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Efficacy of 1α(OH)-vitamin D2 in suppressing 2° hyperparathyroidism in hemodialysis patients
Al6
1996
URINARY HEPATOCYTE GROWTH FACTOR (HGFI LEVELS INCREASE IN PATIENTS WITH ACUTE TUBULAR NECROSIS (ATN). MaEed Taman, Youhua Liu, Evelyn Tolbert, Lance D. Dworkin. Brown Univ. & Rhode Island Hosp., Providence, RI. HGF is a novel growth factor with potent mitogenic and morphogenic effects on renal tubular cells. HGF is highly expressed in the kidneys of rats with acute tubular injury and levels also increase in polycystic and in hypertrophic kidneys, implicating it as an important regulator of tubular repair following acute injury and of abnormal renal growth. To determine if kidney HGF production is also increased in human renal disease, we measured urinary HGF concentration by ELISA in normals (CON) and patients with ATN, glomerulonephritis (GN), or polycystic kidney disease (PKD). Values are expressed as the urine HGF/creatinine ratio. PKD CON ATN GN Group 7 5 10 9 N HGF
Ww)
3.21 +1.86
18.12 * -15.06
1.61 M.44
2.30 kO.37
Mean Z!ZS.E., N = number of subjects, * PcO.05 vs. control. Even in normals, HGF concentration in the urine exceeds serum levels by 5-10 fold. Because of its large size, urinary HGF is unlikely to result from filtration, but rather reflects renal production of the cytokine. Consistent with findings in experimental acute renal failure, urinary HGF was markedly increased in patients with ATN. HGF levels were not elevated in chronic GN or PKD natients. even those with renal dysfunction. Increased HGF should to stimulate tubular cell proliferation and differentiation and promote recovery from ATN. Urine HGF levels might also provide a marker for the presence of tubular injury in patients with acute renal failure.
INCREASED RISK OF DIABETIC NEPHROPATHY AS A CAUSE OF ESRD IN BLACK FEMALES: A POPULATION PRONE TO LATE REFERRAL. Robert Tavlor and Errol D. Crook. University of Mississippi Medical Center, Jackson, MS. Diabetes (DM) is the primary etiology of End Stage Renal Disease (ESRD) in the U.S. Recent articles have recommended more aggressive screening and treatment of microalbuminuria. We sought to investigate the impact of DM as a cause for ESRD in a predominantly poor, 193 patients rural, African American (AA) population. were started in the ESRD program at our institution in We reviewed the charts of 1993-1994, 88% AA. patients who started dialysis in 1993-1994 (70) at the Uni of Mississippi with an ESRD diagnosis of DM. DM nephropathy accounted for 48% of ESRD in all AA females, which is 40-50% higher than the general U.S. population. AA females comprised 69% (N=Sl)of patients followed in our clinic and were further analyzed. Their characteristics: duration of DM=17 years, Cr=5.4mg/dl, CrCl 1 Smllmin, 24 hour urine protein=8.lgm, MAP 118.3mm/Hg, mean time to dialysis 454 days. Only 23% presented on an ACE inhibitor (ACE i). Those presenting on ACE i had lower Cr despite being older, having a similar duration of DM, and a higher MAP than those not on ACE i. Starting ACE i at presentation in those with advanced disease did not prolong the time to dialysis when CrCl was considered. Our findings show that AA females are more predisposed to DM nephropathy as a cause for ESRD. Our patients had disease which had progressed far beyond where currently outlined recommendations could have Institution of currently outlined practice benefited. measures are likely to require aggressive education and dissemination of information among primary care physicians in our state.
SPRING
EFFICACY
OF
CLINICAL
NEPHROLOGY
IcK(OH)-VITAMIN
HYPERPARATHYROIkSk
IN
MEETINGS
D, IN SUPPRESSING 2' EEMObIALYSIS PATIENTS.
