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315: Polycystin-1 Interacts With ARF4 and Rab Gtpases to Traffic to Renal Primary Cilia
A110
NKF 2010 Spring Clinical Meetings Abstracts
313
315
FIRST-TRIMESTER PREGNANCY LOSS ASSOCIATED WITH PLASMA EXCHANGE THERAPY Steven Wagner, Iasmina Craici, Carl Rose, Joseph Grande, Vesna Garovic Mayo Clinic, Rochester, MN, USA A 19 year old G2P1 female with a 6 year history of systemic lupus presented to an outpatient clinic for progressive dyspnea and hemoptysis. Six months previously, a renal biopsy confirmed lupus nephritis; she was currently on mycophenolate and prednisone. A screening pregnancy test was positive, and ultrasound confirmed a fiveweek intrauterine gestation. Mycophenolate was discontinued, and her predisone dose was increased. She was treated with antibiotic therapy for suspected bronchitis for three weeks with minimal improvement, and consequently was admitted for piperacillin therapy. Chest X-ray revealed bilateral infiltrates, and she was transferred to our institution at 8 weeks gestation for further evaluation. On arrival she was noted to be hypoxemic, with a hemoglobin of 6.8 g/dL. Methylprednisolone was started, and bronchoscopy revealed extensive intra-alveolar hemorrhage. Blood and urine cultures were negative, and echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 50 mmHg. The patient developed renal failure, and started a six-day course of plasma exchange (PLEX) therapy with pulse-dose methylprednisolone. Over the next four days, serial β-hCG and progesterone levels declined from 48,152 mIU/mL and 10 ng/mL to 12,686 mIU/mL and 5 ng/mL respectively, at which time she underwent a D&C for an incomplete abortion. Her pulmonary and renal function recovered; she was discharged on mycophenolate and prednisone. This case illustrates a potential risk of PLEX therapy during the first trimester. Serial β-hCG and progesterone levels successively declined during the course of PLEX treatment, suggesting iatrogenic elimination of hormones critical to maintenance of early pregnancy. Although PLEX is generally considered to be safe during pregnancy, the majority of cases have been reported in the second and third trimesters. While her pregnancy loss may have been secondary to her underlying disease process, we suggest that physicians exercise caution when using PLEX in the first trimester.
314
316
IMPACT OF IMPAIRED eGFR ON HEMOGLOBIN A1C AND AVERAGE GLUCOSE CORRELATION IN DIABETES MELLITUS Salman Waheed, Mark E. Williams, Renal Unit, Joslin Diabetes Center, Boston, MA, USA The optimal target for glycemic control in diabetic Chronic Kidney Disease (CKD) has not been established, partly because hemoglobin A1c (A1c) as the standard marker has been called into question, due to physiologic and pathologic factors related to CKD. We evaluated the correlation between A1c and average glucose levels in 1600 CKD patients at a large diabetes referral center. Average A1c was positively correlated with average glucose levels with a Pearson correlation coefficient of 0.52 (p<0.0001). Average eGFR was negatively correlated with average serum creatinine levels, as expected (-0.76, p<0.0001). We then categorized eGFR according to CKD classifications into groups of 1-15, 16-30, and 31-60 cc/min/1.73m2, and derived correlations between average A1c and average glucose levels in each category. eGFR (1 to 60) (cc/min/1.73m2) 1 to 15 16 to 30 31 to 60
POLYCYSTIN-1 INTERACTS WITH ARF4 AND RAB GTPASES TO TRAFFIC TO RENAL PRIMARY CILIA Heather Ward1, Dusanka Deretic2, Angela Wandinger-Ness1. Departments of 1Pathology and 2Surgery, University of New Mexico, Albuquerque, NM. USA. The primary cilium plays a central role in kidney development and homeostasis. This specialized organelle sits on the apical surface of renal epithelial cells where it senses the tubular environment and initiates intracellular signaling cascades. Mutant polycystin-1 (PC1) or polycystin-2 (PC2) proteins exhibit defects in cilial localization and function, which are central to Autosomal Dominant Polycystic Kidney Disease (ADPKD). However, the molecular mechanisms that enable targeting of the polycystins to cilia have not been described. The purpose of this study was to identify the chaperones involved in membrane transport of PC1 to cilia. We used