Hostname: page-component-8448b6f56d-42gr6 Total loading time: 0 Render date: 2024-04-24T22:03:30.127Z Has data issue: false hasContentIssue false

New imaging tools to measure nephron number in vivo: opportunities for developmental nephrology

Published online by Cambridge University Press:  27 January 2020

K.M. Bennett*
Affiliation:
Department of Radiology, Washington University, Saint Louis, MO, USA
E.J. Baldelomar
Affiliation:
Department of Radiology, Washington University, Saint Louis, MO, USA
D. Morozov
Affiliation:
Department of Radiology, Washington University, Saint Louis, MO, USA
R.L Chevalier
Affiliation:
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
J.R Charlton
Affiliation:
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
*
Address for correspondence: K.M. Bennett, PhD, Washington University School of Medicine, Biomedical Magnetic Resonance Laboratory, 4525 Scott Ave, Room 2313, St. Louis, MO63110, USA. Email: kmbennett@wustl.edu

Abstract

The mammalian kidney is a complex organ, requiring the concerted function of up to millions of nephrons. The number of nephrons is constant after nephrogenesis during development, and nephron loss over a life span can lead to susceptibility to acute or chronic kidney disease. New technologies are under development to count individual nephrons in the kidney in vivo. This review outlines these technologies and highlights their relevance to studies of human renal development and disease.

