Bettina H. Ault

Factor H and the pathogenesis of renal diseases

Abstract Complement factor H is a potent inhibitor of alternative pathway complement activation. The factor H gene, a member of the regulators of complement activation (RCA) gene cluster, encodes two plasma proteins, one 150 kilodaltons (kDa) and one 43 kDa. Homozygous deficiency of factor H results in low plasma levels of complement factor B and C3 and depletion of the terminal complement proteins C5-C9; heterozygotes may have reduced or normal levels of factor B, C3, and C5-C9. Although factor H deficiency is infrequently reported, it has been associated with a number of types of renal disease, the most common being atypical membranoproliferative glomerulonephritis and idiopathic (non-diarrhea-associated) hemolytic uremic syndrome (HUS). The molecular defects responsible for factor H deficiency have been described in only two cases; clearly more research is needed in this area. The possible role of factor H deficiency or dysfunction in the pathogenesis of HUS is discussed.

Predominance of nocturnal hypertension in pediatric renal allograft recipients

Abstract:  Hypertension is common in children with end‐stage renal disease who have undergone renal transplantation. We performed ambulatory blood pressure monitoring (ABPM) in renal allograft recipients who were on stable maintenance immunosuppressive medications and were more than six months post‐transplant. Echocardiographic measurement of left ventricular mass index (LVMI) was obtained at the time of ABPM. Twenty‐nine children with a mean age of 14.8 yr (8–18 yr) were evaluated 4.3 yr (0.6–12.8 yr) after deceased donor (n = 13) or living donor (n = 16) transplantation. BP levels were higher during sleep compared with when awake using the 95th percentile to standardize mean BP for each period: mean BP was expressed as a standard deviation score (SDS) for each time period, awake vs. sleep: systolic (s) BP SDS were 0.43 ± 1.3 vs. 1.29 ± 1.2 (p < 0.001) and diastolic (d) BP SDS were 0.04 ± 1.3 vs. 1.34 ± 1.2 (p < 0.001). Significant differences between awake and sleep BP were also confirmed using the mean BP for each period expressed as a BPI. Hypertension (HTN) during sleep was more common than awake HTN. Based upon BPI, 21% had sHTN when awake compared with 48% during sleep and 7% had dHTN when awake compared with 41% during sleep (p < 0.05). Based upon mean BP load, 38% had sHTN when awake compared with 55% during sleep and 21% demonstrated dHTN when awake compared with 52% during sleep (p < 0.05). Left ventricular mass (LVM) was abnormally increased in six of 17 children (35%); LVM was not correlated with BP. Children prescribed angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEi/ARB) had significantly lower systolic BP compared with those on calcium channel blocking agents (CCB). Mean sSDS was −0.11 ± 1.1 in those children on ACEi/ARB compared with 1.6 ± 1.2 in those on CCB (p = 0.02): sSDS during sleep was significantly lower in the ACEi/ARB group compared with CCB (0.70 ± 1.1 vs. 2.0 ± 1.1, p = 0.04). Isolated nocturnal HTN is more common than daytime HTN among clinically stable pediatric renal allograft recipients. Detection and treatment of nocturnal HTN in pediatric allograft recipients could potentially affect graft survival.

Induction Therapy for Pediatric Focal Proliferative Lupus Nephritis: Cyclophosphamide Versus Mycophenolate Mofetil

PURPOSE OF THE STUDY Although cyclophosphamide has been used with success in children, mycophenolate may be a better alternative with less toxicity. The objective of this study is to determine the efficacy of mycophenolate compared with cyclophosphamide as induction therapy in children with class III lupus nephritis. METHODS We retrospectively studied pediatric patients with class III lupus nephritis from two pediatric centers from January 1991 to December 2005 who were treated either with monthly cyclophosphamide or mycophenolate mofetil for the first 6 months. Thirteen patients were studied, with seven patients in the cyclophosphamide group and six patients in the mycophenolate group. RESULTS At 6 months, in the cyclophosphamide group, no patient had achieved complete remission, while 57% were in partial remission. In the mycophenolate group, 66% had achieved complete remission, 17% were in partial remission, and 17% were not in remission. DISCUSSION In a small group of children with class III lupus nephritis, we observed a trend of more patients in the mycophenolate group achieving remission at 6 months. However, the long-term benefit of using mycophenolate as an induction agent is still unclear.

