Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Pathophysiology of Renal Disease
You have accessRestricted Access

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Hiroaki Ogata, Eberhard Ritz, Giulio Odoni, Kerstin Amann and Stephan R. Orth
JASN April 2003, 14 (4) 959-967; DOI: https://doi.org/10.1097/01.ASN.0000056188.23717.E5
Hiroaki Ogata
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eberhard Ritz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giulio Odoni
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kerstin Amann
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephan R. Orth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

ABSTRACT. In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated + vehicle-treated rats (controls); (2) SNX + vehicle-treated rats (SNX); (3) parathyroidectomized SNX + vehicle-treated rats (SNX+PTX); and (4) SNX + calcimimetic R-568-treated rats (SNX+R-568). R-568 (50 μmol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568-treated and parathyroidectomized SNX compared with vehicle-treated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicle-treated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.

E-mail: stephan.orth@gmx.net

Secondary hyperparathyroidism (sHPT) is a known complication of chronic renal failure. Elevated concentrations of parathyroid hormone (PTH) play a role not only in the pathogenesis of renal bone disease (1,2 ⇓), but also in the development of cardiovascular risk factors such as disturbed lipid metabolism (3,4 ⇓), glucose intolerance (5), and hypertension (6–8 ⇓ ⇓). Parathyroidectomy (PTX) attenuates progression of renal failure in subtotally nephrectomized rats (SNX) on a high protein (9) or high phosphate (10,11 ⇓) diet. sHPT is also known to play an important role in the development of structural abnormalities of the heart in renal failure, including left ventricular hypertrophy, interstitial fibrosis, and arteriolar wall thickening of the heart (7,12–14 ⇓ ⇓ ⇓).

Allosteric activators of the calcium sensing receptor, e.g., NPSR-568 (R-568), reduce PTH secretion in rats or patients with primary and secondary hyperparathyroidism (15–20 ⇓ ⇓ ⇓ ⇓ ⇓). There is no information on whether calcimimetics also affect abnormalities of uremia other than calcemia, phosphatemia (21), PTH concentrations (22), and skeletal abnormalities (17).

Therefore, it was the purpose of this study to compare the effects of the calcimimetic R-568 and of parathyroidectomy on progression of renal failure, BP, lipid parameters, and structure of kidney and heart.

Materials and Methods

Animals

Male Sprague-Dawley (SD) rats weighing 180 to 200 g were housed in single cages at constant room temperature (20°C) and humidity (75%) under a controlled light/dark cycle. The rats were fed a high-protein diet containing 40% protein, 0.6% NaCl, 0.75% phosphate, and 0.9% calcium (Altromin Co., Lage/Lippe, Germany).

Experimental Groups

After a 3-d adaptation period, the animals were randomly allotted to four groups (study 1):

  • Control (n = 7): sham-operated (sham-op) control animals treated with vehicle

  • SNX (n = 12): Subtotally nephrectomized animals treated with vehicle

  • SNX+PTX (n = 11): Subtotally nephrectomized and parathyroidectomized animals treated with vehicle

  • SNX+R-568 (n = 10): Subtotally nephrectomized animals treated with NPS R-568 50 μmol/kg per d

A pair-feeding protocol was used throughout the experiment.

For subtotal nephrectomy, the right kidney was removed in a first session under anesthesia with ketamine (100 mg/kg body wt) and xylazine (2 mg/kg body wt). The weight of the right kidney was measured directly after excision. At the time of the first operation, SNX+PTX animals underwent PTX using microsurgical techniques and were subsequently given 5% calcium gluconate in the drinking water throughout the study to prevent development of hypocalcemia (3,4 ⇓). Rats were given water ad libitum throughout the experiment. Seven days after uninephrectomy, cortical tissue of the hypertrophied remnant left kidney was removed, so that the amount removed corresponded to 75% of the weight of the previously excised right kidney. Care was taken to remove the tissue preferentially from the upper and lower pole without damaging large arteries. In sham-operated animals, the kidneys were decapsulated in two consecutive sessions.

Twenty-four hours after the second operation, treatment was started in each group. NPS R-568 was dissolved in 10% aqueous cyclodextrin (2-hydroxypropyl-β-cyclodextrin; Sigma-Aldrich Chemie GmbH, Steinheim, Germany) and was administered daily by gavage (50 μmol/kg per d) between 8:00 a.m. and 10:00 a.m. Systolic BP was measured by tail cuff plethysmography at 2-wk intervals. The rats were weighed and placed in a metabolic cage for the collection of a 24-h urine sample. A blood sample was taken from the subclavian artery at week 4. One control rat did not complete the study (injured during gavage).

In a separate ancillary experiment (study 2), the same protocol was used to study animals (n = 5 to 6 per group) 2 wk after surgery using immunohistologic techniques.

Measurements

Blood was obtained 2 h after the administration of the calcimimetic. Blood (taken at week 4 and at the end of the experiment, i.e., week 8) and urine samples (taken at the indicated time points) were measured using standard laboratory methods with an automated multiparametric analyzer (Autoanalyzer; Hitachi, Japan). Serum PTH was determined using a rat PTH1–34 immunoradiometric assay (Nichols Institute Diagnostics; San Juan Capistrano, CA). Urinary albumin was quantitated using the microplate technique and a rabbit anti-rat albumin peroxidase conjugate (23). BP was measured by tail cuff plethysmography.

