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86 Recurrent AA-Amyloidoisis in Kidney Transplant Allograft
NKF 2011 Spring Clinical Meetings Abstracts
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87 CELL LINES AND TRANSGENIC MICE MODELS TO STUDY POLYCYSTIC KIDNEY DISEASE Wassim El-Jouni and Jing Zhou Harvard Center for Polycystic Kidney Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Polycystic kidney disease (PKD) is a group of genetically inherited disorders that leads to renal failure. The major form of the disease results from mutations in PKD1 encoding polycystin-1 (PC1) and PKD2 encoding polycystin-2 (PC2) genes. The molecular basis of cyst formation remains under intensive investigation but the disease is associated in part with abnormalities in cell division in the epithelial cells forming the kidney tubules. Abnormal primary cilia formation and function are associated with the pathogenesis of polycystic kidney disease. PC2, localized to the cilia of tubular epithelial cells, interacts with PC1 and mediates calcium signaling that can be induced by shear stress. To understand PC2 mediated calcium signaling, we went on to develop cell and animal models with a PC2 channel mutation. Due to the embryonic lethality of germline knockout of Pkd2, we have developed a Pkd2 floxed allele in which the lox-P sites flank part of the pore region of PC2. Two transgenic mice models were generated using this allele, the Col2-cre.Pkd2f/f and the Ubc-cre.SV40.Pkd2f/f mice. Using the mouse line Ubc-cre.Sv40.Pkd2f/f mice, we have derived a tamoxifen inducible Pkd2 floxed kidney cell line from 5 weeks old mice. These cells have been sorted using a collecting tubule epithelial marker lectin Dolichos biflorus agglutinin (DBA). DBA positive tubular epithelial cells were purified and expanded to establish tamoxifen inducible Pkd2 floxed collecting tubule line. Knockout of Pkd2 after tamoxifen induction is evident by western blot. I isolated 36 human primary cell cultures from individual cyst lining epithelium from human cystic kidneys removed by nephrocotmies. I characterized and immortalized several of those cultures to generate ADPKD human cell lines. These cell lines and kidney sections from the mice models are in use to understand the mechanism leading to centrosome amplification and aberrant cell division observed in PC2 defective cell lines and mice models. Also the cell lines are being used to understand the effect of shear stress induced calcium rise on the observed centrosomal and cell division defects.
86 RECURRENT AA-AMYLOIDOISIS IN KIDNEY TRANSPLANT ALLOGRAFT Mireille El Ters , Sanjeev Sethi , Srividya Voutukuru , Qi Qian Mayo Clinic, Rochester, MN Recurrent AA-amyloidosis in kidney allograft is rare, with only a few case series described in patients with familial Mediterranean fever, ankylosing spondylitis and rheumatoid arthritis. To our knowledge, recurrent AA-amyloid in kidney allograft related to Crohn’s disease has not been previously described, especially in the setting where the underlying inflammatory condition is under control. A 59-year-old man who underwent a living-donor kidney transplant 17 years ago for renal failure due to AA-amyloid nephropathy in the setting of longstanding Crohn’s disease. His Crohn’s disease was quiescent prior to and post kidney transplant. His allograft function was stable until a month prior to the presentation when he developed worsening proteinuria and kidney dysfunction. Allograft biopsy revealed Congo red stains and reddish-brown material in the glomeruli, interstitium, and vessels typical for AA-amyloidosis. Because repeat esophageal gastroscopy and colonoscopy showed no histological evidence of Crohn’s flare, specific treatments for Crohn’s disease were not initiated. At 3-months follow-up, his serum creatinine was at 3.6 mg/dL. He was not on renal replacement therapy. As exemplified in this case, despite clinical and histological control of underlying inflammatory condition (Crohn’s disease in this case), AA-amyloidosis can still recur in the kidney allograft. The recurrence should be suspected when patients exhibit worsening proteinuria and kidney dysfunction. Allograft biopsy is critical in establishing the diagnosis. Moreover, conventional therapy for AA-amyloidosis with controlling underlying inflammation may not always be sufficient. Therapy directly targeting amyloid fibril formation, such as eprodisate, represents a promising future treatment addition for patients with AAamyloidosis.
