Thorium Complexation with Aliphatic and Aromatic Hydroxycarboxylates: A Combined Experimental and Theoretical Study.

Hydroxycarboxylic acids, viz., α-hydroxyisobutyric acid (HIBA) and mandelic acid (MA), have been widely employed as eluents for inner transition metal separation studies. Both extractants have identical functional groups (OH and COOH) with different side-chains. Despite their similarities in binding motifs, they show different retention behaviors for thorium and uranium in liquid chromatography. To understand the mechanism behind the trend, a detailed study on the aqueous phase interaction of thorium with both extractants is carried out by speciation, spectroscopy, and density functional theory-based calculations. Potentiometric titration experiments are carried out to reveal the stability and species formed. Electrospray ionization mass spectrometry is performed to identify the formation of different species by Th with both HIBA and MA. It is seen that for Th-HIBA and Th-MA, the dominating species are ML3 and ML4, respectively. A similar pattern observed in potentiometric speciation analysis supports the tendency of Th to form higher stoichiometric species with MA than with HIBA. The difference in the dominating species thus helps in explaining the reversal in the retention behavior of uranium and thorium in the reverse-phase liquid chromatographic separation. The results obtained are corroborated with extended X-ray absorption fine structure spectroscopic measurements and density functional theory (DFT) calculations.

Sustainable Synthesis of Novel Green-Based Nanoparticles for Therapeutic Interventions and Environmental Remediation.

The advancement in nanotechnology has completely revolutionized various fields, including pharmaceutical sciences, and streamlined the potential therapeutic of many diseases that endanger human life. The synthesis of green nanoparticles by biological processes is an aspect of the newly emerging scientific field known as "green nanotechnology". Due to their safe, eco-friendly, nontoxic nature, green synthesis tools are better suited to produce nanoparticles between 1 and 100 nm. Nanoformulation of different types of nanoparticles has been made possible by using green production techniques and commercially feasible novel precursors, such as seed extracts, algae, and fungi, that act as potent reducing, capping, and stabilizing agents. In addition to this, the biofunctionalization of nanoparticles has also broadened its horizon in the field of environmental remediation and various novel therapeutic innovations including wound healing, antimicrobial, anticancer, and nano biosensing. However, the major challenge pertaining to green nanotechnology is the agglomeration of nanoparticles that may alter the surface topology, which can affect biological physiology, thereby contributing to system toxicity. Therefore, a thorough grasp of nanoparticle toxicity and biocompatibility is required to harness the applications of nanotechnology in therapeutics.

Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE): Design and Methods.

Background and Aim: Primary glomerular disease accounts for one-sixth of all chronic kidney diseases (CKDs) in India. We remain limited in our ability to effectively treat these conditions because of lack of understanding of the disease mechanisms and lack of predictors to identify the clinical course and therapeutic responsiveness. We propose to develop a network of investigators in glomerular diseases, collect information in a systematic fashion to understand the clinical outcomes, answer translational research questions better, and identify and recruit patients for clinical trials. Materials and Methods: This is a prospective, observational study. The Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE) cohort will enroll patients (>18 years) with biopsy-proven minimal change disease (MCD), focal segmental glomerulonephritis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), or membranoproliferative glomerulonephritis (MPGN) (immune complex- and complement-mediated), with first biopsy taken within 2 years of enrollment. Patients with estimated glomerular filtration (eGFR) rate <15 ml/min/1.73 m2 for >3 months at the time of screening, kidney transplant or bone marrow transplant recipients, patients with active malignancy, and patients with active hepatitis B/C replication or human immunodeficiency virus (HIV)-I/II will be excluded. Clinical details including history, medication history and details, and family history will be obtained. Consenting patient's blood and urine samples will be collected and stored, aligned to their clinical follow-up. Expected Outcomes: The network will allow accurate ascertainment of disease burden of glomerular diseases across study sites, establishment of the treatment pattern of common glomerular diseases, investigation of medium- and long-term outcomes (remission, relapse, rate of eGFR decline), and building a suitable infrastructure to carry out clinical trials in primary glomerular disease.

