Effect of prenatal programming and postnatal rearing on glomerular filtration rate in adult rats.

The present study examined whether a prenatal low-protein diet programs a decrease in glomerular filtration rate (GFR) and an increase in systolic blood pressure (BP). In addition, we examined whether altering the postnatal nutritional environment of nursing neonatal rats affected GFR and BP when rats were studied as adults. Pregnant rats were fed a normal (20%) protein diet or a low-protein diet (6%) during the last half of pregnancy until birth, when rats were fed a 20% protein diet. Mature adult rats from the prenatal low-protein group had systolic hypertension and a GFR of 0.38 ± 0.03 versus 0.57 ± 0.05 ml·min(-1)·100 g body wt(-1) in the 20% group (P < 0.01). In cross-fostering experiments, mothers continued on the same prenatal diet until weaning. Prenatal 6% protein rats cross-fostered to a 20% mother on day 1 of life had a GFR of 0.53 ± 0.05 ml·min(-1)·100 g body wt(-1), which was not different than the 20% group cross-fostered to a different 20% mother (0.45 ± 0.04 ml·min(-1)·100 g body wt(-1)). BP in the 6% to 20% group was comparable with the 20% to 20% group. Offspring of rats fed either 20% or 6% protein diets during pregnancy and cross-fostered to a 6% mother had elevated BP but a comparable GFR normalized to body weight as the 20% to 20% control group. Thus, a prenatal low-protein diet causes hypertension and a reduction in GFR in mature adult offspring, which can be modified by postnatal rearing.

Effect of postnatal maternal protein intake on prenatal programming of hypertension.

This study examined whether postnatal maternal dietary protein deprivation during the time of nursing can program hypertension when the offspring are studied as adults. Rats were fed either a 6% or 20% protein diet during the second half of pregnancy and continued on the same diet while rats were nursing their pups. The neonates of all of the rats were cross-fostered to a different mother and studied as adults. Adult rats that had a normal prenatal environment but were reared by mothers fed a low-protein diet until weaning (20%-6%) were hypertensive, had a higher renal Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) and Na(+)-Cl(-) cotransporter (NCC) protein abundance yet a comparable number of glomeruli, and had higher plasma renin and angiotensin II levels compared to control (20%-20%). Rats whose mothers were fed a 6% protein diet and cross-fostered to a different rat fed a 6% protein diet until weaning (6%-6%) were hypertensive, had elevated plasma renin and angiotensin II levels, and had a reduction in nephron number but had NKCC2 and NCC levels comparable to 20% to 20% offspring. The 6% to 20% had blood pressure and glomerular numbers comparable to 20% to 20% rats. The hypertension resulting from prenatal dietary protein deprivation can be normalized by improving the postnatal environment. Combined prenatal and postnatal maternal dietary protein deprivation and maternal dietary protein deprivation while nursing alone (20%-6%) results in hypertension, but the mechanism for the hypertension in these groups is different.

Validation of the CKiD formulae to estimate GFR in children post renal transplant.

BACKGROUND: The Chronic Kidney Disease in Children (CKiD) study reported new formulae to estimate glomerular filtration rate (eGFR). The study reported here aimed to assess the accuracy of these formulae in estimating levels and changes in GFR in pediatric renal transplant recipients and generate a new formula in our cohort. METHODS: Two hundred and fifty-two studies of plasma disappearance of (125)I-iothalamate (CIO) were used to measure GFR in 155 renal transplant recipients. The CKiD bedside formula (CKiD-BS) was compared with CIO. A mixed logistic regression model was fit to evaluate the performance of estimating change in posttransplant CIO using CKiD-BS. We used mixed-effects linear regression to fit a multiplicative model of CIO. The CKiD cystatin-C-based formula (CKiD-Cys) was also used for comparison in 32 additional transplant recipients. Comparisons were made using Bland-Altman plots. RESULTS: CKiD-BS underestimates CIO by 20 % for GFR >25 ml/min per 1.73 m(2). Percentage change in CKiD-BS performed reasonably well in estimating 15 % change of CIO beginning 6 months posttransplant [area under the curve (AUC) = 0.791)] The multiplicative constant in the CKiD-BS was recalibrated [R-Bedside = 0.461 × ht(cm)/SCr).]A GFR model [GFR-M) = 10.73 × [(ht(cm)]0.51/(SCr)0.90 × (BUN)0.23] has higher specificity but similar sensitivity for CIO compared with R-Bedside. CKiD-Cys overestimates CIO by 10 ml/min per 1.73 m(2) across a broad range of GFR. CONCLUSIONS: In our cohort, the CKiD-BS underestimates CIO; however, changes in CKiD-BS can be used to estimate changes in CIO. CKiD-Cys overestimates CIO and is not accurate in estimating CIO.

Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats.

