Browsing by Subject "Kidney Diseases"

Now showing 1 - 15 of 15

Open Access
Advancing drug discovery for glomerulopathies using stem-cell-derived kidney models.
(Trends in pharmacological sciences, 2023-04) Barreto, Amanda D; Burt, Morgan A; Musah, Samira
Chronic kidney disease (CKD) is an epidemic that affects millions worldwide. The glomerulus, a specialized unit of the nephron, is highly susceptible to injury. Human induced pluripotent stem cells (iPSCs) have emerged as an attractive resource for modeling kidney disease and therapeutic discovery.
Open Access
APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease.
(Journal of the American Society of Nephrology : JASN, 2016-12) Bruggeman, Leslie A; Wu, Zhenzhen; Luo, Liping; Madhavan, Sethu M; Konieczkowski, Martha; Drawz, Paul E; Thomas, David B; Barisoni, Laura; Sedor, John R; O'Toole, John F
APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes from Tg-G0 and Tg-G2 mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.
Open Access
APOL1-Mediated Kidney Disease.
(JAMA, 2024-04) Hopper, Timothy; Olabisi, Opeyemi A
This JAMA Insights reviews the origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease, and discusses recommendations for screening and management.
Open Access
APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
(The Journal of clinical investigation, 2024-01) Datta, Somenath; Antonio, Brett M; Zahler, Nathan H; Theile, Jonathan W; Krafte, Doug; Zhang, Hengtao; Rosenberg, Paul B; Chaves, Alec B; Muoio, Deborah M; Zhang, Guofang; Silas, Daniel; Li, Guojie; Soldano, Karen; Nystrom, Sarah; Ferreira, Davis; Miller, Sara E; Bain, James R; Muehlbauer, Michael J; Ilkayeva, Olga; Becker, Thomas C; Hohmeier, Hans-Ewald; Newgard, Christopher B; Olabisi, Opeyemi A
Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.
Open Access
Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease.
(Diabetes care, 2012-05) Wahl, Patricia; Xie, Huiliang; Scialla, Julia; Anderson, Cheryl AM; Bellovich, Keith; Brecklin, Carolyn; Chen, Jing; Feldman, Harold; Gutierrez, Orlando M; Lash, Jim; Leonard, Mary B; Negrea, Lavinia; Rosas, Sylvia E; Anderson, Amanda Hyre; Townsend, Raymond R; Wolf, Myles; Isakova, Tamara; Chronic Renal Insufficiency Cohort Study Group
Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status.Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30-39 vs. 20-29, P < 0.001; FGF23: eGFR 50-59 vs. 40-49, P < 0.001).Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.
Open Access
Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.
(Kidney Int, 2016-05) Madan, Babita; Patel, Mehul B; Zhang, Jiandong; Bunte, Ralph M; Rudemiller, Nathan P; Griffiths, Robert; Virshup, David M; Crowley, Steven D
Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.
Open Access
Fenestrated Endothelial Cells across Organs: Insights into Kidney Function and Disease.
(International journal of molecular sciences, 2024-08) Mou, Xingrui; Leeman, Sophia M; Roye, Yasmin; Miller, Carmen; Musah, Samira
In the human body, the vascular system plays an indispensable role in maintaining homeostasis by supplying oxygen and nutrients to cells and organs and facilitating the removal of metabolic waste and toxins. Blood vessels-the key constituents of the vascular system-are composed of a layer of endothelial cells on their luminal surface. In most organs, tightly packed endothelial cells serve as a barrier separating blood and lymph from surrounding tissues. Intriguingly, endothelial cells in some tissues and organs (e.g., choroid plexus, liver sinusoids, small intestines, and kidney glomerulus) form transcellular pores called fenestrations that facilitate molecular and ionic transport across the vasculature and mediate immune responses through leukocyte transmigration. However, the development and unique functions of endothelial cell fenestrations across organs are yet to be fully uncovered. This review article provides an overview of fenestrated endothelial cells in multiple organs. We describe their development and organ-specific roles, with expanded discussions on their contributions to glomerular health and disease. We extend these discussions to highlight the dynamic changes in endothelial cell fenestrations in diabetic nephropathy, focal segmental glomerulosclerosis, Alport syndrome, and preeclampsia, and how these unique cellular features could be targeted for therapeutic development. Finally, we discuss emerging technologies for in vitro modeling of biological systems, and their relevance for advancing the current understanding of endothelial cell fenestrations in health and disease.
