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1.  FGF23 and PTH—double agents at the heart of CKD 
Nephrology Dialysis Transplantation  2012;27(5):1715-1720.
PMCID: PMC3471546  PMID: 22447519
FGF23; left ventricular hypertrophy; mineral metabolism; phosphorus; PTH
2.  Effects of Sodium Thiosulfate on Vascular Calcification in End-Stage Renal Disease: A Pilot Study of Feasibility, Safety and Efficacy 
American Journal of Nephrology  2011;33(2):131-138.
Background and Objectives
Vascular calcification is a major contributor to morbidity and mortality in hemodialysis. The objective of this pilot study was to determine the feasibility, safety and efficacy of sodium thiosulfate (STS) in the progression of vascular calcification in hemodialysis patients.
Chronic hemodialysis patients underwent a battery of cardiovascular tests. Those with coronary artery calcium (Agatston scores >50) received intravenous STS after each dialysis for 5 months (n = 22) and the tests were repeated. Changes in MDCT-determined calcification were assessed as the mean annualized rate of change in 3 vascular beds (coronary, thoracic and carotid arteries) and in L1-L2 vertebral bone density.
Although individual analyses showed coronary artery calcification progression in 14/22 subjects, there was no progression in the mean annualized rate of change of vascular calcification in the entire group. The L1-L2 vertebral bone density showed no changes. There were no correlations between rates of progression of vascular calcification and phosphorus, fetuin or C-reactive protein levels. Changes in coronary artery calcification scores correlated with those of the thoracic aorta.
STS treatment is feasible, appears safe and may decrease the rate of progression of vascular calcification in hemodialysis patients. A large, randomized, controlled trial is warranted.
PMCID: PMC3064860  PMID: 21242673
Hemodialysis; Sodium thiosulfate; Vascular calcification
4.  The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder 
Kidney International. Supplement  2011;79(S121):S3-S8.
Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the ‘intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that ‘as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca2+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca2+ sensing receptor, and Klotho–fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an ‘intestinal phosphatonin'. These observations suggest a possible ‘phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-α–epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function.
PMCID: PMC3260962  PMID: 21346721
fractional excretion; intact nephron hypothesis; intestinal phosphatonin; phosphate
5.  Myocardial Effects of VDR Activators in Renal Failure 
Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Traditional causes such as diabetes, smoking, aging and hypertension do not fully explain the high rate of morbidity from cardiovascular disease seen in these patients. The renin-angiotensin-aldosterone system (RAAS) regulates extracellular volume homeostasis, which contributes to blood pressure stability. Overactivity of this system is involved in the pathophysiology of cardio-renal disease. New evidence suggests that vitamin D receptor activators (VDRAs) have a suppressive effect on the RAAS; However, VDRAs also have anti-inflammatory and anti-fibrotic effects. We have demonstrated that paricalcitol, a VDRA, ameliorates left ventricular hypertrophy (LVH) in uremic rats by up-regulating the VDR, decreasing myocardial PCNA and also decreasing myocardial oxidative stress.
Thus, paricalcitol can suppress the progression of LVH, myocardial and perivascular fibrosis and myocardial arterial vessel thickness presumably by up regulating the VDR. Paricalcitol may prove to have a substantial beneficial effect on cardiac disease and its outcome in patients with CKD. Prospective randomized studies in CKD patients are necessary to confirm these results.
PMCID: PMC2906634  PMID: 20236614
6.  Novel Markers of Left Ventricular Hypertrophy in Uremia 
American Journal of Nephrology  2010;31(4):292-302.
Left ventricular hypertrophy (LVH) is the most frequent cardiac complication in chronic renal disease. Previous studies implicate elevated serum phosphorus as a risk factor for LVH.
We treated 5/6 nephrectomized rats with enalapril or enalapril + sevelamer carbonate for 4 months to determine if sevelamer carbonate had an additional beneficial effect on the development of LVH and uremia-induced left ventricle (LV) remodeling.
