Search

This study identified challenges affecting medical oncologists, nephrologists, physician assistants, nurse practitioners, and registered nurses involved in the care of advanced (unresectable and metastatic) renal cell carcinoma. Challenges included staying current with emerging therapies, weighing in patient's preferences for treatment, promoting a collaborative approach to care, and sharing patient information. Insights can inform the development of educational interventions. Introduction: Systemic treatments for metastatic or unresectable renal cell carcinoma (mRCC) are rapidly evolving. This study aimed at investigating challenges in the care of mRCC to inform future educational interventions for health care providers (HCPs). Materials and Methods: The sequential mixed-method design consisted of a qualitative phase (semistructured interviews) followed by a quantitative phase (online surveys). Participants included US-based medical oncologists, nephrologists, physician assistants, nurse practitioners, and registered nurses. Interview transcripts were thematically analyzed. Survey data was descriptively and inferentially analyzed. Results: Forty interviews and 265 surveys were completed. Analysis revealed four challenges in the care of mRCC patients. A challenge in staying current with emerging evidence and treatment recommendations was found with 33% of surveyed HCPs reporting suboptimal skills interpreting published evidence on the efficacy and safety of emerging agents. A challenge weighing patient health and preferences in treatment decisions was found, especially among HCPs with 3 to 10 years of practice (37%) who reported suboptimal skills in assessing patients' tolerance to side effects. Promoting a collaborative care approach to the management of immune-related adverse events was a challenge, specifically related to barriers involving nephrologists (eg, diverging treatment goals). Breakdowns in communication were reported (46% of HCPs), especially in the monitoring of side effects and treatment adherence. Conclusion: This study revealed key challenges faced by HCPs when treating and managing patients with mRCC across multiple providers. Future interventions (eg, community of practice) should aim to address the identified gaps and promote a team-based approach to care that strengthens the complementary competencies of HCPs involved. [ABSTRACT FROM AUTHOR]

The incidence of kidney cancer has been increasing steadily and, until recently, there was a substantial lack of effective therapies for a cancer that is now among the 10 most common cancers in men and women. During the past 10 years, novel therapies have been developed including antiangiogenic drugs targeting vascular endothelial growth factor and its receptors, immune checkpoint inhibitors, and mammalian target of rapamycin inhibitors that have resulted in a significant improvement in clinical outcomes in a traditionally difficult-to-treat cancer. These new drugs, however, also have important side effects and toxicities that often have an impact on the treatment of these patients. The use of anti-angiogenic drugs often results in the development of hypertension and, less frequently, varying degrees of proteinuria including nephrotic range proteinuria. A variety of agents are used for the treatment of hypertension and proteinuria including blockers of the renin angiotensin system and calcium channel blockers, but there are no randomized clinical trials comparing different therapeutic agents in these patients. Immune checkpoint inhibitors have become one of the cornerstones of therapy in kidney cancer, but their use is linked to a variety of side effects that affect almost every organ and resemble autoimmune diseases. In the kidney, these drugs can induce acute interstitial nephritis in close to 5% of patients with varying degrees of severity that in some cases require discontinuation of treatment and systemic treatment with corticosteroids. Although mammalian target of rapamycin inhibitors now also are part of the therapeutic armamentarium available for these patients, all clinical trials have been performed in patients with normal renal function and therefore their effects in patients with abnormal renal function are not known. [ABSTRACT FROM AUTHOR]

Abstract: Novel trivalent antimony complexes with the nitrogen donor heterocyclic ligand 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen) or dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq) have been synthesized by the reaction with SbCl3 or PhSbCl2. The crystal structures of [Sb(phen)Cl3] and [PhSb(phen)Cl2]CH3COOH were determined and shown to adopt a distorted square pyramid geometry with a five-coordinated Sb center. Surprisingly, all the complexes, the ligands and PhSbCl2 showed very high antileishmanial activities, with IC50 in the nanomolar range against SbIII-sensitive and -resistant Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis strains. These compounds were much more active against these Leishmania strains than the old trivalent drug potassium antimonyl tartrate. [PhSb(phen)Cl2]CH3COOH complex was found to be the most active compound and the lack of cross-resistance of PhSbCl2 suggests that the transport pathways of this compound across the cell membrane differ from those responsible for the resistance of Leishmania to Sb(OH)3. In the case of the complexes with PhSbCl2, our data supports the model that both ligand and metal contributed to the overall activity of the complex. Furthermore, among the complexes with SbCl3, only bipy showed an improved activity upon complexation. Cytotoxicity evaluations of these compounds against murine peritoneal macrophages showed high selective indexes in the range of 7–70 for [Sb(phen)Cl3], [Sb(bipy)Cl3] and [Sb(dpq)Cl3] complexes, being much more selective than potassium antimonyl tartrate. In conclusion, this study presents a set of new antileishmanial agents including one of the most active Sb-based compounds ever reported, which can contribute to the development of new chemotherapeutic strategies against leishmaniasis including Sb-resistant cases. [Copyright &y& Elsevier]

