- Email: [email protected]
Skin Blood Flow and Vascular Endothelium Function in Uremia
ICURT PROCEEDINGS
Skin Blood Flow and Vascular Endothelium Function in Uremia Miroslaw J. Smogorzewski, MD, PhD Prevalence of dermatological disorder in patients with end-stage kidney disease is estimated as 50% to 100% in various studies. Some of the skin lesions are specific for the diseases causing chronic kidney disease (CKD), some are associated with CKD, and still others are the dermatological manifestation of uremia. Microangiopathy was also found in both arterioles and venule in the skin biopsy of ‘‘normal looking’’ skin in patients with end-stage kidney disease. In a cross-sectional study in patients on dialysis, we measured skin blood flow (SBF) using laser Doppler device in a standardized way at various areas of lower extremities at 2 different local skin temperatures: 35 C and 44 C. Local heating increases skin perfusion by mechanisms dependent on nitric oxide (NO). SBF was impaired in CKD patients Stage 5 on HD, particularly in those with diabetes mellitus as a cause of CKD. The reduced response in the SBF to the heat in our patients may be due to decreased generation of NO in uremia. Endothelium-dependent vasodilatation in patients on dialysis and the response of the skin microcirculation to acetylcholine was diminished in hypertensive patients on dialysis. Similarly, patients with diabetes mellitus had decreased SBF during intradermal microdialysis with a NO synthase inhibitor. Multiple uremic toxins have been studied in vitro and show to cause various degree of endothelial cell dysfunction. Unfortunately, no clear benefit has been described in CKD patients to different intervention aimed to reduce uremic toxin effect on endothelium. There are no long-term data on the factors which can modify endothelium function in uremia, but non pharmacologic interventions, diet, and several pharmacologic approaches could be beneficial. Measurement of SBF can be useful in evaluation of vasculopathy in CKD population and can potentially be used for assessment of vascular response during specific clinical intervention. Ó 2017 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
Introduction
H
ISTORICALLY, THE BRITISH dermatologist, Dyce Duckworth in the year 1900, noticed that in a uremic patient, the skin irritation was ‘‘due to toxic matters resulting from disordered renal metabolism,’’ suggesting a role of uremic toxins in skin pathology in these patients.1 Skin diseases are very common in patients during progression of chronic kidney diseases (CKD) and eventually close to 100% of end-stage renal disease (ESRD) patients are affected by at least 1 dermatological disorder.2-4 The skin pathology findings are 5 to 10 times more common than in the general age-matched population.5-6 There are some differences in the type of skin pathology depending on the cause of renal failure. Cross-sectional study of 220 patients from our dialysis unit show that of 96 patients with diabetes mellitus (DM) as a cause of CKD Stage 5, 60% had diabetic dermatopathy, 11% scleredema, 20% skin pebbling, and 25% Division of Nephrology and Hypertension, Department of Medicine at Keck School of Medicine, University of Southern California, Los Angeles, California. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Miroslaw J. Smogorzewski, MD, PhD, Division of Nephrology and Hypertension, Department of Medicine, LAC/USC Medical Center, 2020 Zonal Avene IRD # 805, Los Angeles, CA 90033. E-mail:
[email protected] Ó 2017 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2017.04.012
Journal of Renal Nutrition, Vol 27, No 6 (November), 2017: pp 465-469
acanthosis nigricans, whereas patients with diagnosis of hypertensive nephropathy (n 5 39) and those with non-DM CKD Stage 5 (n 5 85) had high rate of xerosis (55% and 43%, respectively) and skin hyperpigmentation (36% and 27%, respectively).7 Skin disorders were associated with excessive morbidity, and skin pathology affects the quality of life and general appearance of CKD patients. Our epidemiologic findings also suggested that diabetic patients with renal diseases experience significant metabolic differences compared with non-DM CKD patients. Diabetic patients with normal kidney function, without evidence of cutaneous disease in the skin, have abnormal skin blood flow (SBF) as a manifestation of diabetic microangiopathy. Their SBF at basal body temperature was not different from that in healthy subjects, but there was a 40% to 50% reduction in heat stimulated flow in diabetic patients compared with the nondiabetic control population.8 Significant microangiopathy was also found in both arterioles and venules in skin biopsy of ‘‘normal looking’’ skin in patients with end-stage kidney disease.9,10 Australian observational study did compare the arterial and venous size of the retinal vasculature in CKD Stages 1 to 2 versus CKD Stages 3 to 5 (n 5 126 in each group). They found, after proper adjustment, that central retinal artery and vein equivalent were smaller in more advance renal failure11 and the higher diameter of retinal arteries predicts better renal event-free survival.12 We hypothesized that diabetic patients with ESRD on dialysis might have different and perhaps more severe decrement 465
466
SMOGORZEWSKI
in SBF and skin abnormalities than patients with CKD due to other causes.
