Browsing by Author "Lieske, John C."

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    Geobiology reveals how human kidney stones dissolve in vivo
    (Springer Nature, 2018-09-13) Sivaguru, Mayandi; Saw, Jessia J.; Williams, James C. Jr.; Lieske, John C.; Krambeck, Amy E.; Romero, Michael F.; Chia, Nicholas; Schwaderer, Andrew L.; Alcalde, Reinaldo E.; Bruce, Wililam J.; Wildman, Derek E.; Fried, Glenn A.; Werth, Charles J.; Reeder, Richard J.; Yau, Peter M.; Sanford, Robert A.; Fouke, Bruce W.; Anatomy and Cell Biology, IU School of Medicine
    More than 10% of the global human population is now afflicted with kidney stones, which are commonly associated with other significant health problems including diabetes, hypertension and obesity. Nearly 70% of these stones are primarily composed of calcium oxalate, a mineral previously assumed to be effectively insoluble within the kidney. This has limited currently available treatment options to painful passage and/or invasive surgical procedures. We analyze kidney stone thin sections with a combination of optical techniques, which include bright field, polarization, confocal and super-resolution nanometer-scale auto-fluorescence microscopy. Here we demonstrate using interdisciplinary geology and biology (geobiology) approaches that calcium oxalate stones undergo multiple events of dissolution as they crystallize and grow within the kidney. These observations open a fundamentally new paradigm for clinical approaches that include in vivo stone dissolution and identify high-frequency layering of organic matter and minerals as a template for biomineralization in natural and engineered settings.
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    In Vivo Entombment of Bacteria and Fungi during Calcium Oxalate, Brushite, and Struvite Urolithiasis
    (Wolters Kluwer, 2020-12-23) Saw, Jessica J.; Sivaguru, Mayandi; Wilson, Elena M.; Dong, Yiran; Sanford, Robert A.; Fields, Chris J.; Cregger, Melissa A.; Merkel, Annette C.; Bruce, William J.; Weber, Joseph R.; Lieske, John C.; Krambeck, Amy E.; Rivera, Marcelino E.; Large, Timothy; Lange, Dirk; Bhattacharjee, Ananda S.; Romero, Michael F.; Chia, Nicholas; Fouke, Bruce W.; Urology, School of Medicine
    Background: Human kidney stones form via repeated events of mineral precipitation, partial dissolution, and reprecipitation, which are directly analogous to similar processes in other natural and manmade environments, where resident microbiomes strongly influence biomineralization. High-resolution microscopy and high-fidelity metagenomic (microscopy-to-omics) analyses, applicable to all forms of biomineralization, have been applied to assemble definitive evidence of in vivo microbiome entombment during urolithiasis. Methods: Stone fragments were collected from a randomly chosen cohort of 20 patients using standard percutaneous nephrolithotomy (PCNL). Fourier transform infrared (FTIR) spectroscopy indicated that 18 of these patients were calcium oxalate (CaOx) stone formers, whereas one patient formed each formed brushite and struvite stones. This apportionment is consistent with global stone mineralogy distributions. Stone fragments from seven of these 20 patients (five CaOx, one brushite, and one struvite) were thin sectioned and analyzed using brightfield (BF), polarization (POL), confocal, super-resolution autofluorescence (SRAF), and Raman techniques. DNA from remaining fragments, grouped according to each of the 20 patients, were analyzed with amplicon sequencing of 16S rRNA gene sequences (V1-V3, V3-V5) and internal transcribed spacer (ITS1, ITS2) regions. Results: Bulk-entombed DNA was sequenced from stone fragments in 11 of the 18 patients who formed CaOx stones, and the patients who formed brushite and struvite stones. These analyses confirmed the presence of an entombed low-diversity community of bacteria and fungi, including Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Aspergillus niger. Bacterial cells approximately 1 μm in diameter were also optically observed to be entombed and well preserved in amorphous hydroxyapatite spherules and fans of needle-like crystals of brushite and struvite. Conclusions: These results indicate a microbiome is entombed during in vivo CaOx stone formation. Similar processes are implied for brushite and struvite stones. This evidence lays the groundwork for future in vitro and in vivo experimentation to determine how the microbiome may actively and/or passively influence kidney stone biomineralization.
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    Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia
    (PLOS, 2017-11-16) Ma, Lijie; Liu, Yan; Landry, Nichole K.; El-Achkar, Tarek M.; Lieske, John C.; Wu, Xue-Ru; Medicine, School of Medicine
    Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys’ thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance. Both the young and the old transgenic mice had significantly higher serum uric acid and its catabolic product, allantoin, than age-matched wild-type mice. This THP mutation apparently caused primary defects in TAL by compromising the luminal translocation and reabsorptive functions of NKCC2 and ROMK and secondary responses in proximal tubules by upregulating NHE3 and URAT1. Our results strongly suggest that the progressive worsening of kidney functions reflects the accumulation of the deleterious effects of the misfolded mutant THP and the compensatory responses. Transgenic mice recapitulating human THP/uromodulin-associated kidney diseases could be used to elucidate their pathogenesis and test novel therapeutic strategies.