Tissue Preparation

After 8 wk (study 1) or 2 wk (study 2), the experiments were terminated by retrograde perfusion fixation at a controlled pressure of 110 mmHg via the abdominal aorta with glutaraldehyde (3%) or ice-cold saline, respectively (13,23 ⇓). The hearts and the kidneys were processed and examined using morphometric and stereologic techniques as described below (23–25 ⇓ ⇓).

Indices of Renal Damage

Glomerulosclerosis (measured in 100 systematically subsampled glomeruli per animal) and tubulointerstitial changes (tubular atrophy, dilation, casts, interstitial inflammation, and fibrosis) were determined on PAS-stained paraffin sections using a semiquantitative scoring system as described previously in detail (23). The resulting glomerulosclerosis and tubulointerstitial indices in each animal were expressed as the arithmetic mean of all scores obtained.

Immunohistochemistry of the Kidney

For staining of the proliferating cell nuclear antigen (PCNA), an anti-PCNA antibody (Immunotech 1510; Marseille, France) was used at a dilution of 1:150 as described previously in detail (23). The sections were examined using light microscopy at a magnification of ×400. The number of PCNA-positive glomerular cells was counted per glomerular area in 50 systematically subsampled glomeruli (23). The number of tubular cells per mm2 of tubulointerstitial area was counted on 50 systematically subsampled fields (0.1681 mm2) randomly sampled from all cortical zones.

Quantitative Stereology of the Heart

All investigations were performed in a blinded fashion. Eight random samples of differently orientated left ventricular section per animal were embedded in epon araldite. Semithin sections were cut, stained with methylene blue and basic fuchsin, and investigated using the orientator method (26–28 ⇓ ⇓). The length density (Lv) of capillaries, i.e., the length of capillaries per unit tissue volume, and the volume density (Vv) of cardiac capillaries, i.e., the volume of capillaries per unit volume of myocardial tissue, were measured in eight systematically subsampled areas per section. The length density of myocardial capillaries (Lv) was determined using the equation Lv = 2QA, where QA is area density (for example, the number of capillary transects per area of myocardial reference tissue) (24,27,28 ⇓ ⇓).

Volume density (Vv) of capillaries, interstitial tissue, and myocytes was obtained using the point-counting method (27–29 ⇓ ⇓) according to the equation Pp = Vv, where Pp is point density. Intercapillary distance, defined as the distance between the centers of two adjacent intramyocardial capillaries, was calculated according to a modification of the formula of Henquell and Honig (27,29 ⇓).

Wall thickness and lumen diameter of intracardial arteries were determined planimetrically using a semiautomatic image analyzing system (Videoplan, Kontron Co., Eching, Germany). Wall-to-lumen ratio was calculated by dividing wall thickness and lumen diameter (27,28 ⇓).

Statistical Analyses

Data are given as mean ± SD. Kruskal-Wallis test or ANOVA were used for analysis, followed by the Bonferroni test. The zero hypothesis was rejected at P < 0.05.

Results

Animal Data

Body and Organ Weights.

At the end of the experiment, body weight was lower in all SNX groups (SNX, SNX+PTX, SNX+R-568) as compared with pair-fed sham-op controls, but it was not significantly different between the SNX groups. The weights of the (remnant) left kidney, heart, and left ventricle were significantly higher in vehicle-treated SNX rats compared with controls as well as with SNX+intervention, either PTX, or R-568 treatment, respectively (Table 1).

View this table:
  • View inline
  • View popup

Table 1. Organ weights and serum parameters at the end of the experiment (week 8)a

PTH Concentration.

PTH concentrations increased progressively with time in vehicle-treated SNX (at 4 wk, 270 ± 151; at 8 wk, 817 ± 899 pg/ml). No PTH was detectable in PTX rats. The efficacy of R-568 in suppressing PTH secretion is documented by the very low PTH levels in SNX+R-568 animals (at week 4, 11.8 ± 21.7; at week 8, 59.3 ± 65.6 pg/ml) (Figure 1). There was no significant difference of serum alkaline phosphatase concentration between the different groups.

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 1. Effects of NPSR-568 (R-568; 50 μmol/kg per d) or parathyroidectomy (PTX) on parathyroid hormone (PTH) concentration (A), serum calcium (B), serum phosphate concentration (C), and serum creatinine concentration (D) 4 wk (□) and 8 wk (▪) after subtotal nephrectomy (SNX). Blood samples were collected 2 h after R-568 or vehicle administration, respectively. a P < 0.05 versus sham-operated control; b P < 0.05 versus vehicle-treated SNX; c P < 0.05 versus SNX+R-568; nd, not detectable.

Calcium and Phosphate Concentrations.

Serum calcium concentrations tended to be slightly higher in vehicle-treated SNX than in controls (this was not statistically significant), but they were significantly lower in SNX+PTX and SNX+R568 than in vehicle-treated SNX (Figure 1).

At the end of the 8-wk experiment, serum phosphate was significantly higher in SNX compared with controls. It was significantly higher in SNX+PTX compared with SNX, but it was not significantly different between SNX+R-568 and SNX (Figure 1).

After 8 wk, urinary calcium excretion (mg/d) was 0.31 ± 0.06 in controls, 0.83 ± 0.09 in SNX treated with vehicle, 0.86 ± 0.09 in SNX+PTX and 0.71 ± 0.11 in SNX+R-568. The values in all SNX groups were significantly higher than in controls (P < 0.01), but there were no significant differences among the SNX groups.

