- Email: [email protected]
The goddess of the waters
co m m e nta r y
PKD1 alleles exist and may account for the considerable variability in disease seen in some families. Further analysis of and additional large-scale mutation screens in ADPKD supported by detailed phenotypic analysis and family studies are now required to determine whether the total burden of all sequence variants and missense changes, either in cis or trans, is correlated with disease severity. It is an intriguing thought that total sequence variation in PKD1 itself may be a major determinant of disease severity and variability.
in polycystic kidney disease. Kidney Int 2009; 75: 848–855. 14. MacDermot KD, Saggar-Malik AK, Economides DL et al. Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis
DISCLOSURE The author declared no competing interests.
The renal lymphatic system is cardinal in circulatory physiology and immunology. Sakamoto et al. report that lymphatic angiogenesis is increased in tubulointerstitial lesions in human chronic renal disease and correlates with tissue damage. Moreover, lymphatic growth was associated with vascular endothelial growth factor-C (VEGF-C) expression in mononuclear and tubular epithelial cells. Diabetic nephropathy had the highest level of VEGF-C and the most extensive lymphangiogenesis. The data suggest that lymphangiogenesis is a common feature in the progression of tubulointerstitial fibrosis.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 2008; 3: 1197–1204. Rossetti S, Consugar MB, Chapman AB et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2007; 18: 2143–2160. Yoder BK. Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol 2007; 18: 1381–1388. Rossetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol 2007; 18: 1374–1380. Torra R, Badenas C, Darnell A et al. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol 1996; 7: 2142–2151. Harris PC, Bae KT, Rossetti S et al. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2006; 17: 3013–3019. Pei Y, Paterson AD, Wang KR et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am J Hum Genet 2001; 68: 355–363. Paterson AD, Magistroni R, He N et al. Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2005; 16: 755–762. Garcia-Gonzalez MA, Jones JG, Allen SK et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab 2007; 92: 160–167. Rossetti S, Burton S, Strmecki L et al. The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 2002; 13: 1230–1237. Magistroni R, He N, Wang K et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2003; 14: 1164–1174. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ et al. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 2004; 13: 3069–3077. Rossetti S, Kubly VJ, Consugar MB et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation
Kidney International (2009) 75
for very early onset disease. J Med Genet 1998; 35: 13–16. 15. Bergmann C, Bruchle NO, Frank V et al. Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation. N Engl J Med 2008; 359: 318–319.
see original article on page 828
The goddess of the waters Harry van Goor1 and Henri G.D. Leuvenink2
Kidney International (2009) 75, 767–769. doi:10.1038/ki.2009.45
Why not start with a reference to Hippocrates, who is thought to have first discovered the existence of lymph? Lympha originates from the Greek word nymphe, a goddess of the waters. So, it is crystal clear that lymph is a colorless fluid— except for the lymph found in the lacteal vessels of the mesentericum, which turns white after a meal because of the absorption of dietary fats as first described by Asellio during the Renaissance. The traditional functions of the lymphatic system are ascribed to circulatory physiology and immunology. Fluid leaking through the semipermeable capillary bed into the interstitium, after picking up antigens and immunologically active cells, is collected in lymph capillaries, drained to regional lymph nodes, and exposed to the lymphoid 1Department of Pathology, University Medical
Center Groningen, Groningen, The Netherlands; 2Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands Correspondence: Harry van Goor, Department of Pathology, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. E-mail: [email protected]
system. After filtration, the lymph fluid returns to the blood and continues its lifelong task: the draining of organs under physiological conditions. The lymph drainage system becomes especially challenged during disease conditions such as wound healing, inflammation, and infection, when excessive fluid, lymphocytes, and dendritic cells travel through the lymphatic vessels to the lymph nodes. This is not an indolent process, but a masterminded system in which adhesion molecules, cytokines, and chemokines are crucially involved. During disease states, the number and maturation state of dendritic cells increase dramatically. Knowledge of how leukocytes migrate over the lymphatic wall is sparse, although intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are known to be involved, as ICAM-1-deficient mice have a defect in lymph node recruitment of dendritic cells. The role of cellular trafficking through the lymphatic system also painfully reveals unappreciated side effects such as are seen in the dissemination of metastatic cancer cells. 767
com m enta r y
AGEs Tubule
Glucose Fibroblast Macrophage Cytokines ECM
AGEs Capillary
Cytokines VEGF-C
Glucose
Lymphangiogenesis
Figure 1 | Simplified scheme of the development of lymphangiogenesis in interstitial fibrosis associated with diabetic nephropathy. Clusters of macrophages are present in the fibrotic interstitium. These macrophages are activated in an autocrine or paracrine fashion through the production of cytokines such as interleukin-1. Glucose is present in the interstitial fibrotic areas, as are advanced glycation end products (AGEs). All these factors contribute to the production of vascular endothelial growth factor-C (VEGF-C) by macrophages and thereby to the formation of lymphatics. ECM, extracellular matrix.