immunofluorescence and electron microscopy in combination with cell-based and in-vitro biochemical assays to elucidate the ciliary trafficking mechanism of PC1. We show that evolutionarily conserved VxPx motifs within the ciliary targeting domains of PC1 and PC2 form a binding site that is specifically recognized in the Golgi by active Arf4, a GTPase which functions in vesicle coat recruitment. The Arf4-polycystin-1 complex in turn binds a regulatory GTPase activating protein (ASAP1) with membrane curvature inducing activity. PC1 is bound to three further GTPases (Rab6, Rab11 and Rab8) with demonstrated roles in Golgi exocytosis and ciliary delivery. Truncation of the conserved VxPx motif decreases interaction with Arf4, ablates the delivery of PC1 to cilia and causes Golgi retention due to disruption of the trafficking complex binding. Recently a similar complex involving rhodopsin, Arf4, Rab GTPases and effector proteins was shown to be crucial for ciliary rhodopsin trafficking in retinal cells. Thus, we provide evidence for a conserved multimeric GTPase complex and mechanism of ciliary trafficking that is shared between retinal and kidney epithelial cells. Because alterations in cellular protein localization and function contribute to renal cyst formation, we speculate that a disruption in this complex accounts for the loss of PC1 localization to cilia in ADPKD.
N=1600 54 230 1316
Pearson Coefficient (P value) 0.43 (p=0.001) 0.41 (p<0.0001) 0.55 (p<0.0001)
While the correlation remained significant in each category, the level of correlation decreased at lower eGFR. In a regression model using A1c as a dependent variable and glucose, average eGFR, and their interactions as explanatory variables, the interaction term GLU*GFR was statistically significant. The estimate of the coefficient indicated that the correlation between average A1c and glucose values increased as the level of eGFR increased. Hemoglobin A1c may be less valid as a glycemic marker in advanced CKD. Factors which weaken the correlation between A1c and glucose levels even in patients not yet on dialysis need further evaluation.
IGA-DOMINANT STAPHYLOCOCCUS INFECTIONASSOCIATED GLOMERULONEPHRITIS: TWO CASE REPORTS AND REVIEW OF THE LITTERATURE Edgard Wehbe, Sankar D Navaneethan, Charbel A. Salem, James Simon, Marc A. Pohl. Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH, USA. The mesangial deposition of IgA is rarely described with diffuse proliferative glomerulonephritis (DPGN) associated with staphylococcus aureus (SA) infection. We hereby report 2 cases and review the 44 cases reported in the literature. A 73 year old man with right pleural effusion and methicillin sensitive SA bacteremia developed acute kidney injury (AKI) with macroscopic hematuria and nephrotic range proteinuria. Complements were normal. Kidney biopsy showed DPGN with dominant mesangial IgA deposits. He required hemodialysis despite eradication of the infection with vancomycin and short course of steroid therapy. A 69 year old woman developed AKI on top of chronic kidney disease after methicillin resistant SA (MRSA) bacteremia secondary to pacemaker lead infection. Urine studies showed RBC casts and nephrotic range proteinuria. Complements were normal. Kidney biopsy showed an IgA-dominant DPGN. Renal failure improved with eradication of the infection with oxacillin. Literature review of 44 clinically similar cases shows that these patients are elderly (mean age 65) with nephrotic range proteinuria and normal complement present in 47% and 71% respectively. MRSA (66%) is the most common pathogen involved with latent period ranging from 1to16 weeks. Diffuse mesangial proliferation is commonly found while crescents are uncommon (18%). 2+ IgA staining is reported in 66 % of cases and IgG is absent in 32% of cases. Treatment with antibiotics yielded 60 % recovery. Renal replacement therapy was required in 26% of cases. Presence of diabetes, low serum complements, low serum creatinine, tubular atrophy and interstitial fibrosis in renal biopsy were associated with poor prognosis. In conclusion, nephrologists should consider staphylococcal associated DPGN that can mimic primary IgA nephropathy in an elderly patient with AKI, hematuria, proteinuria and mesangial IgA deposit with recent or remote history of SA infection.
