Search

Telehealth plays a critical role in the response of healthcare organizations during the COVID-19 pandemic. While telemedicine offers a real-time patient-provider encounter, the inability to obtain vital signs during virtual visits is a potential limitation. Remote patient monitoring (RPM) uses portable devices in the patient‘s home to collect and electronically transmit physiological data to clinicians. Two kidney transplant recipients were enrolled in RPM in their immediate post-transplant period. Real-time monitoring of their physiological data at home through the RPM in combination with the ability to titrate medications resulted in normalization of the blood pressure and blood glucose measurements by six weeks. Our initial experience demonstrates that RPM is feasible and effective in the post-transplant period and can expand care opportunities on the remote care model. This is more relevant than ever as remote monitoring can facilitate the care of COVID-19-positive transplant patients who require close monitoring while isolated at home.

To evaluate the role of circulating dd-cfDNA in allograft surveillance in immunologically high-risk patients, a retrospective cross-sectional study of 261 kidney transplant recipients who underwent outpatient allograft biopsy at our center between September 2020 and August 2021 was performed. Of the 236 dd-cfDNA results included, 37 samples were obtained at the time of a surveillance biopsy in sensitized recipients and 199 at the time of a clinically indicated biopsy. The median serum creatinine at the time of the biopsy was 1.3 mg/dl and 2.1 mg/dl for surveillance biopsies and clinically indicated biopsies, respectively (P .001). Rejection was diagnosed in 27% of surveillance biopsies and 29% of clinically indicated biopsies. Among surveillance biopsies, sensitivity and specificity to detect rejection were 0% and 89%, respectively, and among clinically indicated biopsies they were 28% and 96%, respectively. The sensitivity and specificity to detect antibody-mediated rejection were 0% and 91% among surveillance biopsies and 50% and 94% among clinically indicated biopsies. Nine biopsies without rejection findings had corresponding dd-cfDNA of ≥1%. Our data does not support dd-cfDNA as a biomarker for kidney allograft rejection, even in immunologically high-risk patients in the absence of graft dysfunction.

Background Medullary sponge kidney (MSK) disease predisposes patients to recurrent nephrolithiasis, which affects one in every 5000 people in the United States. Methods We report a rare case of a pediatric recipient of a living donor MSK transplant and discuss considerations when discussing risks and benefits of accepting MSK allografts for this population. Results The recipient was admitted due to concerns for nephrolithiasis, hydronephrosis, and urinary tract infection at 1-month post-transplant. The hydronephrosis was resolved by surgical removal of an encrusted ureteral stent; this was followed by supplementation with oral medications to prevent future episodes of nephrolithiasis. The recipient did not have any further episodes after this as seen at a 1-year follow-up. The donor has remained well through this period. Conclusions With increasing organ shortages, the use of variety of donors may need to be considered to enlarge the organ pool.

The New York metropolitan region was an early epicenter of the COVID-19 pandemic. The New York State stay-at-home order forced hospitals and health care providers to rethink care algorithms as in-person visits became infeasible or unsafe. In response to the COVID-19 pandemic, the kidney transplant program at Columbia University Irving Medical Center rapidly implemented a telehealth program that offers virtual visits for ambulatory patients.

Summary Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.

Background and objectives Outcomes of kidney transplant recipients diagnosed with coronavirus disease 2019 as outpatients have not been described. Design, setting, participants, & measurements We obtained clinical data for 41 consecutive outpatient kidney transplant recipients with known or suspected coronavirus disease 2019. Chi-squared and Wilcoxon rank sum tests were used to compare characteristics of patients who required hospitalization versus those who did not. Results Of 41 patients, 22 (54%) had confirmed coronavirus disease 2019, and 19 (46%) were suspected cases. Patients most commonly reported fever (80%), cough (56%), and dyspnea (39%). At the end of follow-up, 13 patients (32%) required hospitalization a median of 8 days (range, 1–16) after symptom onset, and 23 (56%) had outpatient symptom resolution a median of 12 days (4–23) after onset. Patients who required hospitalization were more likely to have reported dyspnea (77% versus 21%, P=0.003) and had higher baseline creatinine (median, 2.0 versus 1.3 mg/dl, P=0.02), but there were no other differences between groups. Conclusions In an early cohort of outpatient kidney transplant recipients with known or suspected coronavirus disease 2019, many had symptomatic resolution without requiring hospitalization.

The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial., Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.

Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient's secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor's cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.

