Increase In Filtration Fraction Research Articles

Nuclear factor erythroid 2-related factor 2 activation in streptozotocin-induced diabetic rats normalize renal hemodynamics and oxygen consumption.

Diabetic kidney disease is a major contributor to end stage renal disease. A change in kidney oxygen homeostasis leading to decreased tissue oxygen tension is an important factor initiating alterations in kidney function in diabetes. However, the mechanism contributing to changed oxygen homeostasis is still unclear. Hyperglycemia-induced production of reactive oxygen species and an altered response to them have previously been demonstrated. In the present study, chronic treatment with DL-sulforaphane to induce nuclear factor erythroid 2-related factor 2 (Nrf2) expression, a master transcriptional regulator binding to antioxidant response elements inducing increased protection against reactive oxygen species, is studied. Sprague-Dawley rats were made diabetic using streptozotocin and either left untreated or received daily subcutaneous injections of DL-sulforaphane for 4 weeks. Age-matched non-diabetic rats served as controls. After 4 weeks of treatment, rats were anesthetized using thiobutabarbital, and kidney functions were studied in terms of glomerular filtration rate (GFR), renal blood flow (RBF), sodium transport, kidney oxygen consumption, and kidney oxygen tension. Mitochondria was isolated from kidney cortical tissue and investigated using high-resolution respirometry. GFR was increased in diabetics but not RBF resulting in increased filtration fraction in diabetics. DL-sulforaphane treatment did not affect RBF and GFR in controls but decreased the same parameters in diabetics. Increased GFR resulted in increased sodium transport and oxygen consumption, hence decreased efficiency in diabetics compared to controls. Increased oxygen consumption in diabetics resulted in decreased cortical tissue oxygen tension. DL-sulforaphane treatment decreased oxygen consumption in diabetics, whereas transport efficiency was not significantly affected. DL-sulforaphane treatment increased cortical pO2 in diabetics. DL-sulforaphane treatment affects renal hemodynamics, improving cortical oxygen tension but not mitochondrial efficiency.

S-41-5: NEW INSIGHTS INTO THE OPTIMAL ANTIHYPERTENSIVE THERAPY IN CKD PATIENTS

Chronic kidney disease (CKD) is defined as continuous existence of reduced renal function, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, and/or proteinuria including microalbuminuria. CKD patients are not only prone to progress to renal failure but also at high risk for developing cardiovascular diseases (CVD) as the concept of cardio-renal syndrome is assumed. As the cause of CKD, diabetic kidney disease and nephrosclerosis are dominating and their progression is promoted by aging and lifestyle-related diseases (LSD) such as hypertension and diabetes. Therefore, in order to maximally prevent renal failure and CVD in CKD patients, aggressive intervention achieving strict control of LSD starting at its earliest stage is important. Renal function is generally evaluated by eGFR, however, the fundamental aspect of renal function is renal blood flow or renal plasma flow (RPF), and the decrease of RPF is compensated by the increase in filtration fraction yielding the maintenance of GFR value. Accordingly, if eGFR is less than 60, it should be recognized that the extent of renal injury is not mild but moderate or worse. However, the measurement of RPF requires laborious and invasive procedure. Albuminuria may reflect the increase in glomerular capillary pressure (glomerular hypertension) elicited by reduced nephron number but the urinary albumin excretion is highly variable and is not necessarily parallel to the degree of renal injury. Among LSD, hypertension plays a pivotal role as the risk factor for renal failure and CVD, and the strict blood pressure control targeting < 130/80mmHg is recommended in the guidelines. As antihypertensive agents, renin-angiotensin system inhibitors such as ARB and ACE inhibitors are preferred because of dilating the efferent arterioles resulting in the alleviation of glomerular hypertension and the reduction in albuminuria. Calcium channel blockers have advantage in preserving RPF and GFR by dilating the afferent arterioles. In addition, recent randomized controlled trials have demonstrated that sodium-glucose cotransporter 2 inhibitors retard the GFR decrease in diabetic and non-diabetic CKD patients. Angiotensin receptor neprilysin inhibitor, now used for hypertension, has also been shown to reduce the risks of GFR decrease and worsening of renal function in heart failure patients. Nonsteroidal mineralocorticoid receptor antagonists are expected to provide renoprotective effects such as albuminuria reduction with affordable risk of hyperkalemia. Thus, in future strategy of antihypertensive therapy for CKD aiming maximum renal and cardiovascular protection, practical evaluation of renal injuries at early stages and incorporation of drugs with new evidence are the key issues.