Serum catalytic iron and progression of chronic kidney disease: findings from the ICKD study.

BACKGROUND: The non-transferrin bound catalytic iron moiety catalyses production of toxic reactive oxygen species and is associated with adverse outcomes. We hypothesized that serum catalytic iron (SCI) is associated with progression of chronic kidney disease (CKD). METHODS: Baseline samples of the Indian Chronic Kidney Disease participants with at least one follow up visit were tested for total iron, iron binding capacity, transferrin saturation, SCI, ferritin and hepcidin. SCI was measured using the bleomycin-detectable iron assay that detects biologically active iron. Association with the incidence of major kidney endpoints, (MAKE, a composite of kidney death, kidney failure or > 40% loss of eGFR) was examined using Cox proportional hazards model adjusted for sex and age. RESULTS: 2002 subjects (49.9 ± 11.6 years, 68.1% males, baseline eGFR 41.01 ml/min/1.73m2) were enrolled. After a median follow up of 12.6 (12.2, 16.7) months, the composite MAKE occurred in 280 (14%). After adjusting for age and sex, increase from 25th to 75th percentile in SCI, transferrin saturation, ferritin and hepcidin were associated with 78% (43-122%), 34% (10-62%), 57% (24-100%) and 74% (35-124%) increase in hazard of MAKE, respectively. SCI was associated with MAKE and kidney failure after adjustment for occupational exposure, hypertension, diabetes, tobacco, alcohol use, history of AKI, baseline eGFR, uACR, and allowing baseline hazard to vary by centre. CONCLUSIONS: SCI is strongly and independently associated with composite MAKE in patients with mild to moderate CKD. Confirmation in other studies will allow consideration of SCI as a risk marker and treatment target.

Postpartum Renal Cortical Necrosis Is Associated With Atypical Hemolytic Uremic Syndrome in Developing Countries.

INTRODUCTION: Pregnancy-related acute kidney injury is the most common cause of renal cortical necrosis (RCN). Atypical hemolytic uremic syndrome (aHUS) as a cause of RCN in pregnant/postpartum is underevaluated. In the current article, we describe a series of cases of pregnancy-related RCN. METHODS: All cases with acute kidney injury (AKI) in the setting of pregnancy and postpartum state were included. Diagnosis of RCN was made by contrast-enhanced computerized tomography (nonenhancing renal cortex, enhancing medulla, and no excretion of contrast medium) or on a renal biopsy. aHUS was diagnosed in the presence of microangiopathic hemolytic anemia (thrombocytopenia, elevated lactate dehydrogenase with schistocytes on peripheral smear examination, or low haptoglobin). RESULTS: A total of 21 (17.5%) patients presented with RCN during pregnancy, all in the postpartum state. Twenty patients (95.2%) showed microangiopathic hemolytic anemia consistent with HUS and 1 (4.8%) patient had biopsy-proven thrombotic microangiopathy. Low complement 3 or activation of an alternate complement pathway was seen in 9 of 15 patients in which it was done. At the end of 6 months, only 2 (9.5%) patients had partial recovery of renal functions, 5 (23.8%) patients died, and 14 remained (66.7%) on hemodialysis. CONCLUSION: The clinical and laboratory features are highly suggestive of aHUS in more than three-fourths of cases with postpartum RCN. Investigations are needed to look for genetic abnormalities in the complement pathway.

Membranous nephropathy with light chain restricted deposits.