Adulthood hypertension can be prenatally programmed by maternal dietary protein deprivation. We have shown that the sympathetically mediated pressor response to physical stress is exaggerated in prenatally programmed hypertensive (PPH) rats. The mechanisms underlying this abnormal responsiveness remain undetermined. The renin-angiotensin system is known to affect sympathetic nerve activity. Therefore, the purpose of this study was to determine whether inhibition of the renin-angiotensin system attenuates the enhanced sympathetic and pressor responses to physical stress in PPH rats. Changes in renal sympathetic nerve activity and blood pressure in response to hindlimb contraction, hindlimb stretch, and hindlimb intra-arterial capsaicin administration were assessed in control and PPH rats treated (from age 3 weeks) with either vehicle or the angiotensin-converting enzyme inhibitor enalapril. Conscious resting systolic arterial pressure was significantly greater in PPH rats (142±5 mm Hg) than in control (128±2 mm Hg) after vehicle treatment (P<0.05). Resting systolic pressure was reduced by enalapril treatment in PPH rats (125±2 mm Hg) but had no effect in control (128±2 mm Hg). The pressor and renal sympathetic responses to muscle contraction and stretch were significantly higher in decerebrate PPH rats than in decerebrate control in vehicle-treated groups. Responses to capsaicin were variable. Enalapril significantly attenuated the enhanced contraction-induced elevations in mean pressure (vehicle, 45±6 mm Hg; enalapril, 21±3 mm Hg) and renal sympathetic activity (vehicle, 175±22%; enalapril, 89±23%) in PPH rats. Its effects were similar on responses to stretch in PPH rats but were equivocal during capsaicin administration. The results suggest that the renin-angiotensin system contributes to the enhancement of the renal sympathetic and pressor responses to physical stress in PPH rats.

Prenatal programming of hypertension induces sympathetic overactivity in response to physical stress.

Small-for-gestational-age infants are known to develop hypertension in adulthood. This prenatal programming of hypertension (PPH) can result from several insults including maternal dietary protein deprivation, uteroplacental insufficiency, and prenatal administration of glucocorticoids. The mechanisms underlying the development of hypertension remain unclear although the sympathetic nervous system has been indirectly implicated. This study was designed to directly measure renal sympathetic nerve activity both at rest and during physical stress in an animal model of PPH. The adult male offspring of rats fed either a 6% (PPH) or 20% protein diet (control) were investigated. Conscious systolic blood pressure measured by tail cuff was significantly higher in PPH compared with control (140 ± 3 versus 128 ± 3 mm Hg; P<0.05). Baseline mean arterial pressure, heart rate, and renal sympathetic activity were not different between groups during isoflurane anesthesia or after decerebration. Physical stress was induced in decerebrate animals by activating the exercise pressor reflex during static muscle contraction. Stimulation of the exercise pressor reflex evoked significantly larger changes from baseline in mean arterial pressure (40 ± 7 versus 20 ± 4 mm Hg; P<0.05), heart rate (19 ± 3 versus 5 ± 1 bpm; P<0.05), and renal sympathetic activity (198 ± 29% versus 68 ± 14%; P<0.05) in PPH as compared with control. The data demonstrate that the sympathetic response to physical stress is markedly exaggerated in PPH and may play a significant role in the development of hypertension in adults born small for gestational age.

Patient's outcome of bladder cancer managed by radical cystectomy with lymphadenectomy at a university hospital.

OBJECTIVE: To study the impact of tumour staging and nodal metastases in predicting 5- year's survival after radical cystectomy and bilateral pelvic lymphadenectomy for primary bladder cancer. METHODS: During the period 1995 to 2005, 58 patients underwent radical cystectomy and bilateral pelvic lymphadenectomy and urinary diversion at a University hospital. Patients were identified using medical indexing coding system (ICD 9CM) using standard key words. The patient records were analyzed and follow up data updated. Disease specific survival, death or recurrence was taken as end point. RESULTS: Out of 58 patients, 50 (86%) were males and 8 (14%) females with a mean age of 61 +/- 13.1 years (range from 27 to 87 years). Of 58 patients, 11 (23%) were excluded from the study because of in adequate follow up. The mean follow up was 5.7 years (range, 7 months to 11 years). The overall 5 years survival was 55% with disease specific survival being 66%. Patients with pathological stage TO at cystectomy have 87% 5 years disease specific survival compared to 60%, in patients with pT4 (p = 0.705). The 5-year survival for node positive patients was 16%, compared to 60% for node negative patients (p < 0.01). CONCLUSIONS: Radical cystectomy and bilateral pelvic lymphadenectomy is the standard treatment for muscle invasive and high grade T1 cancers, and as salvage for recurrent cancers. Lymphadenectomy has a potential therapeutic benefit. The pathological stage at cystectomy and nodal status are predictors of 5 years survival.