American journal of physiology. Renal physiology, Jan 9, 2015
Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and ... more Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of CCL2/CCR2 signaling on the development of renal atrophy, mice were treated with CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 weeks. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time fol...
PURPOSE Functional Blood Oxygen Level Dependent (BOLD) MRI is a powerful tool to assess renal med... more PURPOSE Functional Blood Oxygen Level Dependent (BOLD) MRI is a powerful tool to assess renal medullary function, due to its high metabolic rate, but requires its differentiation from the renal cortex, which is difficult in MR images. We have developed and sought to validate a new analysis method of whole-kidney regions of interest (ROI) that eliminates the need for anatomical cortical and medullary definition. METHOD AND MATERIALS Both kidneys of 6 hypertensive patients and 6 domestic pigs were studied with BOLD MRI before and after injection of furosemide, which inhibits medullary oxygen consumption. Half of each group had renal artery stenosis (RAS). R2* relaxivity index (1/sec) in cortex and medulla was estimated using 3 methods: a conventional T2 method, with ROI selected on T2 images; a reference method, using contrast-aided same-kidney MDCT images to define cortex and medulla ROI’s; and a new ‘compartmental’ method, which distinguishes functional R2* distribution patterns of ...
Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function ma... more Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertens...
Restenosis following percutaneous transluminal renal angioplasty (PTRA) remains a concern even in... more Restenosis following percutaneous transluminal renal angioplasty (PTRA) remains a concern even in the era of adjuvant stenting. The optimal form of therapy, and particularly the role of repeat PTRA in the treatment of recurrent hypertension associated with renal artery restenosis, is largely unknown. The aims of this study were to determine the risk factors for restenosis and to evaluate the blood pressure outcomes of patients who underwent repeat PTRA. Clinical and procedural characteristics of 32 patients who developed recurrent hypertension and renal artery restenosis were compared to a control group of patients who maintained renal artery patency and adequate blood pressure control after the first procedure. The groups were matched for sex and initial procedure date. The restenosis group had a mean age of 71 +/- 12 years, a female/male ratio of 24/8, an average blood pressure of 179/87 mm Hg, despite three antihypertensive medications, and a serum creatinine level of 1.5 +/- 0.4...
Historically, the clinical acceptability of pancreas-after-kidney (PAK) transplantation has been ... more Historically, the clinical acceptability of pancreas-after-kidney (PAK) transplantation has been hampered by relatively high acute rejection rates and lower pancreas graft survival rates when compared with the more commonly performed simultaneous pancreas-kidney (SPK) transplantation. The purpose of this study was to compare PAK transplantation to SPK transplantation in the Thymoglobulin induction era. The authors reviewed all bladder-drained PAK (n=47) transplants receiving rabbit antithymocyte globulin induction from June 1998 to June 2002 and compared them with SPK (n=25) transplants during the same time period at their institution. The authors retrospectively studied data on demographics, patient survival, graft (pancreas and kidney) survival, complications, and biopsy-proven rejection episodes. The actuarial 1-year patient survival was 93% for the PAK group versus 100% for the SPK group (P =not significant [NS]). The actuarial 1-year pancreas graft survival was 87% for the PAK ...
Dialysis is not only associated with morbidity, it is also expensive. In developing countries, pr... more Dialysis is not only associated with morbidity, it is also expensive. In developing countries, preemptive renal transplantation (Tx) may be a cost-effective option, offering an additional benefit to conventional renal Tx. Between March 1976 and March 2001, 1,279 first living-donor Txs were performed in our center. The 82 patients (6.4%) who underwent Tx without prior dialysis were compared with 1,197 patients who had been dialyzed before Tx. The dialysis-dependent group received more blood transfusions (65% vs. 30%) before Tx. Actuarial graft and patient survival at 5 years was comparable in both groups (P =0.2 and P =0.8, respectively). The incidence of acute and chronic rejection was not different between the two groups. Mortality rate was also similar in the two groups. The main cause of death with a functioning graft was cardiovascular in the preemptive Tx group and chronic liver disease and infection in the control group. In the context of a developing country, preemptive Tx offers comparable patient and graft survival to conventional renal Tx and eliminates the complications, inconvenience, and cost of dialysis.
