Reliability of urinalysis for identification of proteinuria is reduced in the presence of other abnormalities including high specific gravity and hematuria.

PURPOSE: Chronic kidney disease (CKD) is classified according to cause, glomerular filtration rate, and proteinuria. Identification of proteinuria with urinalysis (UA) is less accurate than quantification via other methods. We investigated factors leading to discordant UA findings when compared against paired albumin-to-creatinine ratio (ACR) testing. METHODS: Four thousand three hundred and twenty-three UAs were grouped by proteinuria level (A1-A3); concordance with ACR was examined. Classification of UA with confounding factors (UA+CF) or without (UA-CF) was based on CF that resulted in >10% increase in false-positive proteinuria readings. The presence of ≥3+ blood, ≥3+ leukocyte esterase, any ketonuria, specific gravity ≥1.020, ≥1+ urobilinogen, ≥2+ bilirubin, ≥2+ bacteria, ≥3 RBC/hpf (high powered field), ≥10 WBC/hpf, and/or ≥6 epithelial cells/hpf led to UA+CF classification. RESULTS: Proteinuria was determined to be present in 14.1% by UA dipstick and 24.9% by ACR. Using ACR as the standard, overall concordance was 80.4%, with 17.2% false-negatives and 2.3% false-positives by UA. UA+CF represented 55.6% of UA overall (n = 2404), and 98.0% of those false-positive for proteinuria. High specific gravity and hematuria are the strongest predictors of false positives. For A2 proteinuria (30-300 mg/g, 1+,2+,3+ on UA) UA-CF had a higher negative predictive value (NPV) (99.8%) than UA+CF (77.6%); NPV for A3 proteinuria (>300 mg/g, 4+ on UA) was 100% for UA-CF and UA+CF. CONCLUSION: Additional abnormalities were noted in >50% of outpatient UAs indicating proteinuria. Given the significant proportion of patients having a false-positive UA for proteinuria when these CFs were present, we recommend that such patients undergo ACR confirmatory testing, according to a clinical algorithm for the incorporation of UA results into the management of CKD.

Evaluation of Urinary Renal Biomarkers for Early Prediction of Acute Kidney Injury Following Partial Nephrectomy: A Feasibility Study.

BACKGROUND: Partial nephrectomy (PN) is the gold standard for the treatment of small renal masses. Urinary biomarkers (UBMs) may serve as early indicators of acute kidney injury (AKI) following PN. OBJECTIVE: To evaluate the timing, specificity, and sensitivity of several candidate UBMs after PN to determine the most promising UBMs in this setting. We hypothesize that some UBMs will have utility as early markers of AKI. DESIGN, SETTING, AND PARTICIPANTS: Twenty-two patients undergoing on-clamp robotic or open PN underwent paired urine collection via ureteral catheterization of the affected kidney and Foley catheterization for the unaffected kidney obtained preoperatively, after anesthesia, and at several points in time after renovascular occlusion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Measured UBMs included albumin, α-glutathione S-transferase, B2M, calbindin, clusterin, cystatin C, epidermal growth hormone, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, osteoactivin, osteopontin, total protein, trefoil factor 3, uromodulin, and vascular endothelial growth factor. RESULTS AND LIMITATIONS: The largest fold changes in UBM levels were observed between the baseline values and just prior to vascular occlusion (time "0"). Albumin, clusterin, and calbindin were among the most consistently and significantly increased UBMs. After vascular occlusion and subsequent reperfusion, some UBMs, most notably albumin, calbindin, and total protein, continued to increase in the affected kidney, peaking at 60-90min, followed by decrease to time "0" measurements after 1 d and to baseline levels 14-42 d after surgery. No striking association of UBMs with parameters such as duration of surgery, ischemia time, and tumor complexity was observed. CONCLUSIONS: The most significant UBM increases were observed when comparing samples obtained at preoperative visit and after anesthesia, but before clamp time. Albumin, clusterin, and calbindin were the most consistently and significantly altered UBMs; further investigation will be necessary to determine whether UBMs can identify AKI earlier in nephrectomy patients. PATIENT SUMMARY: Factors (biomarkers) measured in the blood or urine can indicate the presence and amount of kidney injury. We evaluated 15 different biomarkers at several points in time prior to, during, and after surgery for kidney cancer. We found that three of these biomarkers were most consistently elevated in patients undergoing partial nephrectomy. Interestingly, the largest increases were observed when comparing samples obtained prior to surgery with those obtained just after anesthesia.