Extremity trauma impairs renal tolerance to hemorrhage

BACKGROUDHemorrhage is often accompanied and/or caused by extremity trauma (ET) in both battlefield or civilian trauma scenarios. However, the impacts of ET on tolerance to hemorrhage and resultant renal injury remain unclear. We hypothesize that ET impairs tolerance to hemorrhage and renal ischemia, resulting in increased acute kidney injury (AKI) and mortality.METHODSSprague Dawley rats (11–13 wks) underwent pressure‐controlled hemorrhage (at MAP of 70 or 55 mmHg) with or without ET. Animals were randomly divided into groups: (time) control, ET (without hemorrhage), 70mmHg, 55mmHg, ET+70mmHg, and ET+55mmHg (n ≥ 7 for each group). Rats were anesthetized (inactin), and the femoral and carotid arteries were catheterized to measure MAP and to induce hemorrhage. Renal blood flow (RBF) was measured using a perivascular ultrasonic flow probe. After baselines were recorded, ET was induced via clamping the retrofemoral tissue groups for 30 sec using an L‐shaped hemostat, followed by closed fibula fracture using a 15‐gauge needle. Hemorrhage was induced 5 minutes after ET with target MAP maintained for up to 3 hours by withdrawal or reinfusion of shed blood with a dual direction pump (0.5 ml/min). Blood and urine samples were collected from arterial and bladder catheters before, and 1, 2, and 3 hours after hemorrhage.RESULTSET alone without hemorrhage caused a transient increase in heart rate without significantly affecting other measurements. Less blood withdrawal was required to maintain the target MAP during pressure‐controlled hemorrhage in groups with ET compared to groups without ET, and infusion back of shed blood was required 1 hour after hemorrhage in the 55mmHg+ET group (Figure A). Hemorrhage to 70mmHg caused significant decreases in RBF (Figure B), urine flow, and renal oxygen delivery (RDO2), but increased filtration fraction (FF) with no effect on creatinine clearance (Ccr), potassium, lactate, or urine albumin levels. In ET+70mmHg group, decreases in RBF and RDO2 were exacerbated, and impaired Ccr and FF with significant increases in circulating creatinine, potassium, lactate, and urine albumin levels were observed. All animals in groups 70mmHg and ET+70mmHg survived. Hemorrhage to 55mmHg caused significant decreases in RBF, urine flow, and RDO2 which were greater than observed the 70mmHg group. Hemorrhage to 55mmHg also caused decreases in Ccr and FF and increases in circulating creatinine, potassium, lactate, and urine albumin levels. When ET was combined with hemorrhage to 55mmHg, no further decreases in RBF and RDO2 were observed. However, ET+55mmHg animals showed exacerbated decreases in urine flow and exacerbated increases in circulating creatinine, potassium, and lactate levels. All animals survived for 3 hours following hemorrhage to 55mmHg, but only 50% animals survived in ET+55mmHg group.CONCLUSIONSOur data suggest that ET impairs tolerance to hemorrhage, exacerbates renal hypoperfusion, and increases risks for AKI and mortality. Although underlying mechanisms are unclear, the study provides important evidence that traumatic tissue injury should be considered as a critical component if using animal models to conduct translational studies on hemorrhage.Figures A and B represent the volume loss to maintain target MAP and related renal blood flow following different levels of hemorrhage with or without ET. ET is extremity trauma, Bas is baseline, Pre is Pre‐hemorrhage (5 minutes after ET). * P< 0.05 70mmHg vs ET+70mmHg, + P< 0.01 55 mmHg vs ET+55mmHg, n = 7 for 70mmHg and ET+70mmHg; n = 8 for 55mmHg and ET+55mmHg.Figure 1