Open Access
Ideal high sensitivity troponin baseline cutoff for patients with renal dysfunction.
(The American journal of emergency medicine, 2022-06) Limkakeng, Alexander T; Hertz, Julian; Lerebours, Reginald; Kuchibhatla, Maragatha; McCord, James; Singer, Adam J; Apple, Fred S; Peacock, William F; Christenson, Robert H; Nowak, Richard M
Open Access
Isogenic Kidney Glomerulus Chip Engineered from Human Induced Pluripotent Stem Cells.
(Journal of visualized experiments : JoVE, 2022-11) Roye, Yasmin; Musah, Samira
Chronic kidney disease (CKD) affects 15% of the U.S. adult population, but the establishment of targeted therapies has been limited by the lack of functional models that can accurately predict human biological responses and nephrotoxicity. Advancements in kidney precision medicine could help overcome these limitations. However, previously established in vitro models of the human kidney glomerulus-the primary site for blood filtration and a key target of many diseases and drug toxicities-typically employ heterogeneous cell populations with limited functional characteristics and unmatched genetic backgrounds. These characteristics significantly limit their application for patient-specific disease modeling and therapeutic discovery. This paper presents a protocol that integrates human induced pluripotent stem (iPS) cell-derived glomerular epithelium (podocytes) and vascular endothelium from a single patient to engineer an isogenic and vascularized microfluidic kidney glomerulus chip. The resulting glomerulus chip is comprised of stem cell-derived endothelial and epithelial cell layers that express lineage-specific markers, produce basement membrane proteins, and form a tissue-tissue interface resembling the kidney's glomerular filtration barrier. The engineered glomerulus chip selectively filters molecules and recapitulates drug-induced kidney injury. The ability to reconstitute the structure and function of the kidney glomerulus using isogenic cell types creates the opportunity to model kidney disease with patient specificity and advance the utility of organs-on-chips for kidney precision medicine and related applications.
Open Access
JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.
(JCI insight, 2022-06) Nystrom, Sarah E; Li, Guojie; Datta, Somenath; Soldano, Karen L; Silas, Daniel; Weins, Astrid; Hall, Gentzon; Thomas, David B; Olabisi, Opeyemi A
COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.
Open Access
Kidney Disease Modeling with Organoids and Organs-on-Chips.
(Annual review of biomedical engineering, 2024-07) Musah, Samira; Bhattacharya, Rohan; Himmelfarb, Jonathan
Kidney disease is a global health crisis affecting more than 850 million people worldwide. In the United States, annual Medicare expenditures for kidney disease and organ failure exceed $81 billion. Efforts to develop targeted therapeutics are limited by a poor understanding of the molecular mechanisms underlying human kidney disease onset and progression. Additionally, 90% of drug candidates fail in human clinical trials, often due to toxicity and efficacy not accurately predicted in animal models. The advent of ex vivo kidney models, such as those engineered from induced pluripotent stem (iPS) cells and organ-on-a-chip (organ-chip) systems, has garnered considerable interest owing to their ability to more accurately model tissue development and patient-specific responses and drug toxicity. This review describes recent advances in developing kidney organoids and organ-chips by harnessing iPS cell biology to model human-specific kidney functions and disease states. We also discuss challenges that must be overcome to realize the potential of organoids and organ-chips as dynamic and functional conduits of the human kidney. Achieving these technological advances could revolutionize personalized medicine applications and therapeutic discovery for kidney disease.
Open Access
Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today.
(Kidney international, 2024-02) Trachtman, Howard; Desmond, Hailey; Williams, Amanda L; Mariani, Laura H; Eddy, Sean; Ju, Wenjun; Barisoni, Laura; Ascani, Heather K; Uhlmann, Wendy R; Spino, Cathie; Holzman, Lawrence B; Sedor, John R; Gadegbeku, Crystal; Subramanian, Lalita; Lienczewski, Chrysta C; Manieri, Tina; Roberts, Scott J; Gipson, Debbie S; Kretzler, Matthias; NEPTUNE investigators
Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.
