Compensatory Renal Growth After Unilateral Or Subtotal Nephrectomy in the Ovine Fetus
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nature publishing group Articles Basic Science Investigation Compensatory renal growth after unilateral or subtotal nephrectomy in the ovine fetus Sébastien Sammut1,2,3, Luc Behr1, Mehrak Hekmati1, Marie Claire Gubler4, Kathleen Laborde5 and Martine Lelièvre Pégorier2,3 BACKGROUND: Clinical and experimental studies show that recorded to be larger than that in normal human. Moreover, unilateral (1/2Nx) and subtotal nephrectomy (5/6Nx) in adults kidney ultrasound studies performed during gestation show result in compensatory renal growth without formation of new that the renal compensation begins before birth (11). In con- nephrons. During nephrogenesis, the response to renal mass trast to the adult, as nephrogenesis is not complete before reduction has not been fully investigated. 36 wk of gestation, enlargement of the remaining kidney could METHODS: Ovine fetuses underwent 1/2Nx, 5/6Nx, or sham involve the formation of new nephrons. In this setting, each surgery (sham) at 70 d of gestation (term: 150 d), when nephro- nephron may have normal dimensions with subnormal single genesis is active. At 134 d, renal function was determined, perfusion and filtration, and the risk of glomeruli injury would fetuses were killed, and kidneys were further analyzed at the be proportionately reduced. Unfortunately, in these studies cellular and molecular levels. Additional fetuses subjected to (9–11), nephron number was not reported. Prevalence of uni- 5/6Nx were killed at 80 and 90 d of gestation to investigate the lateral renal agenesis has been reported in 0.48–0.58 per 1,000 kinetics of the renal compensatory process. live births (12); a 13% decrease in renal function and a 47% RESULTS: At 134 d, in 1/2Nx, a significant increase in kidney increase in hypertension incidence have been reported in adult weight and estimated glomerular number was observed. In patients with unilateral agenesis (13). Although function of the 5/6Nx, the early and marked catch-up in kidney weight and remaining kidney has been shown to be stable over many years estimated glomerular number was associated with a striking in healthy adult human kidney–transplant donors, this may butterfly-like remodeling of the kidney that developed within not be wholly reassuring for children whose life expectancy the first 10 d following nephrectomy. In all groups, in utero glo- much exceeds the period of follow-up of uninephrectomized merular filtration rates were similar. adult. CONCLUSION: Compensatory renal growth was observed Few experimental data are available in the developing ani- after parenchymal reduction in both models; however, the mal and are restricted to the 1/2Nx model (14–19). The major- resulting compensatory growth was strikingly different. After ity of these studies was performed in rodents and shows an 5/6Nx, the remnant kidney displayed a butterfly-like remodel- increase in kidney weight but not in the number of newly ing, and glomerular number was restored. formed nephrons. As nephrogenesis continues after birth in these species, studies were carried out in neonate animals, at ithin several weeks after unilateral (1/2Nx) or subtotal the end of the nephrogenesis process and in a different setting, W(5/6Nx) nephrectomy in adults, the remaining kidney ex utero. One study performed in the ewe (15), a species in increases in size in response to hyperfiltration and begins to which nephrogenesis is very similar to humans (20) and ends compensate for its missing partner (1), ensuring homeosta- before birth, showed that for the first time, renal compensa- sis. Renal hypertrophy develops due to glomeruli and tubules tory growth was associated with an increase in nephron num- enlargement (2–4), but as nephrogenesis is complete, there ber, although insufficient to fully compensate for the missing are no more nephrons formed. As single-nephron glomerular kidney. The authors speculated that removing one kidney at filtration rate increases (5,6), the solitary kidney undergoes a time when nephrogenesis is more active may have resulted structural injuries increasing the risk for the development of in activation of unknown genes and prolonged nephrogenesis, proteinuria, hypertension, and, ultimately, renal failure (7,8). allowing additional nephrons endowment. In human fetuses also, studies suggest that compensatory To test further this hypothesis, we performed 1/2Nx in renal hypertrophy can develop in utero, although the placenta sheep fetuses earlier, yet (70 d of gestation) in the course of is the major regulator of fetal homeostasis: the size of the one nephrogenesis (duration: 27–120 d of gestation; term: 150 d) functional kidney in human with either unilateral agenesis (9) expecting that increase in nephron number would be more or contralateral multicystic dysplastic kidney (10) has been important, possibly compensating totally for the missing The first two authors contributed equally to this work. 1IMM Recherche, Institut Mutualiste Montsouris