Proteinuria impacts patient survival differentially based on clinical setting: A retrospective cross-sectional analysis of cohorts from a single health system: Retrospective cohort study.

BACKGROUND: Chronic kidney disease (CKD) staging is improved by adding proteinuria to glomerular filtration rate (GFR). While proteinuria independently predicts CKD progression and mortality, the clinical setting of proteinuria determination has not been well-studied previously. The objective of our study is to determine whether clinical setting differentially impacts survival outcomes. METHODS: Kaplan-Meier and Cox proportional hazards analyses of overall survival were performed retrospectively for cohorts of outpatients (n = 22,918), emergency patients (n = 16,861), and inpatients (n = 12,304) subjected to urinalysis (UA) at a single health system in 2010. GFR (G1-G5) and proteinuria (A1:<30 mg, A2:30-300 mg, A3:>300 mg) were classified under Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. RESULTS: GFR and proteinuria levels varied more in inpatients than in emergency and outpatients. For each clinical population, survival significantly decreased with increasing proteinuria (A1>A2>A3, p < 0.05 for each comparison). The effect of proteinuria on survival differed by clinical setting, with statistical differences in all categories other than A3 in outpatients and emergency patients (p = 0.98). The strongest predictors of mortality were cancer diagnosis (HR: 3.07, p < 0.0001) and very-high KDIGO classification (HR: 2.01, p < 0.0001). Limitations include the retrospective observational study design and single health system analysis. CONCLUSIONS: The value of UA to screen for proteinuria in each clinical setting is evident, but the impact of A2 and A3 level proteinuria on survival varies depending on the clinical scenario in which the determination was made. The clinical setting of proteinuria measurement should be factored into both patient care and clinical research activities.

Comparison of RENAL, PADUA, CSA, and PAVP Nephrometry Scores in Predicting Functional Outcomes After Partial Nephrectomy.

OBJECTIVE: To evaluate the accuracy of radius, exophytic/endophytic, nearness to collecting system/sinus, anterior/posterior, and location relative to polar lines (RENAL), preoperative aspects and dimensions used for anatomical classification (PADUA), contact surface area (CSA), and preoperative assessment of volume preservation (PAVP) nephrometry scores in predicting postoperative renal functional outcomes after partial nephrectomy (PN). Few studies have compared the accuracy of tumor complexity systems directly in the same set of PN patients. MATERIALS AND METHODS: Patients treated with robotic, laparoscopic, or open PN having available imaging (n = 344) were examined. The ability of 4 systems to predict nadir estimated glomerular filtration rate (eGFR [median postoperative day 1]) and new baseline eGFR (median: 0.95 year) was analyzed using univariable and multivariable models. RESULTS: Median preoperative, nadir, and new baseline eGFR were 79 (interquartile range [IQR]: 63-97), 65 (IQR: 47-85), and 80 (IQR: 63-99) mL/min/1.73 m2. Multivariable models incorporating RENAL, PADUA, CSA, or PAVP were similarly predictive of postoperative renal function (nadir eGFR: R2 = 0.683-0.688, new baseline eGFR: R2 = 0.775). In univariable analysis, all 4 complexity systems were predictors of nadir GFR (each P < .05), with RENAL (P = .045), CSA (P = .027), and PAVP (P = .012) also significantly predicting nadir eGFR in multivariable models. No complexity system was significantly associated with new baseline eGFR in multivariable analysis, with only RENAL (P = .023) and PAVP (P = .049) having a statistically significant association in univariable analysis. CONCLUSION: RENAL, PADUA, CSA, and PAVP are all predictors of early postoperative renal function. RENAL and PAVP provided the greatest predictive ability for later renal functional outcomes.

Assessment of volume preservation performed before or after partial nephrectomy accurately predicts postoperative renal function: Results from a prospective multicenter study.

