Early diabetic kidney maintains the cortico-medullary urea and sodium gradient
Haiyun Qi1, Thomas Stokholm Nørlinger1, Per Mose Nielsen1, Lotte Bonde Bertelsen1, Yafang Xu1, Fredrik Palm2, Hans Stødkilde-Jørgensen1, and Christoffer Laustsen1

1MR Research Centre, Aarhus University, Aarhus N, Denmark, 2Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

Synopsis

To investigate the essential intrarenal electrolyte gradients in early diabetic kidneys, hyperpolarized 13C urea was applied to measure urea and sodium gradients. No differences in either intrarenal urea or sodium gradients were observed in early diabetes compared to healthy controls. These results indicate that the early metabolic and hypertrophic changes occurring in the diabetic kidney prelude the later functional alterations in diabetic kidney function, thus driving the increased metabolic demand commonly occurring in the diabetic kidney.

Purpose

To explore whether the pathophysiological and metabolic changes appear concomitant with decreased intrarenal sodium and urea gradient in early diabetes.

Methods

Twelve ten-week female Wistar rats were randomly divided into two groups, one receiving an intravenous injection of freshly prepared streptozotocin (STZ, 55 mg/kg body weight) to induce insulinopenic diabetes, or another group serving as healthy normoglycemic controls. Rats were considered diabetic if blood glucose levels exceeded 15 mmol/L 48hours (h) after administration of STZ. Two weeks after induction of diabetes, the rats were anesthetized and a tail vein catheter was inserted for injection of hyperpolarized 13C urea, the 13C urea was polarized in a SPINLAB (GE Healthcare, Broendby, DK). Temperature, hemoglobin oxygen saturation and respiration rate were monitored throughout the experiment. Each animal received injections of 1.5 ml hyperpolarized urea over 10 seconds (s). The experiments were performed in a 9.4 T pre-clinical MR system (Agilent, UK) equipped with a dual tuned 13C/1H volume rat coil (Doety scientic, US). A 2D balanced steady state imaging sequences were performed every 2 s acquiring 40 images in total initiated at the start of injection with a flip angle=15º, TR/TE = 4.8 ms/2.4 ms, sw = 20kHz, FOV=60x60 mm and a 32 x 32 matrix and an axial slice thickness of 10 mm covering both kidneys. A standard 3D gradient echo sequence was used for thermal 23Na MRI, with TR/TE 50 ms/2 ms, sw = 10kHz, matrix 32 x 32 x 8, FOV 60 mm x 60 mm x 60 mm, with 32 number of transients. Regions-of-interests of left and right kidney cortex, medulla and papilla were manually segmented in order to measure the mean intrarenal urea distribution and blood perfusion, and a region inside the abdominal aorta was used to obtain the arterial input curve. The renal blood flow was estimated by the area under curve (AUC). After scanning; blood sample, kidney tissue and urine were collected for determination of injury parameters.

Results

All rats administered with STZ developed sustained hyperglycemia within 48h. A significant intrarenal cortico-medullary gradient in urea (p<0.0001) was found in both diabetic and control animals, concomitant with a similar cortico-medullary increase in sodium distribution (p<0.0001) (Figure 1). However, there is no significant difference in these gradients between the two groups (Figure 2). The cortical blood perfusion was also similar in the two groups (Figure 3) although the diabetic kidneys showed significant hypertrophy compared to controls (0.93±0.02 versus 0.78±0.03g, p=0.0006).

Discussion

This study demonstrates significant cortico-medullary urea and sodium gradients in both control and diabetic rats using hyperpolarized MR, similarly to what previously has been described using invasive techniques1. Von Morze et al3, have previously reported hyperpolarized urea as a promising maker for investigating intrarenal distribution of urea during diuresis. The finding of similar intrarenal gradients of urea and sodium in both control and early diabetes imply, that the deranged O2 metabolism in the diabetic kidney2, efficiency may drive the development of intrarenal hypoxia and may be a mechanism for the onset and progression of chronic kidney disease.

Conclusion

This study highlights the potential of combining 23Na, hyperpolarized 13C urea and standard 1H anatomical and functional MR thus providing a more complete overview of functional parameters that may influence normal kidney function and contribute to development of chronic kidney disease.

Acknowledgements

The study was supported by The Danish Research Council, The Danish Kidney Foundation, Helen and Ejnar Bjørnows Foundation. Henrik Vestergaard Nielsen is acknowledged for his expert laboratory assistance.

References

1. Knepper MA, H., JD, Packer, RK, and Fenton RA., Urine concentration and dilution. , in The Kidney, B. Brenner, Editor. 2008, Saunders Elsevier: Philadephia. p. 308-329.

2. Laustsen C, Østergaard JA, Lauritzen MH, et al. Assessment of early diabetic renal changes with hyperpolarized [1-(13) C]pyruvate. Diabetes Metab Res Rev. 2013; 29(2):125-129.

3. von Morze C, Bok RA, Sands JM, et al. Monitoring urea transport in rat kidney in vivo using hyperpolarized ¹³C magnetic resonance imaging. Am J Physiol Renal Physiol. 2012; 302(12):F1658-1662.

Figures

Figure 1: Representation of anatomical 1H MR images, renal distribution of sodium (23Na) and hyperpolarized 13C urea signal in a typical diabetic and control rat.

Figure 2: The intra-renal sodium and urea signals show no difference between the diabetic and controls, while there is a significant difference within each group.

Figure 3: The renal perfusion (renal compartment/aorta signal) shows no significant alterations in the early diabetic kidney compare to controls kidneys.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3677