Alterations In Glomerular Filtration Rate Research Articles

Angiotensin type 2 receptor stimulation increases renal function in female, but not male, spontaneously hypertensive rats.

Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT2R stimulation to modulate renal function in hypertension, we examined the influence of the AT2R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18- to 19-week-old anesthetized male and female spontaneously hypertensive rats. AT2R stimulation significantly increased renal blood flow in female hypertensive rats (PTreatment<0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT2R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any significant effect of AT2R stimulation on renal hemodynamic or excretory function in male hypertensive rats. Finally, gene expression studies confirmed greater renal AT2R expression in female than in male hypertensive rats. Taken together, acute AT2R stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT2R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT2R as a therapeutic target for cardiovascular disease, particularly in women.

Urinary biomarkers in assessing the nephrotoxic potential of gentamicin in solitary kidney patients after 7 days of therapy

Introduction: The solitary kidney (SK) may present increased vulnerability to nephrotoxicity because of adaptive phenomena. Aims: Assessing the vulnerability of the SK with urinary tract infections (UTI) to gentamicin by means of urinary biomarkers (N-acetyl-beta-D-glucosaminidase (NAG) and urinary alpha-1-microglobulin), as well as glomerular filtration rate (GFR). Methods: We studied 14 patients with SK with UTI (group A) (mean age 58.07 ± 13.61 years, mean duration of SK 13.55 ± 12.33 years) who were administered gentamicin for 7 days. Group B consisted by 17 patients with SK without any other associated renal pathology (average age 51.17 ± 9.39 years, average existence period of a single kidney 33.23 ± 21.73 years). We also included a third group (group C) represented by nine healthy individuals, with two kidneys. Results: Increased values of urinary NAG were found in group B as compared to group C and alpha-1 microglobulin in group A as compared to group B. During treatment with gentamicin, increased values of both NAG and alpha-1-microglobulin in group A were found on day 7 as compared to values before treatment (day 7 NAG = 18.99 ± 14.07 U/g creat versus day 0, NAG = 5.15 ± 6.54 U/g creat, p = 0.004; day 7 alpha-1-microglobulin = 20.88 ± 18.84 mg/g creat versus day 0, urinary alpha-1-microglobulin = 4.96 ± 6.57 mg/g creat, p = 0.003). No statistically significant alterations of GFR were noticed after 7 days of treatment. Conclusions: We found the nephrotoxic effects of gentamicin at tubular level, but not at glomerular level. The nephrotoxic potential of gentamicin in patients with a SK can be monitored by assessing urinary biomarkers during treatment of UTI.

Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate

Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine-allowing only approximate estimates of GFR-the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with (177)Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by (99m)Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m(2) per year, relative yearly reduction -1.8 ± 18.9%). Fifteen patients (21%) experienced a mild (2-10 ml/min/m(2) per year) and 16 patients (22%) a significant (>10 ml/min/m(2) per year) decline of GFR following PRRT. However, 11 patients (15%) showed an increase of >10 ml/min/m(2) per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3%) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15% of the assessments and led to underestimation in 12% of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function. Serious nephrotoxicity after PRRT with (177)Lu-octreotate is rare (1.3%). However, slight renal impairment (GFR loss >2 ml/min/m(2) per year) can frequently (43%) be detected by (99m)Tc-DTPA clearance assessments. Cumulative administered activity of (177)Lu-octreotate is not a major determinant of renal impairment in our study.

Effects of weight loss on renal function in obese CKD patients: a systematic review