With the introduction of new immunosuppressive medicines, it has become possible to determine the... more With the introduction of new immunosuppressive medicines, it has become possible to determine the extent to which nephrotoxic medicines contribute to CAN. The aim of this study is to compare the safety and efficacy of calcineurin inhibitor (CI) free immunosuppression in a prospective, randomized trial comparing sirolimus-mycophenolate mofetil (MMF)-prednisone to tacrolimus- MMF-prednisone. Patients are randomized at the time of transplant to receive either tacrolimus (target level 12 to 15 ng/mL in the first month) or sirolimus (target level 12 to 18 ng/mL in the first month). All patients also receive MMF (750 mg bid) and prednisone tapered to 10 mg/d by 3 months and thymoglobulin induction (1.5 mg/kg/d on days 0, 1, 2, 4 and 6). At this point we have 4-month follow-up in 85 patients. The acute rejection rate is 7.5% (3/40) in the tacrolimus group and 6.7% (3/45) in the sirolimus group. We have discontinued sirolimus in eight patients so far, with wound complications being the most common indication. Renal function appears to be better in the sirolimus group at 1 month after transplantation, but the difference is not statistically significant. While longer follow-up is needed, these results demonstrate that total avoidance of CI can be achieved with extremely low acute cellular rejection rates using sirolimus-based immunosuppression in combination with thymoglobulin, MMF, and prednisone.
Pancreas transplant alone (PTA) has become accepted therapy for select nonuremic patients with ty... more Pancreas transplant alone (PTA) has become accepted therapy for select nonuremic patients with type 1 diabetes mellitus. However, PTA may lead to significant complications including a decline in native renal function. This study examines trends in native renal function during the first posttransplant year in PTA recipients with a spectrum of pretransplant glomerular filtration rates (GFR). Renal function was studied in 23 recipients of bladder-drained PTA who underwent transplantation from April 1998 through September 2001. GFR was measured by corrected iothalamate clearance at the time of transplant evaluation and 1 year posttransplant and also calculated using the Cockcroft-Gault method at the transplant evaluation; at the day of transplantation; and at 1, 6, and 12 months posttransplant. Iothalamate clearance decreased in the first year in 96% of patients (22 of 23). The mean measured GFR decreased from 84 +/- 33 mL/min/1.73 m2 pretransplant to 52 +/- 26 mL/min/1.73 m2 at 1 year (P <0.001). Calculated creatinine clearance declined in the majority of patients at both 1 and 12 months after PTA, but some patients, including a few with low GFR, maintained stable renal function. Calculated GFR generally correlated well with measured GFR in most patients, with a few notable exceptions. One patient (baseline GFR, 42 mL/min/1.73 m2) developed renal failure in the first year after transplant and required kidney transplantation. Bladder-drained PTA results in a decline in native renal function in the majority of patients regardless of the pretransplant GFR. These data suggest the need for strategies to prevent or minimize the decline in renal function after PTA.
Rising numbers of patients reaching end-stage kidney disease intensify the demand for expansion o... more Rising numbers of patients reaching end-stage kidney disease intensify the demand for expansion of the living-kidney-donor pool. On the basis of low risk in white donors with essential hypertension, our transplant center undertook a structured program of accepting hypertensive donors if kidney function and urine protein were normal. This study reports outcomes of hypertensive donors 1 year after kidney donation. We studied detailed measurements of blood pressure (oscillometric, hypertensive therapy nurse [RN], and ambulatory blood pressure monitoring [ABPM]), clinical, and renal characteristics (iothalamate glomerular filtration rate [GFR], urine protein, and microalbumin) in 148 living kidney donors before and 6 to 12 months after nephrectomy. Twenty-four were hypertensive (awake ABPM>135/85 mm Hg and clinic/RN BP>140/90 mm Hg) before donation. After 282 days, normotensive donors had no change in awake ABPM pressure (pre 121 +/- 1/75 +/- 2 vs. post 120 +/- 1/ 5 +/- 1 mm Hg), whereas BP in hypertensive donors fell with both nonpharmacologic and drug therapy (pre 142 +/- 3/85 +/- 2 to post 132 +/- 2/80 +/- 1 mm Hg, P<.01). Hypertensive donors were older (53.4 vs. 41.4 years, P<.001) and had lower GFR after kidney donation (61 +/- 2 vs. 68 +/- 1 mL/min/1.73m, P<.01). After correction for age, no independent BP effect was evident for predicting GFR either before or after nephrectomy. Urine protein and microalbumin did not change in either group after donor nephrectomy. Our results indicate that white subjects with moderate, essential hypertension and normal kidney function have no adverse effects regarding blood pressure, GFR, or urinary protein excretion during the first year after living kidney donation. Although further studies are essential to confirm long-term safety, these data suggest that selected hypertensive patients may be accepted for living kidney donation.