In the experimental setting, the functional role of lymphatics has become more evident. Acute ureteral obstruction causes dilation and reflux into intrarenal lymphatics. Interestingly, in chronic obstruction, Tamm-Horsfall proteins leak from tubules into the lymphatics and can be found in lymph nodes in the hilum of the kidney. In short-term hilar lymph duct ligation, Wilcox et al. noted that lymphatic drainage is required to maintain a low renal cortical hydraulic pressure and that ligation decreases sodium and fluid reabsorption.1 The relation of lymphatics to renal fibrosis has been studied in several models. In reflux nephropathy, fibrosis follows the distribution of lymphatics. In remnant kidneys, proliferation of lymphatic vessels was observed in the fibrotic tubulointerstitial areas.2 Disturbance of the lymph circulation by lymphatic duct ligation alone or in combination with nephrectomy causes proteinuria and renal fibrosis.3 Several markers of the endothelial cells lining the lymphatic vessels are now available, including LYVE-1 (hyaluronate receptor), Prox-1 (lymphatic transcription factor), podoplanin (a type I integral membrane glycoprotein), factors of the vascular endothelial growth factor family (VEGF), and the sialoglycoprotein D2-40 (a lymphatic endothelium-specific protein). The localization of the normal renal lymphatic vessels has been described in animals and humans and reveals the abundant presence around intrarenal arteries and veins, with 768
a more scarce localization around glomeruli and between tubules. Medullary lymphatics are extremely rare. Lymphatics have been of special interest in the field of renal transplantation, in which the lymphatic system is not restored during implantation, in contrast to the vascular system. One of the key physiological questions was whether disruption of lymphatic drainage would influence functioning of the graft. Early studies provided evidence that the disruption is not harmful for the kidney and that the lymphatic system is restored over time.4 Even more crucial is the role of renal lymphatics in the immunological response after renal transplantation. In allograft rejection, cellular infiltrates are key elements, and lymphatics provide an exit route for lymphocytes and macrophages. Recently, the presence of newly formed lymphatic vessels in human renal transplant biopsies near the nodular cell infiltrates was reported.5 The presence of these lymphatic structures is thought to be involved not only in removal of the rejection infiltrate but also in the continuing alloreactive immune response leading to chronic rejection.6 Newly formed lymphatic vessels presumably also organize the perivascular lymphocytes into immunologically active follicular structures, that are involved in the survival of the transplant. Interestingly, lymphangiogenesis occurs early, within 72 h after transplantation. Findings of Stuht et al.7 indicate that the
number of lymphatic vessels does not increase in time, nor is it correlated with rejection in the first year, but that it is correlated with worse functional graft outcome. This suggests that early damage to the graft during the transplantation, or maybe even in the donor situation, increases the susceptibility of the graft to rejection. This is also illustrated by the report of Franksson et al. in which lymphocyte depletion by drainage of lymph via thoracic duct fistula was found to be a beneficial supplementary treatment modality in regard to one-year graft survival when combined with anti-thymocyte serum in cadaveric graft recipients but not in recipients receiving a living-donor organ.8 The renewed interest and novel findings in the field of cell traffic and lymphatic endothelium indicate that the lymphatic endothelium is a potential target for immunosuppressive therapy.9 An intact lymphatic system might be pivotal, not only for the immune surveillance of the alloresponse, but also for the clearance of all kinds of pathogens attacking the transplant—for example, viruses such as herpes, as well as polyoma viruses. The macrophage is central in the pathogenesis of renal fibrosis and repair10 and also contributes to the formation of lymphatic vessels through production of VEGF-C (Figure 1). The lymphatic vessels and interstitium of remnant kidneys contain mononuclear cells that express VEGF-C mRNA. Maruyama et al. studied lymphangiogenesis in diabetes and found that renal macrophages contribute to the formation of lymphatics.11 Surprisingly, glucose per se or interleukin-1 decreased the production of VEGF-C in macrophages, whereas the combination of the two caused a significant increase in VEGF-C production, revealing the lymphangiogenic potential of these cells in inflammatory diabetic conditions (Figure 1). Moreover, application of interleukin-1 to wounds in db/db mice induced lymphatic vessel formation and accelerated wound healing. A second phenomenon central to the pathogenesis of diabetic nephropathy is the formation and accumulation of advanced glycation end products (AGEs).12 AGEs have also been shown to be able to activate macrophages and induce induction of VEGF in these cells. In this way AGEs may also contribute to the Kidney International (2009) 75
co m m e nta r y
formation of lymphatics. Hypoxia induced by vessel damage and fibrosis is another crucial factor involved in the pathogenesis of diabetic renal disease damage. It is known from the oncology field that the invasion and migration of microvascular endothelial cells is increased during hypoxia.13 Sakamoto et al.14 (this issue) investigated the expression of D2-40–positive lymphatic vessels, with special interest in VEGF-C, a crucial mediator of lymphan-giogenesis in chronic renal disease. They meticulously mapped the presence of lymphatic vessels in a wide range of renal diseases using D2-40 and VEGF-C antibodies. They confirmed the absence of corticomedullary lymphatics in control kidneys but found lymphangiogenesis in tubulointerstitial fibrosis and inflammatory interstitial areas in various renal diseases. These vessels were often filled with mononuclear cells. Interestingly, lymphangiogenesis and VEGF-C expression were elevated in diabetic nephropathy as compared with other renal diseases. The study is a solid base for continuing research, as several questions remain and have to be resolved. For instance, do glucose and AGEs have any effect on the production of VEGF-C by resident glomerular cells and the subsequent growth of lymphatic vessels? This question can easily be resolved in an in vitro setup. What are the other signals involved in lymphangiogenesis? Do components of the extracellular matrix per se have any effect on lymphangiogenesis? And what about ischemia, a central event in chronic renal disease and renal transplantation; does it provoke VEGF-C expression and lymphangiogenesis? What is the role of cyclosporine in the formation of lymphatics? Despite all these questions, this elegant, elaborate study of Sakamoto et al.14 definitely paves the way for further research in the field of lymphatics in chronic renal disease. Novel therapeutic interventions aiming at the modulation of growth and proliferation of lymphatic cells may lead to better treatment modalities and understanding of chronic renal disease. DISCLOSURE The authors declared no competing interests. ACKNOWLEDGMENTS This work was supported by funds from the Dutch Kidney Foundation. The authors thank Willem van Son for helpful discussions. Kidney International (2009) 75
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Wilcox CS, Sterzel RB, Dunckel PT et al. Renal interstitial pressure and sodium excretion during hilar lymphatic ligation. Am J Physiol 1984; 247: F344–F351. Matsui K, Nagy-Bojarsky K, Laakkonen P et al. Lymphatic microvessels in the rat remnant kidney model of renal fibrosis: aminopeptidase p and podoplanin are discriminatory markers for endothelial cells of blood and lymphatic vessels. J Am Soc Nephrol 2003; 14: 1981–1989. Zhang T, Guan G, Liu G et al. Disturbance of lymph circulation develops renal fibrosis in rat with and without contralateral nephrectomy. Nephrology (Carlton) 2008; 13: 128–138. Mobley JE, O’Dell RM. The role of lymphatics in renal transplantation. Renal lymphatic regeneration. J Surg Res 1967; 7: 231–233. Kerjaschki D, Regele HM, Moosberger I et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 2004; 15: 603–612. Thaunat O, Patey N, Morelon E et al. Lymphoid neogenesis in chronic rejection: the murderer is in the house. Curr Opin Immunol 2006; 18: 576–579. Stuht S, Gwinner W, Franz I et al. Lymphatic neoangiogenesis in human renal allografts: results
8.
9.
10.
11.
12.
13.