Obesity is an independent risk factor for the development and progression of chronic kidney disease (CKD). We conducted a systematic review to assess the benefits of intentional weight loss in obese subjects with altered glomerular filtration rate (GFR), proteinuria or albuminuria. MEDLINE, EMBASE and CENTRAL databases were searched for articles reporting longitudinal data on the effect of weight loss on renal parameters in obese patients with altered kidney function. Thirty-one (2013 subjects) were included. In the 13 studies where weight loss was achieved by bariatric surgery, body mass index (BMI) significantly decreased in all studies; GFR decreased in six studies on hyperfiltration patients and increased in one study on patients with CKD Stage 3-4. Albuminuria decreased in six studies and proteinuria decreased in five studies. In six studies, weight loss was achieved by antiobesity agents: BMI decreased in all studies; GFR decreased in four studies and albuminuria in three. Eleven studies analysed the effects of diet, alone or in combination with lifestyle modifications. A significant decrease in BMI was reported in all studies; GFR increased in two studies, remained stable in four studies and decreased in two studies on hyperfiltration patients. Albuminuria decreased in six studies and remained stable in one study. Proteinuria decreased in five studies. In obese patients with altered renal function, weight loss, particularly if achieved by surgical interventions, improves proteinuria, albuminuria and normalizes GFR. Larger, long-term studies are needed to analyse the durability of this improvement and the effects on renal outcomes, such as CKD progression and the development of ESKD.

Association of high blood pressure with renal insufficiency: role of albuminuria, from NHANES, 1999-2006.

BackgroundThe relationship between hypertension and kidney disease is complicated. Clinical trials found intense blood pressure control was not associated with alterations in glomerular filtration rate (GFR) in all patients but did slow the rate of GFR decline among those with a higher baseline proteinuria. However, the underlying mechanism has been unclear.MethodsWe tested the hypothesis that the association between high blood pressure and renal function is modified by albuminuria status by conducting analyses in a cross-sectional study with 12,440 adult participants without known kidney diseases, diabetes or cardiovascular diseases, participating in the National Health and Nutrition Examination Survey (NHANES) 1999–2006.Results1226 out of 12440 were found to have unknown high blood pressure and 4494 were found to have reduced renal function. Overall, a moderate association was found between high blood pressure and renal function insufficiency in all participants analyzed. However, among participants with albuminuria, the prevalence of moderate-severe renal insufficiency substantially and progressively increased from normal subjects to prehypertensive and undiagnosed hypertensive subjects (1.43%, 3.44%, 10.96%, respectively, P for trend<0.0001); on the other hand, the prevalence of undiagnosed hypertension was also significantly higher among subjects with moderate-severe renal insufficiency than those with mild renal insufficiency (35.54% Vs 19.09%, P value <0.05), supporting an association between hypertension and renal function damage. In contrast, no association between hypertension and renal insufficiency was observed among those without albuminuria in this population. Similar findings were observed when the CKD-EPI equation was used.ConclusionsThe association between high blood pressure and reduced renal function could be dependent upon the albuminuria status. This finding may provide a possible explanation for results observed in clinical trials of intensive blood pressure control. Further studies are warranted to confirm our findings.

Safety and Feasibility of Intravascular Optical Coherence Tomography Using a Nonocclusive Technique to Evaluate Carotid Plaques Before and After Stent Deployment

To evaluate the safety and feasibility of optical coherence tomography (OCT) in patients with carotid stenosis undergoing carotid artery stenting (CAS). In a prospective study, 25 consecutive patients (15 men; mean age 74±4 years) undergoing protected CAS were enrolled and underwent high-definition (homoaxial resolution 10 µm) OCT image acquisition before stent deployment, immediately after stent placement, and following postdilation of the stent (3 scans/patient). Pullbacks were started during a nonocclusive flush, mechanically injecting 24 mL of 50% diluted contrast at 6 mL/s to displace blood from the artery. Two independent physicians judged the quality of images on a predefined 1-10 scale. The proportions of specific agreement and kappa values (κ) were calculated. No procedural or in-hospital neurological complications occurred (any stroke/death 0%). The technical success of OCT pullbacks was 97.3% (73/75). The total amount of contrast was 86±18 mL/patient. No significant alteration in glomerular filtration rate or any other significant adverse event occurred. The images obtained were of high quality (mean value 8.1 out of 10), with good inter- and intraobserver agreement (κ = 0.81-0.87 and κ = 0.95, respectively). OCT images revealed innovative features such as rupture of the fibrous cap, plaque prolapse, and stent malapposition in a high percentage of the patients (range 24%-100%). Intravascular OCT during a nonocclusive flush appears to be feasible and safe in carotid arteries. Since some original and unexpected information after CAS has been made available for the first time at such a high definition, future studies with OCT should focus on the interaction between carotid plaque and stent design, which might revolutionize our understanding of the mechanisms of carotid stenting, as well as influence our clinical policies.

