Differences In Renal Responses Research Articles

#5163 RATIONAL USE OF ECULIZUMAB IN SECONDARY ATYPICAL HAEMOLYTIC UREMIC SYNDROME

Abstract Background and Aims Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in treating secondary aHUS since the two main series in the literature that investigate this subject show discrepant results. Our work aims to reassess Eculizumab's efficacy in treating secondary aHUS. Method Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 24 patients diagnosed with secondary aHUS who received treatment with Eculizumab compared with a control cohort of 14 patients who did not receive Eculizumab. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of Eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 47.8% of patients and partial in 17.4%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (87% in the eculizumab cohort and 85.7% in the control cohort). Conclusion Rational and early use of Eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, guaranteeing better renal recovery compared to patients who do not receive complement blockade.

Abstract P031: Reduced Augmentation Of The Intrarenal Renin-angiotensin System (ras), Lower Systolic Blood Pressure, And Preserved Renal Function In Female Compared To Male Rats With Unilateral Renal Artery Stenosis

Despite growing evidence of sex differences in the progression of hypertension, there are no guidelines that differentiate treatment between men and women. Intrarenal renin-angiotensin system (RAS) activation and tissue injury in 2-kidney, 1-clip (2K1C) hypertensive rats have been characterized in previous studies of male but not female rats. To evaluate possible sex differences in response to renovascular hypertension, urinary angiotensinogen (uAGT) excretion, systolic blood pressure (BP), urinary protein excretion, and renal function were assessed in female rats.Female (n=8) and male (n=6) rats underwent placement of a 0.2 mm clip on the left renal artery to simulate unilateral renal artery stenosis. BP was measured by tail-cuff plethysmography, and clearance studies were conducted in anesthetized rats to assess renal function. Urine protein concentration was determined by pyrogallol red method. uAGT was measured by ELISA as an index of intrarenal RAS activity. Systolic BP increased from 120±1 to 176±8 mmHg, and urinary protein excretion reached 20.2±5.6 mg/day in female rats. Although uAGT excretion increased from 13.2±7.7 ng/day to 74.1±29.9 ng/day in female rats, male rats had a significantly higher uAGT excretion of 1572.6±750 ng/day. Nonclipped kidneys exhibited more uAGT excretion compared to clipped kidneys, consistent with previous findings in males. Although 2K1C female rats demonstrate significantly lower renal function than sham females, they show more preserved renal function than male rats. Female rats also demonstrate significantly lower increases in systolic BP and urinary protein excretion compared to male rats. The data support substantial sex-dependent differences in renal responses to unilateral renal artery stenosis. The results show substantial increases in systolic BP, uAGT, and urinary protein excretion and decreased renal function after renal artery clipping in females, but the magnitude of the changes is markedly lower than in males. Nonclipped kidneys of both sexes exhibit greater uAGT excretion than clipped kidneys. Notably, females show less augmentation of the intrarenal RAS compared to male rats in renovascular hypertension.

The Effect Of An Active Versus Inactive Lifestyle On Renal Response To Exercise-induced Dehydration

PURPOSE: Exercise by itself as well as exercise-induced dehydration cause a decrease in renal blood flow and an increase in glomerular permeability, leading to a decrement in renal function and temporarily renal damage. An active lifestyle may precondition the kidneys, resulting in attenuated decrease in kidney function and a reduction in kidney damage in response to exercise and dehydration determined as body weight loss. Therefore, we examined the differences in renal responses to exercise-induced dehydration between healthy young men with a physically active versus inactive lifestyle. METHODS: A total of 12 active and 6 inactive healthy male participants (23±3 years, 23.9±3.6 kg/m2, eGFR: 111.0±12.5 mL/min) were included, based on a physical activity questionnaire. Participants performed an incremental exercise test to determine physical fitness and maximum heart rate (HRmax). On a separate day, a submaximal exercise test was performed on 80% of the individual HRmax, until 3% dehydration. Blood and urine samples were taken pre- and post-exercise to assess renal function (estimated glomerular filtration ratio; eGFR) and renal damage (urinary albumin). RESULTS: Maximum oxygen uptake (VO2max) was higher in the active (59.7±8.6 mL/min/kg) compared to the inactive group (49.1±7.3 mL/min/kg; p=0.018). All subjects cycled on a comparable exercise intensity (79±2% HRmax), resulting in a body mass loss of 3.2±0.7% and 2.5±0.4% for the active and inactive group, respectively (p=0.013). After exercise, a significant decrease in eGFR was found for the active (17.4±10.2 mL/min; p=0.007) and inactive group (21.7±17.8 mL/min; p=0.05), which did not differ between groups (p=0.60). Moreover, 33.3% of the active subjects and 50% of the inactive subjects had a post-exercise eGFR<90 mL/min, which indicates a decrease in renal function. Furthermore, we found a significant increase in urinary albumin concentration in the active (24.6±30.9 mg/L; p=0.011) and inactive group (33.6±27.5 mg/L; p=0.016), which did not differ between groups (p=0.55). CONCLUSION: In short, exercise induces a decrease in renal function and an increase in urinary albumin concentration, suggesting temporary renal damage of the glomerulus or proximal tubulus. However, these changes do not differ between physically active and inactive subjects.

