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The use of pembrolizumab has been largely accepted in several advanced types of cancers. PURE 01 study (NCT02736266) enrolled consecutively 143 patients with muscle-invasive bladder cancer who received 3 cycles of pembrolizumab 200 mg every 3 weeks before planned radical cystectomy (RC). Clinical, pathological and laboratory data were collected to investigate the relationship between renal function, immunotherapy and cancer-related outcomes. Serum creatinine and estimated glomerular filtration rate (eGFR) using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-equation 2009 were reported at baseline and after every cycle of pembrolizumab; the T stage from clinical classification TNM (cTNM) was stated before the treatment. Our analysis did not demonstrate a significant impairment of eGFR after any cycle of pembrolizumab, neither in the overall cohort nor in subgroups considering the T stages or the CKD G-categories according to K-DIGO 2012 classification. In conclusion, in neoadjuvant setting before RC our results suggest that pembrolizumab administration is safe for renal function preservation.

INTRODUCTION AND OBJECTIVE:Frailty is a key aspect, related to-but distinct from-comorbidities and age. Partial nephrectomy (PN) use has increased during the last decades. However, PN is a complex ...

Introduction The clinical-histologic correlation in diabetic nephropathy is not completely known. Methods We analyzed nephrectomy specimens from 90 patients with diabetes and diverse degrees of proteinuria and glomerular filtration rate (GFR). Results Thirty-six (40%) subjects had normoalbuminuria, 33 (37%) microalbuminuria, and 21 (23%) non-nephrotic proteinuria. Mean estimated GFR (eGFR) was 65±23 (40% 10% to 20% of the sample. Moderate hyalinosis and arteriolar sclerosis were observed in 80% to 100% of cases with normoalbuminuria, microalbuminuria, proteinuria, as well as in class I, II, or III. Conclusions Weak correspondence between analytical parameters and kidney histology was found. Thus, disease may progress undetected from the early clinical stages of the disease. Finally, vascular damage was a very common finding, which highlights the role of ischemic intrarenal disease in diabetes., Graphical abstract

Background and Aims Controlled low-normal protein (LNP) diet in CKD patient is effective in controlling the progression of renal impairment. Oncological guidelines explain how a high protein level should be always required in patients (pts) affected by malignancies in order to compensate the cancer derived metabolism and avoid catabolism. But what about the onco-nephrological pts? Aim of our study is to investigate the metabolic impact of a low-normal protein diet in a consecutive cohort of 103 nephrological pts affected or not by urological non-metastatic malignancies. Method A consecutive cohort of 103 pts was enrolled in the Urological Department at San Raffaele Scientific Institute between 2018-2020. Inclusion criteria were: Age (>18 years old), eGFR (< 90 ml/min/1.73), Malnutritional Screening Tool (MTS Results Population divided as follows: average age: 69.8 (+/- 10.3); ♂ : ♀ ratio: 2.4; Hypertension: 57.28%; Diabetes: 19,41%; CKD classification: 3,88% stage 2, 87,37% above stage 3. At time zero no pts were underweight and 51 % were overweight or obese with difference condition of FM percentage (FM % average: 24.3 % ♀ and 18.1 % ♂for CS pts vs 31.6 % ♀ and 18.2 % ♂for CT pts). Only 2.1% of pts had a PA of less than 4°, considered a negative prognostic index (PA average: 5.6° for CS pts vs 5.5° for CT pts) and 6.3 % of pts had a value of cell mass less than 8 kg/m2 indicative of reduced lean mass (BCMI average: 10.4 kg / m2 for CS pts vs 11 kg / m2 for CT pts). An increase in ECW/ICW ratio greater than 1 was more present in CT pts in respect to CS pts (41.6 % vs 22.8 % and ECW/ICW average: 1.01 for CT pts vs 0.93 for CS pts) as well as WC measurement associated with increased cardiovascular risk (WC average: 87 cm ♀ and 99 cm ♂ for CS pts vs 97 cm ♀ and 104 cm ♂ for CT pts). After 6 months of diet, we observed a similar behavior between the CS and the CT cohorts in terms of renal metabolites and eGFR profile. In fact, the 65% of onco-nephrological and the 55% of nephrological pts displayed a significative decrease in urea plasmatic levels (- 27,76 mg/dl) and eGFR improvement (+ 6,27 ml/min/1,73). The nutritional status, as assessed by the MST, was preserved in both groups during the study. In addition, all pts had an improvement in BMI (CS: 2.8 kg/m2; CT :1.3 kg/m2) PA (CS: 2.8°; CT: 1.3°), BCMI (CS: 1.31 kg / m2; CT :0.38 kg / m2) and FFMI (CS; 0.1 ♀ and 0.1 ♂; CT; 2.9 ♀ and 1.1 ♂) and a decrease of WC (CS: - 1.3 cm; CT– 1,65), FM percentage (CS: 0 %; CT – 2.7) and ECW/ICW (CS: 0.02; CT 0.03). Conclusion Our study suggests that LNP high calorie diet ameliorates the nephrological scenarios, the metabolic complications, and the nutritional perspective in uro-oncological pts with stage 2-5 CKD. A larger prospective study to validate these results is on-going.