OP.7D.04] CHANGES IN RENAL HEMODYNAMIC AND TUBULAR SODIUM HANDLING ONE YEAR AFTER TRANSCATHETER RENAL DENERVATION IN RESISTANT HYPERTENSION

Objective: The sympathetic nervous system is implicated in most form of hypertension. In resistant hypertension, transcatheter renal denervation (RDN) has been proposed as an adjunctive therapy to antihypertensive drugs at maximum tolerated doses. The results on blood pressure (BP) reduction have been the source of debate. Few studies have explored the effect on renal hemodynamics and tubular sodium handling. The objective was to assess these two parameters before RND and after 1 and 12 months. Design and method: Patients with confirmed resistant hypertension and no contraindications for RDN could be included in the study. Systemic hemodynamic, renal hemodynamic using inulin and PAH clearances, sodium and endogenous lithium clearances (a marker of proximal sodium reabsorption), hormones were measured in standardized condition before RDN and after 1 and 12 months. Variables were compared with an analysis of variance. Results: 13 patients were included in the study. Mean age was 56.1 ± 9.9 years, body mass index was 30.9 ± 9.9 Kg/m2. Mean number of ablation points was 4.7 ± 1.2 points on the left artery and 5.0 ± 1.6 points on the right artery. The following table displays the systemic and renal hemodynamics, the sodium tubular handling and the hormonal profile before RDN and after 1 and 12 months.BP and heart rate remained constant while glomerular filtration rate and filtration fraction decreased. Proximal sodium reabsorption, assed by lithium clearances, increased with time. Plasma renin activity tended to increase which could not be explained by the use of diurectics which was similar before and 12 months after RDN. Conclusions: One year after renal denervation, renal hemodynamics and tubular sodium handling seem to be altered with increased filtration fraction and proximal sodium reabsorption. The long term effects of these changes on renal function and blood pressure need to be assed in long term follow-up studies.

Renal hemodynamic and morphological changes after 7 and 28 days of leptin treatment: the participation of angiotensin II via the AT1 receptor.

The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin’s action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED-1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-α and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-α and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects.

Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration

Diabetes is associated with increased risk for development of kidney disease, and an increased glomerular filtration rate is an early indication of altered kidney function. Here we determine whether reduced adenosine A2a receptor-mediated vasodilation of the efferent arteriole contributes to the increased glomerular filtration rate in diabetes. The glomerular filtration rate, renal blood flow, and proximal tubular stop flow pressure were investigated in control and streptozotocin-diabetic rats during baseline and after administration of the adenosine A2a receptor antagonist ZM241385 or the adenosine A2a receptor agonist CGS21680. The diabetes-induced glomerular hyperfiltration was reduced by 24% following A2a receptor stimulation but was unaffected by A2a receptor inhibition. Contrarily, glomerular filtration rate in controls increased by 22% after A2a receptor inhibition and was unaffected by A2a stimulation. The increased glomerular filtration rate after A2a receptor inhibition in controls and decreased glomerular filtration rate after A2a receptor activation in diabetics were caused by increased and decreased stop flow pressure, respectively. None of the interventions affected renal blood flow. Thus, the normal adenosine A2a receptor-mediated tonic vasodilation of efferent arterioles is abolished in the diabetic kidney. This causes increased efferent arteriolar resistance resulting in increased filtration fraction and hyperfiltration.

Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study.

Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure are unknown. In this double-blind, randomized, placebo-controlled, multicenter study, patients with New York Heart Association Class II to III chronic heart failure, left ventricular ejection fraction ≤45%, and estimated glomerular filtration rate (GFR) 30 to 89 mL/min per 1.73 m(2) received intravenous serelaxin 30 μg/kg per day or placebo for 24 hours. Primarily, we assessed the difference between serelaxin and placebo on renal plasma flow (para-aminohippuric acid clearance) and GFR (iothalamate clearance) over 8 to 24 hours. All 22 patients from 1 clinical site were excluded from primary analyses before unblinding because of implausible measurements. The primary analysis comprised 65 patients, mean age was 68 (±10) years, 89% were male, mean estimated GFR was 64 (±19) mL/min per 1.73 m(2), and 34% had New York Heart Association Class III symptoms. Renal plasma flow increased by 29% with serelaxin and 14% with placebo (13% relative increase with serelaxin; P=0.0386), whereas GFR changes did not differ significantly during 8 to 24 hours. Filtration fraction increased by 36% with serelaxin and 62% with placebo (16% relative decrease with serelaxin; P=0.0019) during 8 to 24 hours. Changes in systolic blood pressure were largely similar, and creatinine clearance did not differ between groups. Adverse event rates were similar with serelaxin (20.5%) and placebo (25.0%). In patients with chronic heart failure, serelaxin increased renal plasma flow and reduced the increase in filtration fraction compared with placebo, but did not affect GFR. These results suggest beneficial renal hemodynamic effects in patients with chronic heart failure. http://www.clinicaltrials.gov. Unique identifier: NCT01546532.

Nucleoside monophosphorothioates as the new hydrogen sulfide precursors with unique properties

Hydrogen sulfide (H2S) is the gasotransmitter enzymatically synthesized in mammalian tissues from l-cysteine. H2S donors are considered as the potential drugs for the treatment of cardiovascular, neurological and inflammatory diseases. Recently, it has been demonstrated that synthetic nucleotide analogs, adenosine- and guanosine 5′-monophosphorothioates (AMPS and GMPS) can be converted to H2S and AMP or GMP, respectively, by purified histidine triad nucleotide-binding (Hint) proteins. We examined if AMPS and GMPS can be used as the H2S donors in intact biological systems. H2S production by isolated rat kidney glomeruli was measured by the specific polarographic sensor. H2S production was detected when glomeruli were incubated with AMPS or GMPS and ionotropic purinergic P2X7 receptor/channel agonist, BzATP. More H2S was generated from GMPS than from equimolar amount of AMPS. Nucleoside phosphorothioates together with BzATP relaxed angiotensin II-preconstricted glomeruli. In addition, infusion of AMPS or GMPS together with BzATP into the renal artery increased filtration fraction and glomerular filtration rate but had no effect on renal vascular resistance or renal blood flow. AMPS but not GMPS was converted to adenosine by isolated glomeruli, however, adenosine was not involved in AMPS-induced H2S synthesis because neither adenosine nor specific adenosine receptor agonists had any effect on H2S production. AMPS, but not GMPS, increased phosphorylation level of AMP-stimulated protein kinase (AMPK), but AMPK inhibitor, compound C, had no effect on AMPS-induced H2S production. In conclusion, nucleoside phosphorothioates are converted to H2S which relaxes isolated kidney glomeruli in vitro and increases glomerular filtration rate in vivo. AMPS and GMPS can be used as the H2S donors in experimental studies and possibly also as the H2S-releasing drugs.

The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.

Body mass index and body fat distribution as renal risk factors: a focus on the role of renal haemodynamics

Weight excess and/or central body fat distribution are associated with increased long-term renal risk, not only in subjects with renal disease or renal transplant recipients, but also in the general population. As the prevalence of weight excess is rising worldwide, this may become a main renal risk factor on a population basis, even more so because the risk extends to the overweight range. Understanding the mechanisms of this detrimental effect of weight excess on the kidneys is needed in order to design preventive treatment strategies. The increased risk associated with weight excess is partly attributed to associated comorbid conditions, such as hypertension, dyslipidaemia, insulin resistance and diabetes; however, current evidence supports a direct pathogenetic role for renal haemodynamics as well. Weight excess is associated with an altered renal haemodynamic profile, i.e. an increased glomerular filtration rate relative to effective renal plasma flow, resulting in an increased filtration fraction (FF). This renal haemodynamic profile is considered to reflect glomerular hyperfiltration and glomerular hypertension, resulting from a dysbalance between afferent and efferent arterial vasomotor balance. This unfavorable renal haemodynamic profile was found to be associated with renal outcome in experimental models and in human renal transplant recipients, and is associated with a blunted sodium excretion, and reversible by weight loss, renin-angiotensin-aldosterone system blockade or by dietary sodium restriction. More recent evidence showed that a central body fat distribution is also associated with an increased FF, even independent of overall weight excess. In this review, we provide an overview on current literature on the impact of weight excess and central body fat distribution on the renal haemodynamic profile in humans, and its possible role in progressive renal damage.

