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Thadhani, Ravi

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Thadhani

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Ravi

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Thadhani, Ravi
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    Low-Molecular Weight Heparin Increases Circulating sFlt-1 Levels and Enhances Urinary Elimination
    (Public Library of Science, 2014) Hagmann, Henning; Bossung, Verena; Belaidi, Abdel Ali; Fridman, Alexander; Karumanchi, S. Ananth; Thadhani, Ravi; Schermer, Bernhard; Mallmann, Peter; Schwarz, Guenter; Benzing, Thomas; Brinkkoetter, Paul T.
    Rationale: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. Objective: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. Methods and Results: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. Conclusion: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.
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    Induced Human Decidual NK-Like Cells Improve Utero-Placental Perfusion in Mice
    (Public Library of Science, 2016) Cavalli, Ricardo C.; Cerdeira, Ana Sofia; Pernicone, Elizabeth; Korkes, Henri A.; Burke, Suzanne; Rajakumar, Augustine; Thadhani, Ravi; Roberts, Drucilla; Bhasin, Manoj; Karumanchi, Subbian; Kopcow, Hernan D.
    Decidual NK (dNK) cells, a distinct type of NK cell, are thought to regulate uterine spiral artery remodeling, a process that allows for increased blood delivery to the fetal-placental unit. Impairment of uterine spiral artery remodeling is associated with decreased placental perfusion, increased uterine artery resistance, and obstetric complications such as preeclampsia and intrauterine growth restriction. Ex vivo manipulation of human peripheral blood NK (pNK) cells by a combination of hypoxia, TGFß-1 and 5-aza-2’-deoxycytidine yields cells with phenotypic and in vitro functional similarities to dNK cells, called idNK cells. Here, gene expression profiling shows that CD56Bright idNK cells derived ex vivo from human pNK cells, and to a lesser extent CD56Dim idNK cells, are enriched in the gene expression signature that distinguishes dNK cells from pNK cells. When injected into immunocompromised pregnant mice with elevated uterine artery resistance, idNK cells homed to the uterus and reduced the uterine artery resistance index, suggesting improved placental perfusion.
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    Circulating Angiogenic Factors and the Risk of Adverse Outcomes among Haitian Women with Preeclampsia
    (Public Library of Science, 2015) March, Melissa I.; Geahchan, Carl; Wenger, Julia; Raghuraman, Nandini; Berg, Anders; Haddow, Hamish; Mckeon, Bri Ann; Narcisse, Rulx; David, Jean Louis; Scott, Jennifer; Thadhani, Ravi; Karumanchi, Subbian; Rana, Sarosh
    Objective: Angiogenic factors are strongly associated with adverse maternal and fetal outcomes among women with preterm preeclampsia (PE) in developed countries. We evaluated the role of angiogenic factors and their relationship to adverse outcomes among Haitian women with PE. Material and Methods We measured plasma antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) levels in women with PE (n=35) compared to controls with no hypertensive disorders (NHD) (n=43) among subjects with singleton pregnancies that delivered at Hospital Albert Schweitzer (HAS) in Haiti. We divided the preeclamptic women into two groups, early onset (≤ 34 weeks) and late onset (>34 weeks) and examined relationships between sFlt1/PlGF ratios on admission and adverse outcomes (abruption, respiratory complications, stroke, renal insufficiency, eclampsia, maternal death, birth weight <2500 grams, or fetal/neonatal death) in women with PE subgroups as compared to NHD groups separated by week of admission. Data are presented as median (25th-75th centile), n (%), and proportions. Results: Among patients with PE, most (24/35) were admitted at term. Adverse outcome rates in PE were much higher among the early onset group compared to the late onset group (100.0% vs. 54.2%, P=0.007). Plasma angiogenic factors were dramatically altered in both subtypes of PE. Angiogenic factors also correlated with adverse outcomes in both subtypes of PE. The median sFlt1/PlGF ratios for subjects with early onset PE with any adverse outcome vs. NHD <=34 weeks with no adverse outcome were 703.1 (146.6, 1614.9) and 9.6 (3.5, 58.6); P<0.001). Among late onset group the median sFlt1/PlGF ratio for women with any adverse outcome was 130.7 (56.1, 242.6) versus 22.4 (10.2, 58.7; P=0.005) in NHD >34 weeks with no adverse outcome. Conclusion: PE-related adverse outcomes are common in women in Haiti and are associated with profound angiogenic imbalance regardless of gestational age at presentation.
