Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child.

NC, with renal failure secondary to bilateral dysplastic kidneys, received an LRD renal transplant (tx) at 17 months of age. Her early post-tx course was complicated by persistently elevated blood polyoma BK virus DNA loads. A protocol biopsy at six months post-transplant revealed BKVAN. Blood viral loads did not respond to decreased immunosuppression or treatment with ciprofloxacin and leflunomide. Six months post-tx, her serum creatinine began to rise and we sought experimental therapy to prevent the loss of her graft. At seven months post-tx, with FDA approval under an eIND, the patient was started on a 36-wk course of treatment with the investigational drug. The patient is now more than 24 months after stopping treatment with CMX. BKV viral DNA loads remain at low, but still detectable levels. Urine viral loads have declined, but remain elevated. EBV DNA loads become undetectable. The patient's serum creatinine has declined back to a baseline of 0.5-0.7 mg/dL and has been stable for two yr. Renal function was preserved in association with the use of CMX001 to treat BKV nephropathy in a young pediatric kidney transplant recipient. There were no serious adverse events associated with the use of CMX001. This novel medication may be of value in the treatment of BKVAN in pediatric renal transplant recipients.

Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone.

Prenatal administration of dexamethasone and a low-protein diet has been shown to result in hypertension in the offspring when they are adults. The cause for the hypertension is unknown. The purpose of this study was to examine whether there was prenatal programming of thick ascending limb transport. Rats were administered either dexamethasone for 4 days (0.2 mg/kg body wt) by intraperitoneal injection daily between the 15th and 18th day of gestation, or they were fed a low-protein diet (6% protein) or an isocaloric normal protein diet (20% protein) from day 12 gestation until birth. The offspring were studied as adults. Prenatal dexamethasone and dietary protein deprivation resulted in an increase in blood pressure. Offspring of mothers fed a low-protein diet had an increase in medullary but not cortical bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) protein abundance (P < 0.01). There was not a statistically significant increase in medullary NKCC2 by prenatal dexamethasone (P = 0.07). Both prenatal administration of dexamethasone and a low-protein diet resulted in an increase in medullary thick ascending limb chloride transport compared with control (298 +/- 33 pmoles x mm(-1) x min(-1), 280 +/- 26 pmoles x mm(-1) x min(-1), and 191 +/- 21 pmoles x mm(-1) x min(-1), respectively P < 0.05). There was a higher lumen-positive transepithelial potential difference in the prenatal dexamethasone and low-protein group compared with control as well. Administration of furosemide for 24 h resulted in a decrease in blood pressure in the low-protein group but not the control group. This study demonstrates that insults administered to the fetus can program altered sodium transport. Increased tubular sodium transport is a likely cause for the hypertension by prenatal programming.

Highlights for management of a child with a urinary tract infection.

Urinary tract infections remain the most common bacterial infection in childhood. Escherichia coli is responsible for over 80% of Pediatric UTIs. Other common gram negative organisms include Kleibsiella, Proteus, Enterobacter and occasionally Pseudomonas. Signs and symptoms vary greatly by age of the patient becoming more specific as the child grows older. Even in the absence of specific signs a UTI should be included in the differential diagnosis of high grade fever. In younger children, presence of upper respiratory infections, otitis media or gastroenteritis does not eliminate the possibility of a UTI. Culture of the urine remains the gold standard for diagnosing UTIs. All males and females with well documented UTIs should be imaged for the presence of urological anomalies associated with UTI. Depending on patient's clinical symptoms and tolerance, therapy can be oral or parenteral as they have both been found equally efficacious. Healthcare professionals should ensure that when a child or young person has been identified as having a suspected UTI, they and their parents are given information about the need for treatment, the importance of completing any course of treatment and advice about prevention and possible long-term management.

Prenatal programming of hypertension in the rat: effect of postnatal rearing.