Abstract: The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the α7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD. [Copyright &y& Elsevier]

Abstract: Previously, we reported the efficacy of aliskiren/amlodipine in US minority adults with stage 2 hypertension, with additional blood pressure (BP) lowering from the addition of hydrochlorothiazide (HCTZ). A subgroup analysis in patients with hypertension and comorbidities of diabetes, cardiometabolic syndrome, or obesity, and in black participants is reported. This 8-week, multicenter, double-blind study included 412 self-identified minority patients with mean sitting systolic BP (msSBP) ≥160 mm Hg and <200 mm Hg). Patients were randomized to receive either combination aliskiren/amlodipine 150/5 mg or amlodipine 5 mg. Doses were forced-titrated to a maximum of aliskiren/amlodipine/HCTZ 300/10/25 mg or aliskiren/amlodipine 300/10 mg, respectively. There were 256 black (62%), 118 diabetic (29%), 284 cardiometabolic syndrome (69%), and 249 obese (60%) randomized patients. Baseline msSBP was ∼167 mm Hg across all subgroups. Least-square mean reductions in msSBP, the primary efficacy outcome, from baseline to week 8 across all subgroups, ranged from 35 to 37 mm Hg with aliskiren/amlodipine/HCTZ and 28 to 30 mm Hg with aliskiren/amlodipine (P < .01 for all between-treatment comparisons). Both regimens were well tolerated. Among high-risk patients, such as diabetics or those with cardiometabolic syndrome, combination aliskiren/amlodipine is effective in lowering BP; the addition of HCTZ provided incremental BP-lowering efficacy while maintaining tolerability. However, because our subgroups were not mutually exclusive, the generalization of our findings to the population seen in clinical practice is limited. [Copyright &y& Elsevier]

Abstract: Minority patients with hypertension generally require combination therapy to reach blood pressure (BP) goals. We examined the BP-lowering efficacy and safety of combination aliskiren/amlodipine therapy in self-identified minority patients in the United States with stage 2 hypertension and the impact of adding hydrochlorothiazide (HCTZ) to this combination. In this 8-week double-blind study, 412 patients were randomized to receive aliskiren/amlodipine (150/5 mg) or amlodipine (5 mg) with forced titration up to aliskiren/amlodipine/HCTZ (300/10/25 mg) or aliskiren/amlodipine (300/10 mg), respectively. Overall, mean age was 55.2 years, mean body mass index was 32 kg/m2, 62.3% were black, 28.2% were Hispanic/Latino, and 69.1% had metabolic syndrome. Mean sitting systolic blood pressure (MSSBP), the primary efficacy outcome, was reduced from 167.1 mm Hg at baseline to 130.7 mm Hg at week 8 with aliskiren/amlodipine/HCTZ and from 167.4 mm Hg to 137.9 mm Hg with aliskiren/amlodipine (P < .0001 between groups). At week 8, BP goal (<140/90 mm Hg) was achieved in 72.6% and 53.2% of patients in the two treatment groups, respectively (P < .0001). Adverse events were experienced by 34.2% and 40.2%, respectively. Combination aliskiren/amlodipine therapy was effective in treating these high-risk patients but inclusion of HCTZ provided greater antihypertensive efficacy. Both treatments were similarly well tolerated. [Copyright &y& Elsevier]

Background. Prostaglandins such as prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) counteract the angiotensin II (Ang II)–induced vasoconstriction in the glomerular microcirculation. We have shown that Ang II promotes mesangial cell hypertrophy via reactive oxygen species (ROS), which originate from nicotinamide adenine dinucleotide phosphate and its reduced form (NADH/NADPH) oxidase. It has been reported that conditions associated with activation of the renin-angiotensin system result in increased glomerular cyclooxygenase-2 (COX-2) expression and activity. Methods. We designed studies to determine ( 1) whether Ang II induces COX-2 in the glomerulus in vivo in the glomerulus as well as in vitro in mesangial cells, ( 2) whether ROS originated from Ang II are involved, and ( 3) whether COX-2–derived prostaglandins modulate the growth promoting effects of Ang II in mesangial cells. Rats were infused with Ang II (0.7 mg/kg/day) for 5 days and glomerular COX-2 expression and activity assessed in isolated glomeruli. Results. Ang II increased glomerular PGE2 production (100%) accompanied by a concomitant increase in glomerular COX-2 expression at the mRNA (1.7-fold) and protein level (sixfold). In mesangial cells, Ang II significantly increased mesangial cell PGE2 (200%) and PGI2 (100%) production as well as COX-2 mRNA that was prevented by the angiotensin type 1 (AT1) receptor blocker irbesartan and the COX-2 inhibitor NS-398. The NADPH oxidase inhibitor diphenyleneiodonium (DPI), the ROS scavenger tiron as well as catalase, inhibited Ang II–induced PGE2 production suggesting that Ang II–induced ROS mediate COX-2 up-regulation. Strikingly, COX-2 inhibition as well as blockade of the type 1 PGE2 receptor (EP1) prevented Ang II–induced mesangial cell hypertrophy suggesting that COX-2–derived prostaglandins, and specifically PGE2, importantly contribute to the growth promoting effects of Ang II. Conclusion. These studies suggest that blockade of specific PGE2 receptors may be a novel strategy to modulate the pathologic effects of COX-2–derived prostaglandins without simultaneously affecting protective vasodilatory mechanisms. [ABSTRACT FROM AUTHOR]