Lipid Parameters.

At the end of the experiment, total cholesterol, HDL cholesterol, and LDL cholesterol concentrations were significantly higher in SNX compared with controls. The LDL-cholesterol concentration was significantly lower in SNX+PTX and SNX+R-568 than in SNX. There was no significant difference in LDL-cholesterol concentration between SNX+PTX and SNX+R-568 (Table 2).

View this table:
  • View inline
  • View popup

Table 2. Lipid parameters at the end of the experiment (week 8)a

Blood Pressure.

Systolic BP (SBP) was significantly higher in SNX rats compared with control rats as early as 2 wk after SNX and increased progressively with time thereafter. SBP was significantly lower in SNX+PTX and SNX+R-568 compared with vehicle-treated SNX and was not significantly different from controls (Figure 2).

Figure2
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 2. Effects of R-568 (50 μmol/kg per d) or PTX during 8 wk on systolic BP in subtotally nephrectomized (SNX) rats. a P < 0.05 versus sham-operated control; b P < 0.05 versus vehicle-treated SNX.

Renal Function.

Serum creatinine concentrations (Figure 1) 4 wk after SNX were significantly higher in vehicle-treated SNX compared with controls. The concentration increased subsequently more markedly in SNX than in SNX+PTX or SNX+R-568, respectively.

Urinary Albumin Excretion Rate.

As early as 2 wk after SNX, urinary albumin excretion rate (UAE) was significantly higher in vehicle-treated SNX compared with controls. At the end of the experiment, UAE was markedly higher in SNX compared with controls; despite a similar initial increase of UAE at 2 wk, the final UAE was significantly lower in SNX+PTX and SNX+R-568 compared with vehicle-treated SNX (Table 3).

View this table:
  • View inline
  • View popup

Table 3. Urinary albumin excretion (mg/24 h) at different time points of the experiment

Structural Abnormalities of the Kidney

In vehicle-treated SNX rats, the glomerulosclerosis index (GSI) and the tubulointerstitial damage index (TID) were significantly higher than in control rats (Figure 3). Both indices were significantly lower but did not reach control values in SNX+PTX and SNX+R-568 rats, respectively.

Figure3
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 3. Effects of of R-568 (50 μmol/kg per d) or PTX on glomerulosclerosis (A) and tubulointerstitial index (B) 8 wk after SNX and on number of PCNA-positive cells per glomerulus (C) and PCNA-positive cells per mm2 of tubulointerstitial area (D) 2 wk after SNX. a P < 0.05 versus sham-operated control; b P < 0.05 versus vehicle-treated SNX group.

In an ancillary experiment (experiment 2), the number of PCNA-positive cells per glomerulus as well as the number of PCNA-positive cells per mm2 of tubulointerstitial area were significantly higher 2 wk after SNX compared with controls. PCNA-positive cells as an index of cell proliferation were significantly lower in SNX+PTX and SNX+R-568 than in vehicle-treated SNX rats (Figure 3).

Structural Abnormalities of the Heart

The lumen diameter of the small intramyocardial arteries was similar in all groups, but there was a significant difference of arterial wall thickness (Table 4). It was significantly higher in vehicle-treated SNX compared with control rats. Arterial wall thickness was significantly lower in SNX+PTX and SNX+R-568, respectively, compared with vehicle-treated SNX.

View this table:
  • View inline
  • View popup

Table 4. Effect of R-568 or PTX on small intramyocardial arteries in rats with subtotal nephrectomy

The volume density of interstitial tissue (excluding capillaries) was significantly higher in vehicle-treated SNX compared with controls (Table 5). It was significantly lower in SNX+PTX and strikingly lower in SNX+R-568 compared with vehicle-treated SNX.

View this table:
  • View inline
  • View popup

Table 5. Effect of R-568 or PTX on interstitial tissue in rats with subtotal nephrectomy

Finally, capillary length density was significantly lower in vehicle-treated SNX compared with controls (Table 6). This reduction was completely prevented in SNX+PTX and SNX+R-568, respectively. The values of intercapillary distance varied inversely with the capillary length density.

View this table:
  • View inline
  • View popup

Table 6. Effect of R-568 or PTX on capillaries in rats with subtotal nephrectomy

Discussion

The present study on the calcimimetic agent R-568 in subtotally nephrectomized rats was designed to evaluate the effect of R-568 on progression of renal failure and cardiovascular changes. It yielded three salient results. First, R-568 indeed attenuated the rate of progression as indicated by measurements of serum-creatinine, creatinine clearance (data not shown; an admittedly poor index of GFR), albumin excretion as well as indices of glomerulosclerosis, tubulointerstitial damage, and proliferating cells number in the glomeruli and the tubulointerstitium. Second, we made the serendipitous observation that R-568 had also a beneficial effect on cardiac structure, i.e., less interstitial fibrosis as well as less thickening of the wall of intermyocardial arteries and less diminution of capillary density as indices of less pronounced microvessel disease. Third, lower SBP values as well as less pronounced dyslipidemia were noted in R-568-treated SNX rats.

Several aspects of the methodology require comment. We deliberately used a model of fast progression first by surgical removal of 70% of renal cortical mass and second by administration of a high-protein diet.