Type
Review
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Little, MH, McMahon, AP. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb Perspect Biol. 2012; 4, pii: a008300. 1–18.10.1101/cshperspect.a008300CrossRefGoogle ScholarPubMed
Jain, S, Encinas, M, Johnson, EM Jr., Milbrandt, J. Critical and distinct roles for key RET tyrosine docking sites in renal development. Genes Dev. 2006; 20, 321.10.1101/gad.1387206CrossRefGoogle ScholarPubMed
Hinchliffe, SA, Sargent, PH, Howard, CV, Chan, YF, van Velzen, D. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest. 1991; 64, 777.Google ScholarPubMed
Hartman, HA, Lai, HL, Patterson, LT. Cessation of renal morphogenesis in mice. Dev Biol. 2007; 310, 379.CrossRefGoogle ScholarPubMed
Charlton, JR, Springsteen, CH, Carmody, JB. Nephron number and its determinants in early life: a primer. Pediatr Nephrol. 2014; 29, 2299.10.1007/s00467-014-2758-yCrossRefGoogle ScholarPubMed
Keller, G, Zimmer, G, Mall, G, Ritz, E, Amann, K. Nephron number in patients with primary hypertension. N Engl J Med. 2003; 348, 101.CrossRefGoogle ScholarPubMed
Gross, ML, Amann, K, Ritz, E. Nephron number and renal risk in hypertension and diabetes. J Am Soc Nephrol. 2005; 16 Suppl 1, S27.Google ScholarPubMed
Nyengaard, JR, Bendtsen, TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992; 232, 194.10.1002/ar.1092320205CrossRefGoogle ScholarPubMed
Bertram, JF, Cullen-McEwen, LA, Egan, GF, et al. Why and how we determine nephron number. Pediatr Nephrol. 2014; 29, 575.10.1007/s00467-013-2600-yCrossRefGoogle ScholarPubMed
Hayman, JM, Johnston, SM. Experiments on the relation of creatinine and urea clearance tests of kidney function and the number of glomeruli in the human kidney obtained at autopsy. J Clin Invest. 1933; 12, 877.10.1172/JCI100546CrossRefGoogle ScholarPubMed
Zhang, Z, Quinlan, J, Hoy, W, et al. A common RET variant is associated with reduced newborn kidney size and function. J Am Soc Nephrol. 2008; 19, 2027.10.1681/ASN.2007101098CrossRefGoogle ScholarPubMed
Luyckx, VA, Brenner, BM. The clinical importance of nephron mass. J Am Soc Nephrol. 2010; 21, 898.CrossRefGoogle ScholarPubMed
Cullen-McEwen, LA, Kett, MM, Dowling, J, Anderson, WP, Bertram, JF. Nephron number, renal function, and arterial pressure in aged GDNF heterozygous mice. Hypertension. 2003; 41, 335.CrossRefGoogle ScholarPubMed
Bertram, JF, Douglas-Denton, RN, Diouf, B, Hughson, MD, Hoy, WE. Human nephron number: implications for health and disease. Pediatr Nephrol. 2011; 26, 1529.10.1007/s00467-011-1843-8CrossRefGoogle ScholarPubMed
Brenner, BM, Mackenzie, HS. Nephron mass as a risk factor for progression of renal disease. Kidney Int Suppl. 1997; 63, S124.Google ScholarPubMed
Chevalier, RL. Evolution, kidney development, and chronic kidney disease. Semin Cell Dev Biol. 2019; 91, 119.10.1016/j.semcdb.2018.05.024CrossRefGoogle ScholarPubMed
Lindstrom, NO, McMahon, JA, Guo, J, et al. Conserved and divergent features of human and mouse kidney organogenesis. J Am Soc Nephrol. 2018; 29, 785.10.1681/ASN.2017080887CrossRefGoogle ScholarPubMed
Lindstrom, NO, Tran, T, Guo, J, et al. Conserved and divergent molecular and anatomic features of human and mouse nephron patterning. J Am Soc Nephrol. 2018; 29, 825.10.1681/ASN.2017091036CrossRefGoogle ScholarPubMed
Wessely, O, Cerqueira, DM, Tran, U, Kumar, V, Hassey, JM, Romaker, D. The bigger the better: determining nephron size in kidney. Pediatr Nephrol. 2014; 29, 525.10.1007/s00467-013-2581-xCrossRefGoogle ScholarPubMed
Maluf, NSR, Gassman, JJ. Kidneys of the killer whale and significance of reniculism. Anat Rec. 1998; 250, 34.10.1002/(SICI)1097-0185(199801)250:1<34::AID-AR4>3.0.CO;2-E3.0.CO;2-E>CrossRefGoogle Scholar
Lane, N. A unifying view of ageing and disease: the double-agent theory. J Theor Biol. 2003; 225, 531.CrossRefGoogle ScholarPubMed
Denic, A, Lieske, JC., Chakkera, HA., et al. The substantial loss of nephrons in healthy human kidneys with aging. J Am Soc Nephrol. 2016; 28, 313.CrossRefGoogle ScholarPubMed
Bertram, JF, Soosaipillai, MC, Ricardo, SD, Ryan, GB. Total numbers of glomeruli and individual glomerular cell types in the normal rat kidney. Cell Tissue Res. 1992; 270, 37.10.1007/BF00381877CrossRefGoogle ScholarPubMed
Cullen-McEwen, LA, Armitage, JA, Nyengaard, JR, Moritz, KM, Bertram, JF. A design-based method for estimating glomerular number in the developing kidney. Am J Physiol Renal Physiol. 2011; 300, F1448.10.1152/ajprenal.00055.2011CrossRefGoogle ScholarPubMed
Kanzaki, G, Puelles, VG, Cullen-McEwen, LA, et al. New insights on glomerular hyperfiltration: a Japanese autopsy study. JCI Insight. 2017; 2, 111.10.1172/jci.insight.94334CrossRefGoogle ScholarPubMed
Bennett, KM, Zhou, H, Sumner, JP, et al. MRI of the basement membrane using charged nanoparticles as contrast agents. Magn Reson Med. 2008; 60, 564.10.1002/mrm.21684CrossRefGoogle ScholarPubMed
Danon, D, Goldstein, L, Marikovsky, Y, Skutelsky, E. Use of cationized ferritin as a label of negative charges on cell surfaces. J Ultrastruct Res. 1972; 38, 500.10.1016/0022-5320(72)90087-1CrossRefGoogle ScholarPubMed