L-arginine is a semi essential amino acid and also a substrate for the synthesis of nitric oxide (NO), polyamines, and agmatine. These L-arginine metabolites may participate in the pathogenesis of renal disease and constitute the rationale for manipulating L-arginine metabolism as a strategy to ameliorate kidney disease. Modification of dietary L-arginine intake in experimental models of kidney diseases has been shown to have both beneficial as well as deleterious effects depending on the specific model studied. L-arginine supplementation in animal models of glomerulonephritis has been shown to be detrimental, probably by increasing the production of NO from increased local expression of inducible NO synthase (iNOS). L-arginine supplementation does not modify the course of renal disease in humans with chronic glomerular diseases. However, beneficial effects of L-arginine supplementation have been reported in several models of chronic kidney disease including renal ablation, ureteral obstruction, nephropathy secondary to diabetes, and salt-sensitive hypertension. L-arginine is reduced in pre- eclampsia and recent experimental studies indicate that L-arginine supplementation may be beneficial in attenu- ating the symptoms of preeclampsia. Administration of exogenous L-arginine has been shown to be protective in ischemic acute renal failure. In summary, the role of L-arginine in the pathogenesis and treatment of renal disease is not completely understood and remains to be established. [ABSTRACT FROM AUTHOR]

Angiotensin II induces superoxide anion production by mesangial cells. Background. The recognized role of angiotensin II (Ang II) in the pathogenesis of the progression of renal disease cannot be solely attributed to Ang II's hemodynamic effects. Indeed, growth stimulating signals driven by Ang II promote mesangial cell (MC) hypertrophy and extracellular matrix production, prominent features of progressive glomerular injury. Superoxide anion (O2 - ) avidly interacts with nitric oxide, an endogenous vasodilator that inhibits growth factor stimulated MC growth and matrix production. In addition, O2 - acting as an intracellular signal is linked to growth related responses such as activation of mitogen activated protein (MAP) kinases. The studies reported herein were designed to investigate: (a ) whether Ang II induces MC O2 - production and (b ) if increased O2 - production elicits growth responses in MC. Methods. MC were exposed to Ang II for 24 or 48 hours. In some experiments, in addition to Ang II, MC were exposed to: diphenylenieodonium (DPI), an inhibitor of the flavin containing NADH/NADPH oxidase; losartan (LOS), an Ang II type 1 (AT1) receptor blocker; PD 98059, a MAP kinases inhibitor; the protein kinase C inhibitors Calphostin C or H-7; and the tyrosine kinase inhibitors, herbymycin A or genistein. Results. Ang II (10-5 M to 10-8 M) dose dependently increased MC O2 - production up to 125% above control (ED 50 5 × 10-7 M). LOS as well as DPI, and the PKC inhibitors blocked Ang II stimulated MC O2 - production. Ang II dose dependently increased MC 3 H-leucine incorporation, and MC protein content, two markers of MC hypertrophy, as well as 3 H-thymidine incorporation, a marker of MC hyperplasia. PD98059, a specific inhibitor of MAP kinases prevented Ang II induced MC... [ABSTRACT FROM AUTHOR]

Five new copper(II) complexes of the type [Cu(N O)(N N)(ClO 4 ) 2 ], in which N O = 4-fluorophenoxyacetic acid hydrazide (4-FH) or 4-nitrobenzoic hydrazide (4-NH) and N N = 1,10-phenanthroline (phen), 4–4′-dimethoxy-2-2′-bipyridine (dmb) or 2,2-bipyridine (bipy) were synthesized and characterized using various spectroscopic methods. The X-ray structural analysis of one representative compound indicates that the geometry around the copper ion is distorted octahedron, in which the ion is coordinated to hydrazide via the terminal nitrogen and the carbonyl oxygen, and to heterocyclic bases via their two nitrogen atoms. Two perchlorate anions occupy the apical positions, completing the coordination sphere. The cytotoxic activity of compounds was investigated in three tumor cell lines (K562, MDA-MB-231 and MCF-7). Concerning K562 cell line, the complexes with 1,10-phenanthroline exhibit high cytotoxic activity and are more active than carboplatin, free ligands and [Cu(phen) 2 ] 2 + . Considering the cytotoxicity results, further investigations for the compounds [Cu(4-FH)(phen)(ClO 4 ) 2 ] I and [Cu(4-NH)(phen)(ClO 4 ) 2 ]∙H 2 O III were performed. Flow cytometric analysis revealed that these complexes induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38 × 10 4 and 2.62 × 10 4 , respectively. These compounds were also evaluated against wild type Mycobacterium tuberculosis (ATCC 27294) and exhibited antimycobacterial activity, displayed MIC values lower than those of the corresponding free ligands. [ABSTRACT FROM AUTHOR]

