Changes In Renal Hemodynamics Research Articles

Effect of orchiectomy on renal function in control and diabetic rats with chronic inhibition of nitric oxide

1. Male gender is associated with higher blood pressure (BP) and more rapid loss of renal function in a spectrum of clinical and experimental renal diseases, including diabetic nephropathy. Consequently, modulation of testosterone levels could exert beneficial effects in the diabetic kidney. 2. The aim of the present study was to determine whether testosterone deficiency (orchiectomy) could influence BP and renal function in streptozotocin-diabetic rats, with or without accelerated endothelial dysfunction achieved by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine methyl ester (l-NAME; 40-100 mg/L in the drinking water for 2 weeks), as well as in age-matched non-diabetic rats subjected to the same interventions. 3. Orchiectomy did not affect L-NAME-induced increases in BP in non-diabetic or diabetic rats. In non-diabetic rats, orchiectomy prevented L-NAME-induced increases in proteinuria. These effects on proteinuria were not observed in diabetic rats. In non-diabetic rats, orchiectomy had no effect on renal haemodynamics in animals receiving vehicle and did not affect L-NAME-induced changes in renal haemodynamics, characterized by reductions in renal plasma flow (RPF) and higher filtration fractions (FF). In intact diabetic rats, L-NAME treatment resulted in lower RPF. This difference was not observed in diabetic rats subjected to orchiectomy, although L-NAME-treated diabetic orchiectomized rats had lower RPF and higher FF compared with vehicle-treated intact diabetic rats. 4. In conclusion, we report modest beneficial effects of orchiectomy on proteinuria in normal, but not in diabetic, rats with inhibition of NO production. This suggests that testosterone reduction does not attenuate the deleterious impact of the diabetic metabolic milieu in the kidney.

COMP-Angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury

During sepsis endothelial dysfunction is an important pathogenetic mechanism in acute kidney injury (AKI). Lipopolysaccharide (LPS)-induced endotoxemia is associated with renal hemodynamic changes such as alterations of renal blood flow (RBF), vascular resistance, and glomerular filtration rate. We used adenoviral delivery of an engineered variant of native angiopoietin-1 (COMP-angiopoietin-1) containing anti-inflammatory and anti-permeability functions, to determine if regulation of renal endothelial cell dysfunction may have a beneficial role in preventing AKI during LPS-induced endotoxemia in mice. This treatment prevented the endotoxin-induced decrease of RBF and mean arterial pressure while improving glomerular filtration rate. Treatment also mitigated the effects of LPS on renal intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 protein expression, the number of ER-HR3-positive macrophages that infiltrated the kidney, serum nitrate/nitrite levels, renal inducible nitric oxide synthase protein expression, the induction of tubular epithelial reactive oxygen and nitrogen species, and renal microvascular permeability. Our findings show that COMP-angiopoietin-1, an endothelium-oriented therapeutic agent, protects against AKI caused by endotoxemia.

N‐acetylcysteine improves renal hemodynamics in rats with cisplatin‐induced nephrotoxicity

This work investigated the effect of N-acetylcysteine (NAC), on renal hemodynamics in cisplatin (CP)-induced nephrotoxicity in Wistar-Kyoto (WKY) rats. The animals were divided into four groups (n = 5 or 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) N-acetylcysteine (500 mg kg(-1) per day for 9 days), respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (5 mg kg(-1)) and an i.p. injection of CP (5 mg kg(-1)) together with i.p. NAC (500 mg kg(-1) per day for 9 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE) for measurement of renal vasoconstrictor responses. CP caused a significant reduction in renal blood flow but did not affect NE-induced renal vasoconstriction. In addition, CP significantly increased plasma concentrations of urea and creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and kidney relative weight. CP decreased body weight and creatinine clearance. Histopathologically, CP caused remarkable renal damage compared with control. NAC alone did not produce any significant change in any of the variables measured. However, NAC significantly ameliorated CP-induced hemodynamic, biochemical and histopathological changes. The concentration of platinum in the kidneys of CP ? NAC treated rats was less than in CP-treated rats by 37%. The results show that administration of i.p. NAC (500 mg kg(-1) per day for 9 days) reversed the renal hemodynamic changes as well as the biochemical and histopathological indices of CP-induced nephrotoxicity in WKY rats.

Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy

Renal fibrosis is the hallmark of progressive renal disease of virtually any etiology. The model of unilateral ureteral obstruction (UUO) in the rodent generates progressive renal fibrosis. Surgically created UUO can be experimentally manipulated with respect to timing, severity, and duration, while reversal of the obstruction permits the study of recovery. The use of genetically engineered mice has greatly expanded the utility of the model in studying molecular mechanisms underlying the renal response to UUO. Ureteral obstruction results in marked renal hemodynamic and metabolic changes, followed by tubular injury and cell death by apoptosis or necrosis, with interstitial macrophage infiltration. Proliferation of interstitial fibroblasts with myofibroblast transformation leads to excess deposition of the extracellular matrix and renal fibrosis. Phenotypic transition of resident renal tubular cells, endothelial cells, and pericytes has also been implicated in this process. Technical aspects of the UUO model are discussed in this review, including the importance of rodent species or strain, the age of the animal, surgical procedures, and histological methods. The UUO model is likely to reveal useful biomarkers of progression of renal disease, as well as new therapies, which are desperately needed to allow intervention before the establishment of irreversible renal injury.

Juan Carlos Romero, MD

Juan Carlos Romero, or Carlitos, as his friends call him, was born in Mendoza, Argentina, on September 15, 1937, and passed away surrounded by family and friends in Jackson, Miss, on December 30, 2008. He studied medicine at the School of Medicine of the National University of Cuyo in Mendoza, from which he graduated in 1964. Carlos was a brilliant medical student, distinguished by a consuming thirst for knowledge and by a powerful and inquisitive mind. In 1962, while still a student, Carlos initiated his research career under the direction of Prof Juan Carlos Fasciolo, head of the Department of Physiopathology and one of the pioneers of research on the renin-angiotensin system and its relation to arterial hypertension. In 1964, Carlos published his first scientific article, “The Renin Content of the Blood of Human and Dogs Under Several Conditions.”1 In 1968, he published a seminal article demonstrating that low sodium intake increases plasma renin and aldosterone …

Calcium‐Sensing Receptor Activation In Vivo Decreases Plasma Renin Activity

The calcium‐sensing receptor (CaR) transmits changes in extracellular calcium to changes in intracellular signaling and hormonal secretion. The CaR is expressed in many different cell types that indirectly or directly regulate renin secretion including endothelial and vascular smooth muscle cells, as well as the renin‐secreting juxtaglomerular (JG) cells. We have demonstrated that Sensipar, a CaR‐activating calcimimetic, decreases renin release in vitro in primary cultures of JG cells. However, the response to CaR activation on renin secretion in vivo is unknown. As such, we hypothesized that activation of the CaR with Sensipar in vivo would also decrease renin secretion in anesthetized, male Sprague‐Dawley rats. We infused Sensipar i.v. into anesthetized rats at a dose of 60 mg/kg/hr over 60 min. Blood pressure and renal blood flow remained constant at 101±3 mm Hg and 6.21±0.39 ml/min/g kidney weight, respectively, during the infusion of Sensipar. Basal plasma renin activity (PRA) was 15.42 ± 4.41 ngAngI/ml/hr. Sensipar decreased PRA by 58% to 6.53 ± 1.88 ngAngI/ml/hr (p<0.05, n=7). While our result can not necessarily be attributed to the JG cell‐expressed CaR, we conclude that CaR activation inhibits renin secretion in vivo in the absence of changes in renal hemodynamics or blood pressure.