Uremia increased LV weight and cardiomyocyte size. Enalapril and enalapril + sevelamer blunted the increase in left ventricular weight. Only enalapril + sevelamer diminished the increase in cardiomyocyte size. Uremia increased cyclin D2 and PCNA and decreased p27 protein expression in the heart. Enalapril + sevelamer diminished the decrease in p27 expression caused by uremia. Uremia increased Ki67-positive and phosphohistone H3-positive interstitial cells. This was not seen in cardiomyocytes. Multivariable regression analysis showed that increased phosphorus was an independent risk factor for both increased LV weight and cardiomyocyte size.
These data suggest left ventricular remodeling consists of cardiomyocyte hypertrophy and interstitial cell proliferation, but not cardiomyocyte proliferation. p27 and cyclin D2 may play important roles in the development of LVH. In addition, phosphorus can be an independent risk factor for the development of LVH.
PMCID: PMC2924237  PMID: 20130393
Left ventricular hypertrophy; Hyperphosphatemia; p27; Cyclin D2
7.  Relation of Serum Fetuin-A Levels to Coronary Artery Calcium in African-American Patients on Chronic Hemodialysis 
Vascular calcium deposition in end-stage renal disease occurs commonly, however its relationship to cardiovascular risk factors and fetuin-A levels in African-Americans is not known. Compliant African-American HD patients (n=17) agreed to undergo a 64-slice multidetector computed tomography for the assessment of coronary artery calcium score (CACS). The relationship between traditional cardiovascular risk factors (i.e., age, gender, dialysis vintage, history of diabetes, means of the previous 3 years of the weekly pre-dialysis blood pressure and hemoglobin, means of monthly values of calcium, phosphorus, alkaline phosphatase, uric acid and albumin, and means of quarterly measures of parathyroid hormone and lipids), and fetuin-A levels and CACS was explored by univariate analyses. Serum phosphorus levels over the previous 3 years were well controlled. The CACS range was 0-3,877 Agatston units (mean: 996; median :196). Among the tested variables, only fetuin-A was significantly and inversely associated with CACS (standardized β = -0.64 [95% confidence limits [CL]: -18.09, -3.62], p=0.006). There was no association between age and fetuin-A level (standardized β = -0.02 [95%CL: -0.10, 0.23]). In conclusion, African-American patients on long-term HD and with good phosphorus control exhibit a strong inverse correlation between fetuin-A levels and CACS which is independent of age.
PMCID: PMC2631229  PMID: 19101228
Fetuin-A; Hemodialysis; Coronary artery calcium score; African-American
8.  Evidence for Skeletal Resistance to Parathyroid Hormone in Magnesium Deficiency 
Journal of Clinical Investigation  1979;64(5):1238-1244.
Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83±0.1 mg/100 ml) and experimental dogs (serum Mg 1.34±0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5±3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1±1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8±0.2 to 17.5±0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5±0.1 pmol/min, and increased to only 7.1±0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.
PMCID: PMC371269  PMID: 227929
9.  Evidence for an Intrinsic Renal Tubular Defect in Mice with Genetic Hypophosphatemic Rickets 
Journal of Clinical Investigation  1979;63(6):1203-1210.
To investigate the role of parathyroid hormone (PTH) and(or) an intrinsic renal tubular reabsorptive defect for phosphate in mice with hereditary hypophosphatemic rickets, we performed clearance and micropuncture studies in hypophosphatemic mutants and nonaffected littermate controls. Increased fractional excretion of phosphate in mutants (47.2±4 vs. 30.8±2% in controls) was associated with reduced fractional and absolute reabsorption in the proximal convoluted tubule and more distal sites. Acute thyropara-thyroidectomy (TPTX) increased phosphate reabsorption in both mutants and controls with a fall in fractional phosphate excretion to ≅7.5% in both groups indicating that PTH modified the degree of phosphaturia in the intact mutants. Absolute reabsorption in the proximal tubule and beyond remained reduced in the mutants, however, possibly because of the reduced filtered load. Serum PTH levels were the same in intact mutants and normals as was renal cortical adenylate cyclase activity both before and after PTH stimulation.