Because calcium sensing receptors occur in numerous organs and are virtually ubiquitous, we considered that evaluating only the effect of R-568 would not permit to distinguish between an intrinsic pharmacologic effect of the calcimimetic on the one hand and abrogation of hyperparathyroidism on the other hand. As a control, we therefore included a group of parathyroidectomized SNX rats. Both R-568 and PTX lowered iPTH concentrations to virtually the same extent. In parallel, the results in PTX animals were practically identical with those obtained in the R-568-treated group. We conclude that the major, if not the only, factor explaining the effect of R-568 on nonclassical organs of PTH is the decrease in iPTH concentration. We acknowledge that the present experiment was not designed to evaluate whether some of the effects of R-568 were caused by an intrinsic action of the blockade of the calcium sensing receptor in tissues outside of the parathyroid. In parallel with low iPTH concentrations, higher phosphate and lower calcium concentrations were noted. This may also have influenced the results; however, there was no significant difference concerning these two parameters in the two intervention groups. This is of note because, independent of PTH and calcitriol, higher phosphate concentrations have a negative effect on structure and function of vascular smooth muscle cells (30) and cardiac fibroblasts (unpublished observation).

The main result of this study is the beneficial effect of R-568 on progression. Evaluation of this problem had been the primary purpose of this study. In a series of experiments, Bonjour and colleagues have shown that PTX prevented progression of chronic renal failure induced by a high-protein diet (9). PTX not only prevented the deterioration of renal function; it also improved survival as had previously been noted in veterinarian literature (31). PTX prevented the increase of the mass of the kidney remnant, i.e., renal hypertrophy, induced by high-protein diet in SNX rats, and the same prevention of renal hypertrophy was noted in uninephrectomized rats (32). In the latter case, this effect was related to increased insulin-like growth factor-1 (IGF-1) concentration. On the other hand, however, there are reports that PTX fails to improve renal function in humans (33), although this latter study comprised only three patients. Furthermore, an increase in serum creatinine and decrease in GFR is noted after PTX of transplanted patients. Such heterogeneity of findings is less surprising in view of the complex results that have recently been reported with respect to renal actions of PTH and PTHrp, respectively. The aminoterminal domain of PTHrp interacts with the receptor that is shared by PTH and PTHrp. Using immunohistochemistry and molecular techniques, the PTH/PTHrp receptor has been demonstrated in the kidney of uninephrectomized rats after a protein overload (34). The PTH/PTHrp receptor is particularly found in the glomerulus and in podocytes (35–38 ⇓ ⇓ ⇓). Micropuncture studies in the rat showed that both PTH and cAMP cause a reduction in the glomerular ultrafiltration coefficient (Kf) (39). Conversely, PTX increases Kf. Further effects that may affect progression are the release of renin induced by PTH (40,41 ⇓). PTH has vasodilatory effects on preglomerular vessels, while efferent arterioles are constricted, presumably secondary to renin release (42). To what extent PTH also has direct effect on renal cells in vivo is uncertain, but such actions of PTH and PTHrp have been demonstrated in cultured human mesangial cells (43). This observation is of interest in view of our observation that the calcimimetic as well as PTX influence renal cell proliferation. It is known that PTHrp is mitogenic for various renal cells (44). We cannot exclude that the lower SBP in our animals played a role in attenuating progression of renal failure, but such near normalization of BP had not been observed in a previous study (9) suggesting that the significant effect of low PTH is at least not fully explained by differences in BP. The calcium sensing receptor is expressed by various types of renal cells (45–47 ⇓ ⇓), but similar changes were seen in R-568 treated and PTX animals; it is therefore unlikely that a direct action of R-568 on the calcium sensing receptor played a role in the beneficial effect on progression observed in the present study. It is noteworthy that we observed no effects of R-568 or 5% dietary calcium supplement on BP in rats with normal renal function (unpublished data). The significantly lower number of PCNA-positive cells in the tubulointerstitium and the trend for fewer PCNA-positive cells in the glomeruli of SNX+PTX and SNX+R-568, respectively, suggest that the lesser weight of the remnant kidney reflects not only less fibrosis, but also less renal growth.

Previous experiments in our laboratory had shown that PTH was a permissive factor for the development of cardiac abnormalities in the renal ablation model such as left ventricular hypertrophy, interstitial fibrosis (12), or wall thickening of postcoronary arteries (13). PTH is significantly correlated to left ventricular mass in patients with essential hypertension (48) as well as in patients with renal failure (49). Experimental studies documented that PTH activates protein kinase C of cardiomyocytes, leading to hypertrophic growth and reexpression of fetal-type proteins (50). The present finding of less cardiac fibrosis and less wall thickening in R-568 treated and PTX+SNX, respectively, is perfectly in line with these observations. The similar effects R-568 and PTX suggest that these findings are indeed due to lower PTH concentration.

One might argue that the effect on cardiac structure was the result of less pronounced hypertension. This is unlikely, however, in view of the fact that in previous studies the development of cardiac structural abnormalities could clearly be dissociated from changes in BP (27,51 ⇓). We acknowledge, however, that further experiments are necessary to formally exclude a confounding effect of higher BP.