Urinary transforming growth factor beta1 in children and adolescents with congenital solitary kidney

The aim of the study was to assess urinary transforming growth factor beta1 (TGF beta1) level in children and adolescents with congenital solitary kidney (CSK), depending on estimated glomerular filtration rate (eGFR) and compensatory overgrowth of the kidney. The study group (I) consisted of 65 children and young adults, 0.5-22 years of age (median 10.0 years) with CSK and no other urinary defects. The control group (C) contained 44 healthy children and adolescents, 0.25-21 years old (median 10.3 years). We used an enzyme-linked immunosorbent assay (ELISA) to determine the urinary level of TGF beta1, the Jaffe method to assess creatinine concentration, and the Schwartz formula to estimate GFR. Kidney length was measured while the patient was in a supine position, and overgrowth (O%) was calculated with reference to the charts. Urinary TGF beta1 level in CSK patients was more than twice as high as that in controls (P < 0.05). Also, eGFR in patients with CSK exceeded the values in the control group (P < 0.01). Compensatory overgrowth of the solitary kidney was found (median 19.44%). Urinary TGF beta1 concentration was positively correlated with eGFR (r = 0.247, P < 0.05), uric acid concentration (r = 0.333, P < 0.01), and percentage of overgrowth (r = 0.338, P < 0.01) and body mass index (BMI) centile (r = 0.274, P < 0.05). We concluded that, although proteinuria and progressive renal insufficiency is not observed in patients with CSK during childhood, the renal haemodynamic changes are present and may be a risk factor for impairment of renal function and hypertension in future life.

Role of Acid‐Sensing Ion Channels in hemodynamic effects following nitric oxide inhibition in the rat

Acid‐sensing ion channels (ASICs), a member of degenerin/ENaC/ASIC family, plays ubiquitous roles in the cardiovascular (CV) system as they contribute to exercise pressor reflex and potentiate myogenic tone. As nitric oxide (NO) is a ubiquitous player in CV regulation, this study evaluated ASICs role and the mechanisms of their involvement regulating systemic and renal hemodynamic changes following NO blockade. In the anesthetized rat, amiloride (AM; 2.5 mg/kg) or benzamil (BENZ; 0.7 mg/kg), ENaC/ASIC inhibitor, increased basal mean blood pressure (MBP) by 25±5 and 55±7 mmHg, respectively, but reduced renal cortical blood flow (RCBF) by 111±7 or 99±6 PU, respectively, suggesting that ASICs helps in maintaining BP and renal perfusion. AM or BENZ enhanced L‐NAME‐induced increase in MBP by 44±6 or 55±7%, respectively, but blunted the decrease in RCBF. Verapamil (1 mg/kg), a voltage‐operated calcium channel (VOCC) blocker, reversed the effects of AM and BENZ on basal and L‐NAME‐induced increase in MBP suggesting the contribution of IC Ca2+ to the effects of ASICs. KB‐R7943 5 mg/kg), a Na+/Ca2+ exchange (NCX) inhibitor, also reversed AM or BENZ effects on basal MBP but enhanced the effects on RCBF suggesting an effect of ionic movement via NCX. We suggest that ASICs regulate systemic and renal hemodynamics and the pressor responses due to NO withdrawal by mechanisms involving ionic movement across VOC and NCX.

Renal impairment resulting from hypothyroidism-or impaired estimated glomerular filtration rate in a patient with hypothyroidsm.