Open Access
Renal Dysfunction and In-Hospital Outcomes in Patients With Acute Ischemic Stroke After Intravenous Thrombolytic Therapy.
(Journal of the American Heart Association, 2019-10-09) Rao, Zhen-Zhen; Gu, Hong-Qiu; Wang, Xian-Wei; Xie, Xue-Wei; Yang, Xin; Wang, Chun-Juan; Zhao, Xingquan; Xian, Ying; Wang, Yi-Long; Li, Zi-Xiao; Xiao, Rui-Ping; Wang, Yong-Jun; Chinese Stroke Center Alliance investigators
Background The impact of estimated glomerular filtration rate (eGFR) on clinical short-term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45-59, 60-89, and ≥90 mL/min per 1.73 m2) and in-hospital mortality and symptomatic intracerebral hemorrhage, adjusting for patient and hospital characteristics and the hospital clustering effect. Of the 18 320 patients receiving tissue plasminogen activator, 601 (3.3%) had an eGFR <45, 625 (3.4%) had an eGFR 45 to 59, 3679 (20.1%) had an eGFR 60 to 89, and 13 415 (73.2%) had an eGFR ≥90. As compared with eGFR ≥90, eGFR values <45 (6.7% versus 0.9%, adjusted odds ratio, 3.59; 95% CI, 2.18-5.91), 45 to 59 (4.0% versus 0.9%, adjusted odds ratio, 2.00; 95% CI, 1.18-3.38), and 60 to 89 (2.5% versus 0.9%, adjusted odds ratio, 1.67; 95% CI, 1.20-2.34) were independently associated with increased odds of in-hospital mortality. However, there was no statistically significant association between eGFR and symptomatic intracerebral hemorrhage. Conclusions eGFR was associated with an increased risk of in-hospital mortality in acute ischemic stroke patients after treatment with tissue plasminogen activator. eGFR is an important predictor of poststroke short-term death but not of symptomatic intracerebral hemorrhage.
Open Access
Shared features in the pathobiology of babesiosis and malaria.
(Trends Parasitol, 2007-12) Krause, Peter J; Daily, Johanna; Telford, Sam R; Vannier, Edouard; Lantos, Paul; Spielman, Andrew
The pathobiology of malaria has been extensively studied in humans but many questions remain, especially regarding fulminant disease associated with Plasmodium falciparum infection. Babesiosis, recognized since biblical times as an important disease of livestock and more recently as an emerging health problem in humans, is caused by related intraerythrocytic protozoa with a similar pathogenesis and clinical course. Recent studies of cytokine activation and erythrocyte cytoadherence in babesiosis and malaria have exploited these similarities to provide new insights into malaria pathobiology. Continued investigation of similarities and differences in the pathogenesis of babesiosis and malaria should lead to additional fundamental insights for both conditions.
Open Access
Ultrafiltration in Acute Heart Failure: Implications of Ejection Fraction and Early Response to Treatment From CARRESS-HF.
(Journal of the American Heart Association, 2020-12-08) Fudim, Marat; Brooksbank, Jeremy; Giczewska, Anna; Greene, Stephen J; Grodin, Justin L; Martens, Pieter; Ter Maaten, Jozine M; Sharma, Abhinav; Verbrugge, Frederik H; Chakraborty, Hrishikesh; Bart, Bradley A; Butler, Javed; Hernandez, Adrian F; Felker, G Michael; Mentz, Robert J
Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (≤40% or >40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (≤24 hours) response to ultrafiltration. Cox-proportional hazards models were used to identify associations between fluid removal <24 hours and composite of death, hospitalization, or unscheduled outpatient/emergency department visit during study follow-up. The intention-to-treat analysis included 93 patients. Within 24 hours, median fluid removal was 1.89 L (Q1, Q3: 1.22, 3.16). The high fluid removal group had a greater urine output (9.08 versus 6.23 L, P=0.027) after 96 hours. Creatinine change from baseline to 96 hours was similar in both groups (0.10 mg/dL increase, P=0.610). The EF >40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy.