The spectrum of autosomal dominant polycystic kidney disease in children and adolescents.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. It is characterized by the development of renal cysts and kidney enlargement and ultimately leads to renal failure typically in the sixth decade of life. Although most patients are asymptomatic until well into adulthood, renal cysts develop much earlier, often in utero. Significant renal anatomic and cystic expansion typically occurs before clinical manifestations in children and young adults with AKPKD. The cyst burden detected by imaging represents the minority of cyst burden, and renal and cardiovascular abnormalities are the most common manifestations in children with ADPKD. Here we review the molecular pathogenesis of ADPKD, discuss the screening, diagnosis and clinical manifestations of this renal disorder in childhood and adolescents and review treatment options and potential therapies currently being tested.

Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy.

BACKGROUND: Argatroban, a direct thrombin inhibitor, is used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). The recommended initial dose is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) values 1.5-3.0 times baseline. However, few argatroban-treated patients with HIT and renal failure requiring renal replacement therapy (RRT) have been described. OBJECTIVE: To evaluate the safety and efficacy of argatroban anticoagulation during RRT in patients with HIT. METHODS: We retrospectively reviewed records from 47 patients with HIT and renal failure requiring RRT who underwent 50 treatment courses with argatroban. Patients with HIT had received argatroban during prospective, multicenter studies. Outcomes, safety, and dosing information were summarized. RESULTS: In the multicenter experience, no patient died due to thrombosis and 2 (4%) patients developed new thrombosis while on argatroban. No adverse outcomes occurred during argatroban reexposure. Starting doses were typically 2 microg/kg/min in patients without hepatic impairment and <1.5 microg/kg/min in those with hepatic impairment. Median (range) infusion doses were 1.7 (0.2-2.8) and 0.7 (0.1-1.7) microg/kg/min, respectively, with associated median (range) aPTT ratios, relative to baseline, of 2.2 (1.6-3.6) and 2.0 (1.4-4.1), respectively. Major bleeding occurred in 3 (6%) of 50 treatment courses. CONCLUSIONS: Argatroban provides effective anticoagulation upon initial and repeated administration in patients with HIT and renal impairment requiring RRT, with an acceptably low bleeding risk. Current dosing recommendations are adequate for these patients.

Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia.

BACKGROUND: Argatroban, a direct thrombin inhibitor, is an effective anticoagulant for patients who have heparin-induced thrombocytopenia (HIT). Anticoagulation is usually required for renal replacement therapy (RRT). OBJECTIVE: To prospectively evaluate the pharmacokinetics, pharmacodynamics, and safety of argatroban during RRT in hospitalized patients with or at risk for HIT. METHODS: Five patients with known or suspected HIT underwent hemodialysis (n = 4) or continuous venovenous hemofiltration (CVVH, n = 1), while receiving a continuous infusion of argatroban 0.5-2 microg/kg/min. Activated partial thromboplastin times (aPTTs), activated clotting times (ACTs), argatroban concentrations (plasma, dialysate, CVVH effluent), and safety were assessed before, during, and after a 4-hour session of RRT. Systemic and dialytic argatroban clearances were calculated. RESULTS: Among the 4 hemodialysis patients, aPTT, ACT, and plasma argatroban concentrations remained stable during RRT, with respective mean +/- SD values of 74.3 +/- 34.2 seconds, 198 +/- 23 seconds, and 499 +/- 353 ng/mL before RRT, and 70.6 +/- 21.4 seconds, 181 +/- 12 seconds, and 453 +/- 295 ng/mL 2 hours after starting RRT (p values NS). Systemic clearance was 17.7 +/- 12.8 L/h before hemodialysis and 17.0 +/- 9.5 L/h during hemodialysis (n = 2). The dialyzer clearance (dialysate recovery method) was 1.5 +/- 0.4 L/h (n = 4). Generally similar responses occurred in the CVVH patient: systemic argatroban clearance was 4.8 L/h before CVVH and 4 L/h during CVVH. The hemofilter argatroban clearance was 0.9 L/h. No bleeding or thrombosis occurred. CONCLUSIONS: Argatroban provides effective alternative anticoagulation in patients with or at risk for HIT during RRT. Argatroban clearance by high-flux membranes during hemodialysis and CVVH is clinically insignificant, necessitating no dose adjustment.

A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease.

BACKGROUND: We prospectively evaluated 3 treatment regimens of argatroban, a direct thrombin inhibitor, for providing adequate, safe anticoagulation in patients with end-stage renal disease (ESRD) during hemodialysis. METHODS: In this randomized, 3-way crossover study, ESRD patients underwent hemodialysis sessions of 3- or 4-hour duration using high-flux membranes and each of 3 argatroban treatment regimens (A: 250-microg/kg bolus, with an additional 250-microg/kg bolus allowed; B: 250-microg/kg bolus followed by 2-microg/kg/min infusion; C: steady-state, 2-microg/kg/min infusion initiated 4 hours before dialysis). Pharmacodynamic effects including activated clotting times (ACTs); hemodialysis efficacy including single-pool Kt/V, urea reduction ratio (URR), and circuit flow; and safety through a 3-day follow-up were monitored. Argatroban pharmacokinetic parameters including dialytic clearance were evaluated during regimen C. RESULTS: Thirteen patients completed 38 hemodialysis sessions (1 patient withdrew consent after 2 sessions). Mean +/- SD ACTs increased from 131 +/- 14 seconds at baseline to 153 +/- 24, 200 +/- 30, and 197 +/- 33 seconds, respectively, after 60 minutes of hemodialysis using regimens A, B, and C. Across regimens, mean Kt/Vs (1.5-1.6) and URRs (70%-73%) were comparable. No dialyzer was changed; 1 session was shortened 15 minutes because of circuit clot formation. Systemic argatroban clearance increased approximately 20% during hemodialysis, without clinically significantly affecting ACTs. Upon argatroban discontinuation, ACTs and plasma argatroban decreased concurrently (elimination half-life, 35 +/- 6 min). No thrombosis, bleeding, serious adverse events, or clinically significant changes in vital signs or routine laboratory measures occurred. CONCLUSION: Argatroban, administered by each treatment regimen, provides safe, adequate anticoagulation to enable successful hemodialysis in ESRD patients. Argatroban dialytic clearance by high-flux membranes is clinically insignificant.