Tubulointerstitial abnormalities are predictive of progression of diabetic kidney disease (DKD) . Proximal tubular (PT) kidney injury molecule (KIM)-1 expression and blood and urinary KIM-1 levels are increased early in human diabetes and can predict rate of progression of disease. We report that KIM-1 mediates PT uptake of fatty acids (FAs) bound to albumin leading to enhanced tubule injury with DNA damage, PT cell cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Injury is ameliorated by inhibition of uptake by genetic ablation of KIM-1 mucin domain or a newly discovered small molecule inhibitor of KIM-1-mediated FA uptake, TW-37. Our findings support KIM-1 as a new therapeutic target for DKD.

Gain-of-function mutations in TRPC6 cause familial focal segmental glomerulosclerosis, and TRPC6 is upregulated in glomerular diseases including diabetic kidney disease. We studied the effect of systemic TRPC6 knockout in the Akita model of type 1 diabetes. Knockout of TRPC6 inhibited albuminuria in Akita mice at 12 and 16 weeks of age, but this difference disappeared by 20 weeks. Knockout of TRPC6 also reduced tubular injury in Akita mice; however, mesangial expansion was significantly increased. Hyperglycemia and blood pressure were similar between TRPC6 knockout and wild-type Akita mice, but knockout mice were more insulin resistant. In cultured podocytes, knockout of TRPC6 inhibited expression of the calcium/calcineurin responsive gene insulin receptor substrate 2 and decreased insulin responsiveness. Insulin resistance is reported to promote diabetic kidney disease independent of blood glucose levels. While the mechanisms are not fully understood, insulin activates both Akt2 and ERK, which inhibits apoptosis signal regulated kinase 1 (ASK1)-p38–induced apoptosis. In cultured podocytes, hyperglycemia stimulated p38 signaling and induced apoptosis, which was reduced by insulin and ASK1 inhibition and enhanced by Akt or ERK inhibition. Glomerular p38 signaling was increased in TRPC6 knockout Akita mice and was associated with enhanced expression of the p38 gene target cyclooxygenase 2. These data suggest that knockout of TRPC6 in Akita mice promotes insulin resistance and exacerbates glomerular disease independent of hyperglycemia.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.

The presence of two APOL1 risk variants (G1/G1, G1/G2, or G2/G2) is an important predictor of focal segmental glomerulosclerosis (FSGS), and chronic kidney disease in individuals of African descent. While recipient APOL1 genotype is not associated with allograft survival, kidneys from deceased African American donors with two APOL1 risk variants demonstrate shorter graft survival. We present a series of cases of presumed de novo collapsing FSGS in five transplanted kidneys from three deceased donors later identified as carrying two APOL1 risk alleles, including two recipients from the same donor whose kidneys were transplanted in two different institutions across United States. Four of these recipients had viremia in the period preceding the diagnosis of collapsing FSGS. Cytomegalovirus (CMV) and BK virus infection was present in three and one of our five cases, respectively, around the time collapsing FSGS occurred. We discuss viral infections including active CMV infection as possible “second hits” that may lead to glomerular injury and allograft failure in these recipients. Further studies to identify additional “second hits” are necessary to better understand the pathologic mechanisms of donor APOL1-associated kidney disease in the recipient.

Interleukin (IL)-8, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF) appear to be critically involved in immune responses associated with inflammation, infection and tumor growth. Regulation of these mediators was studied in the human colon carcinoma cell line DLD-1. Here we report that pyrrolidine dithiocarbamate (PDTC) not only augmented tumor necrosis factor-alpha-induced release of IL-8, but also mediated IL-8 expression as a single stimulus. Mutational analysis of the IL-8 promotor and electrophoretic mobility shift analysis revealed that activation of the transcription factor activator protein-1 (AP-1) and a constitutive nuclear factor-kappaB (NF-kappaB) binding activity in DLD-1 cells were mandatory for PDTC-induced IL-8 expression. Besides IL-8, PDTC also upregulated the expression of HO-1 and VEGF in these cells. Induction of IL-8 by PDTC was not restricted to DLD-1 cells, but was observed in Caco-2 colon carcinoma cells and in peripheral blood mononuclear cells. PDTC is currently advocated for use as a chemotherapeutic drug in the treatment of certain malignancies, among them colorectal cancer. Induction of IL-8, HO-1 and VEGF may affect therapeutic applications of this agent.