The effect of PTH on BP is complex. It is important to keep in mind the possibility of species-related differences and of different short-term versus long-term BP effects of PTH. In the rat, PTH causes acute vasodilation and lowers BP (50), whereas infusion of human 1,34-PTH in healthy volunteers causes an acute modest increase in BP (6). It has been proposed that the acute BP-lowering effect in animals is superseded in the long run by an elevation of BP that results from cellular calcium loading. At least in humans, acute administration of PTH causes acute stimulation of sympathetic activity (52). Recent work in progress showed that PTH does have effects on sympathetic nerve activity in animals as well (53). Another PTH target with potential impact on BP is the endothelial cell. PTH was shown to activate NO production by single endothelial cells (54). In genetically hypertensive rats the BP increase after administration of the NO synthase inhibitor l-NAME is greater after PTX, suggesting less vasodilation. In patients with primary hyperparathyroidism, impaired flow-mediated vasodilation in the brachial artery is improved after PTX (55). A specific effect of PTH on vascular remodeling is suggested by the observation that PTH concentrations in renal patients are related to intima media thickness (56).

We also observed striking amelioration of dyslipidemia in R-568-treated or parathyroidectomized SNX rats. A beneficial effect of PTX on cholesterol levels had been observed by Shigematsu et al. (9) and numerous other authors (57–61 ⇓ ⇓ ⇓ ⇓), but the effect of PTH is probably independent of the presence or absence of renal failure as suggested by the observation of reversible hyperlipoproteinemia in patients with primary hyperparathyroidism (58). This was associated with a decrease in post-heparin LPL activity (60). The observation that administration of insulin corrected the disturbed metabolism of triglyceride-rich particles was interpreted to indicate that the effect of PTH is at least partially indirect, involving inhibition of the secretion of insulin or interference with the peripheral action of insulin (59). On the other hand, in vitro PTH decreased the activity of lipoprotein lipase in adipocytes without affecting LPL mRNA (62). In view of the strong evidence that dyslipidemia is an important risk factor in renal failure (61), our observation that dyslipidemia can be abrogated by R-568 is definitely of interest. One has to keep in mind, however, that there are important species differences of lipid metabolism between the rat and the human.

Calcimimetics are undoubtedly promising agents, with the potential to abrogate hyperparathyroidism (63), parathyroid hyperplasia (22,63 ⇓), and bone disease (17,64 ⇓) in renal failure. The present data further suggest that the benefit from calcimimetics may extend beyond classical target organs of PTH. The data further suggest that calcimimetics have important effects on progression as well as on cardiovascular risk factors such as hypertension and dyslipidemia. Demonstration that the same findings apply to humans will require further studies.

Acknowledgments

We acknowledge the generous gift of NPSR-568 from Dr. Edward F. Nemeth (NPS Pharmaceuticals, Salt Lake City, UT). We also thank Dr. Michihito Wada and Dr. Nobuo Nagano (Pharmaceutical Research Laboratory, Kirin Brewery, Takasaki, Japan) for helpful suggestions.

Footnotes

  • Dr. Donald J. Sherrard served as Guest Editor and supervised the review and final disposition of this manuscript.