14.
from sequential protocol biopsies. Am J Transplant 2007; 7: 377–384. Franksson C, Lundgren G, Magnusson G et al. Drainage of thoracic duct lymph in renal transplant patient. Transplantation 1976; 21: 133–140. Johnson LA, Jackson DG. Cell traffic and the lymphatic endothelium. Ann NY Acad Sci 2008; 1131: 119–133. Ricardo SD, van Goor H, Eddy A. Macrophage diversity in renal injury and repair. J Clin Invest 2008; 118: 3522–3530. Maruyama K, Asai J, Li M et al. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 2007; 170: 1178–1191. Pertyńska-Marczewska M, Kiriakidis S, Wait R et al. Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages. Cytokine 2004; 28: 35–47. Mikhaylova M, Mori N, Wildes FB et al. Hypoxia increases breast cancer cell-induced lymphatic endothelial cell migration. Neoplasia 2008; 10: 380–388. Sakamoto I, Ito Y, Mizuno M et al. Lymphatic vessels develop during tubulointerstitial fibrosis. Kidney Int 2009; 75: 828–838.
see original article on page 793
Regulation of renal arteriolar tone by adenosine: novel role for type 2 receptors Tracy D. Bell1 and William J. Welch1 Tubuloglomerular feedback regulation of glomerular filtration rate (GFR) is mediated by adenosine, which acts on type 1 receptors in the afferent arteriole to increase resistance. However, new findings in isolated mouse tissue suggest that adenosine also dilates the efferent arteriole, which would reinforce the ability of adenosine to reduce GFR. This new information extends the concept that adenosine acts as a paracrine agent on both afferent and efferent arterioles. Kidney International (2009) 75, 769–771. doi:10.1038/ki.2009.18
Regulation of glomerular filtration is a critical element of the homeostatic function of the kidney to maintain stable fluid 1Department of Medicine, Georgetown University, Washington, DC, USA Correspondence: William J. Welch, Department of Medicine, Georgetown University, Building D-395, 4000 Reservoir Road, Washington, DC 20057, USA. E-mail: [email protected]
and electrolyte balance. Much of this regulation is dependent on the control of the renal arterioles surrounding the glomerular capillary. The study by Al-Mashhadi et al.1 (this issue) provides new information and clarification of a potentially important mechanism that targets efferent arteriolar tone. The authors show that adenosine acting on type 2 receptors dilates the efferent arteriole. This provides 769
PKD1 alleles exist and may account for the considerable variability in disease seen in some families. Further analysis of and additional large-scale mutation screens in ADPKD supported by detailed phenotypic analysis and family studies are now required to determine whether the total burden of all sequence variants and missense changes, either in cis or trans, is correlated with disease severity. It is an intriguing thought that total sequence variation in PKD1 itself may be a major determinant of disease severity and variability.
in polycystic kidney disease. Kidney Int 2009; 75: 848–855. 14. MacDermot KD, Saggar-Malik AK, Economides DL et al. Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis
DISCLOSURE The author declared no competing interests.
The renal lymphatic system is cardinal in circulatory physiology and immunology. Sakamoto et al. report that lymphatic angiogenesis is increased in tubulointerstitial lesions in human chronic renal disease and correlates with tissue damage. Moreover, lymphatic growth was associated with vascular endothelial growth factor-C (VEGF-C) expression in mononuclear and tubular epithelial cells. Diabetic nephropathy had the highest level of VEGF-C and the most extensive lymphangiogenesis. The data suggest that lymphangiogenesis is a common feature in the progression of tubulointerstitial fibrosis.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 2008; 3: 1197–1204. Rossetti S, Consugar MB, Chapman AB et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2007; 18: 2143–2160. Yoder BK. Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol 2007; 18: 1381–1388. Rossetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol 2007; 18: 1374–1380. Torra R, Badenas C, Darnell A et al. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol 1996; 7: 2142–2151. Harris PC, Bae KT, Rossetti S et al. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2006; 17: 3013–3019. Pei Y, Paterson AD, Wang KR et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am J Hum Genet 2001; 68: 355–363. Paterson AD, Magistroni R, He N et al. Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2005; 16: 755–762. Garcia-Gonzalez MA, Jones JG, Allen SK et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab 2007; 92: 160–167. Rossetti S, Burton S, Strmecki L et al. The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 2002; 13: 1230–1237. Magistroni R, He N, Wang K et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2003; 14: 1164–1174. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ et al. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 2004; 13: 3069–3077. Rossetti S, Kubly VJ, Consugar MB et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation
Kidney International (2009) 75
for very early onset disease. J Med Genet 1998; 35: 13–16. 15. Bergmann C, Bruchle NO, Frank V et al. Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation. N Engl J Med 2008; 359: 318–319.