A38
TUBULAR INJURY IS COMMON WITH COLLAPSING FSGS, AND OTHER LESSONS LEARNED FROM A CASE OF ABRUPT AKI MISDIAGNOSED AS ATN. Amr El Toukhy, Charbel Salem, James Simon; Cleveland Clinic Foundation, Cleveland, Ohio Collapsing FSGS classically presents with renal failure and nephrotic range proteinuria. It is most often associated with HIV. The abrupt onset of AKI can be mistakenly attributed to acute tubular necrosis (ATN) if proteinuria is not identified. We present a 21-year-old African American female with systemic Lupus erythematosis (SLE) who presented with septic shock and pelvic inflammatory disease (PID). Serum creatinine (Cr) increased from 0.7 mg/dl to 10 mg/dl in 3 days requiring dialysis for 3 weeks. Urinalysis was negative on presentation but within 4 days showed large blood and protein. Protein/creatinine ratio was 3.6gm/gm. Renal ultrasound showed echogenic, large 13 cm kidneys. The low complements and lupus history prompted a renal biopsy which was interpreted as ATN. Prednisone was started and tapered down over two weeks for extra-renal lupus symptoms. Cr dropped to 1.7 mg/dl. She was readmitted after 1 month with gastritis and recurrent AKI (Cr 3.6 mg/dl). Repeat kidney biopsy showed collapsing FSGS with significant tubular injury. The first biopsy was re-read and collapsing FSGS was identified. HIV testing was negative. The patient was restarted on prednisone and Cr fell to 2.2 mg/dl. This case was remarkable in that the onset of disease was sudden, mimicking ATN clinically. The lack of proteinuria on presentation led to the biopsy changes of collapsing FSGS to be disregarded. ATN changes are a hallmark of collapsing FSGS that can help differentiate it from classic FSGS. SLE and PID can cause collapsing FSGS. Prednisone seems to have induced partial remission. It is unclear whether SLE patients with collapsing FSGS are more responsive to prednisone compared to the poor response to steroids seen in other cases of collapsing FSGS.
88 EFFECT OF MEDICARE PART D COVERAGE GAP ON PHOSPHATE BINDER UTILIZATION IN U.S. DIALYSIS PATIENTS IN 2007 Holly Epperly, Wendy St. Peter University of Minnesota/USRDS, Minneapolis, Minnesota Management of hyperphosphatemia with phosphate binders in dialysis patients (pts) has been associated with lower mortality risk. The objectives were 1) to describe the effect of the Medicare Part D coverage gap on phosphate binder utilization, and 2) examine the effect of low-income subsidy (LIS) status on utilization. Data from the United States Renal Data System were used to assess the usage of selected phosphate binders in 2007. All patients alive on December 31, 2007, with Part D coverage during all of 2007, and having entered the Part D coverage gap (CG) prior to October 1, 2007 and stayed in CG through end of 2007 were included (n = 22,693). Estimates for entry into the coverage gap were based on gross drug costs (Medicare plus patient) of >$2,400. 86% of pts included in the cohort had at least one claim for a phosphate binder and 52%, 45%, and 13% had at least one claim for sevelamer, calcium acetate, and lanthanum, respectively. Of all pts receiving sevelamer, 69% had claims in the initial coverage (IC) phase and CG and 19% had a claim during the IC but not the CG; non-LIS patients were less likely to have claims during the CG (71%) versus LIS patients (85%). About 67% of pts receiving calcium acetate had claims in both phases and 79% of both LIS and non-LIS patients had claims during CG. Only 44% of pts using lanthanum had claims in both coverage phases and 67% of LIS pts and 56% of non-LIS pts had claims during the CG. In conclusion, Part D data from 2007 indicate that a lower percentage of dialysis patients entering the CG have claims for high cost phosphate binders (sevelamer and lanthanum) and non-LIS pts are less likely to have claims for high cost binders in the CG compared to LIS pts.