Sir, We read with interest the two cases described by Andrew Connor and Joanne E. Taylor [1]. They summarize the medical literature that the lower cardiac output and renal blood flow is likely to be the predominant mechanism of impaired renal function in hypothyroidism. In the discussion, they also list other possible mechanisms, so that hypothyroidism may increase creatinine release from muscle. This renders creatinine a poor marker of GFR. In case 1 the creatinine kinase (CK) was elevated, as a sign of rhabdomyolysis. We think that in cases with elevated endogenous creatinine, we do not know if there is an impaired renal function or not. Furthermore, we want to highlight some important points, which we have to consider in the treatment of patients with hypothyroidism and rhabdomyolysis. As often described in patients with hypothyroidism, they may suffer from a polymyositis-like syndrome and an elevated CK may be observed [2–7]. In these cases, there is a high amount of released creatine and therefore higher endogenous creatinine production. In all these cases, eGFR would be wrong and measuring the creatinine clearance rate does not improve the results. Cystatin C, an endogenous marker to estimate the GFR, independent from muscle mass, age and alimentation may be a better parameters in diagnosing impaired renal function in a patient with hypothyroidism. But there are also problems with this measurement in patients with thyroid dysfunction [8–11]. Cystatin C levels are lower in hypothyroidosis and higher in the hyperthyroid state as compared with the euthyroid state. Manetti et al. described decreased cystatin C concentrations in 24% of hypothyroid patients [11]. We saw a young patient with hypothyroidism and elevated serum creatinine, normal serum urea, reduced estimated GFR (47 ml/min/1.73 m2, estimated by MDRD-4; 30 ml/min/1.73 m2 estimated with a 24-h urine collection) and CK of 4438 U/l. Cystatin C was 0.72 mg/dl, which resulted in a normal GFR of 117 ml/min. We decided to start hormone replacement therapy and to watch closely the pathological parameters. The therapy led to normal laboratory findings for serum creatinine after 6 weeks. Later, we observed a difference in our patient between cystatin C levels in euthyroidism (0.98 mg/l) and in hypothyroidism (0.72 mg/l). One investigation with radioisotopic filtration markers in patients with hypothyroidism underlines the opinion of A. Connor and J. E. Taylor: Karanikas et al. [12] investigated isotopic renal function in severe hypothyroidism and after hormone replacement therapy. They did not find any influence of thyroid hormones on the outcome of 99m-Tc-MAG3-renography. The Cr-EDTA clearance was significantly lower in hypothyroidism. This reflects a normal tubular function and to these authors it seems that the renal haemodynamic changes mainly affect the GFR. If this is right, perhaps in cases of hypothyroidism and mild rhabdomyolysis we have a combination of both high amounts of creatinine and a change in renal haemodynamics. Only inulin clearance may give the answer, if there is really an impaired renal function. Unfortunately, we did not find any case report where the authors use the inulin clearance for estimation of the GFR in a patient with hypothyroidism. There may be risk factors in patients with hypothyroidism, which lead to renal damage with pathological urine sediment and any other sign for tubular failure, described by Sekine et al. [13]: they reported about a patient and cited three other cases with some precipitating factors such as hypotension with myxoedema coma, certain inflammatory reactions of the muscles or, and this is very important, vigorous exercise which may cause massive rhabdomyolysis. In these special cases, high urine and serum myoglobin levels and tubular necrosis can be observed and perhaps dialysis has to be started. We agree with A. Connor and J. E. Taylor that patients with renal impairment of unknown cause have thyroid function tests undertaken as part of routine investigation. Also, we have to look for signs of rhabdomyolysis. Taking these points into account, as described above, we can decide to start hormone replacement therapy and to watch closely the pathological parameters in patients with hypothyroidism, rhabdomyolysis and elevated serum creatinine as the only evidence for an impaired renal function. The hormonal therapy will lead to normal laboratory findings for serum creatinine after some weeks. In cases with hypothyroidism and myalgia, patients have to avoid muscle training or vigorous exercise. There is an increased risk to develop massive rhabdomyolysis and renal damage. If the renal haemodynamic changes mainly affect the GFR in patients with hypothyroidism, we have to take these into account in the therapy. For instance, COX-inhibitors to treat myalgia should be avoided. Inhibition of COX-mediated prostaglandin synthesis by NSAIDs can promote further reduction in renal haemodynamics and increase the risk for acute renal failure. Editorial Note: Dr Connor et al. had no further comments on this letter. Conflict of interest statement. None declared.