Recherche, Paris, France; 2INSERM U 872, Centre de Recherche des Cordeliers UMRS 872, Université Pierre et Marie Curie – Paris 6, Paris, France; 3Université Paris Descartes – Paris 5, Paris, France; 4INSERM U983, Hôpital Necker – Enfants Malades, Université Paris Descartes – Paris 5, Paris, France; 5Department of Physiology, Hôpital Necker – Enfants Malades, Université Paris Descartes – Paris 5, Paris, France. Correspondence: Sébastien Sammut ([email protected]) Received 19 October 2012; accepted 6 April 2013; advance online publication 16 October 2013. doi:10.1038/pr.2013.149 624 Pediatric RESEarcH Volume 74 | Number 6 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc. renin (24).During cells nephrogenesis, epithelial to cells enchymal (23); totic Pax-2 that known is (21);it development inrenal role amajor play and stages early at inmesenchyme expressed both strongly process. pensatory the com initiating identify the mechanisms to process, genesis the nephro during 90days, killed80and at were gestation d of 70 at 5/6Nx to subjected fetuses Additional gestation). (134 dof beto complete known is when nephrogenesis levels cellular and functional, the morphological, at investigated were ment renal develop on reduction parenchymal of effects The 5/6Nx. of models ferent dif in two renal development on the effects compared therefore and reduction the initial renal depend on may response satory the compen of the intensity that also hypothesized We kidney. fetal morphological abnormalities were observed. were abnormalities fetal morphological ( animals sham age-matched to different not was reduction nephron to subjected Body infetuses weight models. inour these genes of the expression studied we reduction, observednephron growth renal after inthe compensatory involved activation of the mechanism (UB)branching bud ureteric RESULTS Copyright © 2013 International Pediatric Research Foundation, Inc. Foundation, Research ©2013InternationalCopyright Pediatric * 1/2Nx, nephrectomy; bodyweight; unilateral 5/6Nx, nephrectomy. subtotal BW, asmean ± expressed values are The T Parameter groups parameters Physiological parameters Functional P Total renal mass (g) mass renal Total Total renal mass (g)/ mass renal Total able 1. BW (kg) Kidney weight (g)/BWKidney (kg) weight Kidney weight (g) Kidney weight BW (kg) (mmol/h) Sodium urinary rate (µmol/h) Glucose urinaryGlucose rate (ml/min) Creatinine clearance clearance Creatinine (ml/min/kg of BW) clearance Creatinine weight) (ml/min/g of kidney(ml/min/g clearance Creatinine In fetal kidney, fetal kidney, In <0.05; appears to upregulate upregulate to appears induces cellular proliferation (22) and is also is antiapop (22)and proliferation cellular induces **P Physiological andfunctional 134d at values Physiological < 0.01 (vs. sham). <0.01(vs. WT1 activity is essential for the conversion of mes of the conversion for essential is activity in utero in Pax-2 and Wilms’ tumor 1( tumor Wilms’ and nephron mass reduction: 1/2Nx and and 1/2Nx reduction: mass nephron 2.99 2.78 16.5 8.25 5.56 0.23 2.54 1.24 0.38 0.07 SE ( M. Sham n =5) ± ± ± ± ± ± ± ± ± ± Pax-2 in vitro 0.76 0.45 4.84 2.42 0.90 0.12 2.20 0.70 0.17 0.03 expression and increases increases and expression 3.27 5.13 16.2 16.2 5.13 0.26 0.95 1.73 0.47 0.10 (25,27). To understand (25,27).To understand ( 1/2Nx n ± ± ± ± ± ± ± ± ± ± =5) Tables 1 1.02 1.09* 4.76 4.76** 1.09 0.14 0.31 0.43 0.08 0.02 of gestation inall of gestation WT1 and 11.00 11.00 2.31 4.63 4.63 0.34 1.04 0.84 0.34 0.07 ) genes are are ) genes ( 5/6Nx n =5) 2 ± ± ± ± ± ± ± ± ± ± ). No ). No 0.56 2.01 2.93 2.92 2.02 0.34 0.72 0.20 0.11 0.02 - - - - - - - Fetal compensatory renal growth renal compensatory Fetal Table 2. Physiological and histological values for the 1/2Nx, 5/6Nx, and sham groups during the kinetic study V olume 74 Estimated Total renal Estimated number of Glomerular Average of | N Gestational Total renal KW (g)/ mass (g)/ glomerular S-shaped Cortex area density diameter of CD Group age (d) KW (g) mass (g) BW (kg) BW (kg) BW (kg) number (n) bodies (mm²) (n/mm²) (lumen; µm) umber Sham 70 1.0 ± 0.1 2.0 ± 0.2 0.3 ± 0.8 3.2 ± 0.5 6.4 ± 1 472 ± 68 102 ± 40 61 ± 52 10 ± 5 ND 6 | 80 2.1 ± 0.1 4.2 ± 0.2 0.4 ± 0.0 5.6 ± 0.2 11.2 ± 0.4 963 ± 4 213 ± 6 82 ± 17 12 ± 3 17.42 ± 1.97 December 90 4.0 ± 0.7 8 ± 1.4 0.8 ± 0.1 5.3 ± 0.9 10.6 ± 1.8 1,345 ± 212 165 ± 36 135 ± 17 10 ± 2 16.43 ± 0.23 134 8.2 ± 2.9 16.4 ± 5.8 3.0 ± 0.7 2.7 ± 0.4 5.4 ± 0.8 2,479 ± 303 0 145 ± 28 29 ± 5 11.34 ± 0.55 2013 5/6Nx 70 0.5 ± 0.1** 0.5 ± 0.1** 0.3 ± 0.7 1.5 ± 0.3 1.5 ± 0.3** ND ND ND ND ND 80 1.9 ± 0.7 1.9 ± 0.7** 0.4 ± 0.0 5.3 ± 1.1 5.3 ± 1.1** 419 ± 75** 89 ± 32* 69 ± 5 6 ± 1* 21.43 ± 0.62* 90 3.6 ± 1.0 3.6 ± 1.0** 0.8 ± 0.0 4.2 ± 1.2 4.2 ± 1.2** 758 ± 73** 72 ± 26** 129 ± 18 6 ± 1* 22.18 ± 1.00** Articles Pediatric Pediatric 134 11.0 ± 2.9 11.0 ± 2.9 2.3 ± 0.5 4.7 ± 2.0 4.7 ± 2.0 2,844 ± 304 12 ± 8 158 ± 16 20.9 ± 9 14.09 ± 1.23 RESE 1/2Nx 134 16.2 ± 4.76** 16.2 ± 4.76** 3.27 ± 1.02 5.13 ± 1.09* 5.13 ± 1.09* 2,950 ± 612 5 ± 2 160 ± 17 16.5 ± 4.5** 14.93 ± 0.43 arc The values are expressed as mean ± SEM.