Background and Aims Acute kidney injury (AKI) is a major postoperative complication in renal surgery for cancer, both in radical than in partial nephrectomy. One of the most intriguing arguments is to understand if normal renal function patients without renal urinary abnormalities can develop post-operative AKI after renal surgery. Aim of our study was to compare the AKI incidence in the two major renal surgeries approaches (radical and partial nephrectomies) in a selected cohort of patients with normal renal function. Method We performed a retrospective study of 216 patients who underwent radical (RN) or partial nephrectomy (PN) due to the presence of a kidney mass from 2000-2020 in a tertiary care Institution. Inclusion criteria: 1) Age> 18; 2) eGFR >;80 ml/min/1,73 using CKD-EPI formula 2012 3) absence of urinary abnormalities 4) presence of two kidneys at time operation. The following data were considered: age, gender, body mass index (BMI), TNM staging, hypertension, diabetes. Serum creatinine values were collected before surgery (t 0), at 48 hours after surgery and at dismissal. GFR was estimated at each time point using creatinine-based estimated glomerular filtration rate (eGFR) formula: CKD-EPI. We evaluated eGFR variation from the pre-surgical value to 48 h post and at dismissal. eGFR categories were created according to the KDIGO guidelines for G categories. Comparisons between groups were performed using Kruskal-Wallis ranks sum test for numerical variables and Pearson’s Chi square test for categorical variables. Logistic regression was used to identify variables ODDS Ratio for AKI onset after surgery. Results Clinical and pathological characteristics are reported in table 1. The cohort was composed by 216 patients with median Age 55 (IQR: 47, 64), M/F ratio 2.4, median BMI 25.8 (IQR: 23.3, 28.4), median eGFR 94.3 (IQR: 89.1, 101.6). According to CKD G classes, 79% were stage 1 and 2 1 were stage 2. The cohort was divided in two groups according to the type of surgery: 51% as RN and 49% as PN. Differences between the two groups were detected for Gender (Radical M/F ratio: 3.3; Partial M/F ratio: 1.8; p=0.4), basal eGFR (Radical Median:92.9 (88.1, 101.0); Partial Median:95.3 (90.7, 102.4); p=0.03) and CKD G class (Radical I:64%, II:36%; Partial I:78%, II:22%; p=0.02). Logistic regression for AKI onset showed as significant parameter (p Conclusion Our study highlights that both radical (55%) than partial (21%) nephrectomies harbor a non-negligible risk of post-operative AKI even in normal renal function patients without renal abnormalities. In addition, the impact of RN in normal renal function patients shows a dramatic incidence of AKI in the 50% of cases, suggesting that nephron sparing surgeries techniques should be always indicated to preserve renal function also in patients with an eGFR> 80 ml/min/1,73. A prospective comparison multicentric study with kidney living donor is on going.