• The incidence of acute kidney injury following chimeric antigen receptor T cell (CAR-T) cell therapy is low. • Previous hematopoietic cell transplantation, intensive care unit admission, and grade 3-4 cytokine release syndrome after CAR-T therapy may increase the risk of acute kidney injury (AKI). • Most patients who experience AKI after CAR-T therapy recover kidney function. Chimeric antigen receptor (CAR) T cell therapy using engineered cytotoxic T cells has shown promising responses in various hematologic malignancies. Cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS) are recognized toxicities of CAR-T, whereas kidney injury remains less well recognized. The objective of the present study was to identify the incidence of acute kidney injury (AKI) after CAR-T cell therapy, potential risk factors, and recovery of kidney function. We performed a retrospective review of 46 adult patients with non-Hodgkin lymphoma treated with CAR-T therapy between February 2018 and February 2019 at our institution. Serum creatinine values before CAR-T therapy through day 100 were used to assess AKI, as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria: grade 1, 1.5- to <2-fold of baseline; grade 2, 2- to <3-fold of baseline; grade 3, ≥3-fold of baseline. CRS and ICANS were graded using the consensus criteria of the American Society of Transplantation and Cellular Therapy. The overall incidence of CRS was 78.3% (95% confidence interval [CI], 66% to 90.5%), of whom 13% (95% CI, 3.3% to 22.8%) developed grade 3-4 CRS, whereas the overall incidence of ICANS was lower at 45.7% (95% CI, 3.1% to 60.3%). The cumulative incidence of any grade AKI by day 100 was 30% (95% CI, 16.9% to 43.9%), with a grade 1 AKI incidence of 21.7% (95% CI, 9.7% to 33.8%) and a grade 2-3 AKI incidence of 8.7% (95% CI,.4% to 17%). No patients developed severe AKI necessitating renal replacement therapy. Patients with previous autologous or allogeneic stem cell transplantation, those requiring intensive care unit level care and with grade 3-4 CRS had a higher incidence of AKI. Most patients recovered, with kidney function returning to baseline within 30 days. We conclude that with early recognition and management of CAR-T complications, the incidence of AKI is low, the severity of injury is mild, and most patients recover kidney function within 30 days. [ABSTRACT FROM AUTHOR]

• Day 100 grade 2 to 3 acute kidney injury (AKI) incidence is high after adult cord blood transplantation. • Grade 1 to 2 AKI can be present with a normal creatinine. • A higher pretransplant serum albumin protects against AKI. • Critical illness and nephrotoxic drugs increase AKI risk. • Early post-transplant AKI increases 2-year chronic kidney disease risk. Although cord blood transplantation (CBT) extends allograft access, patient comorbidities, chemoradiation, and nephrotoxic medications all contribute to acute kidney injury (AKI) risk. We analyzed AKI in adult myeloablative CBT recipients who underwent transplantation from 2006 to 2017 for hematologic malignancies using cyclosporine A (CSA)/mycophenolate mofetil immunosuppression. Maximum grades of AKI were calculated using Kidney Disease: Improving Global Outcomes (grade 1, 1.5 to <2-fold; grade 2, 2 to <3-fold; or grade 3, ≥3-fold over baseline) definitions. In total, 153 patients (median 51 years [range, 23-65], 114/153 [75%] acute leukemia, 27/153 [18%] African, 88/153 [58%] cytomegalovirus seropositive, median age-adjusted hematopoietic cell comorbidity index 3 [range, 0-9], median pretransplant albumin 4.0 g/dL [range, 2.6-5.2]) underwent transplantation. The day 100 cumulative incidence of grade 1-3 AKI was 83% (95% confidence interval [CI], 77%-89%) (predominantly grade 2, median onset 40 days, range 0 to 96), and grade 2-3 AKI incidence was 54% (95% CI, 46%-62%) (median onset 43 days, range 0 to 96). Mean CSA level preceding AKI onset was high (360 ng/mL, target range 300-350). In multivariate analysis, African ancestry, addition of haploidentical CD34+ cells, low day –7 albumin, critical illness/intensive care admission, and nephrotoxic drug exposure (predominantly CSA and/or foscarnet) were associated with AKI. In a day 100 landmark analysis, 6% of patients with no prior AKI had chronic kidney disease (CKD) at 2 years versus 43% with prior grade 1 and 38% with prior grade 2-3 AKI (overall P =.02). Adult CBT recipients are at significant AKI risk, and AKI is associated with increased risk of CKD. Prevention strategies, early recognition, and prompt intervention are critical to mitigate kidney injury. [ABSTRACT FROM AUTHOR]