American journal of physiology. Renal physiology, Jan 9, 2015
Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and ... more Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of CCL2/CCR2 signaling on the development of renal atrophy, mice were treated with CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 weeks. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time fol...
PURPOSE Functional Blood Oxygen Level Dependent (BOLD) MRI is a powerful tool to assess renal med... more PURPOSE Functional Blood Oxygen Level Dependent (BOLD) MRI is a powerful tool to assess renal medullary function, due to its high metabolic rate, but requires its differentiation from the renal cortex, which is difficult in MR images. We have developed and sought to validate a new analysis method of whole-kidney regions of interest (ROI) that eliminates the need for anatomical cortical and medullary definition. METHOD AND MATERIALS Both kidneys of 6 hypertensive patients and 6 domestic pigs were studied with BOLD MRI before and after injection of furosemide, which inhibits medullary oxygen consumption. Half of each group had renal artery stenosis (RAS). R2* relaxivity index (1/sec) in cortex and medulla was estimated using 3 methods: a conventional T2 method, with ROI selected on T2 images; a reference method, using contrast-aided same-kidney MDCT images to define cortex and medulla ROI’s; and a new ‘compartmental’ method, which distinguishes functional R2* distribution patterns of ...
Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function ma... more Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertens...
Restenosis following percutaneous transluminal renal angioplasty (PTRA) remains a concern even in... more Restenosis following percutaneous transluminal renal angioplasty (PTRA) remains a concern even in the era of adjuvant stenting. The optimal form of therapy, and particularly the role of repeat PTRA in the treatment of recurrent hypertension associated with renal artery restenosis, is largely unknown. The aims of this study were to determine the risk factors for restenosis and to evaluate the blood pressure outcomes of patients who underwent repeat PTRA. Clinical and procedural characteristics of 32 patients who developed recurrent hypertension and renal artery restenosis were compared to a control group of patients who maintained renal artery patency and adequate blood pressure control after the first procedure. The groups were matched for sex and initial procedure date. The restenosis group had a mean age of 71 +/- 12 years, a female/male ratio of 24/8, an average blood pressure of 179/87 mm Hg, despite three antihypertensive medications, and a serum creatinine level of 1.5 +/- 0.4...
Historically, the clinical acceptability of pancreas-after-kidney (PAK) transplantation has been ... more Historically, the clinical acceptability of pancreas-after-kidney (PAK) transplantation has been hampered by relatively high acute rejection rates and lower pancreas graft survival rates when compared with the more commonly performed simultaneous pancreas-kidney (SPK) transplantation. The purpose of this study was to compare PAK transplantation to SPK transplantation in the Thymoglobulin induction era. The authors reviewed all bladder-drained PAK (n=47) transplants receiving rabbit antithymocyte globulin induction from June 1998 to June 2002 and compared them with SPK (n=25) transplants during the same time period at their institution. The authors retrospectively studied data on demographics, patient survival, graft (pancreas and kidney) survival, complications, and biopsy-proven rejection episodes. The actuarial 1-year patient survival was 93% for the PAK group versus 100% for the SPK group (P =not significant [NS]). The actuarial 1-year pancreas graft survival was 87% for the PAK ...
Dialysis is not only associated with morbidity, it is also expensive. In developing countries, pr... more Dialysis is not only associated with morbidity, it is also expensive. In developing countries, preemptive renal transplantation (Tx) may be a cost-effective option, offering an additional benefit to conventional renal Tx. Between March 1976 and March 2001, 1,279 first living-donor Txs were performed in our center. The 82 patients (6.4%) who underwent Tx without prior dialysis were compared with 1,197 patients who had been dialyzed before Tx. The dialysis-dependent group received more blood transfusions (65% vs. 30%) before Tx. Actuarial graft and patient survival at 5 years was comparable in both groups (P =0.2 and P =0.8, respectively). The incidence of acute and chronic rejection was not different between the two groups. Mortality rate was also similar in the two groups. The main cause of death with a functioning graft was cardiovascular in the preemptive Tx group and chronic liver disease and infection in the control group. In the context of a developing country, preemptive Tx offers comparable patient and graft survival to conventional renal Tx and eliminates the complications, inconvenience, and cost of dialysis.