Background and Aims Despite major advance in surgical techniques in the last decade, Chronic Kidney Disease (CKD) is still a major postoperative long-term complication in renal surgery for renal cancer, both in radical than in partial nephrectomy. However, it is still debatable if the renal hyperfiltration mechanism which happens after an acute loss of nephron mass could promote in oncological patients an effective vicariant process over time able to replace a new renal function comparable with the pre-operative one. Aim of our study was to compare the eGFR decay over time from pre-operative time surgery to 5 years follow up in the two major renal surgeries approaches (radical-RN- and partial nephrectomies- PN) in a selected cohort of patients with normal renal function at baseline. Method We performed a retrospective cohort-study of 271 consecutive patients who underwent radical (RN) or partial nephrectomy (PN) due to the presence of a kidney mass suspected of malignancy from 2000-2020 in a tertiary care urological Institution. Inclusion criteria were: 1) Age > 18 years old 2) eGFR > 80 ml/min/1,73 using CKD-EPI formula 2012 3) absence of urinary abnormalities . The following data were considered: age, gender, body mass index (BMI), TNM staging, hypertension, diabetes. Glomerular Filtration rate (GFR) was estimated at each time point using creatinine-based estimated glomerular filtration rate (eGFR) formula. We evaluated eGFR variation at the pre-surgical value, hospital dismissal, 6,12,24,36,48,60 months. eGFR categories were created according to the KDIGO guidelines for G categories in GFR setting different thresholds. Comparisons between groups were performed using Kruskal-Wallis ranks sum test for numerical variables and Pearson’s Chi square test for categorical variables. Logistic regression was used to identify variables ODDS Ratio for AKI onset after surgery. Results The study cohort was composed by 271 patients with median Age 56 (IQR: 48, 64), M/F ratio 2.3, median BMI 25.7 (IQR: 23.3, 28.3), median eGFR 94.3 (IQR: 89.1, 101.3) mL/min/1.73m^2. According to CKD G class, 70% were I and 30% were II. The cohort was divided in two groups according type of surgery: 44% as RN and 56% as PN. Differences between the two groups were detected for Gender (Radical M/F ratio: 3.2; Partial M/F ratio: 1.8; p=0.4), basal eGFR (Radical Median:92.3 (88.0, 99.8) mL/min/1.73m2; Partial Median:95.4 (90.1, 102.0) mL/min/1.73m2; p=0.01) and CKD G class (Radical I:64%, II:36%; Partial I:76%, II:24%; p=0.03). Two-way Anova for time variation of eGFR according other parameters, enlightened a significative difference for the type of surgery (p Conclusion Our study highlights that both RN than PN harbor a non negligible risk of post-operative CKD events even in normal renal function patients without renal abnormalities at 5 years from the operations. However, RN patients display a different behavior in term of renal compensation in respect of PN. In fact, RN pts tend to replace the acute loss of function derived from the absence of the contralateral kidney with an increase of eGFR , whereas PN pts tend to remain stable over time without any effort of hyperfiltration. A prospective comparison multicentric study with kidney living donor is on going.