Relationship Between Glomerular Filtration Rate and 24-Hour Urine Composition in Patients With Nephrolithiasis

To examine the relationship between GFR and 24-hour urine composition in patients with nephrolithiasis to understand how renal function may affect stone risk. Alterations in glomerular filtration rate (GFR) are associated with a number of physiological changes. A retrospective, institutional review board-approved review of patients from 2 metabolic stone clinics was performed. One-way analysis of variance and multivariate linear regression models were used to evaluate the relationship between GFR quintile and 24-hour urine composition. A total of 403 patients (241 male, 162 female) with a mean age of 52.6 ± 14.2 years were included in the study. On univariate analysis, decreasing GFR by quintile was associated with significant reductions in urine calcium, citrate, supersaturation of calcium oxalate, and supersaturation of calcium phosphate (P < .05 for each). In multivariate linear regression models, decreasing GFR by quintile was associated with significant decreases in urine calcium (β = -11.2, 95% CI = -18.3 to 4.01), urine citrate (β = -32.4, 95% CI = -54.1 to 10.8), oxalate (β = -1.83, 95% CI = -2.85 to 0.81), supersaturation of calcium oxalate (β = -0.58, 95% CI = 0.84 to 0.33) and supersaturation of calcium phosphate (β = -0.09, 95% CI = 0.17 to 0.02), as well as an increase in urine magnesium (β = 3.40, 95% CI = 0.7 to 6.1). Reduction in GFR is associated with decreased urine calcium, oxalate, and citrate, and increased urine magnesium. These findings have implications for treatment of patients with stone disease and impaired renal function.

Metabolic Programming during Lactation Stimulates Renal Na+ Transport in the Adult Offspring Due to an Early Impact on Local Angiotensin II Pathways

BackgroundSeveral studies have correlated perinatal malnutrition with diseases in adulthood, giving support to the programming hypothesis. In this study, the effects of maternal undernutrition during lactation on renal Na+-transporters and on the local angiotensin II (Ang II) signaling cascade in rats were investigated.Methodology/Principal FindingsFemale rats received a hypoproteic diet (8% protein) throughout lactation. Control and programmed offspring consumed a diet containing 20% protein after weaning. Programming caused a decrease in the number of nephrons (35%), in the area of the Bowman's capsule (30%) and the capillary tuft (30%), and increased collagen deposition in the cortex and medulla (by 175% and 700%, respectively). In programmed rats the expression of (Na++K+)ATPase in proximal tubules increased by 40%, but its activity was doubled owing to a threefold increase in affinity for K+. Programming doubled the ouabain-insensitive Na+-ATPase activity with loss of its physiological response to Ang II, increased the expression of AT1 and decreased the expression of AT2 receptors), and caused a pronounced inhibition (90%) of protein kinase C activity with decrease in the expression of the α (24%) and ε (13%) isoforms. Activity and expression of cyclic AMP-dependent protein kinase decreased in the same proportion as the AT2 receptors (30%). In vivo studies at 60 days revealed an increased glomerular filtration rate (GFR) (70%), increased Na+ excretion (80%) and intense proteinuria (increase of 400% in protein excretion). Programmed rats, which had normal arterial pressure at 60 days, became hypertensive by 150 days.Conclusions/SignificanceMaternal protein restriction during lactation results in alterations in GFR, renal Na+ handling and in components of the Ang II-linked regulatory pathway of renal Na+ reabsorption. At the molecular level, they provide a framework for understanding how metabolic programming of renal mechanisms contributes to the onset of hypertension in adulthood.