NKF 2010 Spring Clinical Meetings Abstracts
313
315
FIRST-TRIMESTER PREGNANCY LOSS ASSOCIATED WITH PLASMA EXCHANGE THERAPY Steven Wagner, Iasmina Craici, Carl Rose, Joseph Grande, Vesna Garovic Mayo Clinic, Rochester, MN, USA A 19 year old G2P1 female with a 6 year history of systemic lupus presented to an outpatient clinic for progressive dyspnea and hemoptysis. Six months previously, a renal biopsy confirmed lupus nephritis; she was currently on mycophenolate and prednisone. A screening pregnancy test was positive, and ultrasound confirmed a fiveweek intrauterine gestation. Mycophenolate was discontinued, and her predisone dose was increased. She was treated with antibiotic therapy for suspected bronchitis for three weeks with minimal improvement, and consequently was admitted for piperacillin therapy. Chest X-ray revealed bilateral infiltrates, and she was transferred to our institution at 8 weeks gestation for further evaluation. On arrival she was noted to be hypoxemic, with a hemoglobin of 6.8 g/dL. Methylprednisolone was started, and bronchoscopy revealed extensive intra-alveolar hemorrhage. Blood and urine cultures were negative, and echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 50 mmHg. The patient developed renal failure, and started a six-day course of plasma exchange (PLEX) therapy with pulse-dose methylprednisolone. Over the next four days, serial β-hCG and progesterone levels declined from 48,152 mIU/mL and 10 ng/mL to 12,686 mIU/mL and 5 ng/mL respectively, at which time she underwent a D&C for an incomplete abortion. Her pulmonary and renal function recovered; she was discharged on mycophenolate and prednisone. This case illustrates a potential risk of PLEX therapy during the first trimester. Serial β-hCG and progesterone levels successively declined during the course of PLEX treatment, suggesting iatrogenic elimination of hormones critical to maintenance of early pregnancy. Although PLEX is generally considered to be safe during pregnancy, the majority of cases have been reported in the second and third trimesters. While her pregnancy loss may have been secondary to her underlying disease process, we suggest that physicians exercise caution when using PLEX in the first trimester.
314
316
IMPACT OF IMPAIRED eGFR ON HEMOGLOBIN A1C AND AVERAGE GLUCOSE CORRELATION IN DIABETES MELLITUS Salman Waheed, Mark E. Williams, Renal Unit, Joslin Diabetes Center, Boston, MA, USA The optimal target for glycemic control in diabetic Chronic Kidney Disease (CKD) has not been established, partly because hemoglobin A1c (A1c) as the standard marker has been called into question, due to physiologic and pathologic factors related to CKD. We evaluated the correlation between A1c and average glucose levels in 1600 CKD patients at a large diabetes referral center. Average A1c was positively correlated with average glucose levels with a Pearson correlation coefficient of 0.52 (p<0.0001). Average eGFR was negatively correlated with average serum creatinine levels, as expected (-0.76, p<0.0001). We then categorized eGFR according to CKD classifications into groups of 1-15, 16-30, and 31-60 cc/min/1.73m2, and derived correlations between average A1c and average glucose levels in each category. eGFR (1 to 60) (cc/min/1.73m2) 1 to 15 16 to 30 31 to 60
POLYCYSTIN-1 INTERACTS WITH ARF4 AND RAB GTPASES TO TRAFFIC TO RENAL PRIMARY CILIA Heather Ward1, Dusanka Deretic2, Angela Wandinger-Ness1. Departments of 1Pathology and 2Surgery, University of New Mexico, Albuquerque, NM. USA. The primary cilium plays a central role in kidney development and homeostasis. This specialized organelle sits on the apical surface of renal epithelial cells where it senses the tubular environment and initiates intracellular signaling cascades. Mutant polycystin-1 (PC1) or polycystin-2 (PC2) proteins exhibit defects in cilial localization and function, which are central to Autosomal Dominant Polycystic Kidney Disease (ADPKD). However, the molecular mechanisms that enable targeting of the polycystins to cilia have not been described. The purpose of this study was to identify the chaperones involved in membrane transport of PC1 to cilia. We used immunofluorescence and electron microscopy in combination with cell-based