Background: The chronic kidney disease (CKD) classification represents a simple tool to evaluate kidney disease. However, it is not based on kidney histology and this might limit the correlation between renal function and histological damage. The aim of this study was to examine the presence and magnitude of the discordance between CKD classification and kidney histology. Materials and methods: We retrospectively analyzed kidney parenchyma histology in a cohort of 200 patients who underwent radical nephrectomy for a kidney mass to observe its correlation with CKD classification. Kidney tissue of the unaffected part of the removed kidney was analyzed and classified with a chronicity score as described by Sethi et al. Then, all patients were classified according to the respective CKD stage using different equations: CKD-EPI, MDRD, FAS and MCQ. Results: Median age was 67 (57–75). Diabetes, hypertension and overweight were observed in 23%, 60% and 61%, respectively. The CKD-EPI equation stratified 30.5% (n = 61) of the subjects into CKD stage 1, 41.5% (n = 83) into CKD stage 2, 25.5% into CKD stage 3 (n = 51) and 2.5% into CKD stage 4–5 (n = 5). About 30–40% of the patients with CKD stage 3 had mild or no lesions in the histological evaluation (Chronicity Score = 0–1), whereas 7–10% of those with CKD stage 1 had moderate or severe histological lesions (Chronicity Score ≥ 3). Different patients with the same value of estimated glomerular filtration rate (eGFR) had either severe or no histological damage. Conclusions: The variability of kidney histology observed within each CKD stage is not negligible. This may limit the reliability of the current CKD classification. More research is needed to clarify the relationship between CKD stages and kidney damage. Graphic abstract: [Figure not available: see fulltext.]

Purpose: The role of non-tumour renal biopsy in predicting renal function after surgery for renal cell carcinoma (RCC) is poorly investigated. The aim of the study was to assess the impact of renal parenchymal histology on renal function after radical nephrectomy in a cohort of patients with RCC. Methods: This cohort study included 171 patients with RCC submitted to radical nephrectomy between 2006 and 2018. Two biopsy samples from normal parenchyma were collected at nephrectomy and renal parenchyma damage (RPD) was scored on histologic samples according to validated methodology. The outcomes were eGFR after surgery and its reduction > 25% relative to baseline at maximum 12months’ follow-up. Linear and logistic multivariable regression were used, adjusting for age at surgery, presence of hypertension, diabetes, clinical tumour size, time from surgery and basal eGFR. Results: 171 patients were enrolled and RPD was demonstrated in 64 (37%). Patients with RPD had more comorbidities (CCI > 2 in 25 vs. 9%, p < 0.001), in particular hypertension (70 vs. 53%; p = 0.03), diabetes with (5% vs. 0%, p = 0.007) or without (31 vs. 18%; p = 0.007) organ damage, cerebrovascular disease (19 vs. 5%; p = 0.006) and nephropathy (20 vs. 3%; p = 0.0004). At multivariable analyses, RPD was associated with lower eGFR (Est. −5.48; 95% CI −9.27: −1.7; p = 0.005) and with clinically significant reduction of eGFR after surgery (OR 3.06; 95% CI 1.17: 8.49; p = 0.026). Conclusions: Presence of RPD in non-tumour renal tissue is an independent predictor of functional impairment in patients with RCC. Such preliminary finding supports the use of parenchyma biopsy during clinical decision making.

Background and Aims Radical Nephrectomy is usually associated to the risk of future development of a mild to severe chronic kidney disease stage especially for those patients who already present early stages of CKD (e.g CKD class II and IIIa). Any insight on this topic could influence the clinical decision about the surgery. But how can we know for sure the magnitude of the renal function’s decay? In this preliminary work, our aim was to identify a new model able to predict at time surgery the renal function’s variation at 1 year from the operation Method We collected prospectively clinical data of a group of consecutive 114 patients who underwent radical nephrectomy (RN) for the presence of a benign or malignant renal mass. We estimated Glomerular Filtration Rate (eGFR) with MDRD formula. We considered the following clinical varibles: AKI onset (according to RIFLE criteria), age, gender, presence of blood hypertension, diabetes type II and BMI. Moreover, to investigate a possible correlation between renal basal histology and renal functional decay, renal biopsies were performed on each on the healthy part of the removed kidney > 3cm far from tumor. A pathological evaluation using a chronicity score (Remuzzi Score) was subsequently carried out evaluating damage on four parameters: (a) glomerular global sclerosis, (b) tubular atrophy, (c) interstitial fibrosis and (d) arterial narrowing. Statistical analysis were performed using generalized linear model (GLM), Kruskal-Wallis test and chi-square test. Multivariate analysis were applied using stepwise regressions method in order to select the best fitting model. Statistically significant correlations were considered for p-value Results At t0, 21% of the patients had an eGFR>90ml/min/1.73m2, 45% between 60 and 90, 23% between 30 and 45, and 11% under 45. Median observed decay after 12 months was 32.8% (IQR= 17.9%:41.9%).Taking in account the eGFR decay’s percentage there was a strong correlation with AKI onset (decay increased by 22.4%, CI= 14%:30.8%, p Conclusion A precise and reliable prediction of renal function decrease after RN represents a cornerstone for urologist and nephrologist in order to create a personalized medical approach and management.In our cohort of study, CKD stage I and II patients displayed a huge decrease of eGFR in respect to CKD stages III-IV over time. One possible biological explanation can be that the healthy kidney of the patients affected by moderate and severe CKD starts working with a compensatory mechanism before the entire removal of the kidney with cancer so that the surgical acute nephron loss does not represent a shock in comparison to healthy patients with an eGFR >90 ml/min. Our preliminary study identified a new clinical and pathological panel of variables able to predict at time zero the magnitude of eGFR decay after 1 year from surgical operation. Further studies are needed in order to validate and improve this model.