SBF in Patients with Stage 5 CKD on Hemodialysis We studied 24 nondiabetic and 25 diabetic subjects with ESRD on dialysis. Control group consisted of 10 healthy subjects. The SBF studies were performed under the same standardized conditions before hemodialysis procedure at room temperature of 20 C using a Vasamedic Model 403B laser Doppler device (Vasamedics Inc., St. Paul, Minnesota) as described previously.13 The measurements of SBF were performed at (1) the plantar surface of the tip of the index finger (finger pulp); (2) the dorsal surface of the distal phalange of the index finger, immediately proximal to the nail bed (finger dorsum); (3) the plantar surface of the tip of the great toe (toe pulp); (4) the extensor surface of the distal phalange of the great toe, immediately proximal to the nail bed (toe dorsum); and (5) the pretibial surface of the leg. At all sites tested at the probe temperature of 35 C, the SBF was lower in the diabetic patients on dialysis compared with healthy subjects and nondiabetic dialysis patients. However, the SBFs at 35 C of non-DM patients were not different from control subjects. Decrease in SBF in DM patients on dialysis was more severe than previously reported in DM patients without renal diseases,14 suggesting that diabetic skin vasculopathy can be exaggerated by uremia. All subject groups increased SBF in response to increased temperature of the probe to 44 C but there was Figure 1. Skin blood flow measured at temperature of 44 C at unaffected skin in nondiabetic and diabetic patients on hemodialysis and in control subjects. The columns represent mean values and the brackets one standard deviation.
significantly lower (70%-80%) response in patients with diabetes compared with healthy subjects and nondiabetic patients (Fig. 1). Although, non-DM CKD patients showed similar to control group SBF at 35 C, they had impaired response in blood flow at 44 C compared with the response in control subjects.13 Thus, renal failure may cause additional injury to SBF noted in DM. Since local warming causes vasodilatation that is mainly dependent on nitric oxide (NO) generation,15 the reduced response in SBF to the heat in our patients may be due to decreased generation of NO in diabetes as well as in ESRD. In summary, SBF in normal looking skin is impaired in CKD patient’s Stage 5 on HD, particularly 1 with DM as a cause of CKD. These derangements are likely related to impaired vasodilatory response of small vessels in patients with end-stage renal failure and diabetes on dialysis.
Endothelium Function in CKD and Uremia The endothelial cells that are covering the lumens of blood vessels and lymphatic tree participate in the magnitude of physiological function. Their whole body mass is equal to the liver cell mass. The endothelial cells are interacting with surrounding cellular and acellular environment. They are regulating vascular tone and permeability, hemostatic response, angiogenesis, vascular proliferation, inflammatory, and many other metabolic processes. In the following part of this review, I will focus on the role of endothelial dysregulation in CKD and uremia.