Am J Kidney Dis. 2011;57(4):A1-A108
85
87 CELL LINES AND TRANSGENIC MICE MODELS TO STUDY POLYCYSTIC KIDNEY DISEASE Wassim El-Jouni and Jing Zhou Harvard Center for Polycystic Kidney Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Polycystic kidney disease (PKD) is a group of genetically inherited disorders that leads to renal failure. The major form of the disease results from mutations in PKD1 encoding polycystin-1 (PC1) and PKD2 encoding polycystin-2 (PC2) genes. The molecular basis of cyst formation remains under intensive investigation but the disease is associated in part with abnormalities in cell division in the epithelial cells forming the kidney tubules. Abnormal primary cilia formation and function are associated with the pathogenesis of polycystic kidney disease. PC2, localized to the cilia of tubular epithelial cells, interacts with PC1 and mediates calcium signaling that can be induced by shear stress. To understand PC2 mediated calcium signaling, we went on to develop cell and animal models with a PC2 channel mutation. Due to the embryonic lethality of germline knockout of Pkd2, we have developed a Pkd2 floxed allele in which the lox-P sites flank part of the pore region of PC2. Two transgenic mice models were generated using this allele, the Col2-cre.Pkd2f/f and the Ubc-cre.SV40.Pkd2f/f mice. Using the mouse line Ubc-cre.Sv40.Pkd2f/f mice, we have derived a tamoxifen inducible Pkd2 floxed kidney cell line from 5 weeks old mice. These cells have been sorted using a collecting tubule epithelial marker lectin Dolichos biflorus agglutinin (DBA). DBA positive tubular epithelial cells were purified and expanded to establish tamoxifen inducible Pkd2 floxed collecting tubule line. Knockout of Pkd2 after tamoxifen induction is evident by western blot. I isolated 36 human primary cell cultures from individual cyst lining epithelium from human cystic kidneys removed by nephrocotmies. I characterized and immortalized several of those cultures to generate ADPKD human cell lines. These cell lines and kidney sections from the mice models are in use to understand the mechanism leading to centrosome amplification and aberrant cell division observed in PC2 defective cell lines and mice models. Also the cell lines are being used to understand the effect of shear stress induced calcium rise on the observed centrosomal and cell division defects.
86 RECURRENT AA-AMYLOIDOISIS IN KIDNEY TRANSPLANT ALLOGRAFT Mireille El Ters , Sanjeev Sethi , Srividya Voutukuru , Qi Qian Mayo Clinic, Rochester, MN Recurrent AA-amyloidosis in kidney allograft is rare, with only a few case series described in patients with familial Mediterranean fever, ankylosing spondylitis and rheumatoid arthritis. To our knowledge, recurrent AA-amyloid in kidney allograft related to Crohn’s disease has not been previously described, especially in the setting where the underlying inflammatory condition is under control. A 59-year-old man who underwent a living-donor kidney transplant 17 years ago for renal failure due to AA-amyloid nephropathy in the setting of longstanding Crohn’s disease. His Crohn’s disease was quiescent prior to and post kidney transplant. His allograft function was stable until a month prior to the presentation when he developed worsening proteinuria and kidney dysfunction. Allograft biopsy revealed Congo red stains and reddish-brown material in the glomeruli, interstitium, and vessels typical for AA-amyloidosis. Because repeat esophageal gastroscopy and colonoscopy showed no histological evidence of Crohn’s flare, specific treatments for Crohn’s disease were not initiated. At 3-months follow-up, his serum creatinine was at 3.6 mg/dL. He was not on renal replacement therapy. As exemplified in this case, despite clinical and histological control of underlying inflammatory condition (Crohn’s disease in this case), AA-amyloidosis can still recur in the kidney allograft. The recurrence should be suspected when patients exhibit worsening proteinuria and kidney dysfunction. Allograft biopsy is critical in establishing the diagnosis. Moreover, conventional therapy for AA-amyloidosis with controlling underlying inflammation may not always be sufficient. Therapy directly targeting amyloid fibril formation, such as eprodisate, represents a promising future treatment addition for patients with AAamyloidosis.