Sex differences in renal and metabolic responses to a high-fructose diet in mice.

High fructose intake has been associated with increased incidences of renal disease and hypertension, among other pathologies. Most fructose is cleared by the portal system and metabolized in the liver; however, systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high-fructose diet in mice. Two-month-old male and female C57BL6/129/SV mice (n = 6 mice per sex per treatment) were randomized to receive control or high-fructose (65% by weight) diets as pelleted chow ad libitum for 3 mo. Fructose feeding did not significantly affect body weight but led to a 19% and 10% increase in kidney weight in male and female mice, respectively. In male mice, fructose increased the expression (∼50%) of renal cortical proteins involved in metabolism, including glucose transporter 5 (facilitative fructose transporter), ketohexokinase, and the insulin receptor (β-subunit). Female mice had lower basal levels of glucose transporter 5, which were unresponsive to fructose. However, female mice had increased urine volume and plasma K(+) and decreased plasma Na(+) with fructose, whereas male mice were less affected. Likewise, female mice showed a two- to threefold reduction in the expression Na(+)-K(+)-2Cl(-) cotransporter 2 in the thick ascending limb and aquaporin-2 in the collecting duct with fructose relative to female control mice, whereas male mice had no change. Overall, our results support greater proximal metabolism of fructose in male animals and greater distal tubule/collecting duct (electrolyte homeostasis) alterations in female animals. These sex differences may be important determinants of the specific nature of pathologies that develop in association with high fructose consumption.

Increase in renal proximal tubule GLUT5 and ketohexokinase in male mice, but not female mice, in response to high‐fructose feeding may contribute to sex differences in renal responses (1135.3)

High‐fructose corn syrup is a highly cost‐effective sweetener in which the intake of has been associated with increased incidence of renal disease, hypertension, and other pathologies. Most fructose is metabolized by the liver; however systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high fructose (Hfr) diet. Male and female mice (n = 6/sex/diet) were fed control (cornstarch, CS) or a Hfr (65%) diet for 3 months. No differences due to diet in weight gain were observed; however, female mice had increased urine volume, plasma K+, and decreased plasma Na+ with Hfr. This effect was not apparent or markedly attenuated in the male mice. Likewise female mice showed a 2‐3 fold reduction in the expression of the thick ascending limb Na+K+2Cl cotransporter, NKCC2, and the collecting duct, aquaporin‐2 with Hfr, relative to CS‐treated females; while males had no change. In contrast, male mice showed greater changes in proteins directly involved in fructose metabolism, e.g., cortical expression of GLUT5, the facilitative fructose transporter of the proximal tubule (PT) was increased by 54% relative to CS‐treated males. Females showed a significant decrease in this protein (63%, p = 0.02 as compared to CS‐treated females). Likewise, cortical ketohexokinase, the first enzyme in fructose metabolism was increased 198% in HFr males, p = 0.0005 versus CS males, but not changed significantly in females. Moreover, cortical protein levels of the insulin receptor (β‐subunit) was also increased by 77% (p = 0.0001) in males, and not changed in females by Hfr. Overall, our results show marked sex differences in the renal response to fructose feeding. Additional studies are warranted, but one interpretation is that females had a more maladaptive response, with diuresis, changes in distal transporters, and electrolyte disturbances, while males were better able to metabolize fructose in the PT, and avoided downstream effects.Grant Funding Source: Supported by a Marriott Fellowship and NIH DK082507