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    Randomized Placebo-Controlled Trial of Reloxaliase in Enteric Hyperoxaluria
    (NEJM Group, 2022-05-06) Lieske, John C.; Lingeman, James E.; Ferraro, Pietro M.; Wyatt, Christina M.; Tosone, Christine; Kausz, Annamaria T.; Knauf, Felix; Urology, School of Medicine
    BACKGROUND Enteric hyperoxaluria is caused by increased intestinal oxalate absorption and can lead to kidney stones, chronic kidney disease, and kidney failure. Reloxaliase is an orally administered recombinant enzyme that degrades oxalate along the gastrointestinal tract, thereby preventing its absorption. METHODS We randomly assigned participants with enteric hyperoxaluria to reloxaliase or placebo, three to five times per day with food for 4 weeks. The primary end point was percent change from baseline in 24-hour urinary oxalate (UOx) excretion during weeks 1 to 4. Secondary end points included the proportion of participants with more than a 20% reduction in 24-hour UOx and an efficacy assessment in the bariatric surgery subgroup. RESULTS A total of 115 patients underwent randomization. The 24-hour UOx decreased from a baseline geometric mean of 83.2 to 67.4 mg/24 hr during weeks 1 to 4 in reloxaliase-treated participants. Corresponding data for placebo-treated participants were 84.2 to 78.1 mg/24 hr. Estimates from the mixed-effect model repeated-measures (MMRM) analysis showed a 22.6% reduction in geometric mean UOx during weeks 1 to 4 for reloxaliase and 9.7% for placebo, a difference of 14.3 percentage points (95% confidence interval [CI], 4.9 to 22.8; P=0.004). A 20% or greater reduction in 24-hour UOx was observed in 48.3% of reloxaliase-treated participants and 31.6% of placebo-treated participants (P=0.06). In the bariatric surgery subgroup, MMRM analysis showed a 21.2% reduction in geometric mean UOx for reloxaliase and a 6.0% reduction for placebo, for a difference of 16.2 percentage points (95% CI, 4.2% to 26.7%). Adverse events occurred in 69% of reloxaliase-treated participants versus 53% of individuals taking placebo and were most commonly gastrointestinal. All but one of the adverse events were grade 1 or 2 in severity; no reloxaliase-treated participants discontinued the study. CONCLUSIONS Reloxaliase treatment for 4 weeks reduced UOx excretion in patients with enteric hyperoxaluria; adverse events were relatively common, but not dose-limiting. These data establish the foundation for a clinical trial to determine the impact of reloxaliase on nephrolithiasis in patients with enteric hyperoxaluria. (Funded by Allena Pharmaceuticals; ClinicalTrials.gov number, NCT03456830.)
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    Tamm-Horsfall protein/uromodulin deficiency elicits tubular compensatory responses leading to hypertension and hyperuricemia
    (American Physiological Society, 2018-06-01) Liu, Yan; Goldfarb, David S.; El-Achkar, Tarek M.; Lieske, John C.; Wu, Xue-Ru; Medicine, School of Medicine
    Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, and confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses, resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricemia.
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    Understanding, justifying, and optimizing radiation exposure for CT imaging in nephrourology
    (Springer Nature, 2019-04) Ferrero, Andrea; Takahashi, Naoki; Vrtiska, Terri J.; Krambeck, Amy E.; Lieske, John C.; McCollough, Cynthia H.; Urology, School of Medicine
    An estimated 4-5 million CT scans are performed in the USA every year to investigate nephrourological diseases such as urinary stones and renal masses. Despite the clinical benefits of CT imaging, concerns remain regarding the potential risks associated with exposure to ionizing radiation. To assess the potential risk of harmful biological effects from exposure to ionizing radiation, understanding the mechanisms by which radiation damage and repair occur is essential. Although radiation level and cancer risk follow a linear association at high doses, no strong relationship is apparent below 100 mSv, the doses used in diagnostic imaging. Furthermore, the small theoretical increase in risk of cancer incidence must be considered in the context of the clinical benefit derived from a medically indicated CT and the likelihood of cancer occurrence in the general population. Elimination of unnecessary imaging is the most important method to reduce imaging-related radiation; however, technical aspects of medically justified imaging should also be optimized, such that the required diagnostic information is retained while minimizing the dose of radiation. Despite intensive study, evidence to prove an increased cancer risk associated with radiation doses below ~100 mSv is lacking; however, concerns about ionizing radiation in medical imaging remain and can affect patient care. Overall, the principles of justification and optimization must remain the basis of clinical decision-making regarding the use of ionizing radiation in medicine.