Nitric oxide (NO) appears to act as an inflammatory mediator on monocytic cells. Exogenous NO augmented release of chemokines from human promonocytic U937 cells and peripheral blood mononuclear cells. Pharmacological strategies aiming at modulation of NO-induced release of interleukin-8 (IL-8) were investigated in U937 cells in detail. Release of IL-8 was down-regulated by transforming growth factor beta2 (TGF-beta2), by the protein tyrosine-kinase inhibitor genistein, and via rises in intracellular cyclic AMP, generated by prostaglandin E(2), rolipram, pentoxifylline, forskolin, or dibutyryl-cyclic AMP. In addition, incubation with the synthetic glucocorticoid dexamethasone or suppression of activity of p38 mitogen-activated protein (MAP) kinases by SB-203580 modulated release of IL-8. Activation of p38 MAP kinases was confirmed by the demonstration of an augmented appearance of phosphorylated p38 in the presence of NO. The present data suggest that exposure to exogenous NO resembles activation of U937 cells by proinflammatory stimuli. The anti-inflammatory cytokine TGF-beta2, as well as anti-inflammatory or immunosuppressive agents such as genistein, pentoxifylline, rolipram, dexamethasone, and SB-203580 modulate inflammatory, chemokine-inducing actions of NO.

For more than 60 years, warfarin was the only oral anticoagulation agent available for use in the United States. In many recent clinical trials, several direct oral anticoagulants (DOACs) demonstrated similar efficacy with an equal or superior safety profile, with some other notable benefits. The DOACs have lower inter- and intrapatient variability, much shorter half-lives, and less known drug-drug and drug-food interactions as compared to warfarin. Despite these demonstrated benefits, the use of DOACs has not gained uniform acceptance because of lack of supportive data in special patient populations, including recipients of solid organ transplants maintained on immunosuppression. This review describes the properties of several novel DOACs including their pharmacology and mechanisms of action as they relate to use among solid organ transplant recipients. We have particularly focused on (i) dosing in patients with impaired renal and hepatic function; (ii) considerations for drug-drug interactions with immunosuppressive medications; and (iii) management of the anticoagulated patients at the time of unplanned surgery. The risks and benefits of the use of DOACs in solid organ transplant recipients should be carefully evaluated prior to the introduction of these agents in this highly distinct patient population.

Akita mice have type 1 diabetes mellitus caused by a spontaneous point mutation in the Ins2 gene which leads to misfolding of insulin, resulting in pancreatic β-cell failure. Akita mice develop pronounced and sustained hyperglycemia, high levels of albuminuria, and consistent histopathological changes, suggesting that these mice may be suitable as an experimental platform for modeling diabetic nephropathy. One key feature of diabetic kidney disease in Akita mice is that the severity of renal injury is significantly influenced by genetic background. In this chapter, we describe the Akita model and present some of the experimental studies utilizing Akita mice as a model of type 1 diabetes. For example, deficiency in bradykinin receptors, endothelial nitric oxide synthase, or angiotensin-converting enzyme 2 leads to development of functionally and structurally more advanced diabetic nephropathy in these mice, while ketogenic diet has been shown to reverse kidney injury associated with diabetes. This chapter also describes the application of 24-h urine collections from mice for careful measurement of urinary albumin excretion.

Akita mice are a genetic model of type 1 diabetes. In the present studies, we investigated the phenotype of Akita mice on the FVB/NJ background and examined urinary nephrin excretion as a marker of kidney injury. Male Akita mice were compared with non-diabetic controls for functional and structural characteristics of renal and cardiac disease. Podocyte number and apoptosis as well as urinary nephrin excretion were determined in both groups. Male FVB/NJ Akita mice developed sustained hyperglycemia and albuminuria by 4 and 8 weeks of age, respectively. These abnormalities were accompanied by a significant increase in systolic blood pressure in 10-week old Akita mice, which was associated with functional, structural and molecular characteristics of cardiac hypertrophy. By 20 weeks of age, Akita mice developed a 10-fold increase in albuminuria, renal and glomerular hypertrophy and a decrease in the number of podocytes. Mild-to-moderate glomerular mesangial expansion was observed in Akita mice at 30 weeks of age. In 4-week old Akita mice, the onset of hyperglycemia was accompanied by increased podocyte apoptosis and enhanced excretion of nephrin in urine before the development of albuminuria. Urinary nephrin excretion was also significantly increased in albuminuric Akita mice at 16 and 20 weeks of age and correlated with the albumin excretion rate. These data suggest that: 1. FVB/NJ Akita mice have phenotypic characteristics that may be useful for studying the mechanisms of kidney and cardiac injury in diabetes, and 2. Enhanced urinary nephrin excretion is associated with kidney injury in FVB/NJ Akita mice and is detectable early in the disease process.

Akita mice have type 1 diabetes mellitus caused by a spontaneous point mutation in the Ins2 gene which leads to misfolding of insulin, resulting in pancreatic β-cell failure. Akita mice develop pronounced and sustained hyperglycemia, high levels of albuminuria, and consistent histopathological changes, suggesting that these mice may be suitable as an experimental platform for modeling diabetic nephropathy. One key feature of diabetic kidney disease in Akita mice is that the severity of renal injury is significantly influenced by genetic background. In this chapter, we describe the Akita model and present some of the experimental studies utilizing Akita mice as a model of type 1 diabetes. For example, deficiency in bradykinin receptors, endothelial nitric oxide synthase, or angiotensin-converting enzyme 2 leads to development of functionally and structurally more advanced diabetic nephropathy in these mice, while ketogenic diet has been shown to reverse kidney injury associated with diabetes. This chapter also describes the application of 24-h urine collections from mice for careful measurement of urinary albumin excretion.