To evaluate the possibility that the phosphate wasting was caused by an intrinsic tubular defect that was masked by TPTX, glomerular fluid phosphate concentration was raised by phosphate infusion in TPTX mutants to levels approaching those of control mice. Phosphate excretion rose markedly and fractional reabsorption fell, but there was no change in absolute phosphate reabsorption in either the proximal tubule or beyond, indicating a persistent reabsorptive defect in the absence of PTH.
We conclude that hereditary hypophosphatemia in the mouse is associated with a renal tubular defect in phosphate reabsorption, which is independent of PTH and therefore represents a specific intrinsic abnormality of phosphate transport.
PMCID: PMC372069  PMID: 221535
10.  Selective Uptake of the Synthetic Amino Terminal Fragment of Bovine Parathyroid Hormone by Isolated Perfused Bone 
Journal of Clinical Investigation  1978;62(2):256-261.
Studies from our laboratory have shown that the metabolic clearance rate of carboxy terminal immunoreactive parathyroid hormone (i-PTH) can be accounted for by extraction of i-PTH by liver and kidney. In contrast, there was no demonstrable hepatic uptake of the synthetic amino terminal bovine PTH fragment (syn b-PTH 1-34) and the kidney accounted for only 45% of the metabolic clearance rate of amino terminal i-PTH. This suggested that another major site, presumably bone, played a role in the metabolism of syn b-PTH 1-34. Extraction of i-PTH by isolated perfused bone was studied during infusion of purified bovine PTH (b-PTH) 1-84 or syn b-PTH 1-34. In five studies during infusion of syn b-PTH 1-34 the arteriovenous difference for i-PTH across bone was 36%. In contrast, no significant uptake of carboxy terminal i-PTH was observed in nine studies during infusion of b-PTH 1-84. In addition, when H2O2-oxidized (biologically inactive) syn b-PTH 1-34 was used no arteriovenous difference was observed. These findings correlated with the ability of these PTH preparations to stimulate cyclic AMP production by the perfused bone. Syn b-PTH 1-34 increased cyclic AMP production at perfusate PTH concentrations of 1-5 ng/ml, whereas b-PTH 1-84 evoked only a minimal response at concentrations of 10-20 ng/ml. We conclude that bone is a major site of metabolism of the amino terminal PTH fragment, syn b-PTH 1-34. In addition, these data suggest that cleavage of the intact hormone, with the production of amino terminal PTH fragments by peripheral organs (liver and kidney), may play a major role in the regulation of PTH effects on bone.
PMCID: PMC371761  PMID: 209059
11.  The Renal Handling of Parathyroid Hormone 
Journal of Clinical Investigation  1977;60(4):808-814.
