Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

The Pathologic Peritoneal Cancer Index (PCI) Strongly Differs From the Surgical PCI in Peritoneal Metastases Arising From Various Primary Tumors.

BACKGROUND: The surgical peritoneal cancer index (sPCI) is calculated based on a subjective evaluation of the extent of peritoneal disease during surgery. The pathologic PCI (pPCI) may be a more accurate and objective method for determining the PCI. This study aimed to compare the sPCI and pPCI and to study the potential pitfalls and clinical implications of using the pPCI. METHODS: This prospective study (July to December 2018) included all patients undergoing cytoreductive surgery (CRS). The pPCI was calculated for each patient and compared with the sPCI. The impact of potential confounding factors on the difference between pPCI and sPCI was evaluated. RESULTS: Among 191 patients undergoing CRS at four centers, the pPCI and sPCI were concordant for 37 patients (19.3%). The pPCI was lower than the sPCI for 125 patients (65.4%) and higher for 29 patients (15.1%). The concordance between the two groups was maximum for gastric cancer (38.8%) and colorectal cancer (27.6%) and least for mesothelioma (6.7%) and rare primary tumors (5.6%) (p = 0.04). The difference was 0 to 3 points for 119 patients (62.3%), 4 to 5 points for 27 patients (14.1%), and more than 5 points for 45 patients (23.5%). The rate of concordance was not influenced by the use of neoadjuvant chemotherapy (NACT) (p = 0.4), but the difference was greater when NACT was used (p = 0.03). CONCLUSIONS: The pPCI strongly differs from the sPCI for patients undergoing CRS for peritoneal disease and may provide a more accurate evaluation of the peritoneal disease extent. Further studies are needed to determine its prognostic value compared with sPCI, and consensus guidelines are needed for calculating it.

High-resolution HLA genotyping improves PIRCHE-II assessment of molecular mismatching in kidney transplantation.

HLA matching in solid organ transplant is performed with the aim of assessing immunologic compatibility in order to avoid hyperacute rejection and assess the risk of future rejection events. Molecular mismatch algorithms are intended to improve granularity in histocompatibility assessment and risk stratification. PIRCHE-II uses HLA genotyping to predict indirectly presented mismatched donor HLA peptides, though most clinical validation studies rely on imputing high resolution (HR) genotypes from low resolution (LR) typing data. We hypothesized that use of bona fide HR typing could overcome limitations in imputation, improving accuracy and predictive ability for donor-specific antibody development and acute rejection. We performed a retrospective analysis of adult and pediatric kidney transplant donor/recipient pairs (N = 419) with HR typing and compared the use of imputed LR genotyping verses HR genotyping for PIRCHE-II analysis and outcomes. Imputation success was highly dependent on the reference population used, as using historic Caucasian reference populations resulted in 10 % of pairs with unsuccessful imputation while multiethnic reference populations improved successful imputation with only 1 % unable to be imputed. Comparing PIRCHE-II analysis with HR and LR genotyping produced notably different results, with 20 % of patients discrepantly classified to immunologic risk groups. These data emphasize the importance of using multiethnic reference panels when performing imputation and indicate HR HLA genotyping has clinically meaningful benefit for PIRCHE-II analysis compared to imputed LR typing.

Subtle Changes in Tacrolimus Levels Have an Impact on Early Donor-Specific Antibodies in Kidney Transplantation.

