Download sodium in kidney failure patients: new open questions

Nephrology Dialysis Transplantation 28 (Supplement 1): i71, 2013
doi:10.1093/ndt/gft184
SODIUM IN KIDNEY FAILURE PATIENTS:
NEW OPEN QUESTIONS
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GENETIC PROFILE OF SALT SENSITIVITY IN ESSENTIAL
HYPERTENSION
Chiara Lanzani1, Marco Simonini1, Elena Brioni1, Simona Delli Carpini1,
Lorena Citterio1, Laura Zagato1, Stefano Tentori1 and Paolo Manunta1
1
OU Nephrology and Dialysis / Chair of Nephrology San Raffaele Scientific Institute
/ Università Vita Salute San Raffaele Milan Italy
Introduction and Aims: Blood pressure (BP) is controlled primarily by Na and water
balance because of the infinite gain property of the kidneys to rapidly eliminate excess
fluid and salt. Up to fifty percent of patients with essential hypertension are
salt-sensitive, as manifested by a rise in BP with salt loading.
Methods: 626 naive hypertensive patients underwent an acute Na load (310 mEq NaCl
in 2 h ev) to monitor the simultaneous changes in BP and renal Na excretion.
Genotyping was performed by using novel technique that uses arrays with fluorescent
probes and ability to allelic discrimination of 124 SNPs in candidate genes for multiple
mid-throughput genotyping (OpenArray, OA). Associations with genetic markers were
performed with GLM and chi-squared; logistic regression analysis for salt resistant/
sensitive (SR/SS) comparison was also used.
Results: OA genotype association study detected a strong association with variation in
BP after acute sodium load with 8 genes (ADD1, NCX1, NEDD4L, PRKG1, MYO,
MYO32, SIK1 and UMOD). In combined analyses, we found significant epistatic
interactions between these SNPs. A genetic profile is a specific combination of variants
in terms of SNPs or SNP interactions. Furthermore, we built a genetic profile able to
identify the SS and SR hypertensive: those carrying the SS profile display changes in
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systolic BP of 10.4±1.25 vs 2.99±0.39 mmHg p<0.0001). SS genetic profile showed OR
6.13 (IC 95% 3.17-11.86) to be SS, and had a 96% specificity, a 72% PPV.
Pressure-natriuresis relationship was obtained for each patient by plotting urinary Na
excretion in Y axis and mean BP in the X axis. Patients carrying the SS genetic profile
resulted in a right shift along X axis, while was vertically steep in SR profile (GLM
p<0.0001).
Conclusions: Our finding suggests a clear relationship between Na intake, genetic
pathways regulating the contractile state of muscular vascular cells, renal Na excretion
and intracellular activity underline pressure natriuresis and salt sensitive phenotype.
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HIGH SALT DIET MODULATES DISTRIBUTION OF RENAL
VEGF-A AND ITS EXCRETION IN RATS
Krzysztof H. Olszyński1, Janusz Sadowski1, Janina Rafałowska2 and
Elzbieta Kompanowska-Jezierska1
1
Department of Renal and Body Fluid Physiology Mossakowski Medical Research
Centre, Polish Academy of Sciences Warsaw Poland, 2Department of
Experimental and Clinical Neuropathology Mossakowski Medical Research Centre,
Polish Academy of Sciences Warsaw Poland
Introduction and Aims: High sodium intake, a risk factor in hypertension is also
considered to affect kidney function and structure. VEGF-A (Vascular Endothelial
Growth Factor A), established renal protective factor could be involved in renal
response to increased concentration of Nain body fluids and/or to elevated blood
pressure.
Methods: Male Wistar rats and SHR (Spontaneously Hypertensive Rats) were
maintained on standard (STD, 0.25% Na w/w) or high sodium (HS, 4% Na) diet. After
21-days' exposure to the diets, rats were anaesthetized and kidneys and urine were
collected. PFA-fixed paraffin-embedded slices were used for hematoxylin-eosin (HE)
staining or labeling with anti-PCNA (Proliferating Cell Nuclear Antigen)or
anti-VEGF-A antibodies. HE slices were used to calculate glomerular injury index
(GII). 50 randomly selected glomeruli from each kidney were assessed by a
semi-quantitative injury scale: grade 0, entire glomerulus normal; grade 1, injured area
up to 25% (minimal injury); grade 2, injured area 25-50% (moderate i.); grade 3,
injured area 50-75% (moderate-to-severe i.); grade 4, injured area 75-100% (severe i.).
GII was calculated using the formula: GII= [(1 x n1) + (2 x n2) + (n3 x3) + (4 xn4)] /
(n0+n1+n2+n3+n4), where nx is the number of glomeruli in each stage of injury.
Urine was studied to determine osmolality and VEGF-A concentration. VEGF-A
concentration was standardized by urine osmolality.
Results: The exposure to high salt diet affected renal glomerular structure in both
strains, but the damage was much more pronounced in SHR. Anti-PCNA labeling in
the glomeruli was elevated in Wistar rats; in SHR it was independent of the diet and
similar as in Wistar HS group. In Wistar rats, GII only slightly increased (0.78 ± 0.17
HS vs 0.51 ± 0.03 STD; NS) in response to high Na intake; in SHR the rise was much
greater (1.74 ± 0.18 HS vs 0.95 ± 0.12 STD; p < 0.01). Moreover, SHR maintained on
STD diet showed a damage comparable with that observed in HS Wistars. VEGF-A
excretion, which was similar in both strains on STD diet, was much more distinct in
HS SHR group (16.61 ± 1.77 ng/mOsm HS vs 2.08± 1.60 ng/mOsm STD; p < 0.01).
Both parameters: GII and VEGF excretion were positively correlated (r = 0.67; p <
0.05). Anti-VEGF-A labeling revealed a distinct pattern in both strains: in Wistar there
were no differences between outer and inner medulla on STD diet whereas after HS
diet a lack of labeling in the inner medulla was observed. In SHR on both diets the
labeling pattern was similar as in STD Wistars.
Conclusions: The finding that renal excretion of VEGF-A is correlated with the
Glomerular Injury Index supports the notion derived from clinical investigations that
VEGF may be an early marker of glomerular nephropathy. Distinct pattern of VEGF-A
immunoreactivity in the inner medulla could be an index of a predisposition to
hypertension.
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