SKIN BLOOD FLOW MEASURED at VARIOUS AREAS at 44°C
Skin Blood Flow (ml/min/100g tissue)
100
80 NONDIABETIC DIABETIC CONTROL
60
40
20
0
FINGER
TOE
PRETIBIAL
SKIN BLOOD FLOW IN CKD
acetylcholine was diminished in hypertensive patients on dialysis.20,21 Similarly, patients with DM show decrease in SBF to intradermal microdialysis with L-NAME, a NO synthase inhibitor.22 The blunted response in blood flow to skin warming was severely impaired in DM patients on HD suggests greater impairment in NO generation in these patients than in non-DM dialysis patients.23 In our study, ESRD, non-DM patients on dialysis had also impaired vasodilatory response in SBF during skin warming.13 Uremic plasma inhibits endothelial progenitor cells differentiation and migration in vitro and endothelial cell repair.24 Some uremic toxins in vitro are causing endothelial cells and endothelial progenitor cells dysfunction as well. Asymmetrical dimethyl arginine (ADMA) was identified as endogenous inhibitor of NO synthase and increases vascular resistance in humans. ADMA in renal failure binds to protein and accumulates in patients with CKD.25 ADMA accelerates endothelial cell senescence and its capacity for repair and impairs NO synthesis and bioavailability.26 Hemodialysis, although significantly and transiently, decreased the plasma levels of both L-arginine and ADMA, had no acute effect on impaired NOdependent vasodilatory response in the skin microcirculation assessed by SBF.27 Advanced glycation end products (AGEs) derive from modification of proteins by carbohydrates and also accumulate in CKD patients. Endothelial cells exposed in vitro to AGEs display decreased capacity of migration and enhanced apoptosis.28 AGE extract from CKD patients decreases eNOS in human aortic endothelial cells. Homocysteine is a protein-bound uremic toxin. It inhibits endothelium-dependent vasodilatation in patients with DM and in hypertensive patients. Homocysteine impairs endothelial progenitors function and accelerates oxidative inactivation of NO.29,30 Other uremic toxin,
Endothelial cells and smooth muscle cells interaction in control of vascular tone is schematically depicted in Figure 2. Endothelial cells are responding to the changes in pressure, mechanical forces of blood flow (shear stress), circulating agents (norepinephrine, adenosine triphosphate [ATP], angiotensin, and acetylcholine) by generating various cellular signaling molecules. These vasoactive factors include relaxing such as adenosine, NO, prostacyclin and contracting factors (reactive oxygen species, endothelin-1, and angiotensin II).16,17 These chemicals are released from endothelial cells and exert their action on adjacent vascular smooth muscle. Lately, a new mechanism of endothelial cell–smooth muscle interaction was identified as endothelium-derived hyperpolarizing factor (EDHF); EDHF causes hyperpolarization of smooth muscle and its relaxation.18 The endothelial monolayer propagates an electrical signal along the blood vessel by means of myoendothelial gap junctions. These responses involve an increase in the endothelial intracellular calcium concentration. EDHF-mediated response is not a totally separate pathway but it also stimulates endothelial nitric oxide synthase (eNOS) and augments other responses. Endothelium can be evaluated in vivo by assessment of blood flow in an easy accessible area such as skin by laser Doppler flowmetry under specific conditions. The vasodilatory response of the vessels can be measured after application of either endothelial dependent (acetylcholine by iontophoresis or localize heating of the skin) or independent (sodium nitroprusside) stimuli.13 Flow-mediated dilation of the brachial artery by ultrasounds is also frequently used for vascular test to assess endothelium-dependent vasodilation. Other methods include measurement of microcirculatory reactive hyperemia by forearm venous plethysmography.19 Endothelium-dependent vasodilatation in patients on dialysis and the response of the skin microcirculation to
Agonists : Ach, NE, ATP
Shear stress ANG1
Endothelial cell
ANGII
2+
Ca
Arginine ET-1
Endothelium – Derived
EDHF Hyperpolarization Factors PGI2 2+ Ca
NOS
K VSMS 2+
Ca
Constriction
+
Hyperpolarization
VSMS
NO
cAMP
cGMP
Hyperpolarization Relaxation
Relaxation
K
+
467
Figure 2. Schematic presentation of endothelial cell–vascular smooth muscle interaction. Acetylcholine (Ach) interaction with endothelial cell activates nitric oxide synthase (NOS) and generates nitric oxide (NO). NO exerts its action on vascular smooth muscle (VSMS) through cGMP generation and is causing VSMS relaxation. Also endotheliumderived hyperpolarization factor (EDHF) and prostacyclin (PGI2) released from endothelial cell are causing VSMS relaxation. Angiotensin II (ANGII) and endothelin 1 (ET-1) are rising cytosolic calcium in VSMS and causing VSMS constriction. ATP, adenosine triphosphate.