Endothelial nitric oxide synthase: from structure to function in one aspartic substitution

Cherney and co-workers examine the functional phenotype of the G894T eNOS polymorphism in a selected group of apparently healthy subjects. The investigators used L-arginine infusion and induced changes in renal hemodynamics. While L-arginine increased effective plasma flow and glomerular filtration rate in GG subjects, these responses were blunted in GT/TT subjects, suggesting that either the G894T polymorphism impairs eNOS function, or GG subjects exhibit augmented eNOS responsiveness to L-arginine. The complexity of this seemingly straightforward conclusion deserves elaboration.

Renal Vascular Endothelial Function in Hypertensive Patients With Type 2 Diabetes Mellitus

Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy. Prospective observational-study during a mean follow-up of 2.1 years. 66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria. Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician. Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature. 50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P < 0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P < 0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P < 0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04). Patients were treated according to the discretion of the individual primary care physician. During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics.

The Hemodynamic Effects of CO2-induced Pressure on the Kidney in an Isolated Perfused Rat Kidney Model

Variable mechanisms were suggested to mediate the changes in renal hemodynamics during pneumoperitoneum. To assess whether it can be pressure dependent only, we conduct a study in an isolated, pressurized, and perfused organ model. Seventy Wistar rat kidneys were perfused with oxygenated, 3% albumin-contained Krebs-Henseleit solution. Experiments took place within Plexiglass chamber that provided conditions for perfusion of organs, humidity, and maintenance of intracameral CO2 pressures [0 (control), 3, 5, 8, 12, 15, and 18 mm Hg]. All kidneys (10/group) were perfused for 60 minutes. One-half of the groups were perfused for an additional 30 minutes, during which the perfusion pressures were reduced to 0 mm Hg. pH of the perfusate was measured as well. The perfusion pressure increased and the kidney flow decreased slightly, in proportion with the intrachamber pressure. Urine output decreased to a minimum of 40% in >or=8 mm Hg pressure conditions, compared with the control group. The pH values were below normal, during experimental pneumoperitoneum. Pneumoperitoneal conditions are a direct cause of changes in renal urinary output. The increase in pCO2 pressure and consequently low intraorgan pH may contribute to a mild transient renal damage during pneumoperitoneum.

Insights into the Regulation of Renal Hemodynamic Function in Diabetic Mellitus

Diabetes mellitus (DM) is characterized by renal hemodynamic changes which have been purported to contribute to the development of nephropathy. In this review we have focused on the major renal hemodynamic factors that may be associated with glomerular hyperfiltration. Recent animal and human studies have demonstrated that renal hemodynamic alterations occur very early in the natural history of DM. Most of the literature related to renal hemodynamic functional changes in type 1 DM has focused on major neurohormonal influences, such as the renin angiotensin system, cyclooxygenase-related pathways, the nitric oxide system, the autonomic nervous system and hyperglycemia. In addition, gender may have important modulatory effects on some of these putative pathways that have been implicated in the development of alterations in renal hemodynamic function related to DM.

Inhibition of Ang II and renal sympathetic nerve influence dopamine‐and isoprenaline‐induced renal haemodynamic changes in normal Wistar–Kyoto and spontaneously hypertensive rats

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.

Prevention of paracentesis‐induced circulatory dysfunction: midodrine vs albumin. A randomized pilot study