Sex Differences in Renal Responses to Hyperglycemia, l-Arginine, and l-NMMA in Humans With Uncomplicated Type 1 Diabetes

OBJECTIVEWomen exhibit exaggerated renal hemodynamic responses to hyperglycemia, which may promote kidney disease progression. Our aim was to determine if increased nitric oxide generation by l-arginine infusion would reverse this deleterious response to clamped hyperglycemia in women with type 1 diabetes mellitus.RESEARCH DESIGN AND METHODSRenal function, blood pressure, and plasma cyclic guanosine monophosphate (cGMP) were measured in 20 men and 15 women with type 1 diabetes mellitus during clamped euglycemia and clamped hyperglycemia. Renal function, blood pressure, and plasma cGMP responses to graded infusions of intravenous l-arginine and NG-monomethyl-l-arginine (l-NMMA) were measured during clamped hyperglycemia.RESULTSSubjects were young, normotensive, normoalbuminuric men and women who adhered to a high-sodium, moderate-protein diet. Plasma cGMP levels during euglycemia were generally lower in men compared with women, and systolic blood pressure (SBP) was higher in men. In response to hyperglycemia, cGMP levels did not change in men but did decline in women (Δ−1.10 ± 0.20 vs. Δ+0.05 ± 0.20 pmol/L, between-group effect of hyperglycemia on cGMP; P = 0.012). Hyperglycemia also was associated with an increase in SBP, glomerular filtration rate (GFR) (124 ± 6 to 143 ± 7 mL/min/1.73 m2; P = 0.003) and filtration fraction (FF) in women, but these parameters did not change in men. In response to l-arginine during hyperglycemia, the increase in cGMP was exaggerated in women versus men and GFR and FF decreased in women only, back toward baseline values observed during clamped euglycemia. l-NMMA infusion did not exaggerate changes in hemodynamic function in response to hyperglycemia.CONCLUSIONS l-Arginine reversed the renal hemodynamic effects of hyperglycemia in women, suggesting that nitric oxide is an important regulator of sex-dependent vascular responses to hyperglycemia in humans.

Impact of 12 wks Exercise on Renal Nitric Oxide and Antioxidant Status: A Strain Difference Comparison

One mechanism by which the vasculature benefits from exercise (EX) is by increases in blood flow (BF). This causes increases in shear stress and induction of the endothelial nitric oxide synthase (eNOS) and antioxidant, extracellular superoxide dismutase (EC SOD). The kidney, however, undergoes reduced BF during EX and therefore may be at risk for falls in NO and antioxidant bioavailability. Genetic differences may also dictate this response. Therefore, we investigated kidney cortex (KC) responses to EX in the Sprague Dawley (SD) and Fisher 344 (F344) rat. Male SD and F344 rats (10–12 wks old) voluntarily wheel ran for 12 wks (24 hr access) or remained sedentary (SED). Running activity was similar between strains. Nitrate/nitrite (NOx) levels and eNOS and EC SOD abundance in the KC of F344 rats increased with EX (Table; *p≤0.05 vs. SED). In contrast, SD rats decreased their renal eNOS and EC SOD with no change in KC NOx. The oxidative stress marker p22phox also increased in the KC of EX F344 but decreased in the EX SD rat. Another oxidative stress marker, H2O2, measured in KC, increased only in EX F344 rats. These findings indicate that a strain difference exists in the response to 12 wks voluntary EX between the F344 and SD rat. F344 rats increased their KC eNOS and EC SOD and this was interestingly also associated with increased oxidative stress. Conversely, SD rats had the opposite response to EX in their KC: reduced eNOS and EC SOD and either decreased p22phox or no change in H2O2. Mechanisms responsible for these marked differences in renal responses to EX remain to be determined. eNOS NOx EC SOD p22phox H2O2 n Arbitrary Units nmol/mg Arbitrary Units Arbitrary Units nmol/mg F344 SED 12 6±1.2 8±1.7 68±23 5±0.5 0.2±0.04 EX 12 18±3.2* 15±6.3* 122±27* 8±0.6* 0.6±0.14* SD SED 6 64±2.6 9±0.4 13±1.0 9±0.4 0.4±0.07 EX 6 56±2.2* 10±0.4 8±0.7* 7±0.6* 0.5±0.07