Introduction: The impact of each immunosuppressive agent on de novo donor-specific antibodies in kidney transplant recipients varies among extant literature. Project aims: Patterns in immunosuppression and the effects on incidence of de novo donor-specific antibodies were evaluated. Design: Adult kidney transplant recipients from 2017 to 2019 without preformed antibodies were sampled. Allograft function, de novo donor-specific antibodies, tacrolimus concentrations, duration of goal-dose antiproliferatives, and steroid doses were recorded. Outcomes included incidence of de novo donor-specific antibodies, and their relation to tacrolimus concentrations, time at goal-dose antiproliferatives, and steroid doses. Results: Recipients (N = 153) were followed for 1 year; all were crossmatch negative and received rabbit antithymocyte globulin induction. Sixteen (10%) recipients developed de novo donor-specific antibodies in a median of 31 days [interquartile range, IQR: 12-67 days], most were Class II antibodies (87.5%). Incidence of de novo donor-specific antibodies did not differ based on induction dosing. Tacrolimus levels in the first month were lower for patients with de novo donor-specific antibodies (8.8 ng/mL vs 10.4 ng/mL, P < .01). There was no difference in time on goal antiproliferative doses, but higher steroid doses (0.4 vs 0.3 mg/kg/d; P = .02) were noted in patients with antibodies. Steroid dosing was likely impacted by baseline risk factors. Conclusion: A significant association was found between lower tacrolimus concentrations early post-transplant and incidence of de novo donor-specific antibodies. This highlighted the importance of clinician attention to subtle changes in tacrolimus and the impact it can have on antibody risk in the early post-transplant period.

Growth factor-dependent branching of the ureteric bud is modulated by selective 6-O sulfation of heparan sulfate.

Heparan sulfate proteoglycans (HSPGs) are found in the basement membrane and at the cell-surface where they modulate the binding and activity of a variety of growth factors and other molecules. Most of the functions of HSPGs are mediated by the variable sulfated glycosaminoglycan (GAG) chains attached to a core protein. Sulfation of the GAG chain is key as evidenced by the renal agenesis phenotype in mice deficient in the HS biosynthetic enzyme, heparan sulfate 2-O sulfotransferase (Hs2st; an enzyme which catalyzes the 2-O-sulfation of uronic acids in heparan sulfate). We have recently demonstrated that this phenotype is likely due to a defect in induction of the metanephric mesenchyme (MM), which along with the ureteric bud (UB), is responsible for the mutually inductive interactions in the developing kidney (Shah et al., 2010). Here, we sought to elucidate the role of variable HS sulfation in UB branching morphogenesis, particularly the role of 6-O sulfation. Endogenous HS was localized along the length of the UB suggesting a role in limiting growth factors and other molecules to specific regions of the UB. Treatment of cultures of whole embryonic kidney with variably desulfated heparin compounds indicated a requirement of 6O-sulfation in the growth and branching of the UB. In support of this notion, branching morphogenesis of the isolated UB was found to be more sensitive to the HS 6-O sulfation modification when compared to the 2-O sulfation modification. In addition, a variety of known UB branching morphogens (i.e., pleiotrophin, heregulin, FGF1 and GDNF) were found to have a higher affinity for 6-O sulfated heparin providing additional support for the notion that this HS modification is important for robust UB branching morphogenesis. Taken together with earlier studies, these findings suggest a general mechanism for spatio-temporal HS regulation of growth factor activity along the branching UB and in the developing MM and support the view that specific growth factor-HSPG interactions establish morphogen gradients and function as developmental switches during the stages of epithelial organogenesis (Shah et al., 2004).

Neuropeptide Y functions as a facilitator of GDNF-induced budding of the Wolffian duct.

Ureteric bud (UB) emergence from the Wolffian duct (WD), the initiating step in metanephric kidney morphogenesis, is dependent on GDNF; however, GDNF by itself is generally insufficient to induce robust budding of the isolated WD in culture. Thus, additional factors, presumably peptides or polypeptide growth factors, might be involved. Microarray data from in vivo budding and non-budding conditions were analyzed using non-negative matrix factorization followed by gene ontology filtering and network analysis to identify sets of genes that are highly regulated during budding. These included the GDNF co-receptors GFRalpha1 and RET, as well as neuropeptide Y (NPY). By using ANOVA with pattern matching, NPY was also found to correlate most significantly to the budded condition with a high degree of connectedness to genes with developmental roles. Exogenous NPY [as well as its homolog, peptide YY (PYY)] augmented GDNF-dependent budding in the isolated WD culture; conversely, inhibition of NPY signaling or perturbation of NPY expression inhibited budding, confirming that NPY facilitates this process. NPY was also found to reverse the decreased budding, the downregulation of RET expression, the mislocalization of GFRalpha1, and the inhibition of AKT phosphorylation that resulted from the addition of BMP4 to the isolated WD cultures, suggesting that NPY acts through the budding pathway and is reciprocally regulated by GDNF and BMP4. Thus, the outgrowth of the UB from the WD might result from a combination of the upregulation of the GDNF receptors together with genes that support GDNF signaling in a feed-forward loop and/or counteraction of the inhibitory pathway regulated by BMP4.