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005). The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Synthetic oleanane triterpenoids: magic bullets or not?

A recent clinical trial in patients with chronic kidney disease (CKD) and diabetic nephropathy demonstrated that bardoxolone methyl (CDDO-ME) increases estimated glomerular filtration rate (eGFR) by an unknown mechanism. The paper by Ding et al. suggests that short-term administration of a CDDO-ME analog increases GFR by increasing glomerular surface area. However, changes in other renal hemodynamic parameters cannot be excluded. Vigorous testing of CDDO-ME and highly purified analogs is warranted to determine their physiology, pharmacology, and efficacy and to exclude serious side effects.

460 EFFECTS OF URIC ACID ON SYSTEMIC AND RENAL HEMODYNAMICS IN CONSCIOUS RABBITS

Objectives: Experimental animal studies demonstrate that chronic hyperuricemia can induce renal damage as well as elevate blood pressure. This study was designed to investigate the influences of uric acid (UA) on renal hemodynamics in conscious animals. Design and Methods: In 8 conscious rabbits, renal plasma flow (RPF) and glomerular filtration rate (GFR) (estimated by clearance of para-aminohippurate and inulin, respectively) were measured at 20-min intervals before and after the intracutaneous administration of the following drugs at three occasions separately at least 1 week apart: (1) vehicle, (2) oxonic acid (i.e., uricase inhibitor) at 500 mg/kg of BW, (3) oxonic acid at 500 mg/kg of BW plus allopurinol (i.e., xanthine oxidase inhibitor) at 6 mg/kg of BW. Results: Serum UA, blood pressure (BP), pulse rate (PR), RPF and GFR remained unchanged after vehicle. Following the administration of oxonic acid, both BP and PR increased (115 ± 4/88 ± 2 to 126 ± 3/96 ± 1 mmHg, 229 ± 6 to 251 ± 4 /min) concomitantly with the elevation of serum UA (0.19 ± 0.03 to 0.40 ± 0.04 mg/dL). Additionally, RPF decreased (22 ± 2 to 17 ± 1 mL/min/kg of BW) without changes in GFR (3.7 ± 0.2 to 3.7 ± 0.1 mL/min/kg of BW). Consequently, oxonic acid increased filtration fraction (0.18 ± 0.01 to 0.21 ± 0.01). In contrast, allopurinol completely abolished all the changes induced by oxonic acid in serum UA, systemic hemodynamics and renal function. Conclusions: These results indicate that increased serum UA induced renovasoconstriction as well as elevated systemic pressure, and suggest that the renovasoconstriction induced by UA might occur mainly on the efferent arteriole.

Sports anaemia: facts or fiction?

Sports anaemia: facts or fiction?

Induction of hyperglycemia in adult intrauterine growth-restricted rats: effects on renal function

Intrauterine growth restriction (IUGR) leads to a reduction in nephron endowment at birth and is linked to renal dysfunction in adulthood. The aim of the present study was to determine whether kidneys of IUGR rat offspring are more vulnerable to a secondary insult of hyperglycemia. IUGR was induced in Wistar-Kyoto rats by maternal protein restriction. At 24 wk of age, diabetes was induced in male IUGR and non-IUGR offspring by streptozotocin injection; insulin was injected daily to maintain blood glucose levels at either a mild (7-10 mmol/l; n=8/group) or a moderate (10-15 mmol/l; n=8/group) level. At 32 wk of age, renal function was assessed using ultrasound and [(3)H]inulin and [(14)C]para-aminohippurate clearance techniques. Conscious mean arterial blood pressure and heart rate were unchanged in IUGR offspring. Relative kidney length was increased significantly in IUGR offspring, and renal function was altered significantly; of importance, there was a significant increase in filtration fraction, indicative of glomerular hyperfiltration. Induction of hyperglycemia led to marked impairment of renal function. However, the response to hyperglycemia was not different between IUGR and non-IUGR offspring. Maintaining blood glucose levels at a mild hyperglycemic level led to marked improvement in all measures of renal function in IUGR and non-IUGR offspring. In conclusion, while the IUGR offspring showed evidence of hyperfiltration, the response to hyperglycemia was similar in IUGR and non-IUGR kidneys in adulthood. Importantly, maintaining blood glucose levels at a mild hyperglycemic level markedly attenuated the renal dysfunction associated with diabetes, even in IUGR offspring.