To determine the role of Gq signaling and calcineurin (CN) activation in promoting apoptosis of glomerular podocytes, constitutively active Gq [Gq(+)] or CN [CN(+)] proteins were introduced into cultured podocytes using protein transduction by tagging the proteins with the transactivator of transcription peptide. To investigate the role of CN in promoting podocyte apoptosis in vivo, a genetic model of type 1 diabetes mellitus (Akita mice) was treated with the CN inhibitor FK506. In cultured podocytes, Gq(+) stimulated nuclear translocation of nuclear factor of activated T cells (NFAT) family members, activated an NFAT reporter construct, and enhanced podocyte apoptosis in a CN-dependent fashion. CN(+) similarly promoted podocyte apoptosis, and apoptosis induced by either angiotensin II or endothelin-1 was blocked by FK506. Induction of apoptosis required NFAT-induced gene transcription because apoptosis induced by either Gq(+) or CN(+) was blocked by an inhibitor that prevented CN-dependent NFAT activation without affecting CN phosphatase activity. Podocyte apoptosis was mediated, in part, by the NFAT-responsive gene cyclooxygenase 2 (COX2) and prostaglandin E(2) generation because apoptosis induced by Gq(+) was attenuated by either COX2 inhibition or blockade of the Gq-coupled E-series prostaglandins receptor. The findings appeared relevant to podocyte apoptosis in diabetic nephropathy because apoptosis was significantly reduced in Akita mice by treatment with FK506. These data suggest that Gq stimulates CN and promotes podocyte apoptosis both in vitro and in vivo. Apoptosis requires NFAT-dependent gene transcription and is mediated, in part, by CN-dependent COX2 induction, prostaglandin E(2) generation, and autocrine activation of the Gq-coupled E-series prostaglandins receptor.

Background Left-handedness has been considered a simple inconvenience by some or something as convoluted as "the sinister," the Latin word for the left, by others. One in ten medical personnel is left-handed. The perceptions of left-handed surgeons regarding their laterality related inconveniences are unknown. Objectives To determine the perceptions of left-handed surgeons and the way it has affected their surgical training and career. Design and setting Web-based survey of left-handed surgeons. Participants Left-handed surgeons in 2 boroughs of New York City, Manhattan and Brooklyn. Methods Distribution and completion of the survey. Main outcome measure Career-oriented concerns of left-handed surgeons. Results Three percent of left-handed surgeons received laterality related mentoring during medical school. Ten percent of the programs mentored left-handed surgical residents, and 13% of the programs provided left-handed instruments during surgical residency. Laparoscopy and laparoscopic instruments did not eliminate the problems associated with instrument handling to left-handed surgeons. Ten percent of the left-handed surgeons expressed concerns when asked whether they would be comfortable being treated by another left-handed surgeon when they are the patients themselves. Conclusions This study reveals the perceptions of left-handed surgeons in adapting to a right-handed world. Early laterality related mentoring in medical school and during surgical residency with provision of left-handed instruments might reduce the inconveniences of left-handed surgeons learning.

To characterize mechanisms which may determine the fate of apoptotic cells, we investigated chemokine expression in apoptotic promonocytic U937 cells or peripheral blood mononuclear cells (PBMC). Exposure of U937 cells to etoposide (VP-16) or the nitric oxide (NO) donor DETA-NO, both inducers of apoptosis in these cells, was associated with increased expression of the chemokines IL-8 and macrophage inflammatory protein-1 alpha. Up-regulation of IL-8 mRNA expression by VP-16 or DETA-NO was observed as early as 4 h or 6 h, respectively, after onset of treatment and was still detectable after 19 h of exposure. A serine protease inhibitor prevented both VP-16-induced apoptosis and release of IL-8, whereas inhibition of p38 MAP kinases reduced IL-8 secretion only. Moreover, we observed that incubation with 2-chlorodeoxyadenosine (CdA) up-regulated release of IL-8 from adherent PBMC in parallel to induction of apoptosis. In these cells a modest but significant induction of TNF-alpha release by CdA was also detected. In addition, CdA augmented release of IL-8 from whole blood cultures. By facilitating adequate recruitment of phagocytes to sites of cell death, stress-induced up-regulation of chemokines associated with apoptosis may contribute to mechanisms aiming at efficient removal of apoptotic cells.