Highlights • We applied a novel grading system to assess the effects of early fluid overload (FO) on outcomes in patients after ex vivo CD34+ selected allo-HCT. • Patients with grade ≥ 2 FO had significantly higher NRM than those with grade < 2 FO. • Even in the absence of CNI-based GVHD prophylaxis, FO remains a highly relevant early transplant toxicity that should be routinely assessed. Abstract In a recently published and validated definition of fluid overload (FO), grade ≥ 2 FO was significantly associated with an increased risk of nonrelapse mortality (NRM) after unmodified and haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis. We evaluated the effect of FO on outcomes in 169 patients undergoing myeloablative-conditioned ex vivo CD34+ selected allo-HCT using the same grading scale. Thirty patients (17.8%) had grade ≥ 2 FO within the 30 days after ex vivo CD34+ selected allo-HCT with a median onset at day 11 (range, -8 to 28). Age ≥ 55 years (odds ratio, 3.43; P =.005) and chemotherapy-based conditioning (odds ratio, 3.89; P =.007) were associated with an increased risk of grade ≥ 2 FO. Patients with early grade ≥ 2 FO had a significantly higher NRM when compared with patients with grade < 2 FO (24.1% versus 3.6% at day 100, P =.01). The HCT-specific comorbidity index (HCT-CI) ≥ 3, FEV 1 < 80, adjusted DL co < 80, and HLA mismatch were associated with an increased risk of NRM, whereas total body irradiation–based conditioning was associated with a reduced risk of NRM. In a multivariate analysis grade ≥ 2 FO was associated with increased NRM after adjusting for HCT-CI and HLA match (hazard ratio, 2.3; P =.014). There was a trend toward inferior relapse-free survival in patients with grade ≥ 2 FO compared with patients with grade < 2 FO, 62% versus 72% at 1 year (P =.07), and a trend toward inferior overall survival, 69% versus 79% at 1 year (P = 0.06), respectively. Our findings show that FO should be routinely assessed to identify patients at risk for NRM. Despite a CNI-free allo-HCT platform, regimen-related tissue and endothelial injury leads to FO in susceptible patients. FO is a highly relevant post-HCT toxicity that requires further inquiry. [ABSTRACT FROM AUTHOR]

Objectives Chyluria is a medical condition with presence of chyle in urine. The disease is most prevalent in South East Asian countries mostly caused by parasitic ( Wuchereria bancrofti ) infections. Our objective was to investigate the spontaneous remission of non-parasitic chyluria. Design and methods The spontaneous remission of non-parasitic chyluria cases were worked up with diagnostic investigations, clinical assessment and studied in detail with respect to their natural evolution. Results We present two patients who were evaluated in the nephrology clinic with symptoms of milky urine and painless hematuria. Midnight blood smear was negative for filarial parasites. Urine culture was without mycobacteria. Urine cytology and IgG western blot for cysticercus were negative. Imaging for a lymphatic leak by lymphoscintigraphy was unrevealing. Chyluria resolved spontaneously in both patients. Conclusions In our cases, radiologic visualization via lymphoscintigraphy was unrevealing. The patients were managed conservatively and fortunately underwent spontaneous remission marked by the disappearance of chyluria within several months of her initial diagnosis. In our opinion this spontaneous remission could be due to unrevealed lymphatico-renal fistula collapse or sclerosis of lymphatics caused by contrast media. [ABSTRACT FROM AUTHOR]

The cytotoxic activity against human carcinogenic cells of five compounds, three of them containing palladium(II) and one containing platinum(II) was evaluated for the first time. These compounds were synthesized and characterized and present the formula K2(H2opba)·2H2O (1), K2[Pd(opba)]·2H2O (2), [Pd(NH3)4]Cl2·2H2O (3), [Pd(NH3)4][Pd(opba)] (4) and [Pt(H2opba)]·H2O (5), where opba=1,2-phenylenebis(oxamate). Compounds 4 and 5 are novel and their synthesis and characterization are discussed in detail in this paper. The crystal structure of 4 was elucidated by single crystal X-ray diffraction and consists of discrete [Pd(NH3)4]2+cations interacting via hydrogen-bonds with [Pd(opba)]2− anions. Despite the fact that compound 1 has no significant effect on the growth of chronic myelogenous leukemia cells, its PdII and PtII complexes inhibit cellular growth in the following order of activity 2 ∼ 4 > 5. Compounds 2 and 4 are approximately 20 times more cytotoxic against leukemia cells than the free ligand. [ABSTRACT FROM AUTHOR]