Five years' experience with thymoglobulin induction in a pediatric renal transplant population

Abstract:  Antibody induction therapy is used in the majority of pediatric patients undergoing renal transplantation. Our center has previously reported short‐term outcomes with TMG as induction therapy. We now present our experience over the last five yr. Patients received TMG intra‐ and post‐operatively at a dose of 1.5 mg/kg/day. The dose was decreased to 0.75 mg/kg/day or held dependent on the patients WBC and platelet counts. Post‐transplant immunosuppression also included corticosteroids, MMF, and either TAC or CSA. Patient and graft survival, number of acute rejection episodes, creatinine clearance, incidence and type of infections, and trough levels of calcineurin inhibitor drugs were monitored during the follow‐up period. Thirty‐four renal transplants were performed in 33 pediatric patients ranging in age from 1.7 to 17.8 yr. Seventeen rejection episodes occurred during the time of follow‐up with three patients having more than one episode, but only three episodes occurred within the first year after transplantation. Three patients had graft loss in the first week after transplantation from primary non‐function (1) or technical failure/thrombosis (2). Graft losses occurred in seven additional patients during the time of follow‐up with the first loss occurring at 17.7 months. Among patients with functional grafts at one wk after transplant, graft survival at one and three yr was 100% and 73% respectively. There were no patient deaths. There were no cases of post‐transplant lymphoproliferative disease or other malignancy. One patient had symptomatic CMV disease. TMG is safe and effective as induction therapy in pediatric renal transplant patients. Late graft loss remains a challenge in the pediatric patient population, particularly in adolescents.

Gastroenteritis caused by Edwardsiella tarda in a pediatric renal transplant recipient

Abstract:  Edwardsiella tarda, a member of the family Enterobacteriaceae, is a Gram‐negative bacillus that is most often pathogenic in aquatic environments. Human infections with Edwardsiella are rare, with most occurring in immunocompromised or immunosuppressed hosts. Reported infections include meningitis, cholecystitis, endocarditis, osteomyelitis, soft tissue infections, bacteremia and septicemia, dysentery, and gastroenteritis. This report describes a case of E. tarda gastroenteritis in a renal transplant patient receiving immunosuppressive therapy. The epidemiology, diagnosis, clinical presentation, and treatment options pertaining to E. tarda infections are examined.

Diagnosis of de novo localized thrombotic microangiopathy by surveillance biopsy

Thrombotic microangiopathy has been reported in association with calcineurin inhibitors and less frequently with sirolimus in renal transplant patients. The diagnosis of thrombotic microangiopathy is typically made by diagnostic biopsy in the setting of allograft dysfunction. The finding of thrombotic microangiopathy on surveillance biopsy without a significant elevation of baseline serum creatinine is unusual. The optimal treatment of this disorder remains controversial. Treatment strategies have included dose adjustment, drug substitution, plasmapheresis, and intravenous immunoglobulin G. We report a case of de novo thrombotic microangiopathy diagnosed by surveillance biopsy in a patient without hematologic abnormalities or elevated serum creatinine. This patient had resolution of the renal lesion following conversion from tacrolimus to sirolimus-based immunosuppression.

Two cases of hematuria with hemoglobin C trait

Patients with sickle cell disease commonly experience painless hematuria. Hematuria may be found in patients with sickle cell trait, sickle cell anemia, and sickle cell hemoglobin C disease, but it is believed to be uncommon in patients with other hemoglobinopathies, such as hemoglobin C disease and hemoglobin C trait. We report two cases of children with hemoglobin C trait who presented with persistent painless hematuria. Because it is possible that hematuria in a patient with hemoglobin C trait is purely coincidental, all patients with a hemoglobinopathy and hematuria should undergo a complete evaluation so as not to overlook other causes of hematuria.