Is there an obesity–metabolic syndrome related glomerulopathy?

There is an increasing evidence for a specific form of focal segmental glomerulosclerosis (FSGS) related to obesity. Its prevalence has progressively increased in past decades. This form of FSGS represents the tip of an iceberg: a much broader spectrum of renal malfunction is linked to visceral obesity, which is closely connected to, but not completely identical with, the concept of 'metabolic syndrome'. The obesity-associated FSGS (obFSGS) is characterized by massive proteinuria and glomerular lesions which are similar to but less pronounced than in idiopathic FSGS, but the long-term prognosis is still dubious. The patholophysiology underlying obesity-associated renal pathology includes insulin resistance and salt sensitivity of blood pressure (BP); more recently adiponectin deficiency, hyperaldosteronism and many other pathogenetic factors have been identified. The abnormalities of renal structure in obese and morbidly obese individuals include increased kidney weight, glomerulomegaly, disorder of podocytes, mesangial expansion and more recently also abnormalities of the renal interstitium. This is accompanied by functional abnormalities, that is renal hyperperfusion, increased filtration fraction and albuminuria. Both obesity and metabolic syndrome have been identified as powerful predictors of chronic kidney disease (CKD) and end-stage renal disease (ESRD). This correlation is not fully explained by associated hypertension and prediabetes/diabetes. The link between progressive kidney disease and visceral obesity is of enormous public health importance. Apart from causing obFSGS, obesity aggravates most primary kidney diseases. Beyond standard therapy and weight loss, bariatric surgery has recently emerged as a successful intervention for obFSGS.

Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1 mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (-14%), RBF (-19%) and diuresis (-12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia-induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal function.

Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type 1 diabetes mellitus

In experimental studies, cyclooxygenase 2 (COX2)-derived vasodilatory prostaglandins play a more prominent role in arterial vasoregulation in females. The gender-dependent effect of COX2 modulation in humans with type 1 diabetes mellitus (DM) is unknown. Accordingly, we examined the renal hemodynamic role of prostaglandins by assessing the response to COX2 inhibition in young men and women with type 1 DM. We also used a graded ANG II infusion to determine whether gender-based differences were mediated by effects of COX2 inhibition on the renin angiotensin system (RAS). We hypothesized that COX2 inhibition would be associated with preferential vasoconstriction in women and would augment their response to ANG II. Baseline renal function and the response to an ANG II infusion were assessed during clamped euglycemia, and again after COX2 inhibition (200 mg celecoxib daily for 14 days) in 12 men and 9 women after 1 wk on a controlled protein and sodium diet. COX2 inhibition was associated with increases in filtration fraction (P = 0.045) and renal vascular resistance and a decline in renal blood flow (P = 0.04) in women compared with men. Before COX2 inhibition, women exhibited a decline in glomerular filtration rate in response to ANG II. COX2 inhibition abolished this effect, whereas the response was not altered in men. In summary, COX2 inhibition was associated with hemodynamic effects that differed based on gender. The ANG II response suggests that with uncomplicated type 1 DM, prostaglandins may contribute to RAS-mediated gender differences. Our results are consistent with experimental data suggesting augmented female prostanoid dependence.

The implications of aspirin resistance in renal failure.