Large-volume paracentesis in patients with cirrhosis and ascites induces arterial vasodilatation and decreases effective arterial blood volume, termed paracentesis-induced circulatory dysfunction (PICD), which can be prevented by costly intravenous albumin. Vasoconstrictors, e.g. terlipressin, may also prevent PICD. The aim was to compare the less expensive vasoconstrictor midodrine, an alpha-adrenoceptor agonist, with albumin in preventing PICD. Twenty-four patients with cirrhosis and ascites were randomly assigned to be treated with either midodrine (n=11) (12.5 mg three times per day; over 2 days) or albumin (n=13) (8 g/L of removed ascites) after large-volume paracentesis. Effective arterial blood volume was assessed indirectly by measuring plasma renin and aldosterone concentration on days 0 and 6 after paracentesis; renal function and haemodynamic changes were also measured. PICD was defined as an increase in plasma renin concentration on day 6 by more than 50% of the baseline value. PICD developed in six patients of the midodrine group (60%) and in only four patients (31%) of the albumin group. Six days after paracentesis, the aldosterone concentration increased significantly in the midodrine group, but not in the albumin group. This pilot study suggests that midodrine is not as effective as albumin in preventing circulatory dysfunction after large-volume paracentesis in patients with cirrhosis and ascites.

Early changes in renal hemodynamics in children with diabetes: Doppler sonographic findings

Although clinically evident diabetes-related microvascular complications are extremely rare in childhood, early functional and structural abnormalities may be present a few years after the onset of the disease. Renal Doppler resistance index (RI) is widely used for the evaluation of blood flow in renal parenchymal diseases. This study was designed to investigate the possible alteration of intrarenal Doppler RI in children with diabetes compared with healthy children. The study was performed in 42 children with diabetes (age range, 6-18 years) and in 41 age-matched healthy controls, all having normal renal function. RI was measured with Doppler sonography in interlobular renal arteries. RI values were significantly greater in children with diabetes than in age-matched healthy controls (0.64 +/- 0.03 versus 0.60 +/- 0.04, P < 0.035). RI correlated positively with HbA1c (P < 0.001, r = 0.42) and diabetes duration (P < 0.05, r = 0.39). Early changes in renal hemodynamics are detectable on Doppler sonography in children with diabetes without any evidence of renal dysfunction and may suggest a preclinical stage of diabetic nephropathy.

Renal Hypoperfusion Associated with Splenorenal Shunts in Liver Cirrhosis

Purpose: To determine whether spontaneous a splenorenal shunt can be used as an imaging predictor of early renal hemodynamic changes in patients with cirrhosis. Materials and Methods: The study included 82 cirrhotic patients and 41 control subjects. Three-phase CT was performed and CT attenuation values (Hounsfield units) of the renal cortex in three phases were measured to evaluate renal perfusion. Likelihood ratio tests for trend were conducted for age, presence of ascites, and Child’s grade. Results: The mean CT attenuation values of the renal cortex in cirrhotic patients were significantly lower than the values of control subjects in three phases: 153.3 ± 37.9 versus 173.3 ±25.2 in the arterial phase, 172.6 ± 41.0 versus 197.6 ± 26.5 in the portal phase and136.9 ± 26.0 versus 152.7 ± 20.0 in the delayed phase, respectively. The mean CT attenuation value of cortices in patients with renal hypoperfusion was 119.9 ± 11.8 in the portal phase. Child’s class C (aOR: 58.4, 95% CI: 3.6- 956.2; p < 0.01) and the presence of a renal shunt (aOR: 7.5, 95% CI: 1.8- 30.5; p < 0.01) were associated with renal hypoperfusion. The incidence of renal hypoperfusion was associated with Child’s grade (trend: p < 0.01), and not with the grade of ascites or age. Conclusion: A dilated spontaneous splenorenal shunt may be a risk factor for renal hypoperfusion in cirrhosis.

Early renal changes in type 1 diabetes

The relationships between renal structural abnormalities, metabolic, and hemodynamic changes were studied in 35 type diabetic patients with normal creatinine clearance. Sixteen patients had normal urinary albumin excretion (UAE) rates, 17 were microalbuminuric and 2 had proteinuria (0.68 and 0.8 g/day). Light and electron microscopy revealed the early stages of diffuse glomerulosclerosis, tubular dystrophy and atrophy, intestinal and arteriolar sclerosis in the renal biopsy specimens of the examinees. Increased UAE was associated with the reduced percent of glomerular podocytes, the thickening and fusion of small podocytic processes, the increased thickness of the glomerular and tubular basement membrane, the reduced number of endothelial fenestrae, the increased fractional volume of the mesangium, perioglomerular sclerosis, global sclerosis of some glomeruli, tubular endothelial atrophy, and intestinal and arteriolar sclerosis. Clycemic control, diabetes duration, albumin excretion rate, and blood pressure are the predictors of early renal structural changes.