see original article on page 828
The goddess of the waters Harry van Goor1 and Henri G.D. Leuvenink2
Kidney International (2009) 75, 767–769. doi:10.1038/ki.2009.45
Why not start with a reference to Hippocrates, who is thought to have first discovered the existence of lymph? Lympha originates from the Greek word nymphe, a goddess of the waters. So, it is crystal clear that lymph is a colorless fluid— except for the lymph found in the lacteal vessels of the mesentericum, which turns white after a meal because of the absorption of dietary fats as first described by Asellio during the Renaissance. The traditional functions of the lymphatic system are ascribed to circulatory physiology and immunology. Fluid leaking through the semipermeable capillary bed into the interstitium, after picking up antigens and immunologically active cells, is collected in lymph capillaries, drained to regional lymph nodes, and exposed to the lymphoid 1Department of Pathology, University Medical
Center Groningen, Groningen, The Netherlands; 2Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands Correspondence: Harry van Goor, Department of Pathology, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. E-mail: [email protected]
system. After filtration, the lymph fluid returns to the blood and continues its lifelong task: the draining of organs under physiological conditions. The lymph drainage system becomes especially challenged during disease conditions such as wound healing, inflammation, and infection, when excessive fluid, lymphocytes, and dendritic cells travel through the lymphatic vessels to the lymph nodes. This is not an indolent process, but a masterminded system in which adhesion molecules, cytokines, and chemokines are crucially involved. During disease states, the number and maturation state of dendritic cells increase dramatically. Knowledge of how leukocytes migrate over the lymphatic wall is sparse, although intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are known to be involved, as ICAM-1-deficient mice have a defect in lymph node recruitment of dendritic cells. The role of cellular trafficking through the lymphatic system also painfully reveals unappreciated side effects such as are seen in the dissemination of metastatic cancer cells. 767
com m enta r y
AGEs Tubule
Glucose Fibroblast Macrophage Cytokines ECM
AGEs Capillary
Cytokines VEGF-C
Glucose
Lymphangiogenesis
Figure 1 | Simplified scheme of the development of lymphangiogenesis in interstitial fibrosis associated with diabetic nephropathy. Clusters of macrophages are present in the fibrotic interstitium. These macrophages are activated in an autocrine or paracrine fashion through the production of cytokines such as interleukin-1. Glucose is present in the interstitial fibrotic areas, as are advanced glycation end products (AGEs). All these factors contribute to the production of vascular endothelial growth factor-C (VEGF-C) by macrophages and thereby to the formation of lymphatics. ECM, extracellular matrix.
In the experimental setting, the functional role of lymphatics has become more evident. Acute ureteral obstruction causes dilation and reflux into intrarenal lymphatics. Interestingly, in chronic obstruction, Tamm-Horsfall proteins leak from tubules into the lymphatics and can be found in lymph nodes in the hilum of the kidney. In short-term hilar lymph duct ligation, Wilcox et al. noted that lymphatic drainage is required to maintain a low renal cortical hydraulic pressure and that ligation decreases sodium and fluid reabsorption.1 The relation of lymphatics to renal fibrosis has been studied in several models. In reflux nephropathy, fibrosis follows the distribution of lymphatics. In remnant kidneys, proliferation of lymphatic vessels was observed in the fibrotic tubulointerstitial areas.2 Disturbance of the lymph circulation by lymphatic duct ligation alone or in combination with nephrectomy causes proteinuria and renal fibrosis.3 Several markers of the endothelial cells lining the lymphatic vessels are now available, including LYVE-1 (hyaluronate receptor), Prox-1 (lymphatic transcription factor), podoplanin (a type I integral membrane glycoprotein), factors of the vascular endothelial growth factor family (VEGF), and the sialoglycoprotein D2-40 (a lymphatic endothelium-specific protein). The localization of the normal renal lymphatic vessels has been described in animals and humans and reveals the abundant presence around intrarenal arteries and veins, with 768
