This is a comprehensive review on our current understanding of postnatal functional and structural maturation of a kidney. We further explore how these adaptations in the setting of abnormal kidney development or loss of a kidney which result in low nephron number can lead to maladaptive phenotypes such as renal failure and hypertension later in life. ABSTRACT:Compensatory renal growth is a characteristic adaptation to reduced renal mass that appears to recapitulate the normal pattern of maturation of the kidney during the postnatal period. Hypertrophy of tubules (predominantly the proximal tubule) and glomeruli is accompanied by increased single nephron glomerular filtration rate and tubular reabsorption of sodium. We propose that the very factors, which contribute to the increase in growth and function of the renal tubular system, are, in the long term, the precursors to the development of hypertension in those with a nephron deficit. The increase in single nephron glomerular filtration rate is dependent on multiple factors, including reduced renal vascular resistance associated with an increased influence of nitric oxide, and a rightward shift in the tubuloglomerular feedback curve, both of which contribute to the normal maturation of renal function. The increased influence of nitric oxide appears to contribute to the reduction in tubuloglomerular feedback sensitivity and facilitate the initial increase in glomerular filtration rate. The increased single-nephron filtered load associated with nephron deficiency may promote hypertrophy of the proximal tubule and so increased reabsorption of sodium, and thus a rightward shift in the pressure natriuresis relationship. Normalization of sodium balance can then only occur at the expense of chronically increased arterial pressure. Therefore, alterations/adaptations in tubules and glomeruli in response to nephron deficiency may increase the risk of hypertension and renal disease in the long-term.

We determined whether adenine-induced chronic kidney disease (CKD) in rats is associated with renal tissue hypoxia. Adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats, daily by oral gavage, over a 15-day period. Renal function was assessed before, and 7 and 14 days after, adenine treatment commenced, by collection of a 24-hour urine sample and a blood sample from the tail vein. On day 15, arterial pressure was measured in conscious rats via the tail artery. Renal tissue hypoxia was then assessed by pimonidazole adduct immunohistochemistry and fibrosis was assessed by staining tissue with picrosirius red and Masson's trichrome. CKD was evident within 7 days of commencing adenine treatment, as demonstrated by increased urinary albumin to creatinine ratio (30 ± 12-fold). By day 14 of adenine treatment plasma creatinine concentration was more than 7-fold greater, and plasma urea more than 5-fold greater, than their baseline levels. On day 15, adenine-treated rats had slightly elevated mean arterial pressure (8 mmHg), anaemia and renomegaly. Kidneys of adenine-treated rats were characterised by the presence of tubular casts, dilated tubules, expansion of the interstitial space, accumulation of collagen, and tubulointerstitial hypoxia. Pimonidazole staining (hypoxia) co-localised with fibrosis and was present in both patent and occluded tubules. We conclude that renal tissue hypoxia develops rapidly in adenine-induced CKD. This model, therefore, should prove useful for examination of the temporal and spatial relationships between tubulointerstitial hypoxia and the development of CKD, and thus the testing of the 'chronic hypoxia hypothesis'.

The classic dogma of cerebral autoregulation is that cerebral blood flow is steadily maintained across a wide range of perfusion pressures. This has been challenged by recent studies suggesting little to no 'autoregulatory plateau' in the relationship between cerebral blood flow and blood pressure (BP). Therefore, the mechanisms underlying the cerebral pressure-flow relationship still require further understanding. Here we present a novel approach to examine dynamic cerebral autoregulation in conscious Wistar rats (n=16) instrumented to measure BP and internal carotid blood flow (iCBF), as an indicator of cerebral blood flow. Transient reductions in BP were induced by occluding the vena cava via inflation of a chronically implanted intravascular silicone balloon. Falls in BP were paralleled by progressive decreases in iCBF, with no evidence of a steady state plateau. No significant changes in internal carotid vascular resistance (iCVR) were observed. In contrast, intravenous infusions of the vasoactive drug sodium nitroprusside (SNP) produced a similar fall in BP but increases in iCBF and decreases in iCVR. These data suggest a considerable confounding influence of vasodilatory drugs such as SNP on cerebrovascular tone in the rat, making them unsuitable to investigate cerebral autoregulation. We demonstrate that our technique of transient vena cava occlusion produced reliable and repeatable depressor responses, highlighting the potential for our approach to permit assessment of the dynamic cerebral pressure-flow relationship over time in conscious rats.

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