Effects of p38 mitogen-activated protein kinase inhibition on blood pressure, renal hemodynamics, and renal vascular reactivity in normal and diabetic rats

p38 mitogen-activated protein kinase (p38) has been implicated in mediating vascular smooth muscle and mesangial cell contraction in response to several vasoactive factors, including angiotensin II. Early stages of diabetic nephropathy are associated with renal hemodynamic changes that are, at least in part, attributable to the dysbalance of vasoactive factors that control afferent and efferent arteriolar tone resulting in increased glomerular capillary pressure. Vascular and renal p38 have been found to be activated in diabetes. Therefore, p38 may be involved in the control of systemic and renal hemodynamics in diabetes. To address this issue, mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), metabolic parameters, and plasma renin concentrations (PRC) were determined in streptozotocin-diabetic rats (DM), and in age-matched non-diabetic controls (C), administered with the p38 inhibitor SB 239063 (SB, 50 mg/bwt, p.o.) or with vehicle. Furthermore, renal vascular responses to p38 inhibition (SB 202190, 25 microM) before and after stimulation with the endothelium-dependent vasodilator acetylcholine (ACh) were studied in vitro in tertiary branches of the renal artery from separate groups of DM and C rats, using a fixed support and a force transducer in a myograph system. SB treatment was associated with marked reductions in MAP and GFR in both C and DM rats, whereas RPF remained unchanged, as compared with vehicle-treated animals. Observed differences in MAP and renal hemodynamics were not associated with changes in urinary sodium excretion or PRC. Incubation of KCl-contracted renal arteries from both C and DM rats with the p38 inhibitor resulted in progressive and significant vasorelaxation. Also, vessels from control and diabetic rats treated with the p38 inhibitor exhibited enhancement of ACh-induced vasorelaxation. These data indicate the role of p38 in the control of systemic and renal hemodynamics both in normal and in diabetic rats. The observed effects of p38 inhibition could be mediated at least in part by enhancement of endothelium-dependent vasodilation.

Renal hemodynamic changes and renal functional reserve in children with type I diabetes mellitus

Increased glomerular filtration rate (GFR) has been implicated in the development of diabetic nephropathy. Large normal interindividual variations of GFR hamper the diagnosis of renal hemodynamic alterations. We examined renal functional reserve (RFR) in children with type 1 diabetes mellitus to assess whether hyperfiltration occurs. The renal hemodynamic response following dopamine infusion was examined in 51 normoalbuminuric diabetic children (7.7 +/- 3.6 years) with a mean duration of diabetes of 6.2 years and compared them with 34 controls. Mean baseline GFR in diabetic children did not differ from the control population (130.7 +/- 22.9 vs. 124.8 +/- 25 ml/min per 1.73 m(2)), whereas renal plasma flow was significantly lower (463.7 +/- 103.9 vs. 587.2 +/- 105 ml/min per 1.73 m(2), p < 0.001), and filtration fraction was increased (29 +/- 8 vs. 21 +/- 2%, p < 0.001), compared with controls. The mean RFR was lower (p < 0.001) than in control subjects (-0.77 +/- 23 vs. 21 +/- 8 ml/min per 1.73 m(2)). This study documents an increased filtration fraction and reduced or absent RFR in children with type 1 diabetes mellitus in the stage before apparent nephropathy. GFR values were within normal range. Although the reduced RFR and increased filtration fraction indicate the presence of hemodynamic changes, their relevance to the development of hyperfiltration and subsequent diabetic nephropathy remains unknown.