  • © 2003 American Society of Nephrology

References

  1. ↵
    Malluche H, Faugere MC: Renal bone disease 1990: an unmet challenge for the nephrologist. Kidney Int 38: 193–211, 1990
    OpenUrlCrossRefPubMed
  2. ↵
    Salusky IB, Goodman WG: Adynamic renal osteodystrophy: Is there a problem? J Am Soc Nephrol 12: 1978–1985, 2001
    OpenUrlFREE Full Text
  3. ↵
    Liang K, Oveisi F, Vaziri ND: Role of secondary hyperparathyroidism in the genesis of hypertriglyceridemia and VLDL receptor deficiency in chronic renal failure. Kidney Int 53: 626–630, 1998
    OpenUrlCrossRefPubMed
  4. ↵
    Vaziri ND, Wang XQ, Liang K: Secondary hyperparathyroidism downregulates lipoprotein lipase expression in chronic renal failure. Am J Physiol 273: F925–F930, 1997
    OpenUrl
  5. ↵
    Fadda GZ, Hajjar SM, Perna AF, Zhou XJ, Lipson LG, Massry SG: On the mechanism of impaired insulin secretion in chronic renal failure. J Clin Invest 87: 255–261, 1991
    OpenUrlCrossRefPubMed
  6. ↵
    Fliser D, Franek E, Fode P, Stefanski A, Schmitt CP, Lyons M, Ritz E: Subacute infusion of physiological doses of parathyroid hormone raises blood pressure in humans. Nephrol Dial Transplant 12: 933–938, 1997
    OpenUrlCrossRefPubMed
  7. ↵
    Rostand SG, Drueke TB: Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 56: 383–392, 1999
    OpenUrlCrossRefPubMed
  8. ↵
    Vaziri ND, Ni Z, Wang XQ, Oveisi F, Zhou XJ: Downregulation of nitric oxide synthase in chronic renal insufficiency: Role of excess PTH. Am J Physiol 274: F642–F649, 1998
    OpenUrlPubMed
  9. ↵
    Shigematsu T, Caverzasio J, Bonjour JP: Parathyroid removal prevents the progression of chronic renal failure induced by high protein diet. Kidney Int 44: 173–181, 1993
    OpenUrlPubMed
  10. ↵
    Clark I, Rivera-Cordero F: Prevention of phosphate-induced nephrocalcinosis by parathyroidectomy. Proc Soc Exp Biol Med 139: 803–805, 1972
    OpenUrlCrossRefPubMed
  11. ↵
    Hirschel-Scholz S, Caverzasio J, Bonjour JP: Prevention of parathyroid hormone-dependent nephrocalcinosis by chronic administration of the organic phosphorothioate WR-2721. Calcif Tissue Int 40: 103–108, 1987
    OpenUrlPubMed
  12. ↵
    Amann K, Ritz E, Wiest G, Klaus G, Mall G: A role of parathyroid hormone for the activation of cardiac fibroblasts in uremia. J Am Soc Nephrol 4: 1814–1819, 1994
    OpenUrlAbstract
  13. ↵
    Amann K, Törnig J, Flechtenmacher C, Nabokov A, Mall G, Ritz E: Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: Evidence for a permissive action of PTH. Nephrol Dial Transplant 10: 2043–2048, 1995
    OpenUrlPubMed
  14. ↵
    Amann K, Ritz E: Cardiac disease in chronic uremia: pathophysiology. Adv Ren Replace Ther 4: 212–224, 1997
    OpenUrlPubMed
  15. ↵
    Wada M, Nagano N, Furuya Y, Chin J, Nemeth EF, Fox J: Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism. Kidney Int 57: 50–58, 2000
    OpenUrlCrossRefPubMed
  16. ↵
    Fox J, Lowe SH, Conklin RL, Nemeth EF: The calcimimetic NPS R-568 decreases plasma PTH in rats with mild and severe renal or dietary secondary hyperparathyroidism. Endocrine 10: 97–103, 1999
    OpenUrlCrossRefPubMed
  17. ↵
    Wada M, Ishii H, Furuya Y, Fox J, Nemeth EF, Nagano N: NPS R-568 halts or reverses osteitis fibrosa in uremic rats. Kidney Int 53: 448–453, 1998
    OpenUrlCrossRefPubMed
  18. ↵
    Silverberg SJ, Bone HG3rd, Marriott TB, Locker FG, Thys-Jacobs S, Dziem G, Kaatz S, Sanguinetti EL, Bilezikian JP: Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. N Engl J Med 337: 1506–1510, 1997
    OpenUrlCrossRefPubMed
  19. ↵
    Goodman WG, Frazao JM, Goodkin DA, Turner SA, Liu W, Coburn JW: A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 58: 436–445, 2000
    OpenUrlCrossRefPubMed
  20. ↵
    Goodman WG, Hladik GA, Turner SA, Blaisdell PW, Goodkin DA, Liu W, Barri YM, Cohen RM, Coburn JW: The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 13: 1017–1024, 2002
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Chin J, Miller SC, Wada M, Nagano N, Nemeth EF, Fox J: Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats. J Am Soc Nephrol 11: 903–911, 2000
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Wada M, Furuya Y, Sakiyama J, Kobayashi N, Miyata S, Ishii H, Nagano N: The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest 100: 2977–2983, 1997
    OpenUrlCrossRefPubMed
  23. ↵
    Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E: Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int 53: 1696–1705, 1998
    OpenUrlCrossRefPubMed
  24. ↵
    Weibel ER: Stereological methods, In: Practical Methods of Biological Morphometry, London, Academic Press, 1979
  25. ↵
    Amann K, Irzyniec T, Mall G, Ritz E: The effect of enalapril on glomerular growth and glomerular lesions after subtotal nephrectomy in the rat: A stereological analysis. J Hypertens 11: 969–975, 1993
    OpenUrlCrossRefPubMed
  26. ↵
    Mattfeldt T, Mall G, Gharehbaghi H, Moller P: Estimation of surface area and length with the orientator. J Microsc 159: 301–317, 1990
    OpenUrlCrossRefPubMed
  27. ↵
    Törnig J, Amann K, Ritz E, Nichols C, Zeier M, Mall G: Arteriolar wall thickening, capillary rarefaction and interstitial fibrosis in the heart of rats with renal failure: The effects of ramipril, nifedipine and moxonidine. J Am Soc Nephrol 7: 667–675, 1996
    OpenUrlAbstract
  28. ↵
    Amann K, Gassmann P, Buzello M, Orth SR, Törnig J, Gross ML, Magener A, Mall G, Ritz E: Effects of ACE inhibition and bradykinin antagonism on cardiovascular changes in uremic rats. Kidney Int 58: 153–161, 2000
    OpenUrlCrossRefPubMed
  29. ↵
    Henquell L, Honig CR: Intercapillary distances and capillary reserve in right and left ventricles: Significance for control of tissue po2. Microvasc Res 12: 35–41, 1976
    OpenUrlCrossRefPubMed
  30. ↵
    Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM: Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87: E10–E17, 2000
    OpenUrlCrossRefPubMed
  31. ↵
    Finco DR, Brown SA, Crowell WA, Hoenig ME, Ferguson DC, Brown CA, Cooper TA: Effects of parathyroidectomy on induced renal failure in dogs. Am J Vet Res 58: 188–195, 1997
    OpenUrlPubMed
  32. ↵
    Caverzasio J, Shigematsu T, Rizzoli R, Bonjour JP: Potential role of IGF-1 in parathyroid hormone-related renal growth induced by high protein diet in uninephrectomized rats. Kidney Int 48: 33–38, 1995
    OpenUrlPubMed
  33. ↵
    Collier VU, Mitch WE: Accelerated progression of chronic renal insufficiency after parathyroidectomy. JAMA 244: 1215–1218, 1980
    OpenUrlCrossRefPubMed
  34. ↵
    Largo R, Gomez-Garre D, Santos S, Penaranda C, Blanco J, Esbrit P, Egido J: Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage. Kidney Int 55: 82–90, 1999
    OpenUrlCrossRefPubMed
  35. ↵
