectomy.

Functional Comparison of Renal Tumor Enucleation Versus Standard Partial Nephrectomy

BACKGROUND Tumor enucleation (TE) optimizes parenchymal preservation and could yield better function than standard partial nephrectomy (SPN), although data on this are conflicting. OBJECTIVE To compare functional outcomes for TE and SPN strategies. DESIGN, SETTING, AND PARTICIPANTS Patients managed with partial nephrectomy (PN) with necessary data for analysis of preservation of ipsilateral parenchymal mass (IPM) and global glomerular filtration rate (GFR) from two centers were included. All studies were required <2 mo before and 3-12 mo after surgery. Patients with a solitary kidney or multifocal tumors were excluded. INTERVENTION Partial nephrectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Vascularized IPM was estimated from contrast-enhanced CT scans preoperatively and postoperatively. Serum creatinine-based estimates of global GFR were also obtained in the same timeframes. Univariable and multivariable linear regression evaluated factors associated with new-baseline global GFR. RESULTS/LIMITATIONS Analysis included 71 TE and 373 SPN cases. The median preoperative global GFR was comparable for TE and SPN (75 vs 78ml/min/1.73m2; p=0.6). The median tumor size was 3.0cm for TE and 3.3cm for SPN (p=0.03). The median RENAL score was 7 in both cohorts. For TE, warm ischemia and zero ischemia were used in 51% and 49% of cases, respectively. For SPN, warm ischemia and cold ischemia were used in 72% and 28% of patients, respectively. Capsular closure was performed in 46% of TE and 100% of SPN cases (p<0.001). Positive margins were found in 8.5% of TE and 4.8% of SPN patients (p=0.2). The median vascularized IPM preserved was 95% (interquartile range [IQR] 91-100%) for TE and 84% (IQR 76-92%) for SPN (p<0.001). The median global GFR preserved was 101%(IQR 93-111%) and 89% (IQR 81-96%) for TE and SPN, respectively (p<0.001). On multivariable analysis, resection strategy, preoperative GFR, and vascularized IPM preserved were all significantly associated (p<0.001) with new-baseline global GFR. Limitations include the retrospective design and the lack of resection outcome data. CONCLUSIONS Our analysis suggests that TE has potential for maximum IPM preservation compared to SPN and may provide optimized functional recovery. Further investigation will be required to evaluate the clinical significance of these findings. PATIENT SUMMARY Tumor enucleation for kidney cancer involves dissection along the tumor capsule and optimally preserves normal kidney tissue, which may lead to better functional recovery. The importance of this approach in various clinical settings will require further investigation.

Predictors of Long-Term Survival after Renal Cancer Surgery

Purpose: Renal cancer surgery can adversely impact long‐term function and survival. We evaluated predictors of chronic kidney disease 5 years and nonrenal cancer mortality 10 years after renal cancer surgery. Materials and Methods: We analyzed the records of 4,283 patients who underwent renal cancer surgery from 1997 to 2008. Radical and partial nephrectomy were performed in 46% and 54% of patients, respectively. Cumulative probability ordinal modeling was used to predict chronic kidney disease status 5 years after surgery and multivariable logistic regression was used to predict nonrenal cancer mortality at 10 years. Relevant patient, tumor and functional covariates were incorporated, including the preoperative glomerular filtration rate (A), the new baseline glomerular filtration rate after surgery (B) and the glomerular filtration rate loss related to surgery (C), that is C = A – B. In contrast, partial or radical nephrectomy was not used in the models due to concerns about strong selection bias associated with the choice of procedure. Results: Multivariable modeling established the preoperative glomerular filtration rate and the glomerular filtration rate loss related to surgery as the most important predictors of the development of chronic kidney disease (Spearman &rgr; = 0.78). Age, gender and race had secondary roles. Significant predictors of 10‐year nonrenal cancer mortality were the preoperative glomerular filtration rate, the new baseline glomerular filtration rate, age, diabetes and heart disease (all p <0.05). Multivariable modeling established age and the preoperative glomerular filtration rate as the most important predictors of 10‐year nonrenal cancer mortality (c‐index 0.71) while the glomerular filtration rate loss related to surgery only changed absolute mortality estimates 1% to 3%. Conclusions: Glomerular filtration rate loss related to renal cancer surgery, whether due to partial or radical nephrectomy, influences the risk of chronic kidney disease but it may have less impact on survival. In contrast, age and the preoperative glomerular filtration rate, which reflects general health status, are more robust predictors of nonrenal cancer mortality, at least in patients with good preoperative function or mild chronic kidney disease.