A38
TUBULAR INJURY IS COMMON WITH COLLAPSING FSGS, AND OTHER LESSONS LEARNED FROM A CASE OF ABRUPT AKI MISDIAGNOSED AS ATN. Amr El Toukhy, Charbel Salem, James Simon; Cleveland Clinic Foundation, Cleveland, Ohio Collapsing FSGS classically presents with renal failure and nephrotic range proteinuria. It is most often associated with HIV. The abrupt onset of AKI can be mistakenly attributed to acute tubular necrosis (ATN) if proteinuria is not identified. We present a 21-year-old African American female with systemic Lupus erythematosis (SLE) who presented with septic shock and pelvic inflammatory disease (PID). Serum creatinine (Cr) increased from 0.7 mg/dl to 10 mg/dl in 3 days requiring dialysis for 3 weeks. Urinalysis was negative on presentation but within 4 days showed large blood and protein. Protein/creatinine ratio was 3.6gm/gm. Renal ultrasound showed echogenic, large 13 cm kidneys. The low complements and lupus history prompted a renal biopsy which was interpreted as ATN. Prednisone was started and tapered down over two weeks for extra-renal lupus symptoms. Cr dropped to 1.7 mg/dl. She was readmitted after 1 month with gastritis and recurrent AKI (Cr 3.6 mg/dl). Repeat kidney biopsy showed collapsing FSGS with significant tubular injury. The first biopsy was re-read and collapsing FSGS was identified. HIV testing was negative. The patient was restarted on prednisone and Cr fell to 2.2 mg/dl. This case was remarkable in that the onset of disease was sudden, mimicking ATN clinically. The lack of proteinuria on presentation led to the biopsy changes of collapsing FSGS to be disregarded. ATN changes are a hallmark of collapsing FSGS that can help differentiate it from classic FSGS. SLE and PID can cause collapsing FSGS. Prednisone seems to have induced partial remission. It is unclear whether SLE patients with collapsing FSGS are more responsive to prednisone compared to the poor response to steroids seen in other cases of collapsing FSGS.
88 EFFECT OF MEDICARE PART D COVERAGE GAP ON PHOSPHATE BINDER UTILIZATION IN U.S. DIALYSIS PATIENTS IN 2007 Holly Epperly, Wendy St. Peter University of Minnesota/USRDS, Minneapolis, Minnesota Management of hyperphosphatemia with phosphate binders in dialysis patients (pts) has been associated with lower mortality risk. The objectives were 1) to describe the effect of the Medicare Part D coverage gap on phosphate binder utilization, and 2) examine the effect of low-income subsidy (LIS) status on utilization. Data from the United States Renal Data System were used to assess the usage of selected phosphate binders in 2007. All patients alive on December 31, 2007, with Part D coverage during all of 2007, and having entered the Part D coverage gap (CG) prior to October 1, 2007 and stayed in CG through end of 2007 were included (n = 22,693). Estimates for entry into the coverage gap were based on gross drug costs (Medicare plus patient) of >$2,400. 86% of pts included in the cohort had at least one claim for a phosphate binder and 52%, 45%, and 13% had at least one claim for sevelamer, calcium acetate, and lanthanum, respectively. Of all pts receiving sevelamer, 69% had claims in the initial coverage (IC) phase and CG and 19% had a claim during the IC but not the CG; non-LIS patients were less likely to have claims during the CG (71%) versus LIS patients (85%). About 67% of pts receiving calcium acetate had claims in both phases and 79% of both LIS and non-LIS patients had claims during CG. Only 44% of pts using lanthanum had claims in both coverage phases and 67% of LIS pts and 56% of non-LIS pts had claims during the CG. In conclusion, Part D data from 2007 indicate that a lower percentage of dialysis patients entering the CG have claims for high cost phosphate binders (sevelamer and lanthanum) and non-LIS pts are less likely to have claims for high cost binders in the CG compared to LIS pts.
Am J Kidney Dis. 2011;57(4):A1-A108