The literature on membranous nephropathy (MN) with monoclonal deposits on immunofluorescence (IF) and their outcome is very scarce. We report our experience of managing five patients with this clinical entity. The mean age of the patients was 33.2 ± 6.55 years. The mean proteinuria, serum albumin and serum creatinine was 5.73 ± 2.17 g/day, 2.86 ± 0.51 g/dL and 1.34 ± 1.19 mg/dL, respectively. None of the patients had a lymphoproliferative disorder. Only one patient had an elevated free light chain ratio. Four (80%) patients were M-type phospholipase A2 receptor (PLA2R) negative (tissue and serum), and one (20%) was PLA2R related. Three (60%) cases had monoclonal IgG3/k, one IgG3/λ, whereas one patient with PLA2R positivity had an IgG3/IgG4k subtype. Two (67%) patients treated with cyclical cyclophosphamide and steroids (cCYC/GC) achieved complete remission and one patient (33%) with elevated baseline creatinine had a reduction in serum creatinine with persistent proteinuria at the end of the 12th month of follow-up. One patient with PLA2R positive MN was treated with Rituximab and is in complete remission. The patient with an elevated free light chain at baseline was treated with Bortezomib/Thalidomide/Dexamethasone, had complete remission at 12 months, however, had a progressive rise in creatinine over the next 40 months of follow-up. The current series, though limited by numbers, documents the efficacy of conventional therapies in non-malignant associated MN with monoclonal deposits on IF.

Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study.

AIM: This pilot study assesses the safety and feasibility of autologous mesenchymal stromal cell (MSC) transplantation in four patients that underwent living donor renal transplantation, and the effect on the immunophenotype and functionality of peripheral T lymphocytes following transplantation. METHODS: All patients received low dose ATG induction followed by calcineurin inhibitor-based triple drug maintenance immunosuppression. Autologous MSCs were administered intravenously pre transplant and day 30 post-transplant. Patients were followed up for 6 months. The frequency of regulatory T cells and T cell proliferation was assessed at different time points. RESULTS: None of the four patients developed any immediate or delayed adverse effects following MSC infusion. All had excellent graft function, and none developed graft dysfunction. Protocol biopsies at 1 and 3 months did not reveal any abnormality. Compared to baseline, there was an increase in the CD4 + CD25+FOXP3+ regulatory T cells and reduction in CD4 T cell proliferation. CONCLUSION: We conclude that autologous MSCs can be used safely in patients undergoing living donor renal transplantation, lead to expansion of regulatory T cells and decrease in T cell proliferation. Larger randomized trials studies are needed to confirm these findings and evaluate whether this will have any impact on immunosuppressive therapy.

Infusion of autologous bone marrow mononuclear cells leads to transient reduction in proteinuria in treatment refractory patients with Idiopathic membranous nephropathy.

BACKGROUND: The current treatment options for idiopathic membranous nephropathy (IMN) carry significant toxicity. In this prospective, observational pilot study, we used single time infusion of bone marrow derived autologous mononuclear cells (MNCs) in adult patients with treatment refractory IMN. METHODS: Twelve patients of biopsy proven IMN who had failed a cyclical 6-month regimen of steroid and cyclophosphamide were enrolled in the study. Bone-marrow was harvested from the iliac crest and underwent processing to isolate MNCs. Cells were counted and subjected to viability testing before being infused through a peripheral vein on the same day. After the infusion, subjects were followed up monthly for the next six months. Supportive treatment including angiotensin antagonists and statins was continued throughout the study period. RESULT: The proteinuria, serum albumin and creatinine values at entry were 2.97 ± 0.6 gm/1.73 m2/d, 2.27 ± 1.1 gm/l and 0.9 ± 0.8 mg/dl respectively. There was a reduction in proteinuria (p < 0.0001), and increase in serum albumin (p = 0.001) at 1 month, with 64% of the subjects showing >50% reduction in proteinuria. However, the response was ill sustained. At 6 months, only 2 patients had >50% reduction. Serum creatinine remained stable throughout the study period. No infusion related side effects were noted. CONCLUSION: Autologous mononuclear cell infusion leads to transitory reduction in proteinuria and improvement in serum albumin in treatment refractory IMN. This effect, however, is transient. Whether this can be overcome by repeated infusion of cultured mesenchymal cells needs to be investigated.

Heat shock proteins 60 and 70 specific proinflammatory and cytotoxic response of CD4+CD28null cells in chronic kidney disease.