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, producing equimolar amounts of carbon monoxide, iron, and biliverdin. Induction of HO-1 is a beneficial response to tissue injury in diverse animal models of diseases including acute kidney injury. In vitro analysis has shown that the human HO-1 gene is transcriptionally regulated by changes in chromatin conformation, but whether such control occurs in vivo is not known. To enable such an analysis, we generated transgenic mice, harboring an 87-kb bacterial artificial chromosome expressing human HO-1 mRNA and protein and bred these mice with HO-1 knockout mice to generate humanized BAC transgenic mice. This successfully rescued the phenotype of the knockout mice including reduced birth rates, tissue iron overload, splenomegaly, anemia, leukocytosis, dendritic cell abnormalities, and survival after acute kidney injury induced by rhabdomyolysis or cisplatin nephrotoxicity. Transcription factors such as USF1/2, JunB, Sp1, and CTCF were found to associate with regulatory regions of the human HO-1 gene in the kidney following rhabdomyolysis. Chromosome conformation capture and ChIP-loop assays confirmed this in the formation of chromatin looping in vivo. Thus, these bacterial artificial chromosome humanized HO-1 mice are a valuable model to study the human HO-1 gene, providing insight to the in vivo architecture of the gene in acute kidney injury and other diseases. [ABSTRACT FROM AUTHOR]

Two new bismuth(III) complexes, [BiL1Cl 2 ] (1) and [BiL2Cl 2 ] (2), in which L1 is (2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine and L2 is 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol, were synthesized and characterized by elemental and conductivity analyses, atomic absorption spectrometry, infrared and 1H NMR spectroscopies. The molecular structure of 1 reveals that the NN'O ligand forms a 1:1 complex with bismuth through coordination via the nitrogen of the aliphatic amine, the nitrogen of the pyridine ring and the oxygen of the phenolate. The coordination sphere is completed with two chloride anions in a distorted square pyramidal geometry. Bismuth exhibits the same coordination mode in compound 2. The cytotoxic activity of 1 and 2 was investigated in a chronic myelogenous leukemia cell line. The complexes are approximately three times more potent than the corresponding free ligands, with the IC 50 values 0.30 and 0.38 μM for complex 1 and 2 , respectively. To address the cellular mechanisms underlying cell demise, apoptosis was quantified by flow cytometry analysis. From 0.1 μM, both complexes induce apoptosis and there is a remarkable concentration-dependent increase in the population of cells in apoptosis. The complexes were also evaluated against Gram-positive and Gram-negative bacteria. Both inhibited the bacterial growth in a concentration-dependent way, with remarkable activity in some of the tested strains, for example, complex 2 was more active than its free ligand against all bacterial strains and approximately fourteen times more potent against S. dysenteriae and S. typhimurium. Two new Bi(III) complexes with asymmetric [NN'O] ligands were highly cytotoxic to chronic myelogenous leukemia cells, with IC 50 values in the range 0.3–0.4 μmol L−1. Both complexes induce a remarkable concentration-dependent increase in the population of cells in apoptosis. [Display omitted] • Bismuth compounds with asymmetric [NN'O] ligands are cytotoxic to leukemia cells. • Bi(III) binds to an amine N, a pyridine N, a phenolate oxygen, and two chlorides. • Bismuth complexes induce apoptosis in K562 cells at significant low concentrations. • [BiCl 2 (2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine] is active vs. S. aureus. • Complex 2 is 14 times as potent as the ligand in S. dysenteriae and S. typhimurium. [ABSTRACT FROM AUTHOR]

