Elevated Glomerular Filtration Rate Research Articles

SGLT2: A PERSPECTIVE ON PATHOPHYSIOLOGY AND IMPACT OF SGLT2 INHIBITION ON RENAL FUNCTION

In individuals with diabetes, kidney size and glomerular filtration rate (GFR) tend to increase, and elevated GFR is a risk factor for diabetic kidney disease. Hyperfiltration occurs when high glucose levels in the glomerular filtrate causes increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. This hyperfiltration puts additional stress on the filtration barrier and increases the oxygen demand for reabsorption. Tubular growth is associated with a molecular signature that leads to inflammation and fibrosis. SGLT2 inhibitors play a significant role in mitigating hyperfiltration by reducing sodium and glucose reabsorption, normalizing feedback signals, and alleviating the physical stress on the filtration barrier. This tubule-centered model of diabetic kidney physiology explains the positive effects of SGLT2 inhibitors on renal outcomes, as demonstrated in large-scale clinical trials. Although these medications primarily target glucose reabsorption , patients with type 2 diabetes mellitus benefit from reduced blood glucose levels along with various other physiological advantages. Data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.

Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease.

In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium–glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin–angiotensin–aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.

Role of the macula densa sodium glucose cotransporter type 1-neuronal nitric oxide synthase-tubuloglomerular feedback pathway in diabetic hyperfiltration

An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus invitro, micropuncture of kidney tubules invivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.

Are continued policies of prioritizing native vascular access in patients on hemodialysis programs useful?

The guidelines recommend establishing native vascular access as opposed to prosthetic or catheter-based access despite information relating to its effectiveness being scarce from a patient-orientated perspective. We analyzed the effectiveness of a continued policy of native vascular access (CPNVA) in patients undergoing hemodialysis. A retrospective, observational study, including 150 patients undergoing hemodialysis between 2006 and 2012 at our center, and who underwent a CPNVA. Statistical analysis was based on treatment intention. In 138 patients (92%), the first useful access (FUA) was native, and in 12 patients (8%), it was prosthetic. In 50 patients (33.3%), more than one procedure had to be carried out in to order to achieve FUA. The probability of dialysis occurring via a FUA was 67.1% and 45.3% at 1 and 5 years respectively. Over the follow-up period (mean time=30 months), 84 patients (56%) required repairs or new access, extending the effectiveness of the CPNVA to 88.3% and 73.2% at 1 and 5 years respectively. The effectiveness of the CPNVA was reduced if the patient: required a catheter initially (HR: 3.6, p=0.007); in cases of initially elevated glomerular filtration rate (HR: 1.1, p=0.040); in cases of history of previous access failure before FUA (HR: 3.9, p=0.001); and in female patients (HR: 2.4, p=0.031). The long-term effectiveness of a CPNVA is high. However, the percentage of patients requiring diverse procedures in order to achieve FUA and the need for re-interventions yield the necessity to optimize preoperative evaluation and postoperative follow-up.

Peri-renal adipose inflammation contributes to renal dysfunction in a non-obese prediabetic rat model: Role of anti-diabetic drugs

Diabetic nephropathy is a major health challenge with considerable economic burden and significant impact on patients’ quality of life. Despite recent advances in diabetic patient care, current clinical practice guidelines fall short of halting the progression of diabetic nephropathy to end-stage renal disease. Moreover, prior literature reported manifestations of renal dysfunction in early stages of metabolic impairment prior to the development of hyperglycemia indicating the involvement of alternative pathological mechanisms apart from those typically triggered by high blood glucose. Here, we extend our prior research work implicating localized inflammation in specific adipose depots in initiating cardiovascular dysfunction in early stages of metabolic impairment. Non-obese prediabetic rats showed elevated glomerular filtration rates and mild proteinuria in absence of hyperglycemia, hypertension, and signs of systemic inflammation. Isolated perfused kidneys from these rats showed impaired renovascular endothelial feedback in response to vasopressors and increased flow. While endothelium dependent dilation remained functional, renovascular relaxation in prediabetic rats was not mediated by nitric oxide and prostaglandins as in control tissues, but rather an upregulation of the function of epoxy eicosatrienoic acids was observed. This was coupled with signs of peri-renal adipose tissue (PRAT) inflammation and renal structural damage. A two-week treatment with non-hypoglycemic doses of metformin or pioglitazone, shown previously to ameliorate adipose inflammation, not only reversed PRAT inflammation in prediabetic rats, but also reversed the observed functional, renovascular, and structural renal abnormalities. The present results suggest that peri-renal adipose inflammation triggers renal dysfunction early in the course of metabolic disease.