Ethnic Differences in Renal Responses to Furosemide

Blacks have a greater tendency to retain Na than whites. The present study sought evidence for ethnic differences in parameters reflective of Na uptake by the Na,K,2Cl cotransporter in the thick ascending limb, namely, the urine concentration and urinary excretion of certain cations before and after furosemide administration (40 mg IV). Subjects were healthy (ages 18 to 36 years). During the preceding overnight period, urine volume was lower, and osmolality was higher in blacks than in whites, an ethnic difference that disappeared when water intake was restricted to infused normal saline (60 mL/h). Plasma vasopressin levels were higher in black males than in other sex/ethnic groups. Baseline urinary excretion rates of K, Ca, and Mg were significantly lower in blacks than in whites. After furosemide (0 to 1 hour), K and Ca excretion rates increased, but the proportionate ethnic difference decreased from 44% to 22% and from 22% to 10%, respectively, consistent with blacks having more basal Na,K,2Cl cotransporter activity to inhibit. During a later postfurosemide period (1 to 5 hours), urinary concentrations of Ca and Mg recovered more slowly in blacks, consistent with greater reuptake in the thick ascending limb. In summary, there were distinct ethnic differences in renal handling of Ca and Mg basally and in response to furosemide that were consistent with a more active Na,K,2Cl cotransporter in the thick ascending limb in blacks. An increase in vasopressin levels appeared to explain greater urine concentrations in black males but not black females.

Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography

Background The use of safe iodinated contrast media (CM) to prevent contrast-induced nephropathy (CIN) is an important consideration among renally impaired diabetic patients during coronary angiography. Hypothesis Diabetic patients with normal or mild renal dysfunction are less likely to receive renal protective measures during angiography, yet they may also be at risk for CIN. We compared the renal effects of iopamidol and iodixanol in diabetic patients who were referred for angiography. Methods Diabetic patients ( N=122) with a serum creatinine (SCr) level of ≤2 mg/dl were double-blind randomized to receive nonionic CM: iopamidol-370 (low osmolar, monomeric) or iodixanol-320 (iso-osmolar, dimeric). Renal stability was evaluated at baseline and at Days 1, 3, and 7 postangiography. The primary endpoint was a ≥25% increase in SCr. Results Seventeen (10 iopamidol, 7 iodixanol; P=NS) patients had an increase in SCr ≥25% over baseline. Over all days, analysis revealed nonsignificant differences in the incidence of CIN between the two study groups regardless of how CIN was defined. Conclusions Diabetic patients with normal or mild renal dysfunction are at risk for CIN. No significant difference in renal response was observed for these CM in this at-risk population.

Renal Response to Open and Endovascular Repair of Abdominal Aortic Aneurysm: A Prospective Study