A Pilot Trial for Prevention of Hepatitis C Virus Transmission From Donor to Organ Transplant Recipient With Short-Course Glecaprevir/Pibrentasvir.

A 7-day course of glecaprevir/pibrentasvir started in the preoperative period prevented transmission of hepatitis C virus (HCV) from viremic donors to 10 HCV-negative recipients (2 heart, 1 lung, 6 kidney, 1 heart/kidney) with 100% sustained virological response at 12 weeks.

Hs2st mediated kidney mesenchyme induction regulates early ureteric bud branching.

Heparan sulfate proteoglycans (HSPGs) are central modulators of developmental processes likely through their interaction with growth factors, such as GDNF, members of the FGF and TGFbeta superfamilies, EGF receptor ligands and HGF. Absence of the biosynthetic enzyme, heparan sulfate 2-O-sulfotransferase (Hs2st) leads to kidney agenesis. Using a novel combination of in vivo and in vitro approaches, we have reanalyzed the defect in morphogenesis of the Hs2st(-)(/)(-) kidney. Utilizing assays that separately model distinct stages of kidney branching morphogenesis, we found that the Hs2st(-/-) UB is able to undergo branching and induce mesenchymal-to-epithelial transformation when recombined with control MM, and the isolated Hs2st null UB is able to undergo branching morphogenesis in the presence of exogenous soluble pro-branching growth factors when embedded in an extracellular matrix, indicating that the UB is intrinsically competent. This is in contrast to the prevailing view that the defect underlying the renal agenesis phenotype is due to a primary role for 2-O sulfated HS in UB branching. Unexpectedly, the mutant MM was also fully capable of being induced in recombination experiments with wild-type tissue. Thus, both the mutant UB and mutant MM tissue appear competent in and of themselves, but the combination of mutant tissues fails in vivo and, as we show, in organ culture. We hypothesized a 2OS-dependent defect in the mutual inductive process, which could be on either the UB or MM side, since both progenitor tissues express Hs2st. In light of these observations, we specifically examined the role of the HS 2-O sulfation modification on the morphogenetic capacity of the UB and MM individually. We demonstrate that early UB branching morphogenesis is not primarily modulated by factors that depend on the HS 2-O sulfate modification; however, factors that contribute to MM induction are markedly sensitive to the 2-O sulfation modification. These data suggest that key defect in Hs2st null kidneys is the inability of MM to undergo induction either through a failure of mutual induction or a primary failure of MM morphogenesis. This results in normal UB formation but affects either T-shaped UB formation or iterative branching of the T-shaped UB (possibly two separate stages in collecting system development dependent upon HS). We discuss the possibility that a disruption in the interaction between HS and Wnts (e.g. Wnt 9b) may be an important aspect of the observed phenotype. This appears to be the first example of a defect in the MM preventing advancement of early UB branching past the first bifurcation stage, one of the limiting steps in early kidney development.

Protein kinase A regulates GDNF/RET-dependent but not GDNF/Ret-independent ureteric bud outgrowth from the Wolffian duct.