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    Protein carbamylation is associated with heart failure and mortality in diabetic patients with end stage renal disease
    (2015) Drechsler, Christiane; Kalim, Sahir; Wenger, Julia B.; Suntharalingam, Pirianthini; Hod, Tammy; Thadhani, Ravi; Karumanchi, Subbian; Wanner, Christoph; Berg, Anders
    Serum carbamylated albumin (C-Alb) levels are associated with excess mortality in patients with diabetic end stage renal disease. To gain insight into the pathophysiology of carbamylation, we determined associations between C-Alb and causes of death in patients on chronic hemodialysis. The Die Deutsche Diabetes Dialyse Studie (4D study) was a randomized controlled trial testing the effects of atorvastatin on survival in diabetic patients on dialysis during a median follow-up of 4 years. We stratified 1,161 patients by C-Alb to see if differences in carbamylation altered the effects of atorvastatin on survival. Baseline C-Alb significantly correlated with serum cardiac stress markers troponin T and N-terminal pro-B-type-natriuretic peptide, and was associated with history of heart failure and arrhythmia. C-Alb was strongly associated with 1-year adjusted risk of CV mortality, sudden cardiac death and the 4-year risk of death from congestive heart failure (Hazard Ratios of 3.06, 3.78 and 4.64, respectively), but not with myocardial infarction or stroke. Patients with low C-Alb, treated with atorvastatin, experienced a significant improvement in their 4-year survival (Hazard Ratio 0.692). High C-Alb levels are associated with ongoing cardiac damage, risk of congestive heart failure and sudden cardiac death. Thus, carbamylation and uremic cardiomyopathy are associated in patients with diabetes mellitus and kidney disease. Additionally, statins were specifically beneficial to hemodialysis patients with low C-Alb.
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    Copy Number Variation at the APOL1 Locus
    (Public Library of Science, 2015) Ruchi, Rupam; Genovese, Giulio; Lee, Jessica; Charoonratana, Victoria T.; Bernhardy, Andrea J.; Alper, Seth; Kopp, Jeffrey B.; Thadhani, Ravi; Friedman, David; Pollak, Martin
    Two coding variants in the APOL1 gene (G1 and G2) explain most of the high rate of kidney disease in African Americans. APOL1-associated kidney disease risk inheritance follows an autosomal recessive pattern: The relative risk of kidney disease associated with inheritance of two high-risk variants is 7–30 fold, depending on the specific kidney phenotype. We wished to determine if the variability in phenotype might in part reflect structural differences in APOL1 gene. We analyzed sequence coverage from 1000 Genomes Project Phase 3 samples as well as exome sequencing data from African American kidney disease cases for copy number variation. 8 samples sequenced in the 1000 Genomes Project showed increased coverage over a ~100kb region that includes APOL2, APOL1 and part of MYH9, suggesting the presence of APOL1 copy number greater than 2. We reasoned that such duplications should be enriched in apparent G1 heterozygotes with kidney disease. Using a PCR-based assay, we observed the presence of this duplication in additional samples from apparent G0G1 or G0G2 individuals. The frequency of this APOL1 duplication was compared among cases (n = 123) and controls (n = 255) with apparent G0G1 heterozygosity. The presence of APOL1 duplication was observed in 4.06% of cases and 0.78% controls, preliminary evidence that this APOL1 duplication may alter susceptibility to kidney disease (p = 0.03). Taqman-based copy number assays confirmed the presence of 3 APOL1 copies in individuals positive for this specific duplication by PCR assay, but also identified a small number of individuals with additional APOL1 copies of presumably different structure. These observations motivate further studies to better assess the contribution of APOL1 copy number on kidney disease risk and on APOL1 function. Investigators and clinicians genotyping APOL1 should also consider whether the particular genotyping platform used is subject to technical errors when more than two copies of APOL1 are present.