Because of incompatible reports about the renal impairment to abdominal aortic aneurysm (AAA) repair, we conducted a prospective study to determine the differences in renal response between open (OR) and endovascular (EVAR) aneurysm repair. In a prospective, nonrandomized, single-center study, we evaluated 485 patients with AAAs undergoing OR or EVAR between January 2000 and December 2005. Only electively performed procedures were analyzed in detail. The OR group included 229 patients (males/females 203/26, median age 69.8 [range 43-90] years, aneurysm diameter in median 57 [26-95] mm), and the EVAR group integrated 144 patients (males/females 129/15, 73.1 [49-90] years [p=.001], 55 [33-100] mm). Renal function was assessed by determinating the preoperative serum creatinine (SCr) level and SCr clearance according to Cockcroft-Gault. Postoperatively, SCr level and SCr clearance were determined at defined intervals, reported as highest postoperative SCr level, SCr level at time of discharge, lowest postoperative SCr clearance, and SCr clearance at time of discharge. The parameters of height, weight, diabetes, smoking habit, serum cholesterol level, and hemoglobin were not different between the groups. Significantly different were the American Society of Anesthesiologists classification, the Society for Vascular Surgery Comorbidity Score, and the exposure to contrast dye. Moreover, significantly different were intraoperatively measured median blood loss (1,200 vs. 400 mL) and the median time of operation (164 vs. 135 min). Although, the preoperative SCr levels between the groups were not statistically different (OR group 1.0 [0.87-1.23] mg/dL [median, interquartile range], EVAR group 1.0 [0.9-1.3]; p > 0.05), the SCr clearance was (OR group 72.8 [58.2-98.8] mL/min, EVAR group 67.6 [51.3-85.1] mL/min; p = 0.007). In the postoperative period, SCr level did not change significantly in the OR group but did in the EVAR group to a level of 1.08 (0.9-1.36) mg/dL (p = 0.007). Similarly, SCr clearance decreased significantly in the EVAR group to a level of 66.7 (49.9-81.4) mL/min. These results were influenced by the stent graft design (deployment under the renal arteries vs. covering the renals with bared stents). Mortality was 3/229 in the OR group and 4/144 in the EVAR group. Acute renal impairment occurred in a subset of patients with AAAs with regard to the type of repair. EVAR showed a slight deterioration of renal function, but the evaluated tests are insensitive and without prognostic value concerning mortality or hospitalization. More sensitive markers of the differentiated renal functions (cystatin C for renal glomerular function, N-acetyl-ss-d-glucosamidase for proximal tubular function) should be evaluated in future studies.

Expression of osteopontin in rat kidneys: induction during ethylene glycol induced calcium oxalate nephrolithiasis.

Osteopontin is a well-known component of stone matrix and a strong inhibitor of the nucleation, growth and aggregation of calcium oxalate crystals in vitro. To understand its involvement in vivo in calcium oxalate nephrolithiasis we investigated the renal expression and urinary excretion of osteopontin in normal rats, and rats with hyperoxaluria and calcium oxalate crystal deposits in the kidneys. Calcium oxalate nephrolithiasis was induced by administering ethylene glycol. Immunohistochemistry and in situ hybridization were done to localize osteopontin and osteopontin messenger RNA in the kidneys, while sensitive reverse transcriptase quantitative competitive template polymerase chain reaction was performed to detect and quantify osteopontin messenger RNA expression. Urinary excretion was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis, and then quantified by densitometry of the Western blots. Osteopontin expression in the kidneys was significantly increased after hyperoxaluria and it increased further after the deposition of calcium oxalate crystals in the kidneys. Urinary excretion of osteopontin increased concomitantly. The results reveal differences in renal responses after exposure to oxalate and calcium oxalate crystals. In normal kidneys osteopontin expression was limited to a small number of cells of the thin limbs of the loop of Henle and papillary surface epithelium. During hyperoxaluria osteopontin expression in the kidneys was increased but still mostly limited to cells of the thin limb and papillary surface epithelium. However, after calcium oxalate crystal deposition osteopontin expression was observed throughout the kidneys, including segments of the proximal tubules. In response to exposure to oxalate and calcium oxalate crystals renal epithelial cells increase the production of osteopontin, which may have a significant role in calcium oxalate nephrolithiasis.

Gender differences in renal responses to hyperglycemia and angiotensin-converting enzyme inhibition in diabetes

