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NDT Advance Access published online on April 9, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn188
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The relationship between bone morphogenic protein-7 and peritoneal transport characteristics

Cheuk-Chun Szeto, Kai-Ming Chow, Bonnie Ching-Ha Kwan, Ka-Bik Lai, Kwok-Yi Chung, Chi-Bon Leung and Philip Kam-Tao Li

Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China

Correspondence and offprint requests to: C.-C. Szeto, Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. Tel: +852-2632-3126; Fax: +852-2637-3852; E-mail: ccszeto{at}cuhk.edu.hk



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Reference
 
Background. After prolonged peritoneal dialysis (PD) and exposure to a non-physiological dialysis solution, peritoneal mesothelial cells undergo the epithelial-to-mesenchymal transition. In other biological systems, bone morphogenic protein-7 (BMP-7) is a key factor that controls this process. However, the role of BMP-7 in peritoneal physiology has not been studied.

Methods. We studied the peritoneal transport characteristics of 50 consecutive new PD patients at 4 and 52 weeks after PD. Peritoneal permeability will be determined by the standard peritoneal equilibration test (PET). BMP-7 in PD effluent (PDE) at mRNA and protein level at 4 weeks was quantified.

Results. At 4 weeks, the mRNA expression of BMP-7 in PDE significantly correlated with peritoneal transport characteristics, including the dialysate-to-plasma creatinine ratio at 4 h (D/P4) (r = 0.422, P = 0.015) and mass transfer area coefficient (MTAC) of creatinine (r = 0.457, P = 0.008). The PDE BMP-7 level by ELISA also had marginal correlation with D/P4 (r = 0.287, P = 0.072) and MTAC creatinine (r = 0.287, P = 0.073), although the result did not reach statistical significance. For the subgroup of patients who remained free of peritonitis, the PDE BMP-7 level by ELISA had significant correlation with the change in D/P4 (r = 0.441, P = 0.017) and MTAC creatinine in 52 weeks (r = 0.415, P = 0.025). The PDE BMP-7 level remained independently associated with the change in peritoneal transport adjusting for age, sex, serum C-reactive protein and PDE transforming growth factor-beta level. In patients who had peritonitis during the study period, the PDE BMP-7 level did not affect the change in peritoneal transport.

Conclusion. We find that the peritoneal BMP-7 level correlates with peritoneal transport characteristics, and a high PDE BMP-7 level is associated with a gradual increase in peritoneal transport parameters with time. It remains unclear, however, whether this effect is beneficial, and the therapeutic role of exogenous BMP-7 on peritoneal transport requires a further study.

Keywords: growth factor; renal failure; ultrafiltration



   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Reference
 
Peritoneal dialysis (PD) is the first-line treatment of end-stage kidney disease in Hong Kong [1]. The success of PD depends on the sustained ability of the peritoneum to act as a semi-permeable membrane [2]. A peritoneal mesothelial cell (PMC) is important in the homeostasis of the peritoneal membrane and plays active roles in local defence, synthesis and remodelling of an extra-cellular matrix [3]. After prolonged PD and exposure to a non-physiological dialysis solution, PMC undergoes the epithelial-to-mesenchymal transition (EMT), resulting in fibroblast-like phenotype and loss of the semi-permeable characteristics [4,5]. However, the underlying mechanism of EMT is unknown.

In fact, EMT is a central mechanism for diversifying the cells found in complex tissues [6]. In chronic kidney diseases, it has recently been shown that transforming growth factor-beta (TGF-β) and bone morphogenic protein-7 (BMP-7) maintain a delicate balance in the control of renal tubular cell EMT [7]. Activation of the TGF-β receptor on an epithelial cell induces the phosphorylation of Smad2 and Smad3 and its nuclear import with Smad4, which promote the epithelial–mesenchymal transition and repress the mesenchymal–epithelial transition. On the other hand, activation of the BMP-7 receptor induces the phosphorylation of Smad1, Smad5 and Smad8, which in the nucleus engages the mesenchymal–epithelial transition and opposes the epithelial–mesenchymal transition. TGF-β signalling encourages the formation of fibroblasts and an interstitial matrix through the epithelial–mesenchymal transition, while the BMP-7 action tends to preserve the epithelial phenotype [6,7].

The role of TGF-β in PMC function and clinical PD is well studied. For example, glucose stimulates PMC production of TGF-β [8], which in turn up-regulates the collagen, especially type III collagen, synthesis by PMC [9,10]. In vitro, TGF-β induces EMT of PMC after a prolonged exposure [11]. The role of BMP-7 in peritoneal dialysis, in contrast, has not fully been explored, although the reversion from mesenchymal to epithelial phenotype by BMP-7 has recently been demonstrated for transdifferentiated mesothelial cells [12,13]. The present study aimed to examine the relationship between BMP-7 in peritoneal dialysis effluent and the longitudinal change in peritoneal transport characteristics in a cohort of new PD patients.



   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Reference
 
Patient selection
We studied 50 consecutive new PD patients in our unit. We excluded patients who were unlikely to survive, planned to have elective living-related kidney transplant or transferred to other renal centre within 6 months. Informed consent was obtained at the time of Tenckhoff insertion. Baseline clinical data were recorded by chart review. These included age, sex, underlying renal disease and CAPD regimen. A panel of comorbid conditions, including coronary artery disease, heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disorder, peptic ulcer disease, liver disease, diabetes with and without complications, hemiplegia, malignancy and acquired immunodeficiency syndrome (AIDS), was also recorded. The modified Charlson's comorbidity index, which was validated in CAPD patients [14], was used to calculate a comorbidity score. Patients were followed up for 52 weeks. The clinical management was not affected by the study. No patient received amino acid or glucose polymer-based peritoneal dialysis solution. Dialysis prescription was changed only when there was clinical evidence of under-dialysis [1]. Since peritoneal transport may be related to systemic inflammation [15,16], serum C-reactive protein (CRP) was measured at 4 weeks by the Tina-quant CRP (Latex) ultra-sensitive assay (Roche Diagnostics GmbH, Mannheim, Germany) as described in our previous studies [17,18].

Study of the peritoneal transport kinetics
The peritoneal equilibration test (PET) was performed by the method of Twardowski [19] at 4 and 52 weeks after PD. All the measurements were performed when the patients were in the euvolemic state and at least 2 months after an episode of peritonitis. Briefly, a 4-h dwell study was carried out with 2 L of glucose, 2.5% dialysis fluid (Dianeal, Baxter-Travenol, Deerfield, IL, USA). Dialysate creatinine and glucose levels at 0, 2 and 4 h, and plasma creatinine and glucose levels at 2 h were measured. Drainage and ultrafiltration volumes (UF) at 4 h are documented. Creatinine concentration in dialysate is corrected according to a validated formula [20]. Dialysate-to-plasma ratios of creatinine (D/P) at 0, 2 and 4 h were calculated after the correction of glucose interference. Results were plotted on a PET graph. The mass transfer area coefficient of creatinine (MTAC) normalized for BSA was calculated by the formula described by Krediet [21]. Body surface area (BSA) was determined from body weight and height by nomogram [22].

BMP-7 mRNA expression in peritoneal cells
After the PET at 4 weeks, all the dialysis effluent drained (~2 L) was used for RNA extraction. We followed the methods of RNA extraction described previously [23,24]. Briefly, the complete drainage of PDE at 4 h of PET was centrifuged at 3000 g for 30 min at 4°C; the supernatant was stored for ELISA assay (see below). Total RNA is extracted by the RNeasy Mini Kit (Qiagen Inc., Canada). All specimens were pre-treated with deoxyribonuclease.

Around 0.5 µg of RNA was reverse transcribed to complementary DNA. Real-time quantitative polymerase chain reaction (RT-QPCR) was performed by a ABI Prism 7700 Sequence Detector System (Applied Biosystems, Foster City, CA, USA). Taqman primers and probes of BMP-7 were commercially available from Applied Biosystems. BMP-7 mRNA expression for each signal was calculated by using the {Delta}Ct procedure according to manufacturer's instruction, with 18s rRNA used as housekeeping gene for normalization among samples. The results were analysed by Sequence Detection Software version 1.7 (Applied Biosystems).

BMP-7 and TGF-β protein level in dialysis effluent
BMP-7 level in PD effluent was measured after a 4-h dwell of the PET at 4 weeks of PD (see above) by a commercially available ELISA kit (RayBio® Human BMP-7 ELISA kit, RayBiotech Inc., Peterborough, UK), following the manufacturer's instruction. The detection limit of the kit is 15 pg/ mL; the inter-assay coefficient of variation is <12%.

A sandwich enzyme-linked immunosorbent assay was used to measure TGF-β in PDE (R&D Systems, McKinley Place, Minneapolis, MN, USA). The detection limit of the assay was 5 pg/mL; the intra-assay coefficient of variation was <8%.