A.U.Tan.Jr., B.S.Levine, R.B.Mazess, D.M. Kyllo, J.C. Knutson, C.W. Bishop, K.S. Kleinman & J.W. Coburn. Nephrology Section, West Los Angeles VAMC & UCLA Sch Med, CA and Lunar Corp, Madison, WI Calcitriol, useful in treating the 2' hyperparathyroidism (HPT) of renal failure, has a lowl we evaluated the therapeutic index. Therefore, safety and efficacy of the vitamin D analog, . * lo(OH)-vltamrn D, (laDZ), to lower PTH levels in 24 hemodialysis patients (HD)(18/M, 6/F) with 2?-1Pl! and adequate PO,-control (intact PTH > 400 pg/ml & serum phosphorus (P) 5 6.9 mg/dl); ages were 2774 years and duration of dialysis, 4-162 mos. After 8 wks of washout (WO), oral laD, was given for 12 wks (Rx); the dose was initially 4 pg/day or 4 pg 3x/wk and then adjusted to a target PTH of 130-250 pg/ml. Only Ca-based Pod-binders wers used. PTH fell from 672+70 pg/ml (*SE) at WO to The maximal de289*36 (p C 0.05) by end of Rx. crease in PTH from baseline was 48-96%; 21124 patients reached target PTH levels. The initial luD, dose was decreased in 20 HD: 11 for PTH < 130 pg/ml, 8 for PTH in the target range and 1 for SCa of 12.3 maldl: the dose was increased in 2 and unchanged -in .2. The final dose averaged 1.81 SCa rose from 8.8f0.2 mg/dl at baseline m/day. to 9.5f0.2 at the end of Rx (p < 0.001). There were 0.5 episodes/100 wks of hypercalcemia (SCa > 10.5) during WO and 4.7 during Rx (p < 0.02). 11 contrast, SP was similar during WO (5.0f0.3 mg/dl) and Rx (5.1*0.3)(NS). The incidence of hyperphosi phatemia (SP 2 7.0 mg/dl) was similar in WO (6.9 episodes/100 wks) and Rx (lO.l)(NS). There was nq difference between the dose of PO, binders durind Rx (4.1f0.6 gm elementalCa/day) and WO (4.0f0.6): Our study in HD patients demonstrates that oral laD, is highly efficacious in suppressing 2" HPT and is safe despite use with only Ca-based PO,binders and no Al-gels. Future studies should clarify the optimal dosage regimen.
INSULIN TRANSIENTLY STIMULATES SODIUM CONDUCTANCE THROUGH AMILORIDESENSITIVE SODIUM CHANNELS IN HUMAN B LYMPHOCYTES. J. Kevin Tucker, David G. Warnock, and James K. Bubien. University of Alabama at Birmingham, Nephrology Research and Training Center and VAMC, Birmingham, AL. Insulin increases sodium conductance through amiloride-sensitive sodium channels (ASSCs) in epithelia such as toad bladder and A6 cells. Since lymphocytes express an ASSC that is similar in function and regulation to those of epithelial cells, we designed studies to determine whether or not insulin regulates lymphocyte ASSCs. Cells used in these experiments were human B lymphocytes (Daudi) maintained in continuous cell culture using standard techniques. The patch-clamp technique was used to measure whole-cell conductances under basal and insulin-stimulated conditions. The mean chord conductance for Na+ under basal conditions was 367 pS/lOpF. After adding 10 nM insulin to the bath, the mean chord conductance was 707 pS/lOpF, representing a 93% increase. The conductance increase was observed after 7 to 10 minutes, a finding consistent with that of toad bladder. However, unlike what has been reported in epithelia, the activation of the lymphocyte ASSC was transient, lasting 2 to 3 minutes, after which the conductance receded to basal levels. Subsequent perfusion with a membrane permeant analogue of CAMP, 40 FM S-CPT-CAMP, failed to restimulate the inward conductance, indicating a loss of normal ASSC responsiveness to CAMP after insulin treatment. These findings provide direct evidence for insulin-mediated regulation of lymphocyte ASSCs. They also suggest that insulin may interact with other more well characterized regulators of ASSCs such as CAMP.