Diabetes mellitus reduces female gender-mediated protection against progression of renal disease but the mechanisms responsible for this loss of protection are unknown. The impact of gender on the diabetic hyperfiltration state has not previously been studied. Since hyperfiltration is a factor in the development of diabetic renal disease, and is influenced by hyperglycemia and renin-angiotensin system (RAS) blockade, we examined gender differences in the renal response to hyperglycemia and angiotensin-converting enzyme (ACE) inhibition in young males and females with uncomplicated type 1 diabetes mellitus. Ten male and 12 female normoalbuminuric, normotensive, adolescents with type 1 diabetes mellitus were studied before ACE inhibition during clamped euglycemia and hyperglycemia, and then after 21 days treatment with enalapril (0.1 mg/kg daily x 1 week and then 0.1 mg/kg twice a day x 2 weeks). During clamped euglycemia, males exhibited significantly higher effective renal plasma flow (ERPF) and renal blood flow (RBF) and a lower renal vascular resistance (RVR). During clamped hyperglycemia, females exhibited reductions in ERPF and RBF, and increased RVR and filtration fraction (FF). Males exhibited no significant renal hemodynamic changes during hyperglycemia. After ACE inhibition treatment, both genders exhibited significant declines in arterial pressure, but only females displayed a reduction in glomerular filtration rate (GFR) and FF. The renal responses to hyperglycemia and ACE inhibition appear to differ between male and female adolescents with uncomplicated type 1 diabetes mellitus. Hyperglycemia-induced changes in RVR and FF in women may account, at least in part, for the loss of gender-based protection in diabetic renal disease.

Expression of Osteopontin in Rat Kidneys: Induction During Ethylene Glycol Induced Calcium Oxalate Nephrolithiasis

Osteopontin is a well-known component of stone matrix and a strong inhibitor of the nucleation, growth and aggregation of calcium oxalate crystals in vitro. To understand its involvement in vivo in calcium oxalate nephrolithiasis we investigated the renal expression and urinary excretion of osteopontin in normal rats, and rats with hyperoxaluria and calcium oxalate crystal deposits in the kidneys. Calcium oxalate nephrolithiasis was induced by administering ethylene glycol. Immunohistochemistry and in situ hybridization were done to localize osteopontin and osteopontin messenger RNA in the kidneys, while sensitive reverse transcriptase quantitative competitive template polymerase chain reaction was performed to detect and quantify osteopontin messenger RNA expression. Urinary excretion was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis, and then quantified by densitometry of the Western blots. Osteopontin expression in the kidneys was significantly increased after hyperoxaluria and it increased further after the deposition of calcium oxalate crystals in the kidneys. Urinary excretion of osteopontin increased concomitantly. The results reveal differences in renal responses after exposure to oxalate and calcium oxalate crystals. In normal kidneys osteopontin expression was limited to a small number of cells of the thin limbs of the loop of Henle and papillary surface epithelium. During hyperoxaluria osteopontin expression in the kidneys was increased but still mostly limited to cells of the thin limb and papillary surface epithelium. However, after calcium oxalate crystal deposition osteopontin expression was observed throughout the kidneys, including segments of the proximal tubules. In response to exposure to oxalate and calcium oxalate crystals renal epithelial cells increase the production of osteopontin, which may have a significant role in calcium oxalate nephrolithiasis.

Hyperhydration induced by glycerol ingestion: hormonal and renal responses

The simultaneous time courses of hydromineral hormones (renin-aldosterone system, arginine vasopressin, and atrial natriuretic peptide) and renal responses were examined during and after the completion of hyperhydration induced by glycerol and fluid ingestion. Eight healthy young male Caucasian subjects participated in two separate trials, each including three consecutive phases in a thermoneutral environment. Phases 1 and 3 involved a 90-min period at rest, while phase 2 involved a 120-min period at rest designed to provide either (i) euhydration (control trial) or (ii) hyperhydration induced by ingestion of glycerol (1.1 g/kg body mass) and fluid (21.4 mL/kg body mass). During the 2-h time period of glycerol and fluid ingestion, urine flow, urine osmolality, and plasma levels of hydromineral hormones remained at basal values. In contrast, after hyperhydration completion during phase 3, the diuresis increased markedly together with a dilution of the urine (p < 0.05) while hormonal responses did not change. These results indicate significant differences in renal responses during and after hyperhydration completion and suggest that these changes are independent of fluid-regulating hormonal responses.