Brooks, RA, Vymazal, J, Goldfarb, RB, Bulte, JW, Aisen, P. Relaxometry and magnetometry of ferritin. Magn Reson Med. 1998; 40, 227.10.1002/mrm.1910400208CrossRefGoogle ScholarPubMed
Bulte, JW, Douglas, T, Mann, S, et al. Magnetoferritin: Biomineralization as a novel molecular approach in the design of iron-oxide-based magnetic resonance contrast agents. Invest Radiol. 1994; 29 Suppl 2, S214.10.1097/00004424-199406001-00071CrossRefGoogle ScholarPubMed
Beeman, SC, Zhang, M, Gubhaju, L, et al. Measuring glomerular number and size in perfused kidneys using MRI.. Am J Physiol Renal Physiol. 2011; 300, F1454.10.1152/ajprenal.00044.2011CrossRefGoogle ScholarPubMed
Baldelomar, EJ, Charlton, JR, Beeman, SC, et al. Phenotyping by magnetic resonance imaging nondestructively measures glomerular number and volume distribution in mice with and without nephron reduction. Kidney Int. 2016; 89, 498.10.1038/ki.2015.316CrossRefGoogle ScholarPubMed
Heilmann, M, Neudecker, S, Wolf, I, et al. Quantification of glomerular number and size distribution in normal rat kidneys using magnetic resonance imaging. Nephrol Dial Transplant. 2012; 27, 100.10.1093/ndt/gfr273CrossRefGoogle ScholarPubMed
Chacon-Caldera, J, Geraci, S, Kramer, P, et al. Fast glomerular quantification of whole ex vivo mouse kidneys using magnetic resonance imaging at 9.4 Tesla. Z Med Phys. 2016; 26, 54.CrossRefGoogle ScholarPubMed
Beeman, SC, Cullen-McEwen, LA, Puelles, VG, et al. MRI-based glomerular morphology and pathology in whole human kidneys. Am J Physiol Renal Physiol. 2014; 306, F1381.10.1152/ajprenal.00092.2014CrossRefGoogle ScholarPubMed
Charlton, JR, Baldelomar, EJ, deRonde, K, et al. Nephron loss detected by MRI following neonatalacute kidney injury in rabbits. Pediatr Res. (In Press) 2019.Google ScholarPubMed
Perrien, DS, Saleh, MA, Takahashi, K, et al. Novel methods for microCT-based analyses of vasculature in the renal cortex reveal a loss of perfusable arterioles and glomeruli in eNOS-/- mice. BMC Nephrol. 2016; 17, 24.10.1186/s12882-016-0235-5CrossRefGoogle ScholarPubMed
Xie, L, Koukos, G, Barck, K, et al. Micro-CT imaging and structural analysis of glomeruli in a model of Adriamycin-induced nephropathy. Am J Physiol Renal Physiol. 2019; 316, F76.10.1152/ajprenal.00331.2018CrossRefGoogle Scholar
Klingberg, A, Hasenberg, A, Ludwig-Portugall, I, et al. Fully automated evaluation of total glomerular number and capillary tuft size in nephritic kidneys using lightsheet microscopy. J Am Soc Nephrol. 2017; 28, 452.10.1681/ASN.2016020232CrossRefGoogle ScholarPubMed
Sasaki, T, Tsuboi, N, Okabayashi, Y, et al. Estimation of nephron number in living humans by combining unenhanced computed tomography with biopsy-based stereology. Sci Rep. 2019; 9, 14400.CrossRefGoogle ScholarPubMed
Baldelomar, EJ, Charlton, JR, Beeman, SC, Bennett, KM. Measuring rat kidney glomerular number and size in vivo with MRI. Am J Physiol Renal Physiol. 2018; 314, F399.10.1152/ajprenal.00399.2017CrossRefGoogle ScholarPubMed
Baldelomar, EJ, Charlton, JR, deRonde, KA, Bennett, KM. In vivo measurements of kidney glomerular number and size in healthy and Os(/+) mice using MRI. Am J Physiol Renal Physiol. 2019; 317, F865.CrossRefGoogle ScholarPubMed
Qian, C, Yu, X, Chen, DY, et al. Wireless amplified nuclear MR detector (WAND) for high-spatial-resolution MR imaging of internal organs: preclinical demonstration in a rodent model. Radiology. 2013; 268, 228.10.1148/radiol.13121352CrossRefGoogle Scholar
Clavijo Jordan, MV, Beeman, SC, Baldelomar, EJ, Bennett, KM. Disruptive chemical doping in a ferritin-based iron oxide nanoparticle to decrease r2 and enhance detection with T1-weighted MRI. Contrast Media Mol Imaging. 2014; 9, 323.10.1002/cmmi.1578CrossRefGoogle Scholar
Meldrum, FC, Heywood, BR, Mann, S. Magnetoferritin: characterization of a novel superparamagnetic MR contrast agent. Science. 1992; 257, 522.CrossRefGoogle Scholar
Bulte, JW, Douglas, T, Mann, S, et al. Magnetoferritin: characterization of a novel superparamagnetic MR contrast agent. J Magn Reson Imaging. 1994; 4, 497.10.1002/jmri.1880040343CrossRefGoogle ScholarPubMed
Jordan, VC, Caplan, MR, Bennett, KM. Simplified synthesis and relaxometry of magnetoferritin for magnetic resonance imaging. Magn Reson Med. 2010; 64, 1260.10.1002/mrm.22526CrossRefGoogle ScholarPubMed
Xie, L, Dibb, R, Cofer, GP, et al. Susceptibility tensor imaging of the kidney and its microstructural underpinnings. Magn Reson Med. 2015; 73, 1270.10.1002/mrm.25219CrossRefGoogle ScholarPubMed
Xie, L, Bennett, KM, Liu, C, Johnson, GA, Zhang, JL, Lee, VS. MRI tools for assessment of microstructure and nephron function of the kidney. Am J Physiol Renal Physiol. 2016; 311, F1109.CrossRefGoogle ScholarPubMed
Denic, A, Elsherbiny, H, Rule, AD. In-vivo techniques for determining nephron number. Curr Opin Nephrol Hypertens. 2019; 28, 545.10.1097/MNH.0000000000000540CrossRefGoogle ScholarPubMed