and in-vitro biochemical assays to elucidate the ciliary trafficking mechanism of PC1. We show that evolutionarily conserved VxPx motifs within the ciliary targeting domains of PC1 and PC2 form a binding site that is specifically recognized in the Golgi by active Arf4, a GTPase which functions in vesicle coat recruitment. The Arf4-polycystin-1 complex in turn binds a regulatory GTPase activating protein (ASAP1) with membrane curvature inducing activity. PC1 is bound to three further GTPases (Rab6, Rab11 and Rab8) with demonstrated roles in Golgi exocytosis and ciliary delivery. Truncation of the conserved VxPx motif decreases interaction with Arf4, ablates the delivery of PC1 to cilia and causes Golgi retention due to disruption of the trafficking complex binding. Recently a similar complex involving rhodopsin, Arf4, Rab GTPases and effector proteins was shown to be crucial for ciliary rhodopsin trafficking in retinal cells. Thus, we provide evidence for a conserved multimeric GTPase complex and mechanism of ciliary trafficking that is shared between retinal and kidney epithelial cells. Because alterations in cellular protein localization and function contribute to renal cyst formation, we speculate that a disruption in this complex accounts for the loss of PC1 localization to cilia in ADPKD.
N=1600 54 230 1316
Pearson Coefficient (P value) 0.43 (p=0.001) 0.41 (p<0.0001) 0.55 (p<0.0001)
While the correlation remained significant in each category, the level of correlation decreased at lower eGFR. In a regression model using A1c as a dependent variable and glucose, average eGFR, and their interactions as explanatory variables, the interaction term GLU*GFR was statistically significant. The estimate of the coefficient indicated that the correlation between average A1c and glucose values increased as the level of eGFR increased. Hemoglobin A1c may be less valid as a glycemic marker in advanced CKD. Factors which weaken the correlation between A1c and glucose levels even in patients not yet on dialysis need further evaluation.
IGA-DOMINANT STAPHYLOCOCCUS INFECTIONASSOCIATED GLOMERULONEPHRITIS: TWO CASE REPORTS AND REVIEW OF THE LITTERATURE Edgard Wehbe, Sankar D Navaneethan, Charbel A. Salem, James Simon, Marc A. Pohl. Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH, USA. The mesangial deposition of IgA is rarely described with diffuse proliferative glomerulonephritis (DPGN) associated with staphylococcus aureus (SA) infection. We hereby report 2 cases and review the 44 cases reported in the literature. A 73 year old man with right pleural effusion and methicillin sensitive SA bacteremia developed acute kidney injury (AKI) with macroscopic hematuria and nephrotic range proteinuria. Complements were normal. Kidney biopsy showed DPGN with dominant mesangial IgA deposits. He required hemodialysis despite eradication of the infection with vancomycin and short course of steroid therapy. A 69 year old woman developed AKI on top of chronic kidney disease after methicillin resistant SA (MRSA) bacteremia secondary to pacemaker lead infection. Urine studies showed RBC casts and nephrotic range proteinuria. Complements were normal. Kidney biopsy showed an IgA-dominant DPGN. Renal failure improved with eradication of the infection with oxacillin. Literature review of 44 clinically similar cases shows that these patients are elderly (mean age 65) with nephrotic range proteinuria and normal complement present in 47% and 71% respectively. MRSA (66%) is the most common pathogen involved with latent period ranging from 1to16 weeks. Diffuse mesangial proliferation is commonly found while crescents are uncommon (18%). 2+ IgA staining is reported in 66 % of cases and IgG is absent in 32% of cases. Treatment with antibiotics yielded 60 % recovery. Renal replacement therapy was required in 26% of cases. Presence of diabetes, low serum complements, low serum creatinine, tubular atrophy and interstitial fibrosis in renal biopsy were associated with poor prognosis. In conclusion, nephrologists should consider staphylococcal associated DPGN that can mimic primary IgA nephropathy in an elderly patient with AKI, hematuria, proteinuria and mesangial IgA deposit with recent or remote history of SA infection.