Elevated Glomerular Filtration Research Articles

Elevated Baseline Glomerular Filtration Rate Is Associated with a More Rapid Decline in Chinese Patients with Type 2 Diabetes with Normoalbuminuria

Aims: To investigate the association between estimated baseline glomerular filtration rate (GFR) and renal function decline in Chinese patients with type 2 diabetes with normoalbuminuria. Main Methods: A longitudinal study was performed on 368 Chinese patients with type 2 diabetes whose estimated GFR (eGFR) was determined at baseline with a 3.12-year follow-up. The patients were divided into three groups according to baseline eGFR (mL/min/1.73 m2): G1 (eGFR ≥ 120), G2 (90 ≤ eGFR < 120), G3 (60 ≤ eGFR < 90). The association between baseline eGFR and the renal function decline rate was assessed using binary logistic regression. Decliners were defined as a negative change ≥ −3.3% per year. Key Findings: Among G1 patients, the decliners were younger, had a higher baseline eGFR, shorter duration of diabetes, and lower diastolic blood pressure, compared with non-decliners. The G1 eGFR decline slope (% per year) was significantly higher than that in G2 and G3 patients. The percentage of decliners among G1 patients was significantly higher than that among G2 and G3 patients. Baseline eGFR group, HbA1c, hypertension history, and diastolic blood pressure were independent risk factors for progressive renal decline. Patients in the decliners group were more likely to progress to microalbuminuria and macroalbuminuria compared with those in the non-decliners group; however, the albuminruria progression percentage was not significantly different among G1, G2, and G3 decliners. Significance: Patients with baseline eGFR ≥ 120 mL/min/1.73 m2 had a higher risk for more rapid eGFR decline among Chinese patients with type 2 diabetes with nomalbuminuria. Disclosure J. Wan: None. H. Chen: None.

Abstract 220: Nephron Deficient Rats are Highly Susceptible to Hypertension Induced Kidney Injury

It is well known that hypertension can promote decline in renal function, but there is a paucity of information on how hypertension influences single kidney individuals. The HSRA model exhibits a high incidence of congenital single kidney (50-75% offspring) that is characterized by low nephron number (~20% less in solitary kidney vs. control kidney), glomerular and kidney hypertrophy, elevated single nephron glomerular filtration rate (GFR), which culminates in kidney injury and decline in kidney function. We hypothesized that renal hemodynamic stressors, such as DOCA induced hypertension, would accelerate onset and progression of kidney injury in rats born with a solitary kidney (HSRA-S) compared to two-kidney littermates (HSRA-C) or rats that have undergone unilateral nephrectomy (HSRA-UNX). Time course evaluation of blood pressure, renal hemodynamics, and kidney injury was performed in 6 animal groups: (1-2) HSRA-S+DOCA or placebo; (3-4) HSRA-C+DOCA or placebo; and (5-6) HSRA-UNX+DOCA or placebo. At the conclusion of the study (5 weeks), HSRA-S+DOCA treated rats demonstrated a significant (ANOVA; p<0.05) rise in blood pressure (192±4 mmHg), proteinuria (205±31 mg/24hr) and decline in GFR (600+42 μl/min/gKW) relative to HSRA-UNX+DOCA (173±3 mmHg, 76±26 mg/24hr, 963+36 μl/min/gKW) and HSRA-C+DOCA (154±2 mmHg, 7±1 mg/24hr, 1484+121 μl/min/gKW). Animals in placebo groups showed no significant change in blood pressure, proteinuria or GFR from week 13-18 between all three groups. To elucidate the molecular mechanism of nephron deficiency in the HSRA model and better understand how elevated blood pressure promotes rapid decline in renal function, whole transcriptome analysis (RNA sequencing) of embryonic kidney isolated at key stages in nephrogenesis (E14.5, 15.5, and 16.5) was performed which identified a number of novel genes involved in nephrogenesis and kidney development. We are currently working to understand the functional role of these genes and pathways using an in vitro whole organ kidney culture system. In summary, nephron deficient rats are highly susceptible to hypertension induced kidney injury and several novel genes/pathways involved in nephrogenesis likely program the model to develop significant kidney disease with age.

Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension

The high renal oxygen (O(2) ) demand is associated primarily with tubular O(2) consumption (Qo(2) ) necessary for solute reabsorption. Increasing O(2) delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension. The metabolic efficiency for solute transport (Qo(2) /T(Na) ) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na(+) transporters, different levels of oxidative stress and segmental tubular dysfunction. Sustained hyperglycaemia results in increased kidney Qo(2) , partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased Qo(2) is not matched by a similar increase in O(2) delivery. Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O(2) cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function. Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O(2) metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.

Emodin ameliorates high-glucose induced mesangial p38 over-activation and hypocontractility via activation of PPARγ

Early stage diabetic nephropathy is characterized by elevated glomerular filtration. Recent studies have identified high-glucose induced p38 MAPK (p38) over-activation in mesangial cells. Mesangial hypocontractility is the major underlying mechanism, however, no ameliorating agents are currently available. We investigated the protective effects of emodin on high-glucose induced mesangial cell hypocontractility. Mesangial cells were cultured under normal (5.6 mM) and high glucose (30 mM) conditions. Emodin was administrated at doses of 50 mg/l and 100 mg/l. Angiotension II stimulated cell surface reductions were measured to evaluate cell contractility. p38 activity was detected using Western blotting. To further explore the possible mechanism of emodin, expression of the peroxisome proliferator- activated receptorgamma (PPARgamma) was measured and its specific inhibitor, gw9662, was administrated. Our results showed: (1) high-glucose resulted in a 280% increase in p38 activity associated with significant impairment of mesangial contractility; (2) emodin treatment dose-dependently inhibited high-glucose induced p38 over-activation (a 40% decrease for 50 mg/l emodin and a 73% decrease for 100 mg/l emodin), and mesangial hypocontractility was ameriolated by emodin; (3) both the PPARgamma mRNA and protein levels were elevated after emodin treatment; (4) inhibition of PPARgamma using gw9662 effectively blocked the ameliorating effects of emodin on high-glucose induced p38 over-activation and mesangial hypocontractility. Emodin effectively ameliorated p38 over-activation and hypocontractility in high-glucose induced mesangial cells, possibly via activation of PPARgamma.

Renal vascular response to amino acids: effect of pancreatectomy

We ascertained the importance of glucagon in modulating the renal hemodynamic response to amino acid (AA) infusion in anesthetized dogs. In controls (n = 6), AAs (L-serine, alanine, and proline; 0.051 mmol.kg-1.min-1 iv) elevated renal blood flow (RBF) and glomerular filtration rate (GFR) by 35 and 34%, respectively, while elevating arterial plasma glucagon-like immunoreactivity (AGLI) by 96 pmol/l. In control pancreatectomized (PX) dogs (n = 6), all parameters remained at control values over 2 h. In PX dogs, AAs (n = 6) failed to reproduce the renal hemodynamic and AGLI responses elicited by AAs in controls. In PX dogs infused with AAs, replacement of AGLI (n = 6) to an incremental plasma level of 111 pmol/l, a level no different than that produced by AAs in controls, elevated RBF and GFR by 25 and 26.5%, respectively. These hemodynamic responses were 71 and 78%, respectively, of the total responses elicited by AAs in controls. In PX dogs infused with glucagon alone (0.86 pmol.kg-1.min-1; n = 6), an incremental change in AGLI of 112 pmol/l was accompanied by only small increases in RBF and GFR (9%). These data suggest the importance of glucagon in modulating the renal hyperemia and hyperfiltration ascribed to AA infusion in anesthetized dogs.