468
SMOGORZEWSKI
indoxyl sulfate, a degradation product of the tryptophan, also accumulates in CKD and causes in vitro endothelial cell dysfunction. It impairs endothelial repair and induces oxidative stress in human umbilical endothelial cells.31,32 Parathyroid hormone, well recognized and documented uremic toxin, is known to have direct effect on cardiac myocytes33 and vascular constriction and relaxation.34 In human umbilical vein endothelial cell line, parathyroid hormone increases intracellular calcium and cyclic adenosine monophosphate content and stimulated endothelin-1 secretion.35
Therapeutic Options for Amelioration of Endothelial Dysfunction in Uremia There is no long-term data on the factors which can modify endothelium function in uremia, and unfortunately no mortality benefit has been described to different intervention aimed to reduced uremic toxin levels. But a nonpharmacologic and dietary approaches, and several pharmacologic approaches were studied in general population with positive outcome and could potentially improve or even reverse endothelial dysfunction also in CKD patients. Moderate-intensity exercise was shown to increase eNOS activity and to reduce angiotensin II type 1 receptor expression on endothelial cells lowering oxidative stress and increasing NO bioavailability.36 Bioflavonoids contained in fruits and cocoa have also been found to reduce oxidative stress and inflammation and improve endothelial function. Some beta blockers such as Nebivolol and carvedilol could potentiate NO production and reduces endothelin1 expression in endothelial cells.37 Angiotensin converting enzyme (ACE) inhibitors also increase endothelial cell NO and prostacyclin synthesis. Statin therapy increases eNOS activity, decreases oxidative stress by oxidized low-density lipoprotein and other reactive oxygen species and improves vascular smooth muscle migration and proliferation.38
References 1. Duckworth D. A case of chronic interstitial nephritis in which dermatitis exfoliativa supervened. Br J Dermatol. 1900;12:12-15. 2. Robinson-Bostom L, DiGiovanna JJ. Cutaneous manifestations of endstage renal disease. J Am Acad Dermatol. 2000;43:975-990. 3. Knable AL. Cutaneous nephrology. Dermatol Clin. 2002;20:513-521. 4. Galperin TA, Cronin AJ, Leslie KS. Cutaneous manifestations of ESRD. Clin J Am Soc Nephrol. 2014;9:201-218. 5. Schaefer I, Rustenbach SJ, Zimmer L, Augustin M. Prevalence of skin diseases in cohort of 48,665 employees in Germany. Dermatology. 2008;217:169-172. 6. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2003;21:689-697. 7. Ngo BT, Woodley DT, Rendell MS, Campese V, Smogorzewski M. Comparison of skin conditions in hypertensive versus diabetic end stage renal disease patients. J Am Soc Nephrol. 2005;16:A879. 8. Rendell M, Bergman T, O’Donnell G, Drobny E, Borgos J, Bonner RF. Microvascular blood flow, volume, and velocity measured by laser Doppler techniques in insulin dependent diabetes. Diabetes. 1989;38:819-824.
9. Gilchrest BA, Rowe JW, Mihm MC. Clinical and histological skin changes in chronic renal failure: evidence for a dialysis-resistant transplant responsive microangiopathy. Lancet. 1980;2:1271-1275. 10. Lundin PA, Fani K, Berlyne GM, Friedman EA. Dermal angiopathy in hemodialysis patients: the effect of time. Kidney Int. 1995;47:1775-1780. 11. Ooi QL, Tow FK, Deva R, et al. The microvasculature in chronic kidney. Clin J Am Soc Nephrol. 2011;8:1872-1878. 12. Baumann M, Burkhardt K, Heemann U. Microcirculatory marker for the prediction of renal end points: a prospective cohort study in patients with chronic kidney disease stage 2 to 4. Hypertension. 2014;64:338-346. 13. Ngo B, Rongey C, Hiscox B, Rendell M, Woodley D, Smogorzewski M. Skin blood flow in patients with CKD5 on hemodialysis. J Ren Nutr. 2010;20:S89-S94. 14. Wigington G, Ngo B, Rendell M. Skin blood flow in diabetic dermopathy. Arch Dermatol. 2004;140:1248-1250. 15. Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol. 2001;91:1619-1626. 16. Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376. 17. Feletou M, Vanhoutte PM. Endothelial dysfunction : a multifaceted disorder. Am J Physiol Heart Circ Physiol. 2006;291:H985-H1002. 18. Feletou M. Endothelium-dependent hyperpolarization and endothelial dysfunction. J Cardiovasc Pharmacol. 2016;67:373-387. 19. Ghiadoni L, Versari D, Giannarelli C, Faita F, Taddei S. Non- invasive diagnostic tools for investigating endothelial dysfunction. Curr Pharm Des