The mechanisms of uptake of parathyroid hormone (PTH) by the kidney was studied in anesthetized dogs before and after ureteral ligation. During constant infusion of bovine PTH (b-PTH 1-84), the renal arteriovenous (A-V) difference for immunoreactive PTH (i-PTH) was 22±2%. After ureteral ligation and no change in renal plasma flow, A-V i-PTH fell to 15±1% (P < 0.01), indicating continued and significant uptake of i-PTH at peritubular sites and a lesser role of glomerular filtration (GF) in the renal uptake of i-PTH. Since, under normal conditions, minimal i-PTH appears in the final urine, the contribution of GF and subsequent tubular reabsorption was further examined in isolated perfused dog kidneys before and after inhibition of tubular reabsorption by potassium cyanide. Urinary i-PTH per 100 ml GF rose from 8±4 ng/min (control) to 170±45 ng/min after potassium cyanide. Thus, i-PTH is normally filtered and reabsorbed by the tubular cells. The physiological role of these two mechanisms of renal PTH uptake was examined by giving single injections of b-PTH 1-84 or synthetic b-PTH 1-34 in the presence of established ureteral ligation. After injection of b-PTH 1-84, renal A-V i-PTH was 20% only while biologically active intact PTH was present (15-20 min). No peritubular uptake of carboxyl terminal PTH fragments was demonstrable. In contrast, after injection of synthetic b-PTH 1-34, renal extraction of N-terminal i-PTH after ureteral ligation (which was 13.4±0.6% vs. 19.6±0.9% in controls) continued for as long as i-PTH persisted in the circulation. These studies indicate that both GF and peritubular uptake are important mechanisms for renal PTH uptake. Renal uptake of carboxyl terminal fragments of PTH is dependent exclusively upon GF and tubular reabsorption, whereas peritubular uptake can only be demonstrated for biologically active b-PTH 1-84 and synthetic b-PTH 1-34.
PMCID: PMC372428  PMID: 893678
12.  On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog 
Journal of Clinical Investigation  1971;50(3):492-499.
Healthy adult dogs were subjected to stepwise reduction of nephron population so as to create the transition from normal renal function to advanced renal insufficiency. Studies were performed at each level of renal function. Glomerular filtration rate (GFR), renal phosphate clearance, and serum radioimmunoassayable parathyroid hormone (PTH) levels were measured. Two groups of animals were studied. In one, phosphorous intake was maintained at 1200 mg/day. As GFR declined, fractional phosphate excretion rose reciprocally, and PTH levels increased over 20-fold. In the second group, phosphorous intake was maintained at less than 100 mg/day. As GFR fell, fractional phosphate excretion changed little, and no increment in PTH levels occurred. The data suggest that the control system regulating phosphate excretion contributes importantly to the pathogenesis of secondary hyperparathyroidism in advancing renal insufficiency.
PMCID: PMC291955  PMID: 5545116
13.  On the influence of extracellular fluid volume expansion and of uremia on bicarbonate reabsorption in man 
Journal of Clinical Investigation  1970;49(5):988-998.
The patterns of bicarbonate reabsorption during increasing plasma concentrations were studied in subjects with a range of glomerular filtration rates (GFR) from 170 to 2 ml/min. In a group of five subjects with GFR values above 30 ml/min, paired bicarbonate titration studies were performed first under conditions which minimized extracellular fluid (ECF) volume expansion, and second under conditions which were conducive to exaggerated expansion of ECF volume. In patients with GFR values below 30 ml/min, a single protocol was employed. Studies also were performed on two patients with far advanced renal disease who were nephrotic and exhibited a sodium-retaining state. When ECF volume expansion was minimized in the nonuremic subjects, values for bicarbonate reabsorption were well in excess of the usually accepted Tm level and over the range of plasma bicarbonate concentrations employed, no evidence of a Tm phenomenon was observed. A similar pattern emerged in the two nephrotic patients despite the presence of uremia. However, with both exaggerated expansion of ECF volume (GFR greater than 30) and in patients with advanced renal disease in the absence of exaggerated ECF volume expansion a tendency towards saturation kinetics for bicarbonate reabsorption was demonstrable. In comparing the minimized with the exaggerated expansion studies, evidence emerged for a decrease in both bicarbonate reabsorption per unit of GFR and the absolute rate of bicarbonate reabsorption. When ECF volume expansion was exaggerated in uremic patients after stable rates of bicarbonate reabsorption had been achieved, a decrease in reabsorption per unit of GFR and in absolute bicarbonate reabsorption occurred. The possible relationship of the factors controlling sodium excretion to the observed patterns of bicarbonate reabsorption is considered in the text.
PMCID: PMC535771  PMID: 5441550
14.  The metabolic fate of vitamin D3-3H in chronic renal failure 
Journal of Clinical Investigation  1968;47(10):2239-2252.