Statistical analysis
Statistical analysis was performed by SPSS for Windows software version 11.0 (SPSS Inc., Chicago, IL, USA). Data were expressed as mean ± SD. Comparisons between the BMP-7 level in PD effluent (by RT-QPCR and ELISA) and baseline peritoneal transport parameters, as well as their longitudinal change over 1 year, were performed by Spearman's correlation coefficient. To adjust for possible confounding factors, we performed multiple linear regression analysis to identify independent factors associated with the baseline peritoneal transport characteristics as well as the change in peritoneal transport in 1 year. In addition to the PDE BMP-7 and TGF-β levels, we also added age, sex and serum CRP as independent variables for model construction. A P-value <0.05 was considered statistically significant. All probabilities were two-tailed.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Reference
 
The baseline clinical characteristics and major comorbid conditions are summarized in Table 1. The baseline peritoneal transport characteristics are summarized in Table 2. The baseline PDE BMP-7 level was 174.6 ± 58.0 pg/mL, and the TGF-β level was 466.9 ± 337.9 pg/mL. There was a modest but statistically significant correlation between the PDE BMP-7 level by ELISA and its gene expression level by RT-QPCR (r = 0.333, P = 0.036).


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  		Table 1 Baseline characteristics of the patients

 

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  		Table 2 Peritoneal transport characteristics, dialysis adequacy, residual renal function and nutritional indices

 
BMP-7 and baseline peritoneal transport
The mRNA expression of BMP-7 in PDE significantly correlated with peritoneal transport characteristics, including the dialysate-to-plasma creatinine ratio at 4 h (D/P4) (r = 0.422, P = 0.015) and the mass transfer area coefficient (MTAC) of creatinine (r = 0.457, P = 0.008) (Figure 1). The mRNA expression of BMP-7 also had a significant inverse correlation with the serum CRP level (r = –0.427, P = 0.013) (Figure 2). The PDE BMP-7 level by ELISA also had a marginal correlation with D/P4 (r = 0.287, P = 0.072) and MTAC creatinine (r = 0.287, P = 0.073) (Figure 1), although the result did not reach statistical significance. In contrast, the PDE TGF-β level inversely correlated with D/P4 (r = –0.347, P = 0.028) and MTAC creatinine (r = –0.319, P = 0.045). Neither the mRNA expression nor the PDE BMP-7 level by ELISA correlated with the net ultrafiltration volume (details not shown). After adjusting for confounding factors by the multiple linear regression model, however, only age and the PDE TGF-β level were independent factors associated with baseline D/P4 and MTAC creatinine (Table 3).


Figure 1
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  		Fig. 1 The relation between bone morphogenic protein-7 (BMP-7) in peritoneal dialysis effluent and peritoneal transport characteristics: (A) BMP-7 mRNA expression and dialysate-to-plasma (D/P) of creatinine at 4 h; (B) BMP-7 mRNA expression and mass transfer area coefficient (MTAC) of creatinine; (C) BMP-7 level by ELISA and D/P of creatinine at 4 h and (D) BMP-7 level by ELISA and MTAC of creatinine. Data are compared by Spearman's rank correlation coefficient.

 

Figure 2
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  		Fig. 2 The relation between mRNA expression of bone morphogenic protein-7 (BMP-7) in peritoneal dialysis effluent and serum C-reactive protein.

 

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  		Table 3 Multiple linear regression model for independent factors associated with baseline peritoneal transport characteristics

 
BMP-7 and change in peritoneal transport
After 52 weeks of follow-up, two patients had died and three had received kidney transplantation. There were 27 episodes of peritonitis in 15 patients, while 35 patients were free of peritonitis. The change in peritoneal transport characteristics is summarized in Table 2. Although there was a trend of reduction in total ultrafiltration, D/P4 and MTAC creatinine over 52 weeks, there result was not statistically significant.

The PDE BMP-7 level by ELISA had a trend of correlation with the change in D/P4 (r = 0.310, P = 0.052) and MTAC creatinine in 52 weeks (r = 0.276, P = 0.085), but the result did not reach statistical significance. When the subgroup of patients who remained free of peritonitis were analysed, the PDE BMP-7 level by ELISA had a significant correlation with the change in D/P4 (r = 0.441, P = 0.017) and MTAC creatinine in 52 weeks (r = 0.415, P = 0.025) (Figure 3), but not with the net ultrafiltration volume (r = –0.235, P = 0.2). In the subgroup of patients who were peritonitis free, the PDE TGF-β level also had a trend of correlation with the change in D/P4 (r = 0.313, P = 0.09) and MTAC creatinine (r = 0.326, P = 0.08), but the result did not reach statistical significance.


Figure 3
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  		Fig. 3 The relation between bone morphogenic protein-7 (BMP-7) level in peritoneal dialysis effluent by ELISA and change in peritoneal transport characteristics over 52 weeks: (A) dialysate-to-plasma (D/P) of creatinine at 4 h; and (B) mass transfer area coefficient (MTAC) of creatinine.