Introduction While adult double unit CBT (dCBT) has disease-free survival comparable to that of HLA-matched adult donor allografts, frequent patient (pt) comorbidities combined with chemotherapy/TBI & cyclosporine-A (CSA) contribute to AKI risk. Using KDIGO criteria, we analyzed renal injury incidence & risk factors in adults undergoing dCBT. Methods Adult dCBT pts transplanted 2006-2016 for hematologic malignancies using Cy/ Flu/ Thio/ TBI 400 cGy & CSA (therapeutic range 250-450)/ MMF were analyzed. Using day 0 - 100 creatinines, maximum grade (gr.) AKI [gr. 1 (1.5 - < 2-fold baseline), gr. 2 (2 - < 3-fold baseline) or gr. 3 (> 3-fold baseline)] was calculated. If pts had multiple episodes, the highest grade was analyzed. The 2-yr CKD incidence (> 90 days of GFR < 60 & persisting until 2 years post-transplant) was calculated according to max. grade day 0-100 AKI. Results 153 pts [median 51 years (range 23-65), 114/153 (75%) acute leukemia, 27/153 (18%) African, 88/153 (58%) CMV seropositive] were transplanted. No patient had chronic kidney disease pre-dCBT; 32/153 (21%) had hypertension & 12/153 (8%) were diabetic. Median aaHCT-CI was 3 (range 0-9) with 92/153 (60%) pts having a score > 3. 34 (22%) pts had High-Very High rDRI diagnoses. Median pre-dCBT albumin was 4 (range 2.6 - 5.2). 96% of pts engrafted, 76% had grade II-IV acute GVHD by day 100 & 90% were alive & disease-free at day 100 (11 TRM, 3 relapse). 127 pts had AKI (45 gr. 1, 60 gr. 2, & 22 gr. 3) for a day 100 grade 1-3 AKI cumulative incidence of 83% (95%CI: 77-89) (median onset 40 days, range 0-96) & 54% (95%CI: 46-62) for gr. 2-3 AKI (median onset 43 days, range 0-96) (Figure 1). The mean of the 3-day mean CSA level preceding AKI onset was high at 360 ng/ml. African ancestry, CMV seropositivity & low day -7 albumin level & post-dCBT variables of ICU admission, nephrotoxic drug exposure & bacteremia were associated with gr. 1-3 AKI (Table 1A). In multivariate analysis, low day -7 albumin, ICU admission & nephrotoxic drugs were significant (Table 1B). With a median 40 months (range 12-125) survivor follow-up, 34/109 (31%) evaluable pts had CKD at 2-yrs with 1 pt requiring long-term dialysis. Grade 2-3 AKI prior to day 100 was associated with a higher likelihood of having CKD at 2-yrs: 38% vs 25% (Figure 2). Conclusion dCBT recipients are at significant risk for AKI which increases the likelihood of long-term CKD. Early recognition of impending AKI & prompt intervention is critical to mitigate severe kidney injury & long-term impairment. Prevention strategies include adequate hydration, tight CSA level control & substitution of non-nephrotoxic medications (e.g. Letermovir CMV prophylaxis instead of pre-emptive foscarnet, non-aminoglycosides antibiotics, azoles rather than amphotericin, PO cidofovir instead of IV). Investigation of novel GVHD prophylaxis that could permit lower CSA dosing & early AKI detection using biomarkers should also be investigated. [ABSTRACT FROM AUTHOR]

The reported incidence of acute kidney injury (AKI) after allogeneic hematopoietic cell transplantation (allo-HCT) varies from 10 to 73%. The association between GVHD, calcineurin inhibitors (CNIs) and risk for kidney injury remains controversial. We sought to describe the incidence of AKI and identify modifiable risk factors in large cohort of patients undergoing allo-HCT in our institution. All consecutive patients undergoing allo-HCT from 2014 to 2017 in our institution were included. Pre-HCT variables including patient and graft characteristics, as well as post-HCT variables, including nephrotoxic medication exposure, ICU admission, and CNI levels were analyzed in association with AKI. AKI was defined using KDIGO criteria, grades 1, 2 and 3, through post-transplant day 100. Severe AKI was defined as grades 2 or 3. Differences across groups were assessed using either Wilcoxon rank-sum tests or Fisher's exact tests. AKI risk factors were estimated using cause-specific Cox proportional hazards regression. A total of 616 patients underwent allo-HCT during the study period. Median age was 58 (19-79) years, 59% male, 83% Caucasian. Indication for HCT was leukemia in 49%, myelodysplastic syndrome in 16%, and lymphoma in 17%. Median baseline creatinine was 0.8 (0.3-2.7) mg/dL. Median age-adjusted HCT-comorbidity index was 3 (range 0-9). Median baseline albumin was 3.5 (IQR 3.3-3.8) mg/dL and BMI 27.2 (IQR 23.8-30.8). Incidence of acute GVHD was 47%, and 60 patients had severe (grades 3-4) GVHD. Bacteremia occurred in 19% of patients. Amphotericin preceded max-grade AKI in 3.1%, cidofovir in 0.8%, and Foscarnet in 4.4% of patients. Median tacrolimus level preceding AKI was 7.88 (range 4.2-23.2) mg/dL. By day 100 post-HCT, 403 (65.4%) had any AKI, 220 (35.7%) patients had grade 1 AKI, 119 (19.3%) grade 2 AKI, and 64 (10.4%) grade 3 AKI; 19 (3.1%) required hemodialysis. Median time to AKI was 17 (IQR 8-35) days, and median time to max-grade AKI was 31 (IQR 13-53) days. Ex vivo CD34-selected HCT patients had a lower risk for AKI, hazard ratio 0.46 (0.35-0.62), p<0.001 (Table 1). AKI in patients undergoing allo-HCT remains a major concern, affecting 65.4% of patients, with grade 2 and 3 AKI occurring in 19.3% and 10.4%, respectively. Patients receiving CNIs including tacrolimus have a significantly higher risk for AKI, whereas patients undergoing CD34-selected allo-HCT have a lower risk of AKI. The effect of AKI after HCT on long-term kidney function requires further prospective study. [ABSTRACT FROM AUTHOR]