Embryonic kidney development begins with the outgrowth of the ureteric bud (UB) from the Wolffian duct (WD) into the adjacent metanephric mesenchyme (MM). Both a GDNF-dependent and GDNF-independent (Maeshima et al., 2007) pathway have been identified. In vivo and in vitro, the GDNF-dependent pathway is inhibited by BMPs, one of the factors invoked to explain the limitation of UB formation in the unbudded regions of the WD surrounding the UB. However, the exact mechanism remains unknown. Here a previously described in vitro system that models UB budding from the WD was utilized to study this process. Because Protein kinase A (PKA) activation has been shown to prevent migration, morphogenesis and tubulogenesis of epithelial cells (Santos et al., 1993), its activity in budded and non-budded portions of the GDNF-induced WD was analyzed. The level of PKA activity was 15-fold higher in the unbudded portions of the WD compared to budded portions, suggesting that PKA activity plays a key role in controlling the site of UB emergence. Using well-characterized PKA agonists and antagonists, we demonstrated that at various levels of the PKA-signaling hierarchy, PKA regulates UB outgrowth from the WD by suppressing budding events. This process appeared to be PKA-2 isoform specific, and mediated by changes in the duct rather than the surrounding mesenchyme. In addition, it was not due to changes in either the sorting of junctional proteins, cell death, or cell proliferation. Furthermore, the suppressive effect of cAMP on budding did not appear to be mediated by spread to adjacent cells via gap junctions. Conversely, antagonism of PKA activity stimulated UB outgrowth from the WD and resulted in both an increase in the number of buds per unit length of WD as well as a larger surface area per bud. Using microarrays, analysis of gene expression in GDNF-treated WDs in which the PKA pathway had been activated revealed a nearly 14-fold decrease in Ret, a receptor for GDNF. A smaller decrease in GFRα1. a co-receptor for GDNF, was also observed. Using Ret-null WDs, we were able to demonstrate that PKA regulated GDNF-dependent budding but not GDNF-independent pathway for WD budding. We also found that BMP2 was higher in unbudded regions of the GDNF-stimulated WD. Treatment of isolated WDs with BMP2 suppressed budding and resulted in a 3-fold increase in PKA activity. The data suggests that the suppression of budding by BMPs and possibly other factors in non-budded zones of the WD may be regulated in part by increased PKA activity, probably partially through downregulation of Ret/GFRα1 coreceptor expression.

An Adapted Process and Organ Procurement Perspective on Heart Retransplantation for a Healthy Heart's Third Life.

As organ procurement organizations nationwide see an increased opportunity to retransplant already transplanted hearts, we would like to share the overview and process of our 2 successful cases. Heart retransplantation increased our cardiac placement rates by 2.64% and 2% in 2015 and 2019, respectively. Spread across a nation that sees over 3500 heart placements annually, a 2% increase would be substantial. Since 2009, our cases stand as the only documented heart retransplantations in the United States. However, United Network for Organ Sharing data shows that potential exists. From a facilitation perspective, we have developed a protocol to ease the matching process. From a surgical perspective, these cases had no complications and saved 2 lives, with each heart now beating in a third person. We hope that by sharing our process and success, we can familiarize fellow organ procurement organizations and transplant communities with this viable opportunity.

Discrepant histological diagnoses: A cause of early low FJS-12 score and if untreated, unhappy Total Knee Arthroplasty patient.

PURPOSE: Total Knee Arthroplasty (TKA) is one of the most successful operations in orthopedics. Still, a sizable percentage of patients (20%) remain dissatisfied after a well-executed TKA. The study aims to examine the excised synovium from the suprapatellar region in osteoarthritic knees during TKA and evaluate the histopathology (HP) report to know whether discrepant diagnoses affect the Forgotten Joint Score-12 at various time intervals. METHODS: This is a prospective cohort study. Two hundred (160 female; 40 male) end-stage osteoarthritis patients who underwent primary TKA were studied. An inclusion criterion was patient with end-stage osteoarthritis. Clinically and serologically proven rheumatoid arthritis patients were excluded from the study. The synovium excised during the TKA procedure was sent for the HP examination. The statistical significance was measured with the Chi-square test and two-sample t-test. RESULTS: A total of 184 out of the 200 patients (92%) knee synovium showed HP features of osteoarthritis. The discordant diagnoses and discrepant diagnosis rate was 8% and 7%, respectively, which is statistically significant by Chi-square test (p value < 0.0001 and p value = 0.0001). 14 of the patients (12 F:2 M) showed histological features of inflammatory/rheumatoid arthritis who were treated, two patients (all female) showed HP features of villonodular synovitis. The mean (SD) improvement in FJS-12 at six weeks in the concordant group (25.3 [17.6]) is significantly more than the discrepant group (15.3 [12.5]), p-value 0.0385. CONCLUSION: 8% of our patients exhibited unexpected results. The study showed a 7% rate of discrepant diagnosis. This discrepant diagnosis if missed and untreated, would have affected the function and long-term survival of the implanted TKA.