PURPOSE: Partial nephrectomy (PN) is standard for small renal masses, improving renal function by preserving renal parenchyma compared with radical nephrectomy. Recent work demonstrated that postoperative surgeon assessment of volume preservation (SAVP) and 3D imaging measurements agree and correlate with postoperative function. We hypothesize preoperative assessment of volume preservation (PAVP) with PN based on preoperative imaging will reliably indicate postoperative renal function. MATERIALS AND METHODS: Data were collected from 336 patients undergoing PN for suspected renal cancer by 40 surgeons at 12 centers in Europe and the United States within the Surface-Intermediate-Base International Consortium. Surgeons recorded PAVP and SAVP for individual patients; pre- and postoperative glomerular filtration rate (GFR) was estimated by Chronic Kidney Disease Epidemiology Collaboration equations. Correlations between PAVP, SAVP, and postoperative GFR were assessed with linear regression models. Bland-Altman analysis was used to assess agreement between PAVP and SAVP with a significant cutoff of 5%. RESULTS: Median PAVP was 90% (interquartile range [IQR] 85%-100%) and SAVP was 90% (IQR: 80%-94%). PAVP and SAVP were moderately correlated (R2 = 0.67, P < 0.0001) and deemed "interchangeable" by Bland-Altman analysis at a 5% acceptable rate of difference (95% CI: -5.4, -3.1). Median postoperative GFR was 77.3 (IQR: 56.2, 92.0). Both PAVP (R2 = 0.82, P < 0.0001) and SAVP (R2 = 0.83, P < 0.0001) were correlated with postoperative GFR. Multivariable models utilizing volume-adjusted GFR based on PAVP or SAVP significantly and similarly predicted postoperative GFR (R2 = 0.72 for each). CONCLUSION: Renal function is closely linked to the amount of parenchymal volume preservation, whether estimated prior to surgery (PAVP) or afterward (SAVP). PAVP provides reasonably accurate information for decision-making in patients considering PN.

Grade Groups Provide Improved Predictions of Pathological and Early Oncologic Outcomes Compared with Gleason Score Risk Groups.

PURPOSE: The GG (Grade Group) system was introduced in 2013. Data from academic centers suggest that GG better distinguishes between prostate cancer risk groups than the Gleason score (GS) risk groups. We compared the performance of the 2 systems to predict pathological/recurrence outcomes using data from the MUSIC (Michigan Urological Surgery Improvement Collaborative). MATERIALS AND METHODS: Patients who underwent biopsy and radical prostatectomy in the MUSIC from March 2012 to June 2017 were classified according to GG and GS. Outcomes included the presence or absence of extraprostatic extension, seminal vesical invasion, positive lymph nodes, positive surgical margins and time to cancer recurrence (defined as postoperative prostate specific antigen 0.2 ng/ml or greater). Logistic and Cox regression models were used to compare the difference in outcomes. RESULTS: A total of 8,052 patients were identified. When controlling for patient characteristics, significantly higher risks of extraprostatic extension, seminal vesical invasion and positive lymph nodes were observed for biopsy GG 3 vs 2 and for GG 5 vs 4 (p <0.001). Biopsy GGs 3, 4 and 5 also showed shorter time to biochemical recurrence than GGs 2, 3 and 4, respectively (p <0.001). GGs 3, 4 and 5 at radical prostatectomy were each associated with a greater probability of recurrence compared to the next lower GG (p <0.001). GG (vs GS) had better predictive power for extraprostatic extension, seminal vesical invasion, positive lymph nodes and biochemical recurrence. CONCLUSIONS: GG at biopsy and radical prostatectomy allows for better discrimination of recurrence-free survival between individual risk groups than GS risk groups with GGs 2, 3, 4 and 5 each incrementally associated with increased risk.

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production.

STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 106/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production.

Heparanase enhances the insulin receptor signaling pathway to activate extracellular signal-regulated kinase in multiple myeloma.

ERK signaling regulates proliferation, survival, drug resistance, and angiogenesis in cancer. Although the mechanisms regulating ERK activation are not fully understood, we previously demonstrated that ERK phosphorylation is elevated by heparanase, an enzyme associated with aggressive behavior of many cancers. In the present study, myeloma cell lines expressing either high or low levels of heparanase were utilized to determine how heparanase stimulates ERK signaling. We discovered that the insulin receptor was abundant on cells expressing either high or low levels of heparanase, but the receptor was highly phosphorylated in heparanase-high cells compared with heparanase-low cells. In addition, protein kinase C activity was elevated in heparanase-high cells, and this enhanced expression of insulin receptor substrate-1 (IRS-1), the principle intracellular substrate for phosphorylation by the insulin receptor. Blocking insulin receptor function with antibody or a small molecule inhibitor or knockdown of IRS-1 expression using shRNA diminished heparanase-mediated ERK activation in the tumor cells. In addition, up-regulation of the insulin signaling pathway by heparanase and the resulting ERK activation were dependent on heparanase retaining its enzyme activity. These results reveal a novel mechanism whereby heparanase enhances activation of the insulin receptor signaling pathway leading to ERK activation and modulation of myeloma behavior.