    Sraer J, Sraer JD, Chansel D, Jueppner H, Hesch RD, Ardaillou R: Evidence for glomerular receptors for parathyroid hormone. Am J Physiol 235: F96–F103, 1978
    OpenUrl
  36. ↵
    Massfelder T, Stewart AF, Endlich K, Soifer NE, Judes C, Helwig JJ: Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system. Kidney Int 50: 1591–1603, 1996
    OpenUrlCrossRefPubMed
  37. ↵
    Yang T, Hassan S, Huang YG, Smart AM, Briggs JP, Schnermann JB: Expression of PTHrP, PTH/PTHrP receptor, and Ca(2+)-sensing receptor mRNAs along the rat nephron. Am J Physiol 272: F751–F758, 1997
    OpenUrlPubMed
  38. ↵
    Lee K, Brown D, Urena P, Ardaillou N, Ardaillou R, Deeds J, Segre GV: Localization of parathyroid hormone/parathyroid hormone-related peptide receptor mRNA in kidney. Am J Physiol 270: F186–F191, 1996
    OpenUrlPubMed
  39. ↵
    Sraer J, Ardaillou R, Lorean M, Sraer JD: Evidence for parathyroid hormone sensitive adenylate cyclase in rat glomeruli. Mol Cell Endocrinol 1: 285–294, 1974
    OpenUrl
  40. ↵
    Powell HR, McCredie DA, Rotenberg E: Renin release by parathyroid hormone in the dog. Endocrinology 103: 985–989, 1978
    OpenUrlCrossRefPubMed
  41. ↵
    Helwig JJ, Musso MJ, Judes C, Nickols GA: Parathyroid hormone and calcium: interactions in the control of renin secretion in the isolated, nonfiltering rat kidney. Endocrinology 129: 1233–1242, 1991
    OpenUrlCrossRefPubMed
  42. ↵
    Endlich K, Massfelder T, Helwig JJ, Steinhausen M: Vascular effects of parathyroid hormone and parathyroid hormone-related protein in the split hydronephrotic rat kidney. J Physiol 483: 481–490, 1995
    OpenUrlCrossRefPubMed
  43. ↵
    Bosch RJ, Rojo-Linares P, Torrecillas-Casamayor G, Iglesias-Cruz MC, Rodriguez-Puyol D, Rodriguez-Puyol M: Effects of parathyroid hormone-related protein on human mesangial cells in culture. Am J Physiol 277: E990–E995, 1999
    OpenUrlPubMed
  44. ↵
    Esbrit P, Santos S, Ortega A, Fernandez-Agullo T, Velez E, Troya S, Garrido P, Pena A, Bover J, Bosch RJ: Parathyroid hormone-related protein as a renal regulating factor. From vessels to glomeruli and tubular epithelium. Am J Nephrol 21: 179–184, 2001
    OpenUrlCrossRefPubMed
  45. ↵
    Riccardi D, Hall AE, Chattopadhyay N, Xu JZ, Brown EM, Hebert SC: Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am J Physiol 274: F611–F622, 1998
    OpenUrlPubMed
  46. ↵
    Riccardi D, Traebert M, Ward DT, Kaissling B, Biber J, Hebert SC, Murer H: Dietary phosphate and parathyroid hormone alter the expression of the calcium-sensing receptor (CaR) and the Na+-dependent Pi transporter (NaPi-2) in the rat proximal tubule. Pflugers Arch 441: 379–387, 2000
    OpenUrlCrossRefPubMed
  47. ↵
    Chattopadhyay N: Biochemistry, physiology and pathophysiology of the extracellular calcium-sensing receptor. Int J Biochem Cell Biol 32: 789–804, 2000
    OpenUrlCrossRefPubMed
  48. ↵
    Bauwens FR, Duprez DA, De Buyzere ML, De Backer TL, Kaufman JM, Van Hoecke J, Vermeulen A, Clement DL: Influence of the arterial blood pressure and nonhemodynamic factors on left ventricular hypertrophy in moderate essential hypertension. Am J Cardiol 68: 925–929, 1991
    OpenUrlCrossRefPubMed
  49. ↵
    London GM, De Vernejoul MC, Fabiani F, Marchais SJ, Guerin AP, Metivier F, London AM, Llach F: Secondary hyperparathyroidism and cardiac hypertrophy in hemodialysis patients. Kidney Int 32: 900–907, 1987
    OpenUrlCrossRefPubMed
  50. ↵
    Schluter KD, Piper HM: Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide. Cardiovasc Res 37: 34–41, 1998
    OpenUrlCrossRefPubMed
  51. ↵
    Amann K, Neusüss R, Ritz E, Irzyniec T, Wiest G, Mall G: Changes of vascular architecture independent of blood pressure in experimental uremia. Am J Hypertens 8: 409–417, 1995
    OpenUrlCrossRefPubMed
  52. ↵
    Barletta G, De Feo ML, Del Bene R, Lazzeri C, Vecchiarino S, La Villa G, Brandi ML, Franchi F: Cardiovascular effects of parathyroid hormone: A study in healthy subjects and normotensive patients with mild primary hyperparathyroidism. J Clin Endocrinol Metab 85: 1815–1821, 2000
    OpenUrlCrossRefPubMed
  53. ↵
    Vonend O, Schwertfeger E, Frahnert M, Schieren G, Ritz E, Wetterauer U, Beyersdorf F, Rump LC: Increased noradrenaline (NA) release by activation of presynaptic PTH-receptors in human right atria and renal cortex. Hypertension 40: 591, 2002
    OpenUrl
  54. ↵
    Kalinowski L, Dobrucki LW, Malinski T: Nitric oxide as a second messenger in parathyroid hormone-related protein signaling. J Endocrinol 170: 433–440, 2001
    OpenUrlAbstract
  55. ↵
    Kosch M, Hausberg M, Vormbrock K, Kisters K, Gabriels G, Rahn KH, Barenbrock M: Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy. Cardiovasc Res 47: 813–818, 2000
    OpenUrlCrossRefPubMed
  56. ↵
    Suwelack B, Gerhardt U, Witta J, Hillebrandt U, Hohage H: Effect of parathyroid hormone levels on carotid intima-media thickness after renal transplantation. Am J Hypertens 14: 1012–1018, 2001
    OpenUrlCrossRefPubMed
  57. ↵
    Heuck CC, Liersch M, Ritz E, Stegmeier K, Wirth A, Mehls O: Hyperlipoproteinemia in experimental chronic renal insufficiency in the rat. Kidney Int 14: 142–150, 1978
    OpenUrlCrossRefPubMed
  58. ↵
    Lacour B, Roullet JB, Liagre AM, Jorgetti V, Beyne P, Dubost C, Drueke T: Serum lipoprotein disturbances in primary and secondary hyperparathyroidism and effects of parathyroidectomy. Am J Kidney Dis 8: 422–429, 1986
    OpenUrlPubMed
  59. ↵
    Roullet JB, Lacour B, Yvert JP, Drueke T: Correction by insulin of disturbed TG-rich LP metabolism in rats with chronic renal failure. Am J Physiol 250: E373–376, 1986
    OpenUrlPubMed
  60. ↵
    Akmal M, Kasim SE, Soliman AR, Massry SG: Excess parathyroid hormone adversely affects lipid metabolism in chronic renal failure. Kidney Int 37: 854–858, 1990
    OpenUrlCrossRefPubMed
  61. ↵
    Attman PO, Samuelsson O, Alaupovic P: Lipoprotein metabolism and renal failure. Am J Kidney Dis 21: 573–592, 1993
    OpenUrlCrossRefPubMed
  62. ↵
    Querfeld U, Hoffmann MM, Klaus G, Eifinger F, Ackerschott M, Michalk D, Kern PA: Antagonistic effects of vitamin D and parathyroid hormone on lipoprotein lipase in cultured adipocytes. J Am Soc Nephrol 10: 2158–2164, 1999
    OpenUrlAbstract/FREE Full Text
  63. ↵
    Goodman WG: Calcimimetic agents for the treatment of hyperparathyroidism. Curr Opin Nephrol Hypertens 10: 575–580, 2001
    OpenUrlCrossRefPubMed
  64. ↵
    Olgaard K, Lewin E: Prevention of uremic bone disease using calcimimetic compounds. Annu Rev Med 52: 203–220, 2001
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 14 (4)
Journal of the American Society of Nephrology
Vol. 14, Issue 4
1 Apr 2003
  • Table of Contents
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors
Hiroaki Ogata, Eberhard Ritz, Giulio Odoni, Kerstin Amann, Stephan R. Orth
JASN Apr 2003, 14 (4) 959-967; DOI: 10.1097/01.ASN.0000056188.23717.E5

