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NKF 2007 Spring Clinical Meetings Abstracts
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THERE IS NO FREE LUNCH: THE NEGATIVE CONSEQUENCES OF TAKING CYCLOSPORINE WITH FOOD Rodolfo Batarse, Linda Awdishu, Alex Dominguez, James Lane, Robert Steiner. UCSD Medical Center, San Diego, CA.USA. To prolong kidney allograft survival, transplant patients require adequate daily exposure to calcineurin inhibitors (CNI), as measured by area under the concentration time curve (AUC). Cyclosporine (CSA) absorption and overall drug exposure is reduced when taken with food. Pharmacokinetic (PK) modeling was used to examine the AUC effect of nonfasting CSA administration with a strict 12hour dosing interval versus fasting drug administration with a relaxed dosing interval. Changes in AUC with mixed dosing (AM dose fasting, and PM dose nonfasting) was also examined. Standard CNI PK parameters were employed. A population PK model on a data set of 500 patients was determined using nonlinear mixed effects modeling (NONMEM V.1) and Monte Carlo simulation. SAS9.2 was used to compare the AUCs. Model assumptions include a 30%reduction in bioavailability for the nonfasting state and CSA doses of 3.5mg/kg q12h for 7days. The CSA AUC0-24 for the fasting and nonfasting states were 3635mcg*hr/L, 2445mcg*hr/L, respectively. The CSA AUC0-24 with mixed dosing was 3090mcg*hr/L, with the AM C2 being 50% higher in the fasting state. The additional drug needed to overcome the decreased CNI absorption with food was 77316mg/yr, about $3402/year extra drug costs. In some patients, missing 20 fasting doses of CSA will give about the same AUC as perfect compliance with nonfasting CNI. In summary, always taking CNIs with food resulted in markedly lower overall exposure, a lower monthly AUC, equivalent to missing altogether 20 CNI doses/month. Published data indicate that CNI trough levels would not indicate the magnitude of underexposure, and reliable C2 would be impossible sans standardizing for food effects. Reinforcing adherence to fasting CNI dosing instead of a rigid 12hour dosing schedule will reduce the variability in CNI absorption, increase drug exposure, decrease pill burden and cost, and improve compliance. With once-a-day CNI dosing regimens, fasting dosing schedules will become even more important.
PRIMARY AMYLOIDOSIS IN A RENAL TRANSPLANT RECIPIENT: A CASE REPORT Ruchika Batwara, Sharath Subramanian, Parameswaran Hari, Syed Hussain. Medical College of Wisconsin, Milwaukee WI. Primary amyloidosis is a rare form of plasma cell dyscrasia characterized by tissue deposition of monoclonal immunoglobulin light chains. We describe a patient with primary amyloidosis diagnosed eight years after renal transplantation, raising the possibility that it may be a consequence of immunosuppression. A 74-year-old Caucasian man presented with painless jaundice and loose, non-bloody stools for two months. He underwent deceased-donor renal transplantation eight years ago for diabetic nephropathy and his immunosuppression regimen included cyclosporine and prednisone. Initial laboratory exam revealed elevated liver function tests (LFTs); AST 147 U/liter, ALT 48 U/liter, total bilirubin 6.2 mg/dl and alkaline phosphatase 1941 IU/liter. He had mild proteinuria (urine protein 819 mg/24 hours); serum creatinine was stable at a baseline of 1 mg/dl. Review of prior records revealed isolated elevation in alkaline phosphatase to 400 IU/liter with otherwise normal LFTs a year ago. Abdominal CAT scan at that time as well as during this admission revealed diffusely enlarged but otherwise unremarkable liver and normal pancreatico-biliary system. Enteroscopic retrograde cholangiopancreatiography (ERCP) did not show any evidence of pancreatic cancer and serology for viral hepatitis was negative. Laboratory evaluation of his stool revealed marked steatorrhoea. The LFTs continued to worsen with serum bilirubin rising to 24.2 mg/dl. At this point, biopsies of his liver as well as stomach and intestine were performed. All specimens stained positive with Congo-Red stain, consistent with a diagnosis of amyloidosis. Urine protein electrophoresis showed a faint kappa monoclonal peak and bone marrow biopsy showed increased plasma cells (7%) with kappa light chain restriction, consistent with the patient’s amyloid. Chemotherapy was started and his immunosuppression was changed to mycophenolate moefetil and prednisone. He has completed three cycles of melphalan and dexamethasone with an excellent response so far, although the long term prognosis remains grim. To the best of our knowledge, this is the first reported case of post transplant primary amyloidosis. In transplant patients presenting with unexplained GI symptoms, amyloidosis should be considered in the differential and appropriate work up should be undertaken.