a more scarce localization around glomeruli and between tubules. Medullary lymphatics are extremely rare. Lymphatics have been of special interest in the field of renal transplantation, in which the lymphatic system is not restored during implantation, in contrast to the vascular system. One of the key physiological questions was whether disruption of lymphatic drainage would influence functioning of the graft. Early studies provided evidence that the disruption is not harmful for the kidney and that the lymphatic system is restored over time.4 Even more crucial is the role of renal lymphatics in the immunological response after renal transplantation. In allograft rejection, cellular infiltrates are key elements, and lymphatics provide an exit route for lymphocytes and macrophages. Recently, the presence of newly formed lymphatic vessels in human renal transplant biopsies near the nodular cell infiltrates was reported.5 The presence of these lymphatic structures is thought to be involved not only in removal of the rejection infiltrate but also in the continuing alloreactive immune response leading to chronic rejection.6 Newly formed lymphatic vessels presumably also organize the perivascular lymphocytes into immunologically active follicular structures, that are involved in the survival of the transplant. Interestingly, lymphangiogenesis occurs early, within 72 h after transplantation. Findings of Stuht et al.7 indicate that the
number of lymphatic vessels does not increase in time, nor is it correlated with rejection in the first year, but that it is correlated with worse functional graft outcome. This suggests that early damage to the graft during the transplantation, or maybe even in the donor situation, increases the susceptibility of the graft to rejection. This is also illustrated by the report of Franksson et al. in which lymphocyte depletion by drainage of lymph via thoracic duct fistula was found to be a beneficial supplementary treatment modality in regard to one-year graft survival when combined with anti-thymocyte serum in cadaveric graft recipients but not in recipients receiving a living-donor organ.8 The renewed interest and novel findings in the field of cell traffic and lymphatic endothelium indicate that the lymphatic endothelium is a potential target for immunosuppressive therapy.9 An intact lymphatic system might be pivotal, not only for the immune surveillance of the alloresponse, but also for the clearance of all kinds of pathogens attacking the transplant—for example, viruses such as herpes, as well as polyoma viruses. The macrophage is central in the pathogenesis of renal fibrosis and repair10 and also contributes to the formation of lymphatic vessels through production of VEGF-C (Figure 1). The lymphatic vessels and interstitium of remnant kidneys contain mononuclear cells that express VEGF-C mRNA. Maruyama et al. studied lymphangiogenesis in diabetes and found that renal macrophages contribute to the formation of lymphatics.11 Surprisingly, glucose per se or interleukin-1 decreased the production of VEGF-C in macrophages, whereas the combination of the two caused a significant increase in VEGF-C production, revealing the lymphangiogenic potential of these cells in inflammatory diabetic conditions (Figure 1). Moreover, application of interleukin-1 to wounds in db/db mice induced lymphatic vessel formation and accelerated wound healing. A second phenomenon central to the pathogenesis of diabetic nephropathy is the formation and accumulation of advanced glycation end products (AGEs).12 AGEs have also been shown to be able to activate macrophages and induce induction of VEGF in these cells. In this way AGEs may also contribute to the Kidney International (2009) 75
co m m e nta r y
formation of lymphatics. Hypoxia induced by vessel damage and fibrosis is another crucial factor involved in the pathogenesis of diabetic renal disease damage. It is known from the oncology field that the invasion and migration of microvascular endothelial cells is increased during hypoxia.13 Sakamoto et al.14 (this issue) investigated the expression of D2-40–positive lymphatic vessels, with special interest in VEGF-C, a crucial mediator of lymphan-giogenesis in chronic renal disease. They meticulously mapped the presence of lymphatic vessels in a wide range of renal diseases using D2-40 and VEGF-C antibodies. They confirmed the absence of corticomedullary lymphatics in control kidneys but found lymphangiogenesis in tubulointerstitial fibrosis and inflammatory interstitial areas in various renal diseases. These vessels were often filled with mononuclear cells. Interestingly, lymphangiogenesis and VEGF-C expression were elevated in diabetic nephropathy as compared with other renal diseases. The study is a solid base for continuing research, as several questions remain and have to be resolved. For instance, do glucose and AGEs have