IU Indianapolis ScholarWorks :: Browsing by Author "Phillips, Carrie L."

Browsing by Author "Phillips, Carrie L."

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Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease
(MDPI, 2022-03-30) Collins, Kimberly S.; Eadon, Michael T.; Cheng, Ying-Hua; Barwinska, Daria; Ferreira, Ricardo Melo; McCarthy, Thomas W.; Janosevic, Danielle; Syed, Farooq; Maier, Bernhard; El-Achkar, Tarek M.; Kelly, Katherine J.; Phillips, Carrie L.; Hato, Takashi; Sutton, Timothy A.; Dagher, Pierre C.; Medicine, School of Medicine
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.
ANCA-associated vasculitis with cardiac valve vegetations in two teenage males: two case reports and a literature review
(BMC, 2022-10-28) Theisen, Alexandra; Phillips, Carrie L.; Rodriguez, Martha; Pediatrics, School of Medicine
Background: Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is a term used to describe systemic vasculitides that affect small and medium-sized blood vessels. Granulomatosis with Polyangiitis (GPA), a type of ANCA-associated vasculitis (AAV), is rare in children with an estimated prevalence of 3-4 per million, and even more rare is the manifestation of cardiac abnormalities secondary to ANCA-associated vasculitis in the pediatric population. Case presentation: We discuss the cases of two teenage males who presented with cardiac valvular lesions secondary to GPA in addition to sinus, pulmonary, renal, and cutaneous involvement. These findings of cardiac valvular abnormalities in GPA have rarely been described in the literature in pediatrics. Both patients were treated with rituximab, high-dose methylprednisolone, and therapeutic plasma exchange and showed improvement in their disease manifestations. Conclusions: A review of the literature revealed only five pediatric cases of ANCA-associated vasculitis with cardiac manifestations, and interestingly, three of the five had valvular involvement. Subsequent valvular involvement makes obtaining the diagnosis of ANCA-Associated Vasculitis difficult due to concern for underlying infectious endocarditis and can lead to misdiagnosis given the rarity of cardiac involvement in ANCA-associated vasculitis. Routine echocardiogram is not always completed in newly diagnosed AAV, yet cardiac involvement can lead to severe consequences as was seen with our first patient in the form of thromboembolic stroke. We discuss the importance of keeping AAV on the differential when cardiac lesions are present as well as the importance of regular cardiac screening in newly diagnosed patients with AAV, as it is a major factor of cardiac morbidity and mortality in the adult population and can contribute substantially to management decisions.
Application of Laser Microdissection to Uncover Regional Transcriptomics in Human Kidney Tissue
(MyJove Corporation, 2020-06-09) Barwinska, Daria; Ferkowicz, Michael J.; Cheng, Ying-Hua; Winfree, Seth; Dunn, Kenneth W.; Kelly, Katherine J.; Sutton, Timothy A.; Rovin, Brad H.; Parikh, Samir V.; Phillips, Carrie L.; Dagher, Pierre C.; El-Achkar, Tarek M.; Eadon, Michael T.; Medicine, School of Medicine
Gene expression analysis of human kidney tissue is an important tool to understand homeostasis and disease pathophysiology. Increasing the resolution and depth of this technology and extending it to the level of cells within the tissue is needed. Although the use of single nuclear and single cell RNA sequencing has become widespread, the expression signatures of cells obtained from tissue dissociation do not maintain spatial context. Laser microdissection (LMD) based on specific fluorescent markers would allow the isolation of specific structures and cell groups of interest with known localization, thereby enabling the acquisition of spatially-anchored transcriptomic signatures in kidney tissue. We have optimized an LMD methodology, guided by a rapid fluorescence-based stain, to isolate five distinct compartments within the human kidney and conduct subsequent RNA sequencing from valuable human kidney tissue specimens. We also present quality control parameters to enable the assessment of adequacy of the collected specimens. The workflow outlined in this manuscript shows the feasibility of this approach to isolate sub-segmental transcriptomic signatures with high confidence. The methodological approach presented here may also be applied to other tissue types with substitution of relevant antibody markers.
Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation
(John Wiley & Sons, Inc., 2015-05) Evan, Andrew P.; Worcester, Elaine M.; Williams, James C., Jr.; Sommer, Andre J.; Lingeman, James E.; Phillips, Carrie L.; Coe, Fredric L.; Department of Anatomy & Cell Biology, IU School of Medicine
Medullary sponge kidney (MSK) is associated with recurrent stone formation, but the clinical phenotype is unclear because patients with other disorders may be incorrectly labeled MSK. We studied 12 patients with histologic findings pathognomonic of MSK. All patients had an endoscopically recognizable pattern of papillary malformation, which may be segmental or diffuse. Affected papillae are enlarged and billowy, due to markedly enlarged inner medullary collecting ducts (IMCD), which contain small, mobile ductal stones. Patients had frequent dilation of Bellini ducts, with occasional mineral plugs. Stones may form over white (Randall's) plaque, but most renal pelvic stones are not attached, and have a similar morphology as ductal stones, which are a mixture of calcium oxalate and apatite. Patients had no abnormalities of urinary acidification or acid excretion; the most frequent metabolic abnormality was idiopathic hypercalciuria. Although both Runx2 and Osterix are expressed in papillae of MSK patients, no mineral deposition was seen at the sites of gene expression, arguing against a role of these genes in this process. Similar studies in idiopathic calcium stone formers showed no expression of these genes at sites of Randall's plaque. The most likely mechanism for stone formation in MSK appears to be crystallization due to urinary stasis in dilated IMCD with subsequent passage of ductal stones into the renal pelvis where they may serve as nuclei for stone formation.
Clinical, histopathologic and molecular features of idiopathic and diabetic nodular mesangial sclerosis in humans
(Oxford University Press, 2021) Eadon, Michael T.; Lampe, Sam; Baig, Mirza M.; Collins, Kimberly S.; Ferreira, Ricardo Melo; Mang, Henry; Cheng, Ying-Hua; Barwinska, Daria; El-Achkar, Tarek M.; Schwantes-An, Tae-Hwi; Winfree, Seth; Temm, Constance J.; Ferkowicz, Michael J.; Dunn, Kenneth W.; Kelly, Katherine J.; Sutton, Timothy A.; Moe, Sharon M.; Moorthi, Ranjani N.; Phillips, Carrie L.; Dagher, Pierre C.; Medicine, School of Medicine
Background: Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN). Methods: All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed. Results: ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10-6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10-6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN. Conclusions: Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.
Concordance of Solid Organ Biopsy Diagnoses With Hospital Autopsy and the Contribution of Biopsies to Death
(Springer Nature, 2023-01-17) Priemer, David S.; Curran, Joseph M.; Phillips, Carrie L.; Cummings, Oscar W.; Saxena, Romil; Pathology and Laboratory Medicine, School of Medicine
Biopsies of the liver, lung, and kidney are performed for many indications, including organ dysfunction, mass lesions, and allograft monitoring. The diagnosis depends on the sample, which may or may not be representative of the lesion or pathology in question. Further, biopsies are not without risk of complications. Autopsies are a resource for assessing the accuracy of biopsy diagnoses and evaluating possible complications. Herein, we aimed to compare liver, lung, and kidney biopsy diagnoses with those from autopsies conducted soon after the procedure and to assess the contribution of biopsy to mortality. A 28-year search of our database identified 147 patients who were autopsied after dying within 30 days of a liver, lung, or kidney biopsy. The concordance of the biopsy diagnosis with the autopsy findings was determined. Finally, medical records were reviewed to determine the likelihood that a biopsy contributed to the patient's death. The contribution of the biopsy to death was categorized as "unlikely," "possible," or "probable." Overall concordance between biopsy and autopsy diagnoses was 87% (128/147), including 95% (87/92), 71% (32/45), and 90% (9/10) for liver, lung, and kidney biopsies, respectively. Concordance was lower for biopsies of suspected neoplasms versus non-neoplastic diseases. Lung biopsy concordance was higher for wedge biopsy versus needle or forceps biopsy. A biopsy was determined to at least "possibly" contribute to death in 23 cases (16%). In conclusion, an autopsy is an important tool to validate liver, lung, or kidney biopsy diagnoses. Confirmation of biopsy diagnoses via post-mortem examination may be particularly valuable when patients die soon after the biopsy procedure. Furthermore, an autopsy is especially useful when patients die soon after a biopsy in order to determine what role, if any, the procedure played in their deaths. Though biopsy complications are uncommon, a biopsy may still contribute to or precipitate death in a small number of patients.
Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease
(American Society for Clinical Investigation, 2020-11-05) Otterpohl, Karla L.; Busselman, Brook W.; Ratnayake, Ishara; Hart, Ryan G.; Hart, Kimberly R.; Evans, Claire M.; Phillips, Carrie L.; Beach, Jordan R.; Ahrenkiel, Phil; Molitoris, Bruce A.; Surendran, Kameswaran; Chandrasekar, Indra; Pathology and Laboratory Medicine, School of Medicine
Actin-associated nonmuscle myosin II (NM2) motor proteins play critical roles in a myriad of cellular functions, including endocytosis and organelle transport pathways. Cell type–specific expression and unique subcellular localization of the NM2 proteins, encoded by the Myh9 and Myh10 genes, in the mouse kidney tubules led us to hypothesize that these proteins have specialized functional roles within the renal epithelium. Inducible conditional knockout (cKO) of Myh9 and Myh10 in the renal tubules of adult mice resulted in progressive kidney disease. Prior to overt renal tubular injury, we observed intracellular accumulation of the glycosylphosphatidylinositol-anchored protein uromodulin (UMOD) and gradual loss of Na+ K+ 2Cl– cotransporter from the apical membrane of the thick ascending limb epithelia. The UMOD accumulation coincided with expansion of endoplasmic reticulum (ER) tubules and activation of ER stress and unfolded protein response pathways in Myh9&10-cKO kidneys. We conclude that NM2 proteins are required for localization and transport of UMOD and loss of function results in accumulation of UMOD and ER stress–mediated progressive renal tubulointerstitial disease. These observations establish cell type–specific role(s) for NM2 proteins in regulation of specialized renal epithelial transport pathways and reveal the possibility that human kidney disease associated with MYH9 mutations could be of renal epithelial origin.
Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones
(Wiley, 2014-04) Evan, Andrew P.; Lingeman, James E.; Worcester, Elaine M.; Sommer, Andre J.; Phillips, Carrie L.; Williams, James C.; Coe, Fredric L.; Department of Anatomy & Cell Biology, School of Medicine
Our previous work has shown that stone formers who form calcium phosphate (CaP) stones that contain any brushite (BRSF) have a distinctive renal histopathology and surgical anatomy when compared with idiopathic calcium oxalate stone formers (ICSF). Here we report on another group of idiopathic CaP stone formers, those forming stone containing primarily hydroxyapatite, in order to clarify in what ways their pathology differs from BRSF and ICSF. Eleven hydroxyapatite stone formers (HASF) (2 males, 9 females) were studied using intra-operative digital photography and biopsy of papillary and cortical regions to measure tissue changes associated with stone formation. Our main finding is that HASF and BRSF differ significantly from each other and that both differ greatly from ICSF. Both BRSF and ICSF patients have significant levels of Randall's plaque compared with HASF. Intra-tubular deposit number is greater in HASF than BRSF and nonexistent in ICSF while deposit size is smaller in HASF than BRSF. Cortical pathology is distinctly greater in BRSF than HASF. Four attached stones were observed in HASF, three in 25 BRSF and 5-10 per ICSF patient. HASF and BRSF differ clinically in that both have higher average urine pH, supersaturation of CaP, and calcium excretion than ICSF. Our work suggests that HASF and BRSF are two distinct and separate diseases and both differ greatly from ICSF.