A29
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RECURRENCE OF SCLERODERMA RENAL CRISIS IN A KIDNEY TRANSPLANT PATIENT WITH ANTECEDENT CORTICOSTEROID USE. Ruchika Batwara, Nidhi Aggarwal, Brahm Vasudev. Medical College of Wisconsin, Milwaukee, WI. We report an unusual case of recurrent scleroderma renal crisis (SRC) in a renal allograft recipient, possibly due to initiation of highdose prednisone. A 56-year-old woman with history of end-stage renal disease due to SRC presented with dyspnea, hypotension and new onset renal dysfunction. She underwent zero mismatch pediatric en-bloc renal transplantation two years ago. She was diagnosed with post-transplant lymphoproliferative disorder (PTLD) a month ago. At that time her immunosuppression was changed from tacrolimus and mycophenolate mofetil to tacrolimus and high-dose prednisone. On admission, she was hypotensive and required vasopressors. Physical examination revealed jugular venous distension and pedal edema. Laboratory evaluation was significant for a BUN of 51 mg/dL and creatinine of 2.4 mg/dL (baseline 1.1 mg/dL). Echocardiogram and right heart catheterization revealed new onset severe pulmonary hypertension. She was managed with diuretics and vasopressin for heart failure, and intravenous epoprostenol and sildenafil for pulmonary hypertension. Despite improvement in cardiac output with this regimen, her renal function continued to worsen, necessitating continuous venovenous hemofiltration (CVVH). A renal transplant biopsy was performed which demonstrated narrowed arteriolar lumens, fibrinoid necrosis and microthrombi, consistent with SRC. CVVH was changed to slow intermittent hemodialysis and angiotensin-converting enzyme (ACE) inhibitor therapy intiated. She received rituximab for PTLD, and her prednisone was tapered to 2.5 mg per day. Over the next month, her creatinine improved to 1.4 mg/dL and dialysis was discontinued. The reported rate of recurrence of SRC in renal allografts is about 25%. Use of prednisone >15 mg/day has been reported to precipitate renal crisis in patients with scleroderma. Steroids inhibit prostacyclin production and increase ACE activity, both of which can augment the pre-existing reno-vascular injury in this disease. Therefore, high-dose corticosteroids should be used with caution in renal transplant recipients with diffuse scleroderma
RENAL INFARCTION DUE TO PARADOXICAL THROMBOEMBOLISM: AN UNUSUAL CAUSE OF ACUTE KIDNEY INJURY Ruchika Batwara, Jeffrey Wesson. Medical College of Wisconsin, Milwaukee, WI We report an unusual case of acute renal insufficiency due to bilateral kidney infarction caused by paradoxical thromboembolism. A 38-year-old Caucasian man presented to a local emergency room with sudden onset of right sided flank pain. Initial lab studies were remarkable for elevated lactate dehydrogenase (LDH) 1964 units/L and serum creatinine (Cr) 1.6 mg/dl (baseline Cr = 1 mg/dl). Abdominal CT scan with contrast revealed absence of excretory phase of the contrast from the right kidney. With renal infarction as the probable diagnosis, he was started on heparin drip and transferred to our facility for further management. He arrived at our hospital about 36 hours after the onset of symptoms. A radioactive hippuran scan showed absence of uptake in the right kidney and a wedge defect in the upper pole of the left kidney. An arteriogram demonstrated filling defects in the distal right renal artery as well as branches of the left renal artery, confirming the mechanism of renal injury as arterial obstruction. There was no evidence of atherosclerotic disease in the aorta but Doppler ultrasound revealed a large thrombus in the right superficial femoral vein. A subsequent transesophageal echocardiogram with bubble study demonstrated a patent foramen ovale (PFO). Thus, the final diagnosis was determined to be renal infarction secondary to paradoxical embolism from the right lower extremity deep venous thrombosis in the setting of an intracardiac shunt. Due to delay in diagnosis past the window of opportunity, therapy directed at renal revascularization was unwarranted. Initial management was supportive and the patient was started on long term anticoagulation. Renal infarction is an uncommon cause of acute kidney injury and that caused by paradoxical embolism is exceedingly rare. The paucity of reported cases in this regard reflect the under diagnosis of renal infarction largely due to a non-specific clinical presentation and low index of suspicion. The case serves as a useful remainder of the importance of a thorough clinical evaluation and judicious use of laboratory and imaging tests to arrive at the diagnosis expeditiously.