N-acetylcysteine (NAC) Protects Against Acute Kidney Injury (AKI) Following Prolonged Pneumoperitoneum in the Rat

Acute kidney injury (AKI) following prolonged laparoscopy is a documented phenomenon. Carbon dioxide pneumoperitoneum induces oxidative stress. Previous experimental studies have shown that the antioxidant, N-acetylcysteine, protects the rat from AKI following ischemia-reperfusion. The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) on rat renal function after prolonged pneumoperitoneum. Normal rats treated or not with NAC were submitted to abdominal CO(2) insufflation of 10 mmHg, at short and long periods of time of 1 and 3 h, respectively, and evaluated at 24, 72 h, and 1 wk after deinsufflation. Glomerular filtration rate (GFR) was measured by inulin clearance and oxidative stress was evaluated by serum thiobarbituric acid reactive substances (TBARS) RESULTS: No significant alterations in GFR were observed in normal animals submitted to the pneumoperitoneum of 1 h and evaluated after 24 h desufflation. With 3 h of pneumoperitoneum, a significant and progressive decrease in GFR occurred 24 and 72 h after desufflation with an increase in serum TBARS. GFR returned to normal levels a week later. In the NAC-treated rats, a complete protection against GFR drops was observed 24 and 72 h following 3 h of pneumoperitoneum associated with a decrease in TBARS. These results suggest that NAC protects against acute kidney injury following prolonged pneumoperitoneum. These findings have significant clinical implications.

Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to a nitric oxide donor in the pregnant rat

Pregnancy is characterized by plasma volume expansion and renal sodium retention with loss of natriuretic response to atrial natriuretic peptide due to increased medullary phosphodiesterase-5 (PDE5). Here, we determined whether natriuretic responses to nitric oxide (NO) are also blunted in pregnancy due to increased PDE5. Anesthetized 16-day pregnant and virgin rats were studied at baseline and during intrarenal infusion of the NO donor spermine NONOate (2.5 nmol/min), the PDE5 inhibitor sildenafil (SILD; 0.5 μg/min), or a combination. The right (noninfused) kidney served as a control. Intrarenal NONOate had no effect on mean arterial pressure (MAP); however, SILD reduced MAP in virgin rats, and the combination of NONOate+SILD reduced MAP in both virgin and pregnant rats. Neither NONOate nor SILD altered glomerular filtration rate. NONOate and SILD each stimulated sodium excretion (U(Na)V) and fractional excretion of sodium (FE(Na)) in virgin rats, but the combination did not result in an additional natriuretic response. However, NONOate infusion did not increase U(Na)V or FE(Na) in pregnant rats, but the natriuretic response to NONOate was restored with SILD, and SILD alone produced a natriuresis during pregnancy. Sodium nitroprusside (10(-4) mol/l)-stimulated cGMP accumulation from inner medullary collecting duct cells was blunted in cells from pregnant vs. virgin or postpartum rats and was restored by treatment with the PDE5 inhibitor DMPPO (10(-7) mol/l). Therefore, increased intrarenal PDE5 mediates the blunted natriuretic response to NO, and loss of responsiveness to the cGMP-dependent, natriuretic agents may contribute to volume expansion during pregnancy.

An overview of glomerular filtration rate testing in dogs and cats.

Determination of glomerular filtration rate (GFR) is a valuable, yet underused, diagnostic tool for evaluating renal function in dogs and cats. This article first reviews the hormonal and hemodynamic factors which contribute to GFR, followed by a description of considerations when selecting a pharmacokinetic model and methods of animal-to-animal standardization. The best-characterized existing GFR markers, including creatinine, radiolabeled markers, and iohexol, are reviewed in depth, as well as alternative but lesser used techniques. A weighted means analysis of reported GFR measurements in healthy dogs and cats and a review of selected studies that have examined GFR alterations in animals with naturally occurring and experimental diseases provide the reader with preliminary guidelines on expected GFR results in these species and disease conditions.