The absorption and metabolism of vitamin D3-3H was studied in eight patients with chronic renal failure. Although the intestinal absorption of vitamin D3-3H was normal, the metabolic fate of the vitamin was abnormal as characterized by a twofold increase in fractional turnover rate, an abnormal accumulation of biologically inactive lipid-soluble metabolites, and the urinary excretion of both vitamin D3-3H and biologically inactive metabolites. Neither alterations in water-soluble vitamin D3 metabolites nor qualitative abnormalities in protein-binding of vitamin D3 were observed in the uremic subjects. Although hemodialysis proved ineffectual in reversing the observed abnormalities in vitamin D3 metabolism and excretion, renal homotransplantation was completely successful in this regard. These experiments support the conclusion that the resistance to therapeutic doses of vitamin D often seen in patients with chronic renal failure and renal osteodystrophy results from an acquired defect in the metabolism and excretion of vitamin D.
PMCID: PMC297388  PMID: 4300189
15.  Studies on the characteristics of the control system governing sodium excretion in uremic man 
Journal of Clinical Investigation  1968;47(3):521-530.
Sodium excretion was studied in a group of patients with chronic renal disease, (a) on constant salt intakes of varying amounts with and without mineralocorticoid hormone administration and, (b) after acute extracellular fluid volume expansion. The lower the steady-state glomerular filtration rate (GFR), the greater was the fraction of filtered sodium excreted on both a 3.5 and 7.0 g salt diet; and the lower the GFR, the greater was the change in fractional excretion in the transition from the 3.5 to the 7.0 g salt diet. This regulatory capacity did not appear to be influenced by mineralocorticoid hormone administration. After acute expansion of extracellular fluid (ECF) volume, the increment in sodium excretion exceeded the concomitant increment in filtered sodium in six of nine studies and in the remaining three studies, the increment in excretion averaged 59% of the Δ filtered load (i.e., only 41% of the increase in filtered sodium was reabsorbed). During saline loading, the decrease in fractional reabsorption of sodium tended to vary inversely with the steady-state GFR, although all patients received approximately the same loading volume. When an edema-forming stimulus was applied during saline infusion, the natriuretic response was aborted and the lag time was relatively short. When GFR and the filtered load of sodium were increased without volume expansion, the Δ sodium excretion averaged only 19% of the Δ filtered load; moreover, changes in fractional sodium reabsorption were considerably smaller than those observed during saline loading. The data implicate the presence of a factor other than GFR and mineralocorticoid changes in the modulation of sodium excretion in uremic man.
PMCID: PMC297198  PMID: 5637140
16.  Glucose Titration Studies in Patients with Chronic Progressive Renal Disease* 
Journal of Clinical Investigation  1967;46(2):157-163.
Glucose titration studies were performed on 17 patients with either chronic pyelonephritis or chronic glomerulonephritis. Glomerular filtration rates for the group ranged from 4.3 to 58.1 ml per minute. In none of the patients in whom the glomerular filtration rate was over 15 ml per minute was there appreciable splay, and the mean titration curve for these patients resembled that obtained by Smith and associates in normal man (1). In half of this group of eight patients, GFR ranged from 16.6 to 22.7 ml per minute; in the other half values ranged from 42.3 to 58.1 ml per minute. Yet, the mean titration curves were identical for the two groups. In addition, no difference was observed in the titration curves for patients with pyelonephritis and those with glomerulonephritis. In patients with GFR values below 15 ml per minute, increased splay was observed, and below a GFR of 10 ml per minute, the splay was very marked. Both the absence of exaggerated splay in patients with reduction of glomerular filtration rate by as much as 85%, and the emergence of exaggerated splay in patients with more marked reduction of GFR, require explanation. Theoretical considerations are presented in the text.
PMCID: PMC297034  PMID: 6018755

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