Advanced glycation end-products (AGEs) are an assorted group of molecules formed through covalent bonds between a reduced sugar and a free amino group of proteins, lipids, and nucleic acids. Glycation alters their structure and function, leading to impaired cell function. They can be originated by physiological processes, when not counterbalanced by detoxification mechanisms, or derive from exogenous sources such as food, cigarette smoke, and air pollution. Their accumulation increases inflammation and oxidative stress through the activation of various mechanisms mainly triggered by binding to their receptors (RAGE). So far, the pathogenic role of AGEs has been evidenced in inflammatory and chronic diseases such as chronic kidney disease, cardiovascular disease, and diabetic nephropathy. This review focuses on the AGE-induced kidney damage, by describing the molecular players involved and investigating its link to the excess of body weight and visceral fat, hallmarks of obesity. Research regarding interventions to reduce AGE accumulation has been of great interest and a nutraceutical approach that would help fighting chronic diseases could be a very useful tool for patients’ everyday lives.

The aim of the study was to investigate the association of the uromodulin (UMOD) genotype with patient health status and with renal cell carcinoma (RCC) aggressiveness.The UMOD genotype at the top single nucleotide variant rs4293393 was determined in a cohort of 211 patients diagnosed with a renal mass and treated with surgery. Clinical data were prospectively collected. Due to the higher frequency of allele T relative to the lower frequency of allele C, recessive homozygous (CC), and heterozygous (TC) patients were grouped together and compared with homozygous (TT) patients. Mann-Whitney and chi-square tests were used to compare clinical characteristics after stratification for the UMOD genotype. UMOD genotype frequencies resulted TT and TC-CC in 67% (n = 141) and 33% (n = 70) of the population, respectively. The rate of cM1 RCC at clinical staging was higher in patients with genotype TT relative to patients with genotype TC-CC (18% vs 1%, p = 0.001). Similarly, the rate of pT3-pT4 (41% vs 25%, p = 0.047) and lymphovascular invasion (29% vs 13%, p = 0.02) RCC at final pathology were higher in patients with genotype TT relative to patients with genotype TC-CC. Patient summary: In patients diagnosed with renal cell carcinoma and treated with surgery, uromodulin homozygous genotype is associated with more aggressive renal cell carcinoma clinical and pathological characteristics. In patients diagnosed with a renal mass and elected for surgical management, uromodulin homozygous genotype is associated with more aggressive renal cell carcinoma clinical and pathological characteristics. Further investigations are required to study the causal biologic mechanism underlying such relationship.

Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.

AIMS:To study micturition and bladder overactivity in female rats after chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor oleoyl ethyl amide (OEtA).METHODS:Sprague-Dawley rats ...

e18809Background: An accurate assessment of renal function is mandatory in the majority or urological and oncological patients to prevent renal impairment and cancer non-related deaths. Nowadays, t...