With the introduction of new immunosuppressive medicines, it has become possible to determine the... more With the introduction of new immunosuppressive medicines, it has become possible to determine the extent to which nephrotoxic medicines contribute to CAN. The aim of this study is to compare the safety and efficacy of calcineurin inhibitor (CI) free immunosuppression in a prospective, randomized trial comparing sirolimus-mycophenolate mofetil (MMF)-prednisone to tacrolimus- MMF-prednisone. Patients are randomized at the time of transplant to receive either tacrolimus (target level 12 to 15 ng/mL in the first month) or sirolimus (target level 12 to 18 ng/mL in the first month). All patients also receive MMF (750 mg bid) and prednisone tapered to 10 mg/d by 3 months and thymoglobulin induction (1.5 mg/kg/d on days 0, 1, 2, 4 and 6). At this point we have 4-month follow-up in 85 patients. The acute rejection rate is 7.5% (3/40) in the tacrolimus group and 6.7% (3/45) in the sirolimus group. We have discontinued sirolimus in eight patients so far, with wound complications being the most common indication. Renal function appears to be better in the sirolimus group at 1 month after transplantation, but the difference is not statistically significant. While longer follow-up is needed, these results demonstrate that total avoidance of CI can be achieved with extremely low acute cellular rejection rates using sirolimus-based immunosuppression in combination with thymoglobulin, MMF, and prednisone.
Pancreas transplant alone (PTA) has become accepted therapy for select nonuremic patients with ty... more Pancreas transplant alone (PTA) has become accepted therapy for select nonuremic patients with type 1 diabetes mellitus. However, PTA may lead to significant complications including a decline in native renal function. This study examines trends in native renal function during the first posttransplant year in PTA recipients with a spectrum of pretransplant glomerular filtration rates (GFR). Renal function was studied in 23 recipients of bladder-drained PTA who underwent transplantation from April 1998 through September 2001. GFR was measured by corrected iothalamate clearance at the time of transplant evaluation and 1 year posttransplant and also calculated using the Cockcroft-Gault method at the transplant evaluation; at the day of transplantation; and at 1, 6, and 12 months posttransplant. Iothalamate clearance decreased in the first year in 96% of patients (22 of 23). The mean measured GFR decreased from 84 +/- 33 mL/min/1.73 m2 pretransplant to 52 +/- 26 mL/min/1.73 m2 at 1 year (P <0.001). Calculated creatinine clearance declined in the majority of patients at both 1 and 12 months after PTA, but some patients, including a few with low GFR, maintained stable renal function. Calculated GFR generally correlated well with measured GFR in most patients, with a few notable exceptions. One patient (baseline GFR, 42 mL/min/1.73 m2) developed renal failure in the first year after transplant and required kidney transplantation. Bladder-drained PTA results in a decline in native renal function in the majority of patients regardless of the pretransplant GFR. These data suggest the need for strategies to prevent or minimize the decline in renal function after PTA.
Rising numbers of patients reaching end-stage kidney disease intensify the demand for expansion o... more Rising numbers of patients reaching end-stage kidney disease intensify the demand for expansion of the living-kidney-donor pool. On the basis of low risk in white donors with essential hypertension, our transplant center undertook a structured program of accepting hypertensive donors if kidney function and urine protein were normal. This study reports outcomes of hypertensive donors 1 year after kidney donation. We studied detailed measurements of blood pressure (oscillometric, hypertensive therapy nurse [RN], and ambulatory blood pressure monitoring [ABPM]), clinical, and renal characteristics (iothalamate glomerular filtration rate [GFR], urine protein, and microalbumin) in 148 living kidney donors before and 6 to 12 months after nephrectomy. Twenty-four were hypertensive (awake ABPM>135/85 mm Hg and clinic/RN BP>140/90 mm Hg) before donation. After 282 days, normotensive donors had no change in awake ABPM pressure (pre 121 +/- 1/75 +/- 2 vs. post 120 +/- 1/ 5 +/- 1 mm Hg), whereas BP in hypertensive donors fell with both nonpharmacologic and drug therapy (pre 142 +/- 3/85 +/- 2 to post 132 +/- 2/80 +/- 1 mm Hg, P<.01). Hypertensive donors were older (53.4 vs. 41.4 years, P<.001) and had lower GFR after kidney donation (61 +/- 2 vs. 68 +/- 1 mL/min/1.73m, P<.01). After correction for age, no independent BP effect was evident for predicting GFR either before or after nephrectomy. Urine protein and microalbumin did not change in either group after donor nephrectomy. Our results indicate that white subjects with moderate, essential hypertension and normal kidney function have no adverse effects regarding blood pressure, GFR, or urinary protein excretion during the first year after living kidney donation. Although further studies are essential to confirm long-term safety, these data suggest that selected hypertensive patients may be accepted for living kidney donation.
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