Tumor Contact Surface Area As a Predictor of Functional Outcomes After Standard Partial Nephrectomy: Utility and Limitations

OBJECTIVE To evaluate contact surface area (CSA) between the tumor and parenchyma as a predictor of ipsilateral parenchyma and function preserved after partial nephrectomy (PN). Previous studies suggested that CSA is a strong predictor of functional outcomes but the limitations of CSA have not been adequately explored. PATIENTS AND METHODS Four hundred nineteen patients managed with standard PN for solitary tumor with necessary studies to evaluate and analyze ipsilateral preoperative or postoperative parenchymal mass and function. Parenchymal mass and CSA were measured using contrast-enhanced computed tomography <2 months prior and 3-12months after PN. CSA was calculated: 2πrd, where r = radius and d = intraparenchymal depth. Pearson-correlation evaluated relationships between CSA and ipsilateral parenchymal mass or function preserved. Multivariable regression assessed predictors of function preserved. Conceptually, the CSA paradigm should function better for exophytic tumors than endophytic ones. RESULTS Median tumor size was 3.5 cm and R.E.N.A.L. was 8. Median global and ipsilateral glomerular filtration rate preserved were 89% and 79%, respectively. Median ipsilateral parenchymal mass preserved was 85% and significantly higher for exophytic masses (P = .001). Median CSA was 22.8 cm2 and significantly less for exophytic masses (P = .02). CSA associated with both ipsilateral function and mass preserved (both P < .05), but the correlations were only modest (r = 0.25 and 0.36, respectively). On multivariable analysis, CSA associated with function preserved for exophytic masses (P = .01), but not for endophytic ones (P = .27). CONCLUSION CSA associates with functional outcomes after standard PN, although the strength of the correlations was modest, unlike previous studies, and CSA was not an independent predictor for endophytic tumors. Further study will be required to evaluate the utility of CSA in various clinical settings.

Kidney, Ureteral, and Bladder Cancer: A Primer for the Internist

Malignancies of the urinary tract (kidney, ureter, and bladder) are distinct clinical entities. Hematuria is a unifying common presenting symptom for these malignancies. Surgical management of localized disease continues to be the mainstay of treatment, and early detection is important in the prognosis of disease. Patients often require life-long follow-up and assessment for recurrence.

Acute Kidney Injury after Partial Nephrectomy of Solitary Kidneys: Impact on Long-Term Stability of Renal Function

Purpose: Acute kidney injury often leads to chronic kidney disease in the general population. The long‐term functional impact of acute kidney injury observed after partial nephrectomy has not been adequately studied. Materials and Methods: From 2004 to 2014 necessary studies for analysis were available for 90 solitary kidneys managed by partial nephrectomy. Functional data at 4 time points included preoperative serum creatinine, peak postoperative serum creatinine, new baseline serum creatinine 3 to 12 months postoperatively and long‐term followup serum creatinine more than 12 months postoperatively. Adjusted acute kidney injury was defined by the ratio, observed peak postoperative serum creatinine/projected postoperative serum creatinine adjusted for parenchymal mass loss to reveal the true effect of ischemia. The long‐term change in renal function (the long‐term functional change ratio) was defined as the most recent glomerular filtration rate/the new baseline glomerular filtration rate. The relationship between the grade of the adjusted acute kidney injury and the long‐term functional change was assessed by Spearman correlation analysis and multivariable regression. Results: Median patient age was 64 years and median followup was 45 months. Median parenchymal mass preservation was 80%. Adjusted acute kidney injury occurred in 42% of patients, including grade 1 injury in 20 (22%) and grade 2/3 in 18 (20%). On univariable analysis the degree of the adjusted acute kidney injury did not correlate with the long‐term glomerular filtration rate change (p = 0.55). On multivariable analysis adjusted acute kidney injury was not associated with a long‐term functional change (p >0.05) while diabetes and warm ischemia were modestly associated with a long‐term functional decline (each p <0.05). Conclusions: Acute kidney injury after partial nephrectomy was not a significant or independent predictor of long‐term functional decline in our institutional cohort. A prospective study with larger sample sizes and longer followup is required to evaluate factors associated with long‐term nephron stability.

Current Therapeutic Strategies in Clinical Urology

The field of urology encompasses all benign and malignant disorders of the urinary tract and the male genital tract. Urological disorders convey a huge economic and patient quality-of-life burden. Hospital acquired urinary tract infections, in particular, are under scrutiny as a measure of hospital quality. Given the prevalence of these pathologies, there is much progress still to be made in available therapeutic options in order to minimize side effects and provide effective care. Current drug delivery mechanisms in urological malignancy and the benign urological conditions of overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), and urinary tract infection (UTI) will be reviewed herein. Both systemic and local therapies will be discussed including sustained release formulations, nanocarriers, hydrogels and other reservoir systems, as well as gene and immunotherapy. The primary focus of this review is on agents which have passed the preclinical stages of development.