1996
URINARY HEPATOCYTE GROWTH FACTOR (HGFI LEVELS INCREASE IN PATIENTS WITH ACUTE TUBULAR NECROSIS (ATN). MaEed Taman, Youhua Liu, Evelyn Tolbert, Lance D. Dworkin. Brown Univ. & Rhode Island Hosp., Providence, RI. HGF is a novel growth factor with potent mitogenic and morphogenic effects on renal tubular cells. HGF is highly expressed in the kidneys of rats with acute tubular injury and levels also increase in polycystic and in hypertrophic kidneys, implicating it as an important regulator of tubular repair following acute injury and of abnormal renal growth. To determine if kidney HGF production is also increased in human renal disease, we measured urinary HGF concentration by ELISA in normals (CON) and patients with ATN, glomerulonephritis (GN), or polycystic kidney disease (PKD). Values are expressed as the urine HGF/creatinine ratio. PKD CON ATN GN Group 7 5 10 9 N HGF
Ww)
3.21 +1.86
18.12 * -15.06
1.61 M.44
2.30 kO.37
Mean Z!ZS.E., N = number of subjects, * PcO.05 vs. control. Even in normals, HGF concentration in the urine exceeds serum levels by 5-10 fold. Because of its large size, urinary HGF is unlikely to result from filtration, but rather reflects renal production of the cytokine. Consistent with findings in experimental acute renal failure, urinary HGF was markedly increased in patients with ATN. HGF levels were not elevated in chronic GN or PKD natients. even those with renal dysfunction. Increased HGF should to stimulate tubular cell proliferation and differentiation and promote recovery from ATN. Urine HGF levels might also provide a marker for the presence of tubular injury in patients with acute renal failure.
INCREASED RISK OF DIABETIC NEPHROPATHY AS A CAUSE OF ESRD IN BLACK FEMALES: A POPULATION PRONE TO LATE REFERRAL. Robert Tavlor and Errol D. Crook. University of Mississippi Medical Center, Jackson, MS. Diabetes (DM) is the primary etiology of End Stage Renal Disease (ESRD) in the U.S. Recent articles have recommended more aggressive screening and treatment of microalbuminuria. We sought to investigate the impact of DM as a cause for ESRD in a predominantly poor, 193 patients rural, African American (AA) population. were started in the ESRD program at our institution in We reviewed the charts of 1993-1994, 88% AA. patients who started dialysis in 1993-1994 (70) at the Uni of Mississippi with an ESRD diagnosis of DM. DM nephropathy accounted for 48% of ESRD in all AA females, which is 40-50% higher than the general U.S. population. AA females comprised 69% (N=Sl)of patients followed in our clinic and were further analyzed. Their characteristics: duration of DM=17 years, Cr=5.4mg/dl, CrCl 1 Smllmin, 24 hour urine protein=8.lgm, MAP 118.3mm/Hg, mean time to dialysis 454 days. Only 23% presented on an ACE inhibitor (ACE i). Those presenting on ACE i had lower Cr despite being older, having a similar duration of DM, and a higher MAP than those not on ACE i. Starting ACE i at presentation in those with advanced disease did not prolong the time to dialysis when CrCl was considered. Our findings show that AA females are more predisposed to DM nephropathy as a cause for ESRD. Our patients had disease which had progressed far beyond where currently outlined recommendations could have Institution of currently outlined practice benefited. measures are likely to require aggressive education and dissemination of information among primary care physicians in our state.
SPRING
EFFICACY
OF
CLINICAL
NEPHROLOGY
IcK(OH)-VITAMIN
HYPERPARATHYROIkSk
IN
MEETINGS
D, IN SUPPRESSING 2' EEMObIALYSIS PATIENTS.