 
After adjusting for confounding factors by the multiple linear regression model, both PDE BMP-7 and TGF-β levels were independent factors associated with the change in D/P4 in 1 year; the PDE BMP-7 level was the only independent factor associated with the change in MTAC creatinine in 1 year, while the effect of the PDE TGF-β level just fell short of statistical significance (Table 4). In the subgroup of patients who had peritonitis during the study period, the PDE BMP-7 level did not affect the change in any of the peritoneal transport characteristics (details not shown).


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  		Table 4 Multiple linear regression model for independent factors associated with the change peritoneal transport characteristics in 1 yeara

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Reference
 
In the present study we find that the peritoneal BMP-7 level correlates with peritoneal transport characteristics, and a high PDE BMP-7 level is associated with a gradual increase in peritoneal transport parameters with time.

Previous studies suggested a centripetal change of peritoneal transport with time: peritoneal transport tended to decrease for high transporters but the other way round for low transporters [25–27]. At a first glance, our observation that a high peritoneal BMP-7 is related to both a high baseline peritoneal transport and an increase in the peritoneal transport parameter with time may seem contradictory. Nonetheless, it adds weight to the argument that the increase in the peritoneal transport parameter with time in patients with high peritoneal BMP-7 is genuine and not a chance finding due to the low baseline peritoneal transport.

Our finding is consistent with the observations in chronic kidney diseases. For example, Zeisberg et al. [28] reported that BMP-7 induced the mesenchymal-to-epithelial transition in adult renal fibroblasts and facilitated regeneration of injured kidney. The same group subsequently showed that systemic administration of recombinant human BMP-7 led to the repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury in a mouse model [29]. We also observe an inverse correlation between PDE BMP-7 expression and serum CRP level, suggesting that peritoneal BMP-7 may be a negative marker of systemic inflammation.

It remains unclear, however, whether the observed effect of BMP-7 on peritoneal transport represents a beneficial effect. In fact, the high peritoneal transport status was consistently found to be associated with mortality and technique failure in PD patients [30–32]. On the other hand, Vargha et al. [12] recently reported ex vivo reversal of in vivo transdifferentiation in mesothelial cells grown from peritoneal dialysate effluents, supporting the hypothesis that exogenous BMP-7 may have potential therapeutic benefit in peritoneal failure. Further studies are needed to determine whether exogenous BMP-7 would produce clinically meaningful benefit.

There are several limitations of our study. Firstly, we have no data on the peritoneal transport prior to the initiation of PD, and the data on peritoneal BMP-7 and peritoneal transport at 4 weeks may represent post-treatment rather than truly baseline assessment. It is important, however, to bear in mind that PET is only reliable in assessing peritoneal transport at least 4 weeks after the commencement of PD. Secondly, we examined the total mRNA expression of BMP-7 in dialysis effluent, and the cellular origin of the mRNA was not confirmed. However, our previous flow cytometry study showed that macrophage and mesothelial cells are the two major cell types in the effluent of stable peritoneal dialysis patients [33]. Since BMP-7 is largely produced by mesenchymal cells [34], we believe that the BMP-7 mRNA we found in dialysis effluent came from both mesothelial cells and macrophages.

Because of budgetary constrain, we did not measure the level of other relevant cytokines, such as vascular endothelial growth factor, in dialysis effluent or plasma. We did, however, observe a significant negative correlation between peritoneal BMP-7 expression and serum CRP level, suggesting that systemic inflammation may negatively influence BMP-7. We also did not measure the simultaneous plasma BMP-7 level. Theoretically, BMP-7 has a molecular weight of nearly 30 000 Da. Its peritoneal permeability is expectedly poor—any BMP-7 protein detected in PDE should represent local production rather than leakage from systemic circulation. Furthermore, the number of subject who had peritonitis during the study period was small. Although we did not observe any effect of BMP-7 on the change in peritoneal transport in patients who had peritonitis, our study does not have an adequate statistical power to detect such an effect.

In summary, we find that peritoneal BMP-7 level correlates with peritoneal transport characteristics, and a high PDE BMP-7 level is associated with a gradual increase in peritoneal transport parameters with time. It remains unclear, however, whether this effect is beneficial, and the therapeutic role of exogenous BMP-7 on peritoneal transport requires a further study.



   Acknowledgments
 
This study was supported in part by the Hong Kong Society of Nephrology Research Grant, CUHK research account 6901031 and the Richard Yu Peritoneal Dialysis Research Fund.

Conflict of interest statement. None declared.



   Reference
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Reference
 

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Received for publication: 4. 9.07
Accepted in revised form: 11. 3.08


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Perit. Dial. Int., February 1, 2009; 29(Supplement_2): S123 - S127.
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