Time course of the renal functional response to partial nephrectomy: measurements in conscious rats

Abstract

Previous investigations into the functional responses of the surviving nephrons following reductions in renal mass have been performed largely in anaesthetized animals and have taken little account of how the compensatory changes develop with time. The present study has assessed a method for determining glomerular filtration rate (GFR) in unrestrained, uncatheterized, conscious rats (plasma disappearance of 99m Tc-diethylenetriamene pentaacetic acid (DTPA)) and has used this method to document the time course of the changes in GFR over a 32 day period following uninephrectomy or 5/6 nephrectomy. Concurrent measurements of excretion rates and of the clearance of lithium (the latter being an index of end-proximal fluid delivery) provided information on changes in overall tubular function and segmental reabsorption. After uninephrectomy, the GFR of the remaining kidney (compared with that of a single kidney of sham-operated animals) increased maximally (by ∼50%) within 8 days; after 5/6 nephrectomy, the increase in the GFR of the remnant kidney was maximal (at ∼300%) within 16 days. Overall excretion rates of sodium and potassium were well maintained in partially nephrectomized animals throughout the period of study, while the excretion of water increased (by ∼30% after uninephrectomy and by ∼120% after 5/6 nephrectomy), partly as a result of the compensatory increases in GFR but mainly as a consequence of moderate (after uninephrectomy) or marked (after 5/6 nephrectomy) reductions in fractional reabsorption. During the early period after 5/6 nephrectomy, potassium excretion sometimes exceeded the filtered load, indicating net secretion. Lithium clearance data indicated that the changes in tubular function after 5/6 nephrectomy include a reduction in fractional reabsorption in the proximal tubule, whereas after uninephrectomy any such effect on the proximal tubule is minor and transient.

Severe Renal Mass Reduction Impairs Recovery and Promotes Fibrosis after AKI

“…17 During the same surgery, kidneys were left intact in one group of rats (bilateral; n=20), whereas the remaining rats underwent normotensive RMR by right UNX (n=22) or right UNX+surgical excision of both poles of the left kidney (3/4 NX; n=27). 17 After 14-18 days of recovery and compensatory renal adaptations, 67 body weight, BP, S Cr , and 24-hour protein excretion were measured. After this baseline assessment, rats were anesthetized (50 mg/kg sodium pentobarbital), placed on a servo-controlled heated surgical table to maintain body temperature at 37°C, and subjected to a 40-minute I/R through a clamp placed on the left (UNX I/R and Figure 6).…”

Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

“…Another simplification was made in the current analysis such that these physiological parameters were fixed to stationary (time-invariant) values. Although GFR does follow a circadian pattern, the variation around the mean value over 24 h appears to be small in healthy rats and humans (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In addition, although plasma glucose profiles would be expected to vary with time and meals, there also appears to be little variation around the mean value in healthy rats and humans (29)(30)(31)39).…”

“…For purposes of modeling, the physiologically relevant parameters of glucose filtration and reabsorption were fixed to independent estimates obtained from the literature. GFR was set to 0.55 ml/h/g consistent with that previously reported in rats (28). PG was fixed to a mean experimental estimate obtained in an independent, inhouse study of 30 male Sprague-Dawley rats weighing 290±50 g (1.41+0.54 mg/ml determined spectrophotometrically).…”

“…However, as the amount of glucose excreted following a single dose of an SGLT2 inhibitor is small in healthy subjects, acute changes in plasma glucose are neither expected nor observed (26). In contrast, treatment of diabetic patients clearly lowers blood glucose concentration in studies of longer duration (23,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). As such, treatmentrelated changes in plasma glucose with time should be considered when extending this model to the chronic treatment of diabetics.…”

Ultrastructural changes and nestin expression accompanying compensatory renal growth after unilateral nephrectomy in adult rats

“…16,[18][19][20] An increase in fractional excretion of water and solutes following compensatory adaptations in tubules is due to a reduction in the fractional reabsorption of sodium and water, increased potassium secretion or enhanced flow of tubular fluid. [21][22][23][24] Adaptive changes in glomeruli and tubules in response to nephron deficiency can increase the risk of hypertension and renal disease in the long run. 12 Many biochemical parameters were found to be activated during compensatory renal hypertrophic responses, such as angiotensin II, p-aminohippurate, nitric oxide, growth factors and proto-oncogenes.…”