Glomerular Filtration Rate Reference Values in Very Preterm Infants

In very preterm infants, there is a high risk for impaired kidney function; therefore, access to normal ranges of glomerular filtration rate (GFR) for age and definition of a reliable normal range of glomerular clearance is essential. Despite this, updated GFR reference values for use in clinical practice are not available. The objective of this study was to determine GFR reference values in very preterm infants aged 27 to 31 weeks' gestation. This was a multicenter, prospective cohort study. Infants were recruited to the study before 48 hours of life. Glomerular clearance was measured at inclusion, then weekly for the first month. Reference values were determined by measurement of 12-hour urine specimens and generation of a linear regression model with repeated measures after removal of risk factor components. Validation was checked with a bootstrap technique for infants who were not exposed to significant risk factors. This study included 275 infants. Median GFR reference values (mL/min per 1.73 m(2)) in infants aged 27 to 31 weeks' gestation ranged from 7.9 to 30.3 on day 7, 10.7 to 33.1 on day 14, 12.5 to 34.9 on day 21, and 15.5 to 37.9 on day 28. The GFR reference values, presented in this article as 3rd, 10th, 50th, 90th, and 97th percentiles, should be useful in NICUs for adaptation of drug doses to glomerular clearance and in defining infants who present with altered GFR and who need additional investigation and close follow-up to adjust fluid intake and drug dosage.

ATP as a mediator of macula densa cell signalling.

Within each nephro-vascular unit, the tubule returns to the vicinity of its own glomerulus. At this site, there are specialised tubular cells, the macula densa cells, which sense changes in tubular fluid composition and transmit information to the glomerular arterioles resulting in alterations in glomerular filtration rate and blood flow. Work over the last few years has characterised the mechanisms that lead to the detection of changes in luminal sodium chloride and osmolality by the macula densa cells. These cells are true "sensor cells" since intracellular ion concentrations and membrane potential reflect the level of luminal sodium chloride concentration. An unresolved question has been the nature of the signalling molecule(s) released by the macula densa cells. Currently, there is evidence that macula densa cells produce nitric oxide via neuronal nitric oxide synthase (nNOS) and prostaglandin E(2) (PGE(2)) through cyclooxygenase 2 (COX 2)-microsomal prostaglandin E synthase (mPGES). However, both of these signalling molecules play a role in modulating or regulating the macula-tubuloglomerular feedback system. Direct macula densa signalling appears to involve the release of ATP across the basolateral membrane through a maxi-anion channel in response to an increase in luminal sodium chloride concentration. ATP that is released by macula densa cells may directly activate P2 receptors on adjacent mesangial cells and afferent arteriolar smooth muscle cells, or the ATP may be converted to adenosine. However, the critical step in signalling would appear to be the regulated release of ATP across the basolateral membrane of macula densa cells.

Individualizing Therapy in Patients With Chronic Kidney Disease

Patients with chronic kidney diseases have multiple clinical abnormalities that may affect disposition of drugs, including alterations in glomerular filtration rate, excretion of plasma proteins, reductions in serum albumin, and reductions in drug metabolizing enzyme activity. Inflammation may also influence the previous factors. Concomitant drug therapies can lead to drug— drug interactions that may affect the pharmacokinetics of administered drugs. Pharmacogenomics has begun to be evaluated for effects of genotype and haplotype of drug metabolizing enzymes and transporters on drug disposition. Because of the multiple potential etiologies for alterations in drug disposition in patients with chronic kidney diseases, they require appropriate evaluation for implementation of individualized strategies in therapies to enhance efficacy and reduce toxicities. This review will highlight the disease- and patient-specific variables that are targets for patient-centered approaches to therapeutic interventions. The field of pharmacogenomics will be reviewed with reference to common therapies for transplantation and glomerular diseases.

Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats. CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality. MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.

Diffusion-weighted magnetic resonance imaging in the evaluation of renal function: A preliminary study