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THERE IS NO FREE LUNCH: THE NEGATIVE CONSEQUENCES OF TAKING CYCLOSPORINE WITH FOOD Rodolfo Batarse, Linda Awdishu, Alex Dominguez, James Lane, Robert Steiner. UCSD Medical Center, San Diego, CA.USA. To prolong kidney allograft survival, transplant patients require adequate daily exposure to calcineurin inhibitors (CNI), as measured by area under the concentration time curve (AUC). Cyclosporine (CSA) absorption and overall drug exposure is reduced when taken with food. Pharmacokinetic (PK) modeling was used to examine the AUC effect of nonfasting CSA administration with a strict 12hour dosing interval versus fasting drug administration with a relaxed dosing interval. Changes in AUC with mixed dosing (AM dose fasting, and PM dose nonfasting) was also examined. Standard CNI PK parameters were employed. A population PK model on a data set of 500 patients was determined using nonlinear mixed effects modeling (NONMEM V.1) and Monte Carlo simulation. SAS9.2 was used to compare the AUCs. Model assumptions include a 30%reduction in bioavailability for the nonfasting state and CSA doses of 3.5mg/kg q12h for 7days. The CSA AUC0-24 for the fasting and nonfasting states were 3635mcg*hr/L, 2445mcg*hr/L, respectively. The CSA AUC0-24 with mixed dosing was 3090mcg*hr/L, with the AM C2 being 50% higher in the fasting state. The additional drug needed to overcome the decreased CNI absorption with food was 77316mg/yr, about $3402/year extra drug costs. In some patients, missing 20 fasting doses of CSA will give about the same AUC as perfect compliance with nonfasting CNI. In summary, always taking CNIs with food resulted in markedly lower overall exposure, a lower monthly AUC, equivalent to missing altogether 20 CNI doses/month. Published data indicate that CNI trough levels would not indicate the magnitude of underexposure, and reliable C2 would be impossible sans standardizing for food effects. Reinforcing adherence to fasting CNI dosing instead of a rigid 12hour dosing schedule will reduce the variability in CNI absorption, increase drug exposure, decrease pill burden and cost, and improve compliance. With once-a-day CNI dosing regimens, fasting dosing schedules will become even more important.
PRIMARY AMYLOIDOSIS IN A RENAL TRANSPLANT RECIPIENT: A CASE REPORT Ruchika Batwara, Sharath Subramanian, Parameswaran Hari, Syed Hussain. Medical College of Wisconsin, Milwaukee WI. Primary amyloidosis is a rare form of plasma cell dyscrasia characterized by tissue deposition of monoclonal immunoglobulin light chains. We describe a patient with primary amyloidosis diagnosed eight years after renal transplantation, raising the possibility that it may be a consequence of immunosuppression. A 74-year-old Caucasian man presented with painless jaundice and loose, non-bloody stools for two months. He underwent deceased-donor renal transplantation eight years ago for diabetic nephropathy and his immunosuppression regimen included cyclosporine and prednisone. Initial laboratory exam revealed elevated liver function tests (LFTs); AST 147 U/liter, ALT 48 U/liter, total bilirubin 6.2 mg/dl and alkaline phosphatase 1941 IU/liter. He had mild proteinuria (urine protein 819 mg/24 hours); serum creatinine was stable at a baseline of 1 mg/dl. Review of prior records revealed isolated elevation in alkaline phosphatase to 400 IU/liter with otherwise normal LFTs a year ago. Abdominal CAT scan at that time as well as during this admission revealed diffusely enlarged but otherwise unremarkable liver and normal pancreatico-biliary system. Enteroscopic retrograde cholangiopancreatiography (ERCP) did not show any evidence of pancreatic cancer and serology for viral hepatitis was negative. Laboratory evaluation of his stool revealed marked steatorrhoea. The LFTs continued to worsen with serum bilirubin rising to 24.2 mg/dl. At this point, biopsies of his liver as well as stomach and intestine were performed. All specimens stained positive with Congo-Red stain, consistent with a diagnosis of amyloidosis. Urine protein electrophoresis showed a faint kappa monoclonal peak and bone marrow biopsy showed increased plasma cells (7%) with kappa light chain restriction, consistent with the patient’s amyloid. Chemotherapy was started and his immunosuppression was changed to mycophenolate moefetil and prednisone. He has completed three cycles of melphalan and dexamethasone with an excellent response so far, although the long term prognosis remains grim. To the best of our knowledge, this is the first reported case of post transplant primary amyloidosis. In transplant patients presenting with unexplained GI symptoms, amyloidosis should be considered in the differential and appropriate work up should be undertaken.