BACKGROUND: CD4(+)CD28(null) T cells are expanded in peripheral blood of patients with chronic kidney disease and associated with subclinical atherosclerosis. However, triggers for the oligoclonal expansion and activation of these cells are not clear. METHODS: We investigated twenty-five stage V-IV chronic kidney disease (CKD) patients and eight healthy subjects (HC). Peripheral mononuclear cells were isolated and incubated with heat shock protein- (HSP) 60 and 70. CD4(+)CD28(null) and CD4(+)CD28(+) cells were sorted by flowcytometry and antigen specific response was assessed by the mRNA and protein expression of interferon (IFN)-γ, perforin, and granzyme B using qRT-PCR and Elispot. RESULTS: The basal mRNA expression of IFN-γ, perforin, and granzyme B in CD4(+)CD28(null) cells was higher in subjects with CKD compared to that in HC (P < 0.0001). Subjects with CKD also showed expression of IFN-γ, perforin, and granzyme B in the CD4(+)CD28(+) subset, but this was much weaker than that seen in the CD4(+)CD28(null) population (P < 0.0001). We did not note the expression of these molecules at mRNA or protein level in either subset of CD4 cells in HC. After incubation with HSP60 and HSP70, CD4(+)CD28(null) cells showed increased expression at mRNA (P < 0.001) and protein level (P < 0.001). CD4(+)CD28(+) cells also showed a weak increase in expression. No antigen-specific response was noted in HC. CONCLUSION: These data show that CD4(+)CD28(null) cells in subjects with CKD react with HSP60 and HSP70 by upregulating the expression of IFN-γ, perforin and granzyme B. Increased circulating level of HSP60 and HSP70 might play a role in initiation and/or progression of atherosclerosis in CKD subjects through perturbation of CD4(+)CD28(null) cells.

Deferred pre-emptive switch from calcineurin inhibitor to sirolimus leads to improvement in GFR and expansion of T regulatory cell population: a randomized, controlled trial.

BACKGROUND: Measures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (T(reg)) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and T(reg) frequency. METHODS: In this prospective open label randomized trial, primary living donor kidney transplant recipients on CNI-based immunosuppression were randomized to continue CNI or switched to sirolimus 2 months after surgery; 29 were randomized to receive CNI and 31 to SIR. All patients received mycophenolate mofetil and steroids. The main outcome parameter was estimated GFR (eGFR) at 180 days. T(reg) population was estimated by flowcytometry. RESULTS: Baseline characteristics in the two groups were similar. Forty-eight patients completed the trial. At six months, patients in the SIR group had significantly higher eGFR as compared to those in the CNI group (88.94 ± 11.78 vs 80.59 ± 16.51 mL/min, p = 0.038). Patients on SIR had a 12 mL/min gain of eGFR of at the end of six months. Patients in the SIR group showed significant increase in T(reg) population at 30 days, which persisted till day 180. There was no difference in the adverse events in terms of number of acute rejection episodes, death, infections, proteinuria, lipid profile, blood pressure control and hematological parameters between the two groups. Four patients taking SIR developed enthesitis. No patient left the study or switched treatment because of adverse event. CONCLUSIONS: A deferred pre-emptive switch over from CNI to SIR safely improves renal function and T(reg) population at 6 months in living donor kidney transplant recipients. Registered in Clinical Trials Registry of India (CTRI/2011/091/000034).

Management of isolated recurrence of extramedullary myeloid tumor at a single site.

Extramedullary myeloid tumors (EMMT) can precede, occur with or follow AML. Rarely, they can present as isolated relapses. We present a 9-year-old child with t (8, 21) positive AML who was treated with induction regimen and achieved remission. While on high-dose cytarabine consolidation, he had isolated relapse in a single cervical lymph node with uninvolved marrow. He was treated with salvage chemotherapy alone. There are no clear guidelines for treatment of isolated extramedullary relapse. Chemotherapy, radiotherapy followed by stem cell transplant is the usual option. Our patient is unique for the unusual site of relapse and prolonged remission with cladribine-based chemotherapy, mitoxantrone-based consolidation, and oral maintenance therapy.