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors
Hiroaki Ogata, Eberhard Ritz, Giulio Odoni, Kerstin Amann, Stephan R. Orth
JASN Apr 2003, 14 (4) 959-967; DOI: 10.1097/01.ASN.0000056188.23717.E5
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Reversal of Glomerulosclerosis after High-Dose Enalapril Treatment in Subtotally Nephrectomized Rats
  • Protease-Activated Receptor-2 Expression in IgA Nephropathy: A Potential Role in the Pathogenesis of Interstitial Fibrosis
  • Tissue Transglutaminase and the Progression of Human Renal Scarring
Show more Pathophysiology of Renal Disease

Cited By...

  • International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function
  • Induced Pluripotent Stem Cell-Derived Podocyte-Like Cells as Models for Assessing Mechanisms Underlying Heritable Disease Phenotype: Initial Studies Using Two Alport Syndrome Patient Lines Indicate Impaired Potassium Channel Activity
  • Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives
  • Type II Calcimimetics and Polycystic Kidney Disease: Unanswered Questions
  • Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives
  • Novel Role of the Calcium-Sensing Receptor in Blood Pressure Modulation
  • Systemic Activation of the Calcium Sensing Receptor Produces Acute Effects on Vascular Tone and Circulatory Function in Uremic and Normal Rats: Focus on Central versus Peripheral Control of Vascular Tone and Blood Pressure by Cinacalcet
  • Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease (MMKD) Study
  • Cardiovascular Events and Parathyroid Hormone--Suggestion of a Further Link
  • Calcium, Calcium Regulatory Hormones, and Calcimimetics: Impact on Cardiovascular Mortality
  • Acute Blood Pressure Effects and Chronic Hypotensive Action of Calcimimetics in Uremic Rats
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire