Diego H. Aviles

Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients.

Abstract:  Tacrolimus has become an effective alternative to cyclosporine as a component of primary immunosuppression in pediatric renal transplant patients, but the information on the pharmacokinetic characteristics of tacrolimus in young patients is still limited. The primary objective of this study was to determine the effect of patient age, ethnicity, and concurrent steroid administration on tacrolimus pharmacokinetics in pediatric renal transplant patients. The study population consisted of 30 pediatric patients, age 1.5–18.6 yr, who received a kidney transplant between July 1999 and February 2004. After twice daily dosing was stabilized based on clinical judgment, at least 5 days postoperatively, tacrolimus levels were drawn prior to, and 1, 2, 4, 8, and 12 h after the morning dose. The mean dose of tacrolimus was 0.12 mg/kg/dose. Mean trough level was 11.9 ± 5.0 ng/mL. Mean area under the curve (AUC) was 192 ± 84 with a range of 78–360 h × (ng/mL). The correlation between trough level and AUC was only fair (r = 0.74); later time points correlated better with AUC, and an excellent correlation (r = 0.96) was obtained between the mean of trough and 2‐h level (C2) and AUC. There was a negative correlation between age and dose per body weight (r = −0.68). African‐American patients had marginally lower drug exposure with similar dosing. Three age groups (<5, 5–12, and >12 yr) were compared with respect to dosing and AUC. Despite similar AUC in all three groups, the mean dose per kg required to achieve the AUC was 2.7‐ and 1.9‐fold higher in the <5 and 5–12‐yr groups, respectively, compared with the >12‐yr group. Nine of the 30 patients were on a totally steroid‐free regimen. Their tacrolimus dose and trough levels were similar to those of steroid‐exposed patients, but their mean AUC was 41% higher. Our results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid‐free regimen despite no change in trough level.

Results of one-year follow-up of steroid-free immunosuppression in pediatric renal transplant patients

Abstract:  Renal transplantation in children has traditionally required immunosuppression with multiple medications including glucocorticoids. Data collected over almost 30 yr suggest that although glucocorticoids are efficacious as part of a regimen to minimize the incidence of acute rejection episodes, their use is associated with increased risk for post‐transplant hypertension, hyperlipidemia, and reduced growth rates. We desired to reduce these complications and thus used an immunosuppressive protocol including daclizumab, tacrolimus, and mycophenolate mofetil and study the efficacy of this protocol in a population with a high percentage of African‐American recipients. No patient received glucocorticoids at any time post‐transplant. Our results show that at 1 yr post‐transplant, glomerular filtration rate, serum glucose, calcium and phosphorous metabolism, serum magnesium, and serum lipids were similar in patients receiving steroid‐free and those receiving steroid‐based immunosuppression. The incidence of acute rejection was similar in the two groups. Hematocrit and white blood count levels were lower 1 month after transplant in the steroid‐free patients but these levels increased within several months. Systolic blood pressure was similar in the two groups, although this was achieved, in part, in the patients who received steroids by the administration of medications to lower blood pressure. Finally, tacrolimus levels were similar in the two groups, but patients receiving steroids required higher doses of tacrolimus at several time points studied during the first post‐transplant year. Taken together, our data suggests that at one‐year follow‐up, steroid‐free immunosuppression is safe, and efficacious in pediatric renal transplant recipients.

Syndrome of Hypokalemic Metabolic Alkalosis and Hypomagnesemia Associated with Gentamicin Therapy: Case Reports

Nephrotoxicity, as evidenced by renal insufficiency is a well-known consequence of gentamicin therapy. We report two patients with gentamicin-induced syndrome of hypokalemic metabolic alkalosis and hypomagnesemia. Both had complete recovery of renal tubular function after cessation of antibiotic therapy. These cases emphasize the need to routinely monitor patients receiving gentamicin therapy for electrolyte abnormalities to avoid potential morbidity.

Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients

FSGS recurs in approximately 30% of transplanted kidneys and may lead to graft loss. We retrospectively examined the efficacy of early and intensive PP without additional IS in pediatric kidney transplant patients with recurrent FSGS at our center. Seven of 24 patients (29%) had nephrotic proteinuria and histologic evidence of FSGS recurrence within 1–5 days post‐transplantation. PP was initiated early after transplantation and initially performed daily until sustained decline in proteinuria. PP frequency was then individually tapered according to proteinuria. Recurrent FSGS in all seven patients responded to a four‐ to 32‐wk course of PP. Two of seven patients had a second recurrence of FSGS, and both recurrences remitted after an additional 3–6 wk of PP. Median observation period was 4.5 yr (0.8–16.3 yr). Complete remission of recurrent FSGS has been sustained in all seven patients, and all patients have stable graft function with recent plasma creatinine <1.5 mg/dL in six of seven patients. Most recent urine protein/creatinine is 0.13–0.61 mg/mg in six of seven patients. One patient has heavy proteinuria secondary to chronic allograft nephropathy 16 yr post‐transplant. Intensive and prolonged PP, when initiated early in the post‐operative period, is effective in treating recurrent FSGS and preventing graft loss without the use of additional immunosuppressants.

Nephrotic syndrome associated with Toxocara canis infection

This case report describes nephrotic syndrome in a 7-year-old boy coincident with Toxocara canis infection. This rare association was confirmed by elevated Toxocara-specific IgM titres. Treatment with corticosteroids resulted in remission of renal symptoms as well as abatement of the T. canis infection. The relationship between T. canis infection and glomerular disease is still unclear; nephrotic syndrome may be another manifestation of T. canis infection.

Sudden blindness in a child with end-stage renal disease

Continuous peritoneal dialysis (CPD) is the preferred modality for renal replacement therapy in children with end-stage renal disease. Anterior ischemic optic neuropathy (AION) is a rare complication in patients on CPD. AION is characterized by ischemic injury of the optic nerve caused by hypoperfusion of the posterior ciliary arteries. It presents with acute visual loss and disc swelling, without additional neurological findings. We report a 2-year-old child with end-stage renal disease on CPD who developed AION. He was dehydrated and received intravenous fluid on admission. Additional treatment included methylprednisolone and levodopa. On his 3rd admission day, his pupils became reactive to light and his vision showed improvement. The improvement in vision might be due to the early detection and aggressive treatment of hypotension. It is difficult to demonstrate whether steroids or levodopa played a role in the improvement of his vision. Prospective studies to evaluate the effectiveness of levodopa in the treatment of AION are warranted in this potentially devastating condition.

Immunotactoid glomerulopathy in sickle cell anemia

Abstract A 12-year-old African American male with homozygous sickle cell disease (SCD) was admitted with insidious onset of periorbital and scrotal edema. The initial evaluation failed to reveal any underlying monoclonal gammopathy, or cryoglobulinemia, or other systemic causes for the renal disease. A percutaneous renal biopsy was consistent with immunotactoid glomerulopathy (ITG), which is rare in children and is characterized histologically by fibrillar deposits in the glomeruli. Children can present with symptoms of nephrotic syndrome and progress to end stage renal disease. Our patient was treated with an ACE inhibitor and is currently free of edema and with normal renal function on follow-up at 1 year. Immunotactoid glomerulopathy should be considered in the differential diagnosis of nephrotic syndrome in children with sickle cell disease. Renal biopsy is indicated in children with sickle cell disease and nephrotic syndrome and ITG should be considered as potential cause. Although there is no effective treatment for this condition, ACE inhibitors can decrease the proteinuria and possibly delay the progression to end stage renal disease. The side effects related to the use of ACE inhibitors should be monitored. These include renal impairment, hyperkalemia, anemia, neutropenia, and angioedema. Since we have a short follow-up in our patient, the role and safety of ACE inhibitors in the management of ITG need further evaluation.

Biphasic effects of dopamine on 86rubidium uptake in rat renal proximal tubules

The mechanism(s) by which dopamine inhibits Na+ -K+ -ATPase activity in the renal proximal tubule is still controversial. We studied the short-term effects of dopamine on the sodium pump in rat renal proximal tubule suspensions with the 86Rb uptake method. Dopamine and the D1-like agonist, SKF81297, initially stimulated Na+ -K+ -ATPase activity at 5 min and subsequently inhibited it at 10 min and 20 min; the inhibition by 10 μM dopamine at 20 min was 21.3 ± 4.5 %. The inhibitory effect of dopamine on Na+ -K+ -ATPase activity was mimicked by thymeleatoxin (a classical protein kinase C [PKC] agonist) while Sp-8-CPT-cAMPS (a protein kinase A [PKA] agonist) had no effect. However, the combination of the PKC and PKA agonists mimicked the biphasic effects of dopamine and SKF81297. Rp-8-CPT-cAMPS (a PKA inhibitor), U-73122 (a phospholipase C inhibitor), or calphostin C (a PKC inhibitor), blocked the dopamine-mediated biphasic effects on Na+ -K+ -ATPase activity. It is suggested that the biphasic effects of dopamine on Na+ -K+ -ATPase activity (an initial stimulation and a subsequent inhibition) are transduced by activating both PKA and PKC through a D1-like receptor.

False-positive human immunodeficiency virus antibody test in a dialysis patient

A patient developed end-stage renal disease secondary to p-anti-neutrophil cytoplasmic antibody (p-ANCA) positive rapidly progressive glomerulonephritis. He subsequently had human immunodeficiency virus (HIV)-1 antibody screening performed as part of a pre-transplant evaluation. The HIV-1 enzyme immunoassay (EIA) antibody test was repeatedly reactive. The HIV-1 western blot was indeterminate. The western blot pattern revealed “non-specific staining obscuring bands in that region.” Another sample of serum was sent and the results were identical to the first result. An HIV-1 proviral qualitative polymerase chain reaction test was then performed several months later and no HIV-1 DNA was detected. One year later, an HIV-1 RNA test was negative. Thus, the positive antibody EIA test and the indeterminate western blot represent a false-positive result, most likely due to cross-reacting antigens in the patient’s serum with various HIV antibodies. Throughout this period and thereafter, the patient has exhibited no symptoms of HIV infection.

Anemia in nephrotic syndrome: approach to evaluation and treatment

Nephrotic syndrome is one of the most common glomerular diseases that affect in children. Complications may occur in nephrotic syndrome as a result of the disease itself as well as its treatment. Most of these complications result from excessive urinary protein losses, and control of proteinuria is the most effective treatment strategy. Anemia is one of the many complications seen in patients with persistent nephrotic syndrome and may occur as a result of excessive urinary losses of iron, transferrin, erythropoietin, transcobalamin and/or metals. This leads to a deficiency of substrates necessary for effective erythropoiesis, requiring supplementation in order to correct the anemia. Supplementation of iron and erythropoietin alone often does not lead to correction of the anemia, suggesting other possible mechanisms which need further investigation. A clear understanding of the pathophysiologic mechanisms of anemia in nephrotic syndrome is necessary to guide appropriate therapy, but only limited evidence is currently available on the precise etiologic mechanisms of anemia in nephrotic syndrome. In this review we focus on the current state of knowledge on the pathogenesis of anemia in nephrotic syndrome.