Age differences in renal response to atrial natriuretic peptide in rabbits

Plasma levels of atrial natriuretic peptide (ANP) and the effect of exogenous ANP on renal function have been studied in newborn and adult rabbits. In order to investigate an age difference in responsiveness to ANP, we studied the renal effects of alpha-human ANP (1–28) administered at the same dose per kg body weight in adult and neonatal rabbits. Plasma basal ANP levels were similar in 18 newborn (4- to 11-day-old) compared to 7 adult rabbits (150 ± 16 and 151 ± 28 pg/ml, resp.). Eleven newborn and 11 adult rabbits were anesthetized and mechanically ventilated. After a control period, each animal received an hANP loading dose (3 μg/kg i.v.), followed by an infusion of 0.3 μg/kg/min. Blood gases remained stable throughout the experiment in both groups. Mean blood pressure decreased in newborn (28.5 ± 0.8 to 26.2 ± 1.0 mmHg) and adult (92 ± 3 to 84 ± 3 mmHg) animals. Percent hANP-induced changes in renal functions in newborn and adult rabbits were, respectively: urine flow rate: −21 ± 4% and +57 ± 8%; urinary sodium excretion: +4 ± 7% and +81 ± 11%; glomerular filtration rate (GFR): −19 ± 4% and −4 ± 6%; renal blood flow (RBF): −22 ± 4% and −11 ± 5%. As expected, diuresis and natriuresis increased in adult rabbits. Failure of hANP to increase natriuresis and diuresis in newborn rabbits could be related to the marked decrease in GFR, receptor immaturity and/or interactions with other hormonal systems.

Effects of gentamicin on renal function in isolated perfused kidneys from male and female rats

The isolated perfused rat kidney was used to determine whether sex differences in gentamicin nephrotoxicity are related to intrinsic differences in renal response to gentamicin. Acute exposure to gentamicin decreased fractional reabsorption of water and electrolytes without changes in glomerular filtration rate in both sexes. Gentamicin decreased the tubular reabsorption of lysozyme but not glomerular permeability to lysozyme. No sex differences in renal responses were observed following in vitro exposures to gentamicin, suggesting that sex differences in susceptibility to gentamicin in vivo may be attributable to extrarenal factors, such as pharmacokinetics.

THE EFFECT OF DOPAMINE ON RENAL FUNCTION IN NEWBORN PUPPIES

In adults, moderate doses of dopamine (D) (5 to 15 Ug/kg/min) increase renal blood flow; high doses (>20 μg/kg/min) decrease renal blood flow. Although many newborn infants with shock are treated with D, little is known about the effect of moderate dose of D in this age group. Thus we studied the renal effect of intravenous D before (C) during (E) and following (PE) the infusion of dopamine (10 μg/kg/min) in 1 wk old puppies (P). Renal blood flow (RBF), glomerular filtration rate (GFR), urine flow (V) fractional sodium excretion (FENa) free water clearance and distribution of renal blood flow (RBD) were obtained before and during infusion of dopamine. The results are: M±SE, *P<.05 by paired t test.Outer cortical to inner cortical blood flow ratio decreased significantly during D infusion (P<.05). These studies demonstrate that D in moderate doses decreases RBF, GFR, and CH2O; increases FENa, and UV in puppies. These findings are similar to high output renal failure and should be interpreted with caution. Difference in renal response to moderate dose of D in adult and 1 week old may be a function of D receptors.

Influence of Prostaglandin A&lt;sub&gt;1&lt;/sub&gt; on Renal Filtration, Hemodynamics and Excretion

The effect on renal function of a 210-min infusion of PGA&lt;sub&gt;1&lt;/sub&gt; into the aorta of 10 conscious beagle dogs has been investigated. In the sodium-replete group, PGA&lt;sub&gt;1&lt;/sub&gt; caused an increase in the glomerular filtration rate (GFR) (24%), renal blood flow (17%) and sodium excretion (20%). By contrast, in the sodium-depleted group, PGA&lt;sub&gt;1&lt;/sub&gt; caused a considerable reduction of GFR (25%) and sodium excretion (51%). In this group, baseline renal blood flow was lower, and there was no further reduction during PGA&lt;sub&gt;1&lt;/sub&gt; infusion. Fractional sodium excretion was unchanged in the sodium-replete dogs, but was reduced in the sodium-deplete state. Plasma renin activity was markedly elevated and further increased in the sodium-deplete group, but it was nearly unchanged in the sodium-replete group. This difference in renal response to exogenous PGA&lt;sub&gt;1&lt;/sub&gt; might be due to interaction with the renin-angiotensin system, which was markedly stimulated by sodium depletion and additionally by prostaglandin infusion.