Effects of amino acid isomers on canine renal hemodynamics

The major objective of this study was to ascertain whether the renal hemodynamic response to amino acid infusion in dogs is stereospecific. To test this hypothesis, we examined the renal hemodynamic effects of two isomers (L and D) of an amino acid mixture of serine, alanine, and proline (SAP; 0.051 mmol.kg-1.min-1) in anesthetized dogs. Intravenous infusion of L-SAP (n = 6) significantly elevated renal blood flow (RBF) and glomerular filtration rate (GFR) by 33 +/- 3 and 30 +/- 5%, respectively, over 1 h. DL-SAP (n = 6) elevated RBF and GFR by only 14 +/- 3 and 13 +/- 3%, respectively. Yet D-SAP (n = 6) failed to elevate either RBF or GFR over 1 h. Intravenous mannitol (940 mos-mol/kg; osmotic control; n = 6) also failed to elevate renal hemodynamics. In six other dogs, intrarenal infusion of L-, but not D-, SAP marginally elevated RBF and GFR by 13 +/- 2 and 12 +/- 2%, respectively, over 1 h. Infusion of alpha-aminoisobutyric acid (0.051 mmol.kg-1.min-1; n = 6), an amino acid analogue that is cotransported with sodium but not metabolized by renal cells, elevated RBF and GFR by 22 +/- 5 and 18 +/- 6%, respectively, over 1 h. These data indicate that vascular infusion of L, but not D, isomers of amino acids elevate RBF and GFR. We therefore suggest the importance of amino acid stereospecificity in the renal vascular response to amino acid infusion in dogs.

Nature of the renal hemodynamic action of amino acids in dogs

Anesthetized dogs were used to study the nature of the renal hyperemia and hyperfiltration ascribed to amino acids. Intravenous (n = 6) or intraportal venous (n = 6) infusion of a solution of three metabolizable amino acids [serine, alanine, and proline (SAP) approximately 0.051 mmol.kg-1.min-1] elevated renal blood flow (RBF) and glomerular filtration rate (GFR) by a similar amount (30%) over the same time course (60 min). Yet, direct intra-arterial infusion of SAP into the kidney at either approximately 0.0051 or 0.051 mmol.kg-.min-1 (n = 12) failed to significantly elevate either RBF or GFR over 60 min. A transient increase in RBF (approximately 13%) was, however, noted by minute 15 of the infusion. Unlike SAP, intraportal venous infusion of a physiological dose of branched-chain amino acids (valine, leucine, and isoleucine, approximately 0.0195 mmol.kg-1.min-1, n = 6) failed to elevate either RBF or GFR over 60 min. By comparison, either intravenous or intraportal venous infusion of SAP at approximately 0.020 mmol.kg-1.min-1 (n = 12) elevated renal hemodynamics by approximately 14% over 60 min. The data suggest that the liver does not directly mediate amino acid-induced increases in renal hemodynamics but that some other intermediary step activated following amino acid administration may be necessary before the renal hyperemia and hyperfiltration ascribed to amino acids are manifested in anesthetized dogs.

Sodium restriction corrects hyperfiltration of diabetes.

The effect of a low-sodium diet on the abnormal glomerular hemodynamics of early diabetes was studied in rats. Starting 5 to 7 days after onset of streptozotocin-induced insulin-dependent diabetes mellitus (IDDM), rats were fed a low-sodium diet for 4-5 days. Normal rats fed the same diet served as controls. Micropuncture measurements were made during a control period, followed by a second period when saralasin was infused into the left renal artery. During the first period, single-nephron glomerular rate (SNGFR), glomerular plasma flow (QA), glomerular blood flow (SNBF), filtration fraction (SNFF), and glomerular hydraulic pressure (PG) in the diabetic rats were not significantly different from the normal controls. Saralasin infusion resulted in striking increases in SNGFR, QA, SNBF, and Kf, and significant decreases in SNFF, PG, and delta P. The responses to saralasin imply that the low-sodium diet resulted in ANG II-mediated vascular constriction at pre- and postglomerular sites, and probably the glomerular mesangial cells as well. Our observations suggest that the abnormally elevated glomerular blood flow and filtration rate of early IDDM can be corrected by a low-sodium diet via stimulation of endogenous ANG II.