Magnetic resonance diffusion-weighted imaging (MR-DWI) is useful to assess proton motion by the computation of an apparent diffusion coefficient (ADC). This property could be used to assess renal damage, with special regard to unilateral dysfunction. The aim of this study was to estimate the correlation between ADC and the stage of chronic renal failure (CRF) using a spin-echo echo-planar imaging (SE-EPI) sequence with the sensitivity encoding (SENSE) technique. Fourteen patients (nine men and five women, mean age 49 years, range 22-66 years) underwent an MR examination on a 1.5-T system. Seven patients had a history of hypertension or CRF, one had Takayasu disease and one had nephrovascular hypertension. Five subjects without known kidney disease were used as controls. The glomerular filtration rate (GFR) assessed by Cockcroft-Gault's equation was used as a functional marker. The imaging protocol consisted of T1- and T2-weighted sequences followed by a SE-EPI acquisition with a diffusion gradient of 600 s/mm(2) and SENSE factor 2 and pixel-by-pixel ADC map reconstruction. In five patients, the SE-EPI-DWI sequence was repeated after i.v. administration of 1 mg of furosemide. ADC was of 2.44+/-0.24 x 10(-3) mm(2)/s in patients with normal GFR and of 2.05+/-0.33 x 10(-3) mm(2)/s (p<0.05) in subjects with altered GFR; a significant difference was found between stage III and IV (p<0.01), whereas no differences were found between stage I and II (p=0.27) and between stage II and III (p=0.39). A good correlation was found between GFR and ADC (r=0.79; p<0.01), with no significant change after furosemide administration (p=0.7). DWI is a feasible MR technique for assessing renal damage. Further studies with scintigraphic correlation are needed to confirm these results and to establish reference values for this imaging technique.

Allopurinol and Enalapril Failed to Conserve Urinary NOx and Sodium in Ischemic Acute Renal Failure in Spontaneously Hypertensive Rats

Background: Ischemia-reperfusion-induced acute renal failure (ARF) is associated with a high mortality in patients with hypertension and with an unfavorable outcome of kidney transplants from marginal donors. Aim: The influence of allopurinol and enalapril on urinary nitrate/nitrite (UNOx), glomerular filtration rate, plasma and urinary sodium, and hemodynamic parameters was examined in spontaneously hypertensive rats (SHR) with ARF. Methods: ARF was induced by right-kidney removal and clamping the left renal artery for 40 min in 50 male 26-week-old SHR weighing 300 ± 23 g. The rats were randomly allocated to five groups: (1) sham operated; (2) ARF; (3) ARF after pretreatment with 40 mg/kg allopurinol; (4) ARF after pretreatment with 40 mg/kg enalapril, and (5) ARF after pretreatment with 40 mg/kg allopurinol and 40 mg/kg enalapril. Creatinine clearance, UNOx (Griess reaction), cardiac output (dye dilution technique), mean arterial blood pressure, and renal blood flow were measured 24 h after reperfusion. Total vascular resistance and renal vascular resistance were calculated and compared between the groups. Results: A nonsignificant decrease was found in both daily UNOx excretion and creatinine clearance when pretreated ARF groups and the ARF group without pretreatment were compared (p > 0.05). Significantly lower plasma sodium values (139.5 ± 4.86 mmol/l) in the allopurinol-pretreated ARF group were found than in the ARF group without pretreatment, in the ARF group pretreated with enalapril, and in the sham SHR group (p = 0.029). The urinary sodium loss was greater in the enalapril-pretreated than in the allopurinol-pretreated ARF group (p = 0.047). Allopurinol and/or enalapril pretreatment decreased total vascular resistance (p = 0.003) in comparison with the sham SHR group. Conclusion: Neither allopurinol nor enalapril nor both were protective against ischemia-reperfusion injury in SHR, nor altered glomerular filtration rate and UNOx in a favorable direction.

The role of indomethacin and tezosentan on renal effects induced by Bothrops moojeni Lys49 myotoxin I

Renal changes determined by Lys49 myotoxin I (BmTx I), isolated from Bothrops moojeni are well known. The scope of the present study was to investigate the possible mechanisms involved in the production of these effects by using indomethacin (10 μg/mL), a non-selective inhibitor of cyclooxygenase, and tezosentan (10 μg/mL), an endothelin antagonist. By means of the method of mesenteric vascular bed, it has been observed that B. moojeni myotoxin (5 μg/mL) affects neither basal perfusion pressure nor phenylephrine-preconstricted vessels. This fact suggests that the increase in renal perfusion pressure and in renal vascular resistance did not occur by a direct effect on renal vasculature. Isolated kidneys from Wistar rats, weighing 240–280 g, were perfused with Krebs–Henseleit solution. The infusion of BmTx-I increased perfusion pressure, renal vascular resistance, urinary flow and glomerular filtration rate. Sodium, potassium and chloride tubular transport was reduced after addition of BmTx-I. Indomethacin blocked the effects induced by BmTx-I on perfusion pressure and renal vascular resistance, however, it did not revert the effect on urinary flow and sodium, potassium and chloride tubular transport. The alterations of glomerular filtration rate were inhibited only at 90 min of perfusion. The partial blockade exerted by indomethacin treatment showed that prostaglandins could have been important mediators of BmTx-I renal effects, but the participation of other substances cannot be excluded. The blockage of all renal alterations observed after tezosentan treatment support the hypothesis that endothelin is the major substance involved in the renal pathophysiologic alterations promoted by the Lys49 PLA 2 myotoxin I, isolated from B. moojeni. In conclusion, the rather intense renal effects promoted by B. moojeni myotoxin-I were probably caused by the release of renal endothelin, interfering with the renal parameters studied.