Objective This study sought to develop a novel animal model to study the impact of nerve-sparing radical hysterectomy (NSRH) on female genital blood flow. Design In vivo animal study. Population Thirty Sprague-Dawley female rats. Materials and methods Female rats underwent either unilateral pelvic nerve (PN) crush (PNC; n = 9), or crush of both the PNs and all efferent nerves in the pelvic plexus (‘clock-nerve crush’, CNC; n = 9). Under anaesthesia, we electrically stimulated the crushed PN at 3 and 10 days after crush while monitoring blood pressure and recording clitoral and vaginal blood flows by laser Doppler. Uninjured PNs were stimulated as an internal control. Twelve additional rats were assigned either to bilateral PNC or sham surgery, and genital tissues were processed 10 days after injury for in vitro analysis. Main outcome measures Genital blood flow, nNOS, eNOS, collagen I-III. Results Stimulation of the crushed PN in both groups subjected to PNC and CNC induced significantly lower peak genital blood flow at 3 and 10 days (P

INTRODUCTION AND OBJECTIVES: The endocannabinoid system modulates afferent signals under certain conditions. It is not known if the endocannabinoid-regulatory enzyme fatty acid amide hydrolase (FAAH) is located to or has a function in the ejaculatory system. We aimed to examine the expression of FAAH in the seminal vesicle and vas deferens and effects of inhibition of FAAH on seminal vesicle function and ejaculation. METHODS: After ethical approval, anesthetized male Sprague Dawley rats (250gram) were used for (I) recordings of intraluminal pressure of the seminal vesicle, or (II) pressures of the corpus spongiousum during apomorphine-induced (150 g/kg, s.c.) ejaculation. Effects by intraperitoneal oleoyl ethyl amide (OEtA; a FAAH inhibitor; 0.1, 1 and 10 mg/kg) or vehicle were studied. PCR, Western Blot and immunohistochemistry were used for studies of FAAH expression in rat and human tissues. Effect by OEtA (0.1-100 M) on isolated seminal vesicle was studied in organ baths. ANOVA and T-test were used for comparisons. RESULTS: PCR and WB demonstrated FAAH in rat and human seminal vesicles and vas deferens. FAAH was located in epithelial cells of both tissues. In human samples, the FAAH-2 isoform was similarly expressed. In isolated tissues, maximum inhibition by OEtA (100 M) on nerve-induced contractions were 21 9% (human;n 5) and 22 9% (rat;n 7). In vivo, the frequencies of spontaneous seminal vesicle contractions / min. were 1.08 0.32 (baseline) and 0.58 0.13 (OEtA 10mg/kg;p 0.05), and 1.23 0.41 (baseline) and 1.45 0.52 (vehicle; ns). OEtA increased basal pressure by 34 13% (vs. 0.3 2.9% for vehicle; p 0.05). Apomorphine-induced ejaculations were registered as suprasystolic intraspongious pressure spikes with striated muscle contractions and semen-expulsion from the urethra. Latencies to the first, second and third ejaculation were 6.0 1.2, 13.1 1.9, and 19.4 2.2 min. for vehicle (n 7); 12.7 3.2 (p 0.07), 19.6 4, and 22.8 2.6 min; and 21.8 3.3 (p 0.05) for OEtA (0.1 mg/kg; n 8), 26.9 5.1 (p 0.05), and 38.7 9.5 (p 0.05) min. for OEtA (1mg/kg; n 6). No differences in the number or pressure amplitudes of ejaculations were noted for OEtA and vehicle. CONCLUSIONS: FAAH is expressed in the rat and human vas deferens and seminal vesicle. FAAH inhibition seems to depress seminal vesicle excitability and prolongs latency for apomorphine-induced ejaculation in rats. Pharmacological targeting of FAAH may be an interesting principle to further develop in premature ejaculation.