Chimeric Antigen Receptor T cell (CAR T) therapy has shown significant therapeutic potential but carries risk of treatment related toxicity. There is limited data describing risk of acute kidney injury (AKI) related to CAR T therapy. To identify the incidence of AKI and recovery of renal function in patients undergoing CAR T therapy. We analyzed adult patients given FDA approved CAR T cell therapy February 2018 to 2019 for Non-Hodgkin Lymphoma (NHL) at our center. Patients received axicabtagene ciloleucel (Yescarta®) (34/46, 74%) or tisagenlecleucel (Kymriah®) (12/46, 26%). All creatinine's prior to and following CAR T infusion until last follow up were collected. Maximum (max) grade AKI [grade 1 (creatinine 1.5 - < 2-fold baseline), grade 2 (2 - < 3-fold baseline) or grade 3 (> 3-fold baseline)] was calculated based on KDIGO criteria. Renal recovery was assessed using creatinine 30 days post max grade AKI. Forty six patients, median age 63 years (range 19-85) of whom 33 (72%) were men underwent CAR T therapy for relapsed/ refractory NHL. Patients had a median of 4 lines of chemotherapy (range 2-10) prior to CAR T, including autoSCT (n=9, 20%), alloHCT (n=3, 7%), and both auto and alloHCT (n=1). Lymphodepletion regimens were either cyclophosphamide/fludarabine (n=43, 93%) or bendamustine (n=3, 7%). Baseline co-morbidities were hypertension 13/46 (28%) and diabetes mellitus 1/46 (2%). Median baseline creatinine was 0.8 (range 0.5 – 2) mg/dL, and median glomerular filtration rate (GFR) was 88 [(range 36-160) mL/min/1.73m2, GFR ≤ 60 in 4 patients]. No patient was on dialysis prior to infusion. Five of 14 patients with baseline urinalysis had ≥30 mg/dL protein. Median overall follow up was 8.3 (95%CI: 6.8 - 11.4) months. Fourteen patients (30%) had any grade AKI during available follow-up. Of these, 10/14 (71%) had grade 1, 2/14 (14%) had grade 2, and 1/14 (7%) had grade 3. Median day onset for max grade AKI was 48 (range 6 to 100) days. Nephrotoxic medication exposures prior to AKI included acyclovir in 10 (71%), vancomycin in 11 (79%) and ibuprofen in 1 (7%). Of the 14 patients who developed AKI, 11 (79%) also had cytokine release syndrome (CRS). For these patients, median peak C reactive protein level was 12 (range 0.4 to 34) mg/L and median interleukin-6 level was 179 (range 14 to 23,752) pg/ml. After removing competing events (relapse, progression or death), cumulative incidence of grade 1 AKI was 15.2% (95% CI 4.7-25.7) and grade 2 AKI was 2.2% (95% CI 0-6.5) by day +100. Incidence of AKI shown in Figure 1. Creatinine returned to baseline in 11/12 (92%) patients alive at 30 days post AKI. Our study shows that the incidence of AKI is low in patients receiving CAR T therapy. Majority of AKI was grade 1 and returned to baseline within 30 days. A larger study sample will likely help elucidate risk factors associated with development of AKI in these patients. [ABSTRACT FROM AUTHOR]

Background: Postoperative hypophosphatemia is common and is associated with a lower risk of liver failure after hepatectomy, but higher morbidity after pancreatectomy. Whether different physiologic mechanisms underlie the hypophosphatemia associated with these very different clinical outcomes is unclear. This study aims to evaluate the underlying mechanism in postoperative hypophosphatemia.Study Design: We prospectively enrolled 120 patients who underwent major hepatectomy (n = 30), minor hepatectomy (n = 30), pancreatectomy (n = 30), and laparotomy without resection (control group, n = 30). Preoperative and postoperative serum and urinary phosphorus, calcium, and creatinine, as well as phosphaturic factors, including serum nicotinamide phosphoribosyltransferase (NAMPT), fibroblast growth factor-23, and parathyroid hormone were measured. In addition, we evaluated urinary levels of nicotinamide catabolites, N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide.Results: We found that significant hypophosphatemia occurred from postoperative day (POD) 1 to POD 2 in all 4 groups and was preceded by hyperphosphaturia from preoperative day to POD 1. Phosphate level alterations were associated with a significant increase in NAMPT levels from preoperative day to POD 2 in all 3 resected groups, but not in the control group. The fibroblast growth factor-23 levels were significantly decreased postoperatively in all 4 groups, and parathyroid hormone levels did not change in any of the 4 groups. Urine levels of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide decreased significantly in all 4 groups postoperatively.Conclusions: This study demonstrates that the mechanism of hypophosphatemia is the same for both liver and pancreas resections. Postoperative hypophosphatemia is associated with increased NAMPT. The mechanism that upregulates NAMPT and its role on disparate clinical outcomes in postoperative patients warrant additional investigation. [ABSTRACT FROM AUTHOR]