BACKGROUND/AIMS: Dietary protein deprivation during pregnancy causes hypertension in offspring when they become adults. This study examined if postnatal rearing had an effect on blood pressure and glomerular number in male rats whose mothers were fed either a control diet or a low protein diet. METHODS: Neonates were cross fostered at 1 day of age to a different mother. After birth, all nursing and weaned rats were fed a control diet. Blood pressure and glomerular number were measured in adult offspring. RESULTS: Control rats cross fostered to another control mother had a lower blood pressure than low protein rats cross fostered to another low protein mother (133 ± 4 vs. 151 ± 4 mm Hg, p < 0.05) and a greater number of glomeruli (28,388 ± 989 vs. 25,045 ± 851, p < 0.05). Fostering pups from the 20% group to mothers that were fed a 6% diet during pregnancy did not cause hypertension or a reduction in the number of glomeruli. However, fostering the 6% group on to mothers that were fed a 20% protein diet during pregnancy resulted in normalization of the blood pressure and number of glomeruli. CONCLUSION: The hypertension and reduced glomerular number resulting from prenatal dietary protein deprivation can be normalized by improving the postnatal environment.

Evidence that prenatal programming of hypertension by dietary protein deprivation is mediated by fetal glucocorticoid exposure.

BACKGROUND: Prenatal programming by maternal dietary protein deprivation and prenatal dexamethasone result in a reduction in nephron number and hypertension when the offspring are studied as adults. METHODS: To determine whether prenatal dietary protein deprivation results in a reduction in nephron number and hypertension in offspring by exposure to maternal glucocorticoids, we administered metyrapone to rats fed either a 6% or 20% protein diet to inhibit glucocorticoid production and compared the offspring to rats that were the product of mothers fed either a 6% or 20% protein diet during the last half of pregnancy. RESULTS: Male offspring from the 6% group had elevated systolic blood pressure (149 ± 2 vs. 130 ± 5 mm Hg, P < 0.05) and a reduction in glomeruli compared to the 20% group (22,111 ± 627 vs. 29,666 ± 654 glomeruli/kidney, P < 0.001). Maternal metyrapone administration did not affect the blood pressure in the 20% group but ameliorated the increase in blood pressure in the 6% male group to values comparable to the 20% control group (138 ± 6 vs. 130 ± 5 mm Hg). Male offspring of the 6% group that received metyrapone had an increase in the number of glomeruli compared to the vehicle-treated 6% group (26,780 ± 377 vs. 22,111 ± 627 glomeruli/kidney, P < 0.001), but less glomeruli compared to the 20% protein control group (26,780 ± 377 vs. 29,666 ± 654 glomeruli/kidney, P = 0.01). CONCLUSIONS: The reduction in nephron number and hypertension induced by maternal protein deprivation in male offspring is ameliorated by inhibition of glucocorticoid production.

Effect of prenatal dexamethasone on postnatal serum and urinary angiotensin II levels.

BACKGROUND: Prenatal programming of hypertension has been described in humans and in animal models that receive a prenatal insult, but the mechanism for the increase in blood pressure remains elusive. METHODS: In male rats whose mothers received dexamethasone between days 15 and 18 of gestation systemic and urinary levels of angiotensin II were measured to determine whether angiotensin II was a potential factor for the generation (4 weeks of age) or maintenance (8 weeks of age) of hypertension. RESULTS: A group 4- and 8-week-old male rats that were the product of a pregnancy where the mother received prenatal dexamethasone between days 15 and 18 of gestation had comparable plasma renin and angiotensin II levels to the offspring of vehicle-treated controls. Renal angiotensin II levels were not different at 4 and 8 weeks of age between the controls and the prenatal dexamethasone group. Urine angiotensin II/Creatinine levels, a reflection of filtered and renally generated and secreted angiotensin II, were higher at both 4 and 8 weeks of age in male rats that received prenatal dexamethasone compared to controls. CONCLUSIONS: The high-urine angiotensin II levels in prehypertensive and hypertensive rats that were the product of mothers that received dexamethasone compared to vehicle suggest that luminal angiotensin II may play a role in the generation and maintenance of hypertension in this model of prenatal programming.