Development of glomerular hyperfiltration, a multiphasic phenomenon.

The trajectory of glomerular filtration rate (GFR) in relation to glomerular hyperfiltration (GHF) has been unknown. It was evaluated retrospectively in 23,982 GHF-free health examinees who were followed for 2-10 yr (mean: 5.1 yr). GFR was estimated by the serum creatinine concentration, and GHF was defined as age- and sex-specific estimated GFR (eGFR) ≥ 95% of the Japanese general population. The temporal profile of eGFR was plotted in a GHF-centered way, which was fitted to a random coefficient linear mixed model. Of the 23,982 subjects, 797 and 23,185 subjects developed or did not develop GHF, respectively, so that they were termed as the GHF(+) and GHF(-) groups. At baseline, median eGFR was significantly elevated in the GHF(+) group compared with in the GHF(-) group: 94.1 versus 77.3 mL/min/1.73 m2 (P < 0.001). Elevation of basal eGFR lasted for a mean (SD) of 3.3 (1.9) yr in the GHF(+) group; mean eGFR then rose to the GHF range, which was 108.5 mL/min/1.73 m2. The eGFR decline after the peak was steeper in the GHF(+) group than in the GHF(-) group: -0.984 versus -0.497 mL/min/1.73 m2/yr (P < 0.001). Baseline eGFR, but no other variable, well predicted incident GHF, with an area under the receiver operating characteristic curve of 0.87 (95% confidence interval: 0.86-0.88). In conclusion, GHF occurs as a chronic, multiphasic phenomenon: initially with a sustained GFR elevation for years, followed by a GFR surge to the GHF range, which was accompanied by accelerated GFR declining.

Application of Various Equations for Estimating GFR in Patients with Type 1 Diabetes

To compare different methods of estimating glomerular filtration rate (GFR) calculated by creatinine and cystatin C in patients with type 1 diabetes with normal and moderately decreased renal filtration function. The study involved 57 patients with type 1 diabetes, 37 men and 20 women, aged from 21 to 57 years (median 30 years), with disease duration after diagnosis from 33 to 2 years (median 8 years). The control group comprised 15 non-diabetic people aged 19 to 42 years (median – 28 years), with normal levels of albuminuria and blood creatinine. The majority of patients with type 1 diabetes were found to have decompensated diabetes mellitus. The mean value of glycated hemoglobin in patients was 8%. The renal glomerular function was estimated by level of GFR and triple testing of urine albumin excretion. Renal tubular function in type 1 diabetes was tested by examining serum cystatin C. GFR estimating equations, which did not include serum of cystatin C produced higher GFR. As a result, the majority of patients had normal or elevated GFR showing hyperfiltration. Using cystatin-C-based equations resulted in a several-fold reduction in the number of patients with hyperfiltration and increased number of cases with GFR below 90 ml/min/m2 . The assessment of the relationship between SDMA and GFR showed negative correlation with both cystatin-C-based and creatinine-based equations. These findings revealed that GFR estimating equations based on both creatinine and cystatin C produce more accurate results compared with the reference estimating equations.