A.U.Tan.Jr., B.S.Levine, R.B.Mazess, D.M. Kyllo, J.C. Knutson, C.W. Bishop, K.S. Kleinman & J.W. Coburn. Nephrology Section, West Los Angeles VAMC & UCLA Sch Med, CA and Lunar Corp, Madison, WI Calcitriol, useful in treating the 2' hyperparathyroidism (HPT) of renal failure, has a lowl we evaluated the therapeutic index. Therefore, safety and efficacy of the vitamin D analog, . * lo(OH)-vltamrn D, (laDZ), to lower PTH levels in 24 hemodialysis patients (HD)(18/M, 6/F) with 2?-1Pl! and adequate PO,-control (intact PTH > 400 pg/ml & serum phosphorus (P) 5 6.9 mg/dl); ages were 2774 years and duration of dialysis, 4-162 mos. After 8 wks of washout (WO), oral laD, was given for 12 wks (Rx); the dose was initially 4 pg/day or 4 pg 3x/wk and then adjusted to a target PTH of 130-250 pg/ml. Only Ca-based Pod-binders wers used. PTH fell from 672+70 pg/ml (*SE) at WO to The maximal de289*36 (p C 0.05) by end of Rx. crease in PTH from baseline was 48-96%; 21124 patients reached target PTH levels. The initial luD, dose was decreased in 20 HD: 11 for PTH < 130 pg/ml, 8 for PTH in the target range and 1 for SCa of 12.3 maldl: the dose was increased in 2 and unchanged -in .2. The final dose averaged 1.81 SCa rose from 8.8f0.2 mg/dl at baseline m/day. to 9.5f0.2 at the end of Rx (p < 0.001). There were 0.5 episodes/100 wks of hypercalcemia (SCa > 10.5) during WO and 4.7 during Rx (p < 0.02). 11 contrast, SP was similar during WO (5.0f0.3 mg/dl) and Rx (5.1*0.3)(NS). The incidence of hyperphosi phatemia (SP 2 7.0 mg/dl) was similar in WO (6.9 episodes/100 wks) and Rx (lO.l)(NS). There was nq difference between the dose of PO, binders durind Rx (4.1f0.6 gm elementalCa/day) and WO (4.0f0.6): Our study in HD patients demonstrates that oral laD, is highly efficacious in suppressing 2" HPT and is safe despite use with only Ca-based PO,binders and no Al-gels. Future studies should clarify the optimal dosage regimen.
INSULIN TRANSIENTLY STIMULATES SODIUM CONDUCTANCE THROUGH AMILORIDESENSITIVE SODIUM CHANNELS IN HUMAN B LYMPHOCYTES. J. Kevin Tucker, David G. Warnock, and James K. Bubien. University of Alabama at Birmingham, Nephrology Research and Training Center and VAMC, Birmingham, AL. Insulin increases sodium conductance through amiloride-sensitive sodium channels (ASSCs) in epithelia such as toad bladder and A6 cells. Since lymphocytes express an ASSC that is similar in function and regulation to those of epithelial cells, we designed studies to determine whether or not insulin regulates lymphocyte ASSCs. Cells used in these experiments were human B lymphocytes (Daudi) maintained in continuous cell culture using standard techniques. The patch-clamp technique was used to measure whole-cell conductances under basal and insulin-stimulated conditions. The mean chord conductance for Na+ under basal conditions was 367 pS/lOpF. After adding 10 nM insulin to the bath, the mean chord conductance was 707 pS/lOpF, representing a 93% increase. The conductance increase was observed after 7 to 10 minutes, a finding consistent with that of toad bladder. However, unlike what has been reported in epithelia, the activation of the lymphocyte ASSC was transient, lasting 2 to 3 minutes, after which the conductance receded to basal levels. Subsequent perfusion with a membrane permeant analogue of CAMP, 40 FM S-CPT-CAMP, failed to restimulate the inward conductance, indicating a loss of normal ASSC responsiveness to CAMP after insulin treatment. These findings provide direct evidence for insulin-mediated regulation of lymphocyte ASSCs. They also suggest that insulin may interact with other more well characterized regulators of ASSCs such as CAMP.