Effect of pregnancy on diabetic nephropathy and retinopathy.

To determine whether pregnancy worsens renal function in women with diabetic nephropathy and the effect of pregnancy on diabetic retinopathy. Cross-sectional analytical study. The study was conducted in OPD, Bahawal Victoria Hospital, Bahawalpur from September 1997 to June 2003. Thirty-five patients (aged 20-36 years ) identified with diabetic nephropathy and moderate to severe renal dysfunction(creatinine [Cr] > 1.4 mg/dl) at pregnancy onset by retrospective chart review. Alterations in glomerular filtration rate (GFR) were estimated. An equal number of non-pregnant premenopausal type I diabetic women with similar degrees of renal dysfunction served as controls for non-pregnant rate of decline of renal function and potential contributing factors. Student's t-test and repeated measures analysis of variance were analyzed. Mean serum Cr rose from 1.8 mg/dl prepregnancy to 2.5 mg/dl in the third trimester. Renal function was stable in 27%, showed transient worsening in pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased in pregnancy in 79%. Exacerbation of hypertension or pre-eclampsia occurred in 73% and 71% of these showed acceleration of disease during the pregnancy. All the patients had diabetic retinopathy, though proliferative retinopathy was diagnosed and treated in only 54.5.% prepregnancy. The retinopathy progressed, requiring laser therapy, in 45.4%. Macular edema was noted in 6 of the patients. Other diabetic complications included peripheral and autonomic neuropathy in 8 patients. Pregnancy induced progression is seen in the decline of renal functions. Patients with diabetic nephropathy were found to have a > 40% chance of accelerated progression of their disease as a result of pregnancy. Forty-five percent of the patients had permanent decline in GFR in association with pregnancy.

Mycophenolate mofetil-induced reversal of glomerular filtration loss in children with chronic allograft nephropathy.

Mycophenolate mofetil (MMF) has been used for the treatment of chronic allograft nephropathy (CAN) in adults with inconsistent results, but data in children are rare. To evaluate its impact on advanced CAN, we studied changes in glomerular filtration rate (GFR) and the correlation of GFR changes to histology. Thirty-six children (13.1+/-3.6 years) with a progressive decline in GFR of 16.9+/-12.4 mL/min per 1.73 m2/year and biopsy confirmed CAN 4.3+/-2.9 years after transplantation were studied. MMF was added to conventional immunosuppression (IS) consisting of cyclosporine (CsA) and prednisolone (n=26) or tacrolimus (n=1) or replaced azathioprine in triple IS (n=9). Alterations of GFR were correlated to histologic guidelines according to the Banff chronic score (BCS). One year after conversion, 22 (61%) children showed a rise in GFR (7.5+/-6 mL/min per 1.73 m2), 8 (22%) remained stable, and 6 (17%) showed a further decline of GFR (7.4+/-2 mL/min per 1.73 m2). Mean CsA trough levels were 114 ng/mL before and 98 ng/mL 1 year after conversion. MMF side effects required dose reduction in 14 children. Children responding to MMF with increasing GFR showed a trend toward less fibrosis, less incidence of vasculopathy, and transplant glomerulopathy in the initial biopsy but had a similar incidence of borderline tubulitis compared with the other groups. Cotreatment with MMF reversed the progressive loss of GFR in approximately two thirds of children with CAN for at least 1 year. Less chronicity signs in histology seem to indicate a more favorable response to treatment.