Association of glomerular hyperfiltration with serum chemokine levels and metabolic features in prepubertal children with overweight/obesity

Background and aimsGlomerular hyperfiltration (GH) is proposed as one of the earliest events in obesity (OB)-associated renal disease. Children with GH and type-1 diabetes showed increased chemokine levels. Chemokine associations with glomerular filtration rate (GFR) and metabolic features in prepubertal children with overweight (OW)/OB are unknown. Methods and resultsCross-sectional study. 75 prepubertal children (aged: 9.0 ± 1.7 years) with OW/OB were studied. Clinical and metabolic characteristics (including non-esterified fatty acids, NEFA) and GFR (combined Zappitelli equation) were assessed. GH was defined as GFR >135 ml/min.1.73 m2. Serum levels of regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5, interleukin-8 (IL-8)/CXCL8 and monokine-induced by interferon-γ (MIG)/CXCL9 were measured by ELISA. Age- and sex-adjusted correlations and differences were tested. 48% of the cohort was female and 13% were OW, 54% OB and 33% severe OB. Prepubertal children with GH showed lower z-BMI (−12%), NEFA (−26%) and uric acid (−22%) than those without GH (all p < 0.05). Similarly to high sensitivity C-reactive protein (hsCRP), there were no differences in serum chemokines between children with GH or not (all p > 0.05). Adjusted correlations were significant for RANTES and z-BMI (r = 0.26; p < 0.05) and for MIG with z-BMI (r = −0.26; p < 0.05) and with NEFA (r = 0.27; p < 0.05). ConclusionGH was not associated with higher chemokine levels in prepubertal children with OW/OB. Decreased rather than elevated GFR values were correlated with obesity and worse metabolic profiles. Chemokines levels in children with severe OB suggest a regulation of the immune response. Follow-up studies are needed to address the clinical implications of these findings.

The tubular hypothesis of nephron filtration and diabetic kidney disease.

Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.

Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats

The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.

Insulin resistance underlies the elevated cardiovascular risk associated with kidney disease and glomerular hyperfiltration.

The curve that describes the relationship between glomerular filtration rate (GFR) and cardiovascular risk is U-shaped, indicating that both reduced GFR (kidney failure) and elevated GFR (glomerular hyperfiltration) are equivalent cardiovascular risk factors. The elevated cardiovascular risk associated with abnormal GFR is not explained by standard cardiovascular risk factors. The relationship between GFR and all-cause mortality follows a similar pattern, so that altered GFR (either low or high) increases the risk for overall mortality. Glomerular hyperfiltration is an adaptive process that arises under conditions that demand improved kidney excretory capacity, such as animal protein ingestion and kidney failure. Unlike vegetable protein, animal protein consumption increases dietary acid load and requires an elevation of the GFR to restore acid-base balance. The loss of functioning nephrons in diseased kidneys requires a compensatory increase of the GFR in the nephrons that remain working to enhance whole-kidney GFR. A major factor that raises GFR is the pancreatic hormone glucagon. Glucagon infusion and endogenous glucagon release increase GFR in healthy subjects and patients with kidney failure. In addition to its kidney hemodynamic effect, glucagon causes insulin resistance. Like hyperglucagonemia, insulin resistance develops across the entire spectrum of abnormal GFR, from glomerular hyperfiltration to advanced kidney disease. Insulin resistance is associated with subclinical vascular injury in the general population and patients with diabetes and kidney failure, being a strong cardiovascular risk factor in these population groups. Animal protein consumption activates glucagon secretion and promotes insulin resistance, having a detrimental effect on cardiovascular disease and renal outcomes.

Application of Various Equations for Estimating GFR in Patients with Type 1 Diabetes

To compare different methods of estimating glomerular filtration rate (GFR) calculated by creatinine and cystatin C in patients with type 1 diabetes with normal and moderately decreased renal filtration function. The study involved 57 patients with type 1 diabetes, 37 men and 20 women, aged from 21 to 57 years (median 30 years), with disease duration after diagnosis from 33 to 2 years (median 8 years). The control group comprised 15 non-diabetic people aged 19 to 42 years (median – 28 years), with normal levels of albuminuria and blood creatinine. The majority of patients with type 1 diabetes were found to have decompensated diabetes mellitus. The mean value of glycated hemoglobin in patients was 8%. The renal glomerular function was estimated by level of GFR and triple testing of urine albumin excretion. Renal tubular function in type 1 diabetes was tested by examining serum cystatin C. GFR estimating equations, which did not include serum of cystatin C produced higher GFR. As a result, the majority of patients had normal or elevated GFR showing hyperfiltration. Using cystatin-C-based equations resulted in a several-fold reduction in the number of patients with hyperfiltration and increased number of cases with GFR below 90 ml/min/m2. The assessment of the relationship between SDMA and GFR showed negative correlation with both cystatin-C-based and creatinine-based equations. These findings revealed that GFR estimating equations based on both creatinine and cystatin C produce more accurate results compared with the reference estimating equations.