How does the ureteric bud branch?

Many genes that modulate kidney development have been identified; however, the molecular interactions that direct arborization of the ureteric bud (UB) remain incompletely understood. This article discusses how "systems" approaches may shed light on the structure of the gene network during UB branching morphogenesis and the mechanisms involved in the formation of a branched collecting system from a straight epithelial tube in the context of a stage model. In vitro and genetic studies suggest that the stages seem to be governed by a conserved network of genes that establish a "tip-stalk generator"; these genes sustain iterative UB branching tubulogenesis through minimal alterations in the network architecture as a budding system shifts to one that autocatalytically branches through budding. The differential expression of stage-specific positive and inhibitory factors in the mesenchyme, likely presented in the context of heparan sulfate proteoglycans, and effector molecules in the epithelium seems to regulate advancement between stages; similar principles may apply to other branching epithelia such as the lung, salivary gland, pancreas, mammary gland, and prostate. Active mesenchymal interactions with the UB seem to govern vectorial arborization and tapering of the collecting system and its terminal differentiation. Cessation of branching correlates with induction of mesenchyme as well as local extracellular matrix changes. Perturbations of these mechanisms and/or single-nucleotide polymorphisms in genes regulating UB branching may predispose to a variety of renal diseases (e.g., hypertension and chronic kidney disease) by altering nephron number. Decentralization of the gene-protein interaction network may explain the relative paucity of branching phenotypes in mutant mice and in human disease.

Interaction Between Cyclosporine and Palbociclib in a Renal Transplant Patient: Case Report and Pharmacokinetic Perspective.

Solid organ transplant recipients have increased cancer risk due in part to chronic immunosuppression and opportunistic oncogenic viral infections. The management of drug interactions in transplant recipients being treated for cancer is important both to minimize the likelihood of drug-related toxicities and to optimize therapeutic outcomes. We present a case of a 41-year-old woman with a stable living-related kidney transplant maintained on an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and prednisone, who was subsequently diagnosed with a metastatic lobular breast carcinoma and papillary thyroid cancer and started palbociclib, a time-dependent CYP3A inhibitor. After initiation of palbociclib, cyclosporine trough and peak concentrations were increased by 159% and 81%, respectively, relative to the average cyclosporine concentrations pre-palbociclib. Using the Drug Interaction Probability Scale (DIPS), the interaction between palbociclib and cyclosporine was rated as "probable." Dose reductions of immunosuppressive agents that are CYP3A substrates are warranted if palbociclib is initiated, followed by close monitoring of blood concentrations. This report also highlights the challenges of coadministering a time-dependent inhibitor with a narrow therapeutic index drug that is metabolized by the same enzyme, particularly when the inhibitor is given in cycles with off-treatment periods.

Target region resection in patients undergoing cytoreductive surgery for peritoneal metastases-is it necessary in absence of visible disease?