Crystalglobulinemia causing cutaneous vasculopathy and acute nephropathy in a kidney transplant patient
(Elsevier, 2021) Wilson, Chase; Phillips, Carrie L.; Klenk, Alison; Kuhar, Matthew; Yaqub, Muhammad S.; Dermatology, School of Medicine
We present a rare case of crystalglobulinemia causing cutaneous vasculopathy and acute nephropathy in a 66-year-old female kidney transplant recipient. The patient presented with acute kidney injury (AKI), volume overload, anuria, retiform purpura, and blue-black necrosis of her toes. She received a living kidney transplant 7 months earlier with baseline creatinine of 0.6 mg/dl. Transplant kidney biopsy showed massive pseudo-thrombi filling glomerular capillary lumina. Electron microscopy of thrombi revealed an ultrastructural crystalline pattern of linear and curvilinear bundles with ladder-like periodicity typical of crystalglobulin-induced nephropathy. Similar crystalline pseudo-thrombi were detected ultrastructurally in a skin biopsy specimen, indicating systemic involvement. She required several sessions of hemodialysis. Plasmapheresis was initiated to decrease the number of circulating crystalglobulins. In order to treat the underlying paraproteinemia, the patient was started on bortezomib and dexamethasone. After treatment with five cycles of bortezomib, the patient's free kappa to lambda ratio improved to 2.35 from 5.52. Acute kidney injury (AKI) and the cutaneous vasculopathy gradually improved with treatment. This is an extremely rare occurrence of crystalglobulin in a living kidney transplant recipient.
Incidence and Importance of Calcium Deposition in Kidney Biopsy Specimens
(Karger, 2022) Gaddy, Anna; Schwantes-An, Tae-Hwi; Moorthi, Ranjani N.; Phillips, Carrie L.; Eadon, Michael T.; Moe, Sharon M.; Medical and Molecular Genetics, School of Medicine
Introduction: Calcification on native kidney biopsy specimens is often noted by pathologists, but the consequence is unknown. Methods: We searched the pathology reports in the Biopsy Biobank Cohort of Indiana for native biopsy specimens with calcification. Results: Of the 4,364 specimens, 416 (9.8%) had calcification. We compared clinical and histopathology findings in those with calcification (n = 429) compared to those without calcification (n = 3,936). Patients with calcification were older, had more comorbidities, lower estimated glomerular filtration rates (eGFR), were more likely to have hyaline arteriosclerosis, interstitial fibrosis/tubular atrophy, and a primary pathologic diagnosis of acute tubular injury or acute tubular necrosis when compared to patients without calcification. Patients with calcium oxalate deposition alone, compared to calcium phosphate or mixed calcifications, had fewer comorbidities but were more likely to have a history of gastric bypass surgery or malabsorption and take vitamin D. In patients with two or more years of follow-up, multivariate analyses showed the presence of calcification (HR 0.59, 0.38-0.92, p = 0.02) and higher eGFR (HR 0.76, 0.73-0.79, p < 0.001), was associated with decreased likelihood of progressing to end-stage renal disease. The presence of calcification was also associated with a reduced slope/decline in eGFR compared to known biopsy and clinical risk factors for decline in kidney function. We hypothesized this was due to more recoverable acute kidney injury (AKI) and found more severe acute kidney injury network stage in patients with kidney calcification but also greater improvement over time. Discussion/conclusion: In summary, we demonstrated that calcification on kidney biopsy specimens was associated with a better prognosis than those without calcification due to the association with recoverable AKI.

Browsing by Author "Phillips, Carrie L."

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