Do sodium-glucose cotransporter-2 inhibitors affect renal hemodynamics by different mechanisms in type 1 and type 2 diabetes?

Cardiovascular and renal outcome trials demonstrate nephroprotection with sodium-glucose cotransporter-2 inhibitors in people with type 2 diabetes. Attenuation of hyperfiltration is believed to be responsible for the nephroprotection, and studies in young adults with type 1 diabetes suggest that afferent arteriolar vasoconstriction induced by a tubuloglomerular feedback mechanism may be responsible for this effect. The study by van Bommel etal. suggests that this mechanism may not hold true in older adults with type 2 diabetes, who instead attenuate elevated glomerular filtration rate via post-glomerular vasodilation.

NaHCO3 Dilates Mouse Afferent Arteriole Via Na+/HCO3- Cotransporters NBCs.

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO3 dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na+/HCO3- cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6, P<0.05) in response to NaHCO3 (44 mmol/L). Whereas, NaCl solution containing the same Na+ concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6; P<0.05) in the presence of NaHCO3, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 μM nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7; P<0.005) and increases NO generation by 22±3% (n=7; P<0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO3 increased NO generation in Af-Art by 19±4% (n=5; P<0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; P<0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO3-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO3 dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.

Abstract 143: Enhancing Renal Lymphatic Vessel Density Blunts Both Salt-Sensitive and Angiotensin II-Dependent Hypertension in Mice

Sodium retention is a hallmark of most forms of experimental hypertension. Renal lymphatics maintain fluid homeostasis by draining cortical interstitial fluid to the draining lymph node. Our lab has previously demonstrated that augmenting renal lymphatics prevents hypertension, but whether this can treat hypertension and whether expanding renal lymphatics alters renal sodium handling remain unknown. Our hypotheses were that augmenting renal lymphatic vessel density after hypertension is established will treat salt sensitive hypertension (SSHTN) and angiotensin II-induced hypertension (AIIHTN) and that this will be accompanied by an increase in urinary sodium excretion. To test our hypotheses, we utilized transgenic mice that overexpress the lymphangiogenic growth factor VEGF-D specifically in the kidney when administered doxycycline (KidVD+ mice). KidVD+ mice and KidVD- littermates were made salt-sensitive by treatment with L-NAME (0.5 mg/mL) for two weeks, followed by a washout period of two weeks, and then given a 4% high salt diet for four weeks. To induce AIIHTN, mice were infused with angiotensin II (490 ng/kg/min) for four weeks. Doxycycline was administered to all mice a week after beginning the high salt diet or a week after angiotensin II infusion. Prior to doxycycline initiation, KidVD- and KidVD+ mice were hypertensive (SSHTN SBP: 130±2 and 134±2 mmHg, respectively; AIIHTN SBP: 125±2 and 128±2 mmHg, respectively). Compared to KidVD- mice, doxycycline administration for three weeks augmented renal lymphatics in KidVD+ mice and significantly decreased blood pressure after four weeks of high salt diet or angiotensin II (SSHTN SBP: 134±4 vs. 125±2 mmHg; p&lt;0.05; AIIHTN: 145±3 vs. 125±5 mmHg; p&lt;0.05). The reduction in blood pressure was accompanied by an increase in urinary fractional excretion of sodium in SSHTN and AIIHTN KidVD+ mice. AIIHTN induced an elevated glomerular filtration rate (GFR) in KidVD- mice while this was reduced in KidVD+ mice; however, GFR was unaltered in SSHTN KidVD+ mice. Thus, augmenting renal lymphatics increased fractional excretion of sodium and lowered blood pressure in both mouse models of hypertension. Augmenting renal lymphatics may be a promising anti-hypertensive and natriuretic therapeutic strategy.