A29
19
20
RECURRENCE OF SCLERODERMA RENAL CRISIS IN A KIDNEY TRANSPLANT PATIENT WITH ANTECEDENT CORTICOSTEROID USE. Ruchika Batwara, Nidhi Aggarwal, Brahm Vasudev. Medical College of Wisconsin, Milwaukee, WI. We report an unusual case of recurrent scleroderma renal crisis (SRC) in a renal allograft recipient, possibly due to initiation of highdose prednisone. A 56-year-old woman with history of end-stage renal disease due to SRC presented with dyspnea, hypotension and new onset renal dysfunction. She underwent zero mismatch pediatric en-bloc renal transplantation two years ago. She was diagnosed with post-transplant lymphoproliferative disorder (PTLD) a month ago. At that time her immunosuppression was changed from tacrolimus and mycophenolate mofetil to tacrolimus and high-dose prednisone. On admission, she was hypotensive and required vasopressors. Physical examination revealed jugular venous distension and pedal edema. Laboratory evaluation was significant for a BUN of 51 mg/dL and creatinine of 2.4 mg/dL (baseline 1.1 mg/dL). Echocardiogram and right heart catheterization revealed new onset severe pulmonary hypertension. She was managed with diuretics and vasopressin for heart failure, and intravenous epoprostenol and sildenafil for pulmonary hypertension. Despite improvement in cardiac output with this regimen, her renal function continued to worsen, necessitating continuous venovenous hemofiltration (CVVH). A renal transplant biopsy was performed which demonstrated narrowed arteriolar lumens, fibrinoid necrosis and microthrombi, consistent with SRC. CVVH was changed to slow intermittent hemodialysis and angiotensin-converting enzyme (ACE) inhibitor therapy intiated. She received rituximab for PTLD, and her prednisone was tapered to 2.5 mg per day. Over the next month, her creatinine improved to 1.4 mg/dL and dialysis was discontinued. The reported rate of recurrence of SRC in renal allografts is about 25%. Use of prednisone >15 mg/day has been reported to precipitate renal crisis in patients with scleroderma. Steroids inhibit prostacyclin production and increase ACE activity, both of which can augment the pre-existing reno-vascular injury in this disease. Therefore, high-dose corticosteroids should be used with caution in renal transplant recipients with diffuse scleroderma
RENAL INFARCTION DUE TO PARADOXICAL THROMBOEMBOLISM: AN UNUSUAL CAUSE OF ACUTE KIDNEY INJURY Ruchika Batwara, Jeffrey Wesson. Medical College of Wisconsin, Milwaukee, WI We report an unusual case of acute renal insufficiency due to bilateral kidney infarction caused by paradoxical thromboembolism. A 38-year-old Caucasian man presented to a local emergency room with sudden onset of right sided flank pain. Initial lab studies were remarkable for elevated lactate dehydrogenase (LDH) 1964 units/L and serum creatinine (Cr) 1.6 mg/dl (baseline Cr = 1 mg/dl). Abdominal CT scan with contrast revealed absence of excretory phase of the contrast from the right kidney. With renal infarction as the probable diagnosis, he was started on heparin drip and transferred to our facility for further management. He arrived at our hospital about 36 hours after the onset of symptoms. A radioactive hippuran scan showed absence of uptake in the right kidney and a wedge defect in the upper pole of the left kidney. An arteriogram demonstrated filling defects in the distal right renal artery as well as branches of the left renal artery, confirming the mechanism of renal injury as arterial obstruction. There was no evidence of atherosclerotic disease in the aorta but Doppler ultrasound revealed a large thrombus in the right superficial femoral vein. A subsequent transesophageal echocardiogram with bubble study demonstrated a patent foramen ovale (PFO). Thus, the final diagnosis was determined to be renal infarction secondary to paradoxical embolism from the right lower extremity deep venous thrombosis in the setting of an intracardiac shunt. Due to delay in diagnosis past the window of opportunity, therapy directed at renal revascularization was unwarranted. Initial management was supportive and the patient was started on long term anticoagulation. Renal infarction is an uncommon cause of acute kidney injury and that caused by paradoxical embolism is exceedingly rare. The paucity of reported cases in this regard reflect the under diagnosis of renal infarction largely due to a non-specific clinical presentation and low index of suspicion. The case serves as a useful remainder of the importance of a thorough clinical evaluation and judicious use of laboratory and imaging tests to arrive at the diagnosis expeditiously.