any effect on the production of VEGF-C by resident glomerular cells and the subsequent growth of lymphatic vessels? This question can easily be resolved in an in vitro setup. What are the other signals involved in lymphangiogenesis? Do components of the extracellular matrix per se have any effect on lymphangiogenesis? And what about ischemia, a central event in chronic renal disease and renal transplantation; does it provoke VEGF-C expression and lymphangiogenesis? What is the role of cyclosporine in the formation of lymphatics? Despite all these questions, this elegant, elaborate study of Sakamoto et al.14 definitely paves the way for further research in the field of lymphatics in chronic renal disease. Novel therapeutic interventions aiming at the modulation of growth and proliferation of lymphatic cells may lead to better treatment modalities and understanding of chronic renal disease. DISCLOSURE The authors declared no competing interests. ACKNOWLEDGMENTS This work was supported by funds from the Dutch Kidney Foundation. The authors thank Willem van Son for helpful discussions. Kidney International (2009) 75
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Wilcox CS, Sterzel RB, Dunckel PT et al. Renal interstitial pressure and sodium excretion during hilar lymphatic ligation. Am J Physiol 1984; 247: F344–F351. Matsui K, Nagy-Bojarsky K, Laakkonen P et al. Lymphatic microvessels in the rat remnant kidney model of renal fibrosis: aminopeptidase p and podoplanin are discriminatory markers for endothelial cells of blood and lymphatic vessels. J Am Soc Nephrol 2003; 14: 1981–1989. Zhang T, Guan G, Liu G et al. Disturbance of lymph circulation develops renal fibrosis in rat with and without contralateral nephrectomy. Nephrology (Carlton) 2008; 13: 128–138. Mobley JE, O’Dell RM. The role of lymphatics in renal transplantation. Renal lymphatic regeneration. J Surg Res 1967; 7: 231–233. Kerjaschki D, Regele HM, Moosberger I et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 2004; 15: 603–612. Thaunat O, Patey N, Morelon E et al. Lymphoid neogenesis in chronic rejection: the murderer is in the house. Curr Opin Immunol 2006; 18: 576–579. Stuht S, Gwinner W, Franz I et al. Lymphatic neoangiogenesis in human renal allografts: results
8.
9.
10.
11.
12.
13.
14.
from sequential protocol biopsies. Am J Transplant 2007; 7: 377–384. Franksson C, Lundgren G, Magnusson G et al. Drainage of thoracic duct lymph in renal transplant patient. Transplantation 1976; 21: 133–140. Johnson LA, Jackson DG. Cell traffic and the lymphatic endothelium. Ann NY Acad Sci 2008; 1131: 119–133. Ricardo SD, van Goor H, Eddy A. Macrophage diversity in renal injury and repair. J Clin Invest 2008; 118: 3522–3530. Maruyama K, Asai J, Li M et al. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 2007; 170: 1178–1191. Pertyńska-Marczewska M, Kiriakidis S, Wait R et al. Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages. Cytokine 2004; 28: 35–47. Mikhaylova M, Mori N, Wildes FB et al. Hypoxia increases breast cancer cell-induced lymphatic endothelial cell migration. Neoplasia 2008; 10: 380–388. Sakamoto I, Ito Y, Mizuno M et al. Lymphatic vessels develop during tubulointerstitial fibrosis. Kidney Int 2009; 75: 828–838.
see original article on page 793
Regulation of renal arteriolar tone by adenosine: novel role for type 2 receptors Tracy D. Bell1 and William J. Welch1 Tubuloglomerular feedback regulation of glomerular filtration rate (GFR) is mediated by adenosine, which acts on type 1 receptors in the afferent arteriole to increase resistance. However, new findings in isolated mouse tissue suggest that adenosine also dilates the efferent arteriole, which would reinforce the ability of adenosine to reduce GFR. This new information extends the concept that adenosine acts as a paracrine agent on both afferent and efferent arterioles. Kidney International (2009) 75, 769–771. doi:10.1038/ki.2009.18
Regulation of glomerular filtration is a critical element of the homeostatic function of the kidney to maintain stable fluid 1Department of Medicine, Georgetown University, Washington, DC, USA Correspondence: William J. Welch, Department of Medicine, Georgetown University, Building D-395, 4000 Reservoir Road, Washington, DC 20057, USA. E-mail: [email protected]
and electrolyte balance. Much of this regulation is dependent on the control of the renal arterioles surrounding the glomerular capillary. The study by Al-Mashhadi et al.1 (this issue) provides new information and clarification of a potentially important mechanism that targets efferent arteriolar tone. The authors show that adenosine acting on type 2 receptors dilates the efferent arteriole. This provides 769