Urinary Cell Adhesion Molecule 1 Is a Novel Biomarker That Links Tubulointerstitial Damage to Glomerular Filtration Rates in Chronic Kidney Disease.

Cell adhesion molecule 1 (CADM1) is an immunoglobulin superfamily member strongly expressed on renal tubular epithelia in the urinary tract. Enzymatic cleavage of its ectodomain increases in chronic kidney disease (CKD), and is assumed to contribute to tubulointerstitial lesion formation. Because the cleaved ectodomain fragments are likely to be released into the urine, a sandwich enzyme-linked immunosorbent assay (ELISA) system for urinary CADM1 was developed using two anti-ectodomain antibodies. Urinary CADM1 concentrations in patients with CKD based on various forms of glomerulonephritis and nephropathy (n = 127) were measured. A total of 44 patients (35%) had elevated CADM1 concentrations over the normal upper limit (362 pg/mL), with a mean of 1,727 pg/mL. Renal biopsy specimens of all patients were pathologically scored for tubulointerstitial lesions using epithelial degeneration, interstitial inflammation, and fibrosis. There were no correlations between urinary CADM1 concentrations and pathological scores or any widely used renal markers, including glomerular filtration rate (GFR), but there was a weak inverse correlation between pathological scores and GFR (R2 = 0.292). Notably, this correlation gradually increased in patients with increasing CADM1 concentrations, and reached a maximum R2 (0.899) at a cutoff of 1,569 pg/mL. The results of this study suggest that urinary CADM1 is a useful marker indicating tubulointerstitial damage from elevated GFR levels in CKD.

Impaired SIRT1 activity leads to diminution in glomerular endowment without accelerating age-associated GFR decline.

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD +‐dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age‐related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1 Y/Y) mice had lower GFRs and fewer glomeruli than their wild‐type (Sirt1 +/+) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1 Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1 Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.

Correlation Between Baseline GFR and Subsequent Change in GFR in Norwegian Adults Without Diabetes and in Pima Indians

An elevated glomerular filtration rate (GFR), or renal hyperfiltration, maypredispose individuals to subsequent rapidGFR decline in diabetes, obesity, and metabolic syndrome. Although this hypothesis is supported byresults of experimental studies, the importance of hyperfiltration at the population level remains controversial. We investigated whether higher baseline GFR predicts a steeper decline in GFR. Longitudinal cohort studies. 1,594 middle-aged Norwegians without diabetes (the Renal Iohexol Clearance Survey [RENIS]) and 319 Pima Indians (83% with type 2 diabetes). Baseline measured GFR using exogenous clearance methods. Change in measured GFR over time. Linear mixed regression models fit to assess the correlation between the random intercept (reflecting baseline GFR) and random slope (change in GFR over time). Mean baseline GFRs were 104.0 ± 20.1 (SD) and 149.4 ± 43.3 mL/min, and median follow-up durations were 5.6 (IQR, 5.2-6.0) and 9.1 (IQR, 4.0-15.0) years in the RENIS and Pima cohorts, respectively. Correlation between baseline GFR (random intercept) and slope of GFR decline was-0.31 (95% CI,-0.40 to-0.23) in the RENIS cohort and-0.41 (95% CI,-0.55 to-0.26) in the Pima cohort, adjusted for age, sex, height, and weight, suggesting that higher baseline GFRs were associated with steeper GFR decline rates. Different methods for measuring GFR in the 2 cohorts. Renal hyperfiltration may not reflect higher single-nephron GFR. GFR decline is assumed to be linear, which may not match the actual pattern; observed correlations may arise from natural variation. Higher baseline GFR is associated with faster decline in GFR over time. If this relationship were causal, elevated GFR would represent a potentially modifiable risk factor for medium- to long-term GFR decline.