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    Short and Long-Term Effects of Telaprevir on Kidney Function in Patients with Hepatitis C Virus Infection: A Retrospective Cohort Study
    (Public Library of Science, 2015) Sise, Meghan; Backman, Elke S.; Wenger, Julia B.; Wood, Brian R.; Sax, Paul; Chung, Raymond; Thadhani, Ravi; Kim, Arthur
    Background: Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment. Methods: Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine ≥ 0.3mg/dL from baseline during treatment with telaprevir. Results: Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m2 compared to the group with baseline eGFR ≥ 90 mL/min/1.73m2 (12 vs. 18 mL/min/1.73m2, P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m2 decrease in estimated glomerular filtration rate at twelve months in an adjusted model. Conclusions: Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m2 as previously reported.
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    The association of circulating angiogenic factors and HbA1c with the risk of preeclampsia in women with preexisting diabetes
    (Informa UK Limited, 2014) Cohen, Allison L.; Wenger, Julia B.; James-Todd, Tamarra; Lamparello, Brooke M.; Halprin, Elizabeth; Serdy, Shanti; Fan, Shuling; Horowitz, Gary Leigh; Lim, Kee-Hak; Rana, Sarosh; Takoudes, Tamara C.; Wyckoff, Jennifer A.; Thadhani, Ravi; Karumanchi, Subbian; Brown, Florence
    Objective: To assess whether glycemic control, soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) were associated with the development of preeclampsia (PE) or gestational hypertension (GHTN) in women with preexisting diabetes. Methods: Maternal circulating angiogenic factors (sFlt1 and PlGF) measured on automated platform were studied at four time points during pregnancy in women with diabetes (N = 159) and reported as multiples of the median (MOM) of sFlt1/PlGF ratio (median, 25th–75th percentile) noted in non-diabetic non-hypertensive control pregnant population (N = 139). Diagnosis of PE or GHTN was determined by review of de-identified clinical data. Results: PE developed in 12% (N = 19) and GHTN developed in 23% (N = 37) of the women with diabetes. Among diabetic women without PE or GHTN, median sFlt1/PlGF levels at 35–40 weeks was threefold higher than in non-diabetic controls [MOM 3.21(1.19–7.24), p = 0.0001]. Diabetic women who subsequently developed PE had even greater alterations in sFlt1/PlGF ratio during the third trimester [MOM for PE at 27–34 weeks 15.18 (2.37–26.86), at 35–40 weeks 8.61(1.20–18.27), p ≤ 0.01 for both windows compared to non-diabetic controls]. Women with diabetes who subsequently developed GHTN also had significant alterations in angiogenic factors during third trimester; however, these findings were less striking. Among women with diabetes, glycosylated hemoglobin (HbA1c) during the first trimester was higher in subjects who subsequently developed PE (7.7 vs 6.7%, p = 0.0001 for diabetic PE vs diabetic non-PE). Conclusions: Women with diabetes had a markedly altered anti-angiogenic state late in pregnancy that was further exacerbated in subjects who developed PE. Altered angiogenic factors may be one mechanism for the increased risk of PE in this population. Increased HbA1c in the first trimester of pregnancies in women with diabetes was strongly associated with subsequent PE.