BACKGROUND: The aim was to study the patterns of target region (greater omentum, lesser omentum, falciform and umbilical round ligament) involvement in patients undergoing cytoreductive surgery (CRS) from various primary tumors, factors affecting involvement and implications on surgical practice. METHODS: All patients undergoing CRS from July 2018 to December 2018 were included in this prospective study. The incidence of target region involvement in presence and absence of visible disease and the impact of primary tumor site, PCI and other variables on target region involvement was evaluated. RESULTS: In 191 patients, greater omentum was involved in over 15% of patients irrespective of the primary tumor type and in 15.7% in absence of visible disease. 75% of these had PCI <20. The involvement of the other three target regions was higher than 20% in ovarian cancer, appendiceal tumors and peritoneal mesothelioma. Involvement of these 3 regions was associated with a higher PCI (p < 0.001 for all) and omental involvement (p < 0.001for all). 2.1% of colorectal cancer patients had umbilical round ligament involvement, 4.2% had falciform ligament involvement and none had lesser omentum involvement. CONCLUSIONS: Target region involvement varies according to primary tumour site and disease extent. Resection of the greater omentum should be performed during CRS for PM arising from all primary sites. Resection of other target organs may be performed for selected patients with ovarian cancer, peritoneal mesothelioma and mucinous appendiceal tumors in absence of visible disease. For other patients, it should be done only in presence of visible disease.

The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects.

Kidney organogenesis depends on reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM) to form the UB-derived collecting system and MM-derived nephron. With the advent of in vitro systems, it is clear that UB branching can occur independently of MM contact; however, little has been done to detail the role of MM cellular contact in this process. Here, a model system in which the cultured isolated UB is recombined with uninduced MM is used to isolate the effects of the MM progenitor tissue on the development and maturation of the collecting system. By morphometrics, we demonstrate that cellular contact with the MM is required for vectorial elongation of stalks and tapering of luminal caliber of UB-derived tubules. Expression analysis of developmentally significant genes indicates the cocultured tissue is most similar to an embryonic day 19 (E19) kidney. The likely major contributor to this is the functional maturation of the collecting duct and proximal nephron segments in the UB-induced MM, as measured by quantitative PCR, of the collecting duct-specific arginine vasopressin receptor and the nephron tubule segment-specific organic anion transporter OAT1, Na-P(i) type 2 cotransporter, and Tamm-Horsfall protein gene expressions. However, expression of aquaporin-2 is upregulated similarly in isolated UB and cocultured tissue, suggesting that some aspects of functional maturation can occur independently of MM cellular contact. In addition to its sculpting effects, the MM normalized a "branchless" UB morphology induced by FGF7 or heregulin in isolated UB culture. The morphological changes induced by the MM were accompanied by a reassignment of GFRalpha1 (a receptor for GDNF) to tips. Such "quality control" by the MM of UB morphology may provide resiliency to the branching program. This may help to explain a number of knockout phenotypes in which branching and/or cystic defects are less impressive than expected. A second hit in the MM may thus be necessary to make these defects fully apparent.

Efficacy and Safety of Canagliflozin in Kidney Transplant Patients.

INTRODUCTION: There is no report of efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor in post kidney transplant patients with diabetes. MATERIALS AND METHODS: A pilot study was undertaken in stable renal transplant recipients with preexisting diabetes or new onset diabetes after transplantation (NODAT) to look at the efficacy of SGLT2 inhibitor, cangliflozin. With the introduction of canagliflozin (100 mg), the dose of insulin and/or other oral hypoglycemic agents was reduced if the blood sugar control improved. The parameters monitored were body weight, blood pressure (BP), serum creatinine, HbA1c, and tacrolimus trough level. Safety was assessed by adverse event (AE) reports. Each patient was followed for a minimum period of 6 months. RESULTS: The study included 24 (23 males and 1 females) stable kidney transplant patients with diabetes. The mean age of the patients was 53.8 ± 7.12 years. The mean body weight of study subjects was 78.6 ± 12.1 kg before and 76.1 ± 11.2 kg 6 months after starting canagliflozin (P < 0.05). The mean systolic and diastolic BP (mm Hg) was 142 ± 21 and 81 ± 9 before and 134 ± 17 and 79 ± 8, 6 months after starting canagliflozin, respectively (P < 0.05 for systolic BP). There was no significant change in creatinine level (mg/dL). It was 1.1 ± 0.2 before and 1.1 ± 0.3 after starting canagliflozin. The tacrolimus level (ng/mL) was 6.7 ± 3.7 before and 6.1 ± 2, 6 months after starting canagliflozin. The mean HbA1c before was 8.5 ± 1.5%. At 6 months, it was 7.6 ± 1%. Hypoglycemia was not seen. There was no increase in infections. CONCLUSION: Canagliflozin provided reductions in body weight, BP, HbA1c, and the requirement of other hypoglycemic agents without any hypoglycemic episodes and without significant AEs.

The HAALT Non-invasive Scoring System for NAFLD in Obesity.

BACKGROUND: The prevalence of NAFLD increases in obese diabetics. Accurate diagnosis of NAFLD requires invasive liver biopsies, which is costly, and time consuming and labor intensive. Currently, there is a lack of non-invasive diagnostic methods to identify those with NASH, in obese Indians. OBJECTIVES: To develop an accurate non-invasive scoring system using clinical and biochemical parameters to predict the risk of developing non-alcoholic steatohepatitis (NASH). METHODS: Clinical and biochemical parameters were recorded pre-operatively from 290 patients who were posted for bariatric/metabolic surgery, between September 2017 and October 2018 and compared with the result of intra-operative liver biopsy NAFLD activity scores (NAS). RESULTS: The mean weight and BMI of the patients were 120.3 ± 24.6 and 45.5 ± 7.8 respectively. In the final histopathological examination, 196/290 (67.6%) had simple steatosis, 92/290 (31.7%) had NASH, and 2/290 (0.007%) had cirrhosis. Binary logistic regression analysis of multiple independent predictors yielded five independent factors that were statistically significant (HbA1c, AST, ALT, liver span on USG, and serum triglycerides). These were used to create a scoring system, with a range of scores from 0 to 6, with maximum predictability at a score of 6. Patients with scores of ≧ 3 were at high risk of NASH diagnosis. The sensitivity of this scoring system was 85.87% and diagnostic accuracy was 75.35%. CONCLUSIONS: Our study not only confirms the significant association of NAFLD with obesity but also outlines a simple non-invasive scoring system to identify obese individuals at high risk for NASH.

Pathological assessment of cytoreductive surgery specimens and its unexplored prognostic potential-a prospective multi-centric study.

BACKGROUND AND AIM: The grade/histological subtype is one of the most important prognostic markers in patients undergoing cytoreductive surgery (CRS). Our aim was to study other potential prognostic information that can be derived from the pathological evaluation of CRS specimens and provide a broad outline for evaluation of these. METHODS: This prospective study (July to December 2018) included all patients undergoing cytoreductive surgery (CRS). A protocol for pathological evaluation was laid down which was based on existing practices at the participating centers and included evaluation of the pathological PCI, regional node involvement, response to chemotherapy, morphology of peritoneal metastases (PM) and distribution in the peritoneal cavity. RESULTS: In 191 patients undergoing CRS at 4 centers, the pathological and surgical PCI differed in over 75%. Nodes in relation to peritoneal disease were positive in 13.6%. Disease in normal peritoneum adjacent to tumor nodules was seen in >50% patients with ovarian cancer and mucinous apppendiceal tumors. 23.8% of evaluated colorectal PM patients had a complete response and 25.0% ovarian cancer patients had a near complete pathological response to chemotherapy. CONCLUSIONS: Pathological evaluation of extent and distribution of peritoneal disease differs from the surgical evaluation in majority of the patients. Lymph node involvement in relation of peritoneal disease is common. The morphological presentation of PM in ovarian cancer and mucinous appendiceal tumors merits evaluation of more extensive resections in these patients. Standardized methods of synoptic reporting of CRS specimens could help capture vital prognostic information that may in future influence how these patients are treated.

De Novo Postinfectious Glomerulonephritis Secondary to Nephritogenic Streptococci as the Cause of Transplant Acute Kidney Injury: A Case Report and Review of the Literature.

Acute kidney injury is common among kidney transplant recipients. Postinfectious glomerulonephritis secondary to nephritogenic streptococci is one of the oldest known etiologies of acute kidney injury in native kidneys but rarely reported among kidney transplant recipients. This report is of a biopsy-proven case of acute kidney injury in a renal allograft recipient caused by de novo poststreptococcal glomerulonephritis.