Sir, Aspirin resistance is a phenomenon where the expected inhibition of platelet responses is not obtained as evaluated by different biological tests [1]. In addition to non-compliance and other patient-related factors, one of the main reasons for aspirin resistance is its inability to inhibit thromboxane A2 (TXA2) biosynthesis in vivo. Many studies have also shown that patients with aspirin resistance are more likely to have an increased rate of recurrence of vascular events [2,3]. Interestingly, in a recent systematic review by Krasopoulos et al., the relationship between resistance to aspirin and a history of renal impairment was observed (P < 0.03) [4]. This was considered as possibly a chance finding, mainly because of lack of substantial data. However, an abnormality of platelet arachidonic acid metabolism has been well documented to exist in patients with renal impairment [5]. This leads to altered thromboxane synthesis that is a key factor for the development of resistance to aspirin. Initially thought to be due to a ‘functional cyclo-oxygenase defect’, it is now considered to be due to the increased activity of phospholipase A2 in the platelets of patients with uraemia [5,6]. Thromboxane has also been shown to play an important role in the physiological function of the kidney, and TXA2 receptors have been shown to exist in renal vasculature and other nephron segments in animal models [7,8]. Various studies have shown that TXA2 plays a key role in the regulation of renal haemodynamics mainly acting in conjunction with angiotensin II. TXA2, in addition to angiotensin II and arginine–vasopressin constrict larger vessels within the renal vascular tree via activation of a rho-associated kinase pathway [9]. Thromboxane receptor knockout mice demonstrated reduced renal blood flow and increased filtration fraction and renal vascular resistance, despite normal basal mean arterial blood pressure and glomerular filtration rate [10]. Enhanced production of thromboxane in the kidney has been demonstrated in several diseases including lupus nephritis, ureteral obstruction and nephrotoxic renal injury [11,12,13]. In a normal kidney, the production of TXA2 and prostaglandin I2 is well controlled, and the balance between them is important in maintaining homeostasis in vivo. In patients with the above conditions, however, TXA2 synthesis is higher compared to that of prostaglandin I2. The administration of thromboxane antagonists decreased the severity of these diseases, supporting the important role of thromboxane in their pathogenesis. Kwag et al. demonstrated that dietary vitamin E decreased the elevated phospholipase A2 in the kidney tissues of diabetic rats and improved the prostaglandin I2/TXA2 balance in the kidney microsomes thus improving vascular complications [14]. Chronic kidney disease is now recognized as an independent risk factor for cardiovascular events, and cardiovascular disease is the major cause of mortality in patients with the disease [15]. Possibly, the increased aspirin resistance in patients with renal failure may indicate that a similar vascular pathology, involving among others thromboxane, exists in these two different vascular beds. More work on the thromboxane pathway is required in the patients with renal impairment, who develop recurrent cardiovascular events, despite being on aspirin. This would pave the way for novel treatments that would help in preventing the progression of both the renal and cardiovascular pathologies. Conflict of interest statement. None declared.

Pharmacologic Vasopressin Levels May Protect Renal Function in a Porcine (Sus Scrofa) Model of Vasodilatory Septic Shock

Acute renal failure commonly occurs with severe sepsis and is associated with high mortality. Pharmacologic administration of vasopressin (VP) increases urine output in septic shock. To elucidate the mechanism by which pharmacologic VP induces diuresis, VP was administered at a low dose of 10 and a high dose of 100 ng/kg/min to piglets with endotoxin‐induced septic shock. VP‐100 produced a 4‐fold increase in urine flow (0.05 ± 0.02 vs. 0.23 ± 0.04 ml/kg/min), creatinine clearance, and filtration fraction compared to VP‐10 while the mean arterial pressure (MAP), delta MAP, and renal blood flow were similar between the groups. High dose VP demonstrated increased osmolar clearance (0.07 ± 0.05 vs. 0.21 ± 0.13 ml/kg/min), Na excretion, and fractional excretion (FE) of sodium (2.04 ± 0.83 vs. 4.51 ± 0.57) despite an increase in aldosterone and no change in renin levels. There was no change in the FE of urea or potassium between groups. The production of dilute urine was evidenced by increased free water clearance (−0.02 ± 0.01 to 0.03 ± 0.02 ml/kg/min), decreased urine osmolality (415 ± 21 vs. 282 ± 22 mOsm/kg H2O), and decreased urine protein (5.3 ± 0.87 vs. 1.9 ± 0.54 mg/ml) observed in the high but not low dose of VP. Thus at high dose VP, the increase in the filtration fraction and the FENa which lead to an increased excretion of dilute urine suggest a tubular osmotic mechanism that may be renal protective in septic shock.