Glomerular hyperfiltration in excess weight adolescents.

Childhood overweight/obesity burden is on the rise worldwide. Obesity affects virtually all organs. In the kidney, glomerular hyperfiltration that manifests as elevated glomerular filtration rate is a frequent manifestation in obesity. This adaptive renal manifestation to excess metabolic demand on the kidney, in children, has been studied mainly in the severely obese and is uncertain if it is present in less severe forms of excessive weight. In addition, glomerular hyperfiltration has been reported to be associated with high levels of the indicators of cardiometabolic risk, and these latter finding are solely from adult studies. To ascertain if glomerular hyperfiltration occurs in overweight and less severely obese children and to determine any significant relevance of some indicators of cardiometabolic risk associated with hyperfiltration. This cross-sectional study involved 49 adolescents (28 overweight, 21 obese) and 49 normal weight adolescents. The participants were subjected to clinical examination, anthropometric measurement, laboratory investigation using standard techniques. Estimated glomerular filtration rates (eGFR) were calculated using the modified Schwartz equation. Hyperfiltration was defined as eGFR ≥140 ml/min/1.73 m2. Hyperfiltration was observed in 20 (40.8%) of the overweight/obese adolescents. The prevalence of hyperfiltration among the overweight and the obese adolescent was 24.5% and 16.3%, respectively. The mean estimated glomerular filtration rate of the overweight/obese adolescents was 141.0 ± 46.2 ml/min/1.73 m2, whereas that of the normal weight adolescents was 99.2 ± 17.1 ml/min/1.73 m2 (P = 0.0001). A higher prevalence of hypertension was observed among the overweight/obese adolescent with glomerular hyperfiltration. Glomerular hyperfiltration is not limited to morbidly obese children as the burden is also high in overweight and less severely obese adolescents.

Abstract P265: Early Renal Hyperfiltration In Obese Dahl Salt-Sensitive Leptin Receptor Mutant Rats is Associated With Glomerular Leukocyte Extravasation and Renal Disease

Hypertension and diabetes are the major causes of chronic kidney disease (CKD). However, epidemiological studies within the last few decades have revealed obesity as an independent risk factor for CKD. Recently, we reported that the obese Dahl salt-sensitive leptin receptor mutant (SS LepR mutant) strain displays proteinuria and podocyte injury by 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. The current study examined whether the development of renal injury in the SS LepR mutant strain is associated with elevations in glomerular filtration rate (GFR). During the study, the SS LepR mutant strain developed hyperinsulinemia and dyslipidemia but not hyperglycemia. Baseline MAP (via carotid catheter) at 6 weeks of age was similar between SS WT (n=8) and SS LepR mutant (n=8) rats and averaged 124 mmHg. However, by 18 weeks of age, MAP increased significantly in the SS LepR mutant strain compared to the values measured in SS WT rats (192±4 vs 149±6 mmHg, respectively). At baseline, protein excretion was 4-fold higher in the SS LepR mutant strain compared to SS WT rats and remained elevated over the course of the study (778±96 vs 137±25 mg/day, respectively). At 6 weeks of age, GFR was 34% higher in the SS LepR mutant strain compared to age-matched SS WT rats indicating renal hyperfiltration (2.92±0.23 vs 2.18±0.25 mL/min/kwt, respectively). While we observed only a 40% reduction in GFR in SS WT rats (1.30±0.07 mL/min/kwt), GFR markedly decreased by 70% in the SS LepR mutant strain (0.87±0.08 mL/min/kwt). Over time, kidneys from the SS LepR mutant strain displayed more glomerulosclerosis, mesangial expansion, and renal fibrosis in comparison to SS WT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 weeks of age and RNA sequencing was performed to identify genes and pathways driving glomerular injury. The major, most consistent signaling pathways that changed at 6 and 18 weeks of age were involved in leukocyte extravasation. In conclusion, these data provide evidence that renal hyperfiltration may contribute to glomerular capillary leukocyte extravasation leading to the early development of proteinuria during obesity in the absence of hypertension and hyperglycemia.