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    Modeling risk for severe adverse outcomes using angiogenic factor measurements in women with suspected preterm preeclampsia
    (Blackwell Publishing Ltd, 2015) Palomaki, Glenn E; Haddow, James E; Haddow, Hamish R M; Salahuddin, Saira; Geahchan, Carl; Cerdeira, Ana Sofia; Verlohren, Stefan; Perschel, Frank H; Horowitz, Gary Leigh; Thadhani, Ravi; Karumanchi, S Ananth; Rana, Sarosh
    Introduction: Preeclampsia (PE) is a pregnancy-specific syndrome associated with adverse maternal and fetal outcomes. Patient-specific risks based on angiogenic factors might better categorize those who might have a severe adverse outcome. Methods: Women evaluated for suspected PE at a tertiary hospital (2009–2012) had pregnancy outcomes categorized as ‘referent’ or ‘severe’, based solely on maternal/fetal findings. Outcomes that may have been influenced by a PE diagnosis were considered ‘unclassified’. Soluble fms-like tyrosine kinase (sFlt1) and placental growth factor (PlGF) were subjected to bivariate discriminant modeling, allowing patient-specific risks to be assigned for severe outcomes. Results: Three hundred twenty-eight singleton pregnancies presented at ≤34.0 weeks' gestation. sFlt1 and PlGF levels were adjusted for gestational age. Risks above 5 : 1 (10-fold over background) occurred in 77% of severe (95% CI 66 to 87%) and 0.7% of referent (95% CI <0.1 to 3.8%) outcomes. Positive likelihood ratios for the modeling and validation datasets were 19 (95% CI 6.2–58) and 15 (95% CI 5.8–40) fold, respectively. Conclusions: This validated model assigns patient-specific risks of any severe outcome among women attending PE triage. In practice, women with high risks would receive close surveillance with the added potential for reducing unnecessary preterm deliveries among remaining women. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
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    Calciphylaxis in peritoneal dialysis patients: a single center cohort study
    (Dove Medical Press, 2016) Zhang, Yanchen; Corapi, Kristin M; Luongo, Maria; Thadhani, Ravi; Nigwekar, Sagar
    Background: Calciphylaxis is a rare but devastating condition in end-stage renal disease (ESRD) patients. Most research in the field of calciphylaxis is focused on hemodialysis (HD) patients; however, data on calciphylaxis incidence, risk factors, and mortality in peritoneal dialysis (PD) patients are limited. Methods: In this cohort study, we examined data from adult patients who initiated PD for ESRD management at our institute’s PD unit from January 2001 to December 2015. Associations with the development of calciphylaxis were examined for clinical, laboratory, and medication exposures. Incidence of calciphylaxis and mortality in PD patients who developed calciphylaxis were analyzed. Treatments administered to treat calciphylaxis in PD patients were summarized. Results: In this cohort of 63 patients, 7 patients developed calciphylaxis (incidence rate: 9.0 per 1,000 patient-years). Median age of PD patients who developed calciphylaxis was 50 years, 57% were white, 71% females, and 71% were previously on HD. Female sex, obesity, HD as a prior dialysis modality, recurrent hypotension, elevated time-averaged serum phosphorous levels, reduced time-averaged serum albumin levels, and warfarin therapy were associated with increased calciphylaxis risk in univariate logistic regression analyses. Intravenous sodium thiosulfate was administered in 57% of PD patients who developed calciphylaxis. One-year mortality in PD patients who developed calciphylaxis was 71% despite multimodal treatment including sodium thiosulfate, hyperbaric oxygen, cinacalcet, and wound debridement. Conclusion: Calciphylaxis is a rare but frequently fatal condition in PD patients. Our study provides critical early insights into calciphylaxis incidence, risk factors, and prognosis in PD patients. Sample size and characteristics of patients included in our study limit generalizability to overall PD population and warrant examination in larger independent studies.
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    Bioavailable Vitamin D Is More Tightly Linked to Mineral Metabolism than Total Vitamin D in Incident Hemodialysis Patients
    (Nature Publishing Group, 2012) Bhan, Ishir; Powe, Camille; Berg, Anders; Ankers, Elizabeth; Wenger, Julia; Karumanchi, Subbian; Thadhani, Ravi
    Prior studies showed conflicting results regarding the association between 25-hydroxyvitamin D (25(OH)D) levels and mineral metabolism in end-stage renal disease. In order to determine whether the bioavailable vitamin D (that fraction not bound to vitamin D binding protein) associates more strongly with measures of mineral metabolism than total levels, we identified 94 patients with previously measured 25(OH)D and 1,25-dihydroxyvitamin D \((1,25(OH)_2D)\) from a cohort of incident hemodialysis patients. Vitamin D binding protein was measured from stored serum samples. Bioavailable 25(OH)D and \(1,25(OH)_2D\) were determined using previously validated formulae. Associations with demographic factors and measures of mineral metabolism were examined. When compared with whites, black patients had lower levels of total, but not bioavailable, 25(OH)D. Bioavailable, but not total, 25(OH)D and \(1,25(OH)_2D\) were each significantly correlated with serum calcium. In univariate and multivariate regression analysis, only bioavailable 25(OH)D was significantly associated with parathyroid hormone levels. Hence, bioavailable vitamin D levels are better correlated with measures of mineral metabolism than total levels in patients on hemodialysis.