Fever and Rash

revealed a left pleural effusion and left lower lobe atelectasis/consolidation. Fluid obtained from ultrasound-guided thoracentesis had 930 white blood cells/mm with 39% neutrophils, 3% bands, 38% lymphocytes, lactate dehydrogenase 196 IU/L, total protein 2.5 g/dL, pH 8.0, and cultures negative for bacteria. Because of persistent symptoms despite parental doxycycline, ceftriaxone (1 g daily) was added. After 10 days of doxycycline and 7 days of ceftriaxone, his skin rash resolved but he remained febrile (38-40°C) and continued to have generalized fatigue and bilateral lower extremity edema. Serum titers for tick-borne illnesses (Table 1) drawn after 2 weeks of illness were positive for Ehrlichia chaffeensis (immunoglobulin G of 1:512 and immunoglobulin M of 1:80). As no other titers for infectious entities were positive, rifampin was added to treat a possible resistant infection. When fever and proteinuria (4+ proteinuria) persisted despite treatment, the possibility of an underlying systemic illness was entertained. A 24-hour urine specimen was collected that contained 7700 mg (194.2 mg/m/h) protein (Table 1). A renal biopsy was performed, which confirmed the diagnosis of membranous lupus nephritis (International Society of Nephrology/Renal Pathology Society class V) (Figure 3). Other laboratory parameters that supported the diagnosis of systemic lupus erythematosus (SLE) included a positive antinuclear antibody (ANA) titer of 4.79 with a homogenous pattern together with a positive antibody to double-stranded DNA and low serum complement levels (C3 and C4). Taken together, his clinical symptoms and laboratory parameters confirmed the diagnosis of SLE. He was started on prednisone 40 mg twice daily with immediate resolution of his fatigue and fever and a more gradual resolution of the proteinuria and peripheral edema. Case Report

Tularemia infection in a pediatric patient with chronic renal insufficiency and inguinal lymphadenopathy

Abstract: Tularemia is a rare zoonosis caused by the gram-negative coccobacillus Francisella tularensis. We describe a pediatric patient with chronic renal insufficiency who presented with high fever and regional lymphadenopathy caused by tularemia. This case highlights the fact that F. tularensis infection must be considered when investigating a fever of unknown origin, especially in the presence of a history of animal exposure.

Argatroban in Post-Cardiovascular Surgery Patient with Heparin-Induced Thrombocytopenia Requiring Hemodialysis and Continuous Hemofiltration

Objective: To describe the use of argatroban in a postoperative cardiovascular surgery patient with heparin-induced thrombocytopenia (HIT) requiring hemodialysis and continuous veno-veno hemofiltration (CVVH). Case Summary: A 23-year-old white woman with HIT developed acute renal failure after cardiovascular surgery. Argatroban was used as a substitute for heparin during hemodialysis and CVVH. Both activated partial thromboplastin time (aPTT) and activated clotting time (ACT) were used to guide the dosage of argatroban. The patient was successfully dialyzed without clotting of the circuit. The dosage required in our patient was much lower than the manufacturers recommendation. Discussion: Argatroban is a selective thrombin inhibitor that does not cross-react with heparin-induced antibodies. It is metabolized by the liver, and dosage adjustment is recommended in patients with severe hepatic impairment. The correct dosage for patients with unstable hemodynamics is not known. Our patient had apparently normal hepatic function at the initiation of therapy, but the dosage of argatroban recommended by the manufacturer resulted in prolonged elevation of the aPTT and ACT with associated gastrointestinal bleeding. This may be due to hepatic congestion secondary to poor cardiac function and/or severe generalized edema. Conclusions: When argatroban is considered for therapy in place of heparin for CVVH, it needs to be used with extreme caution since the correct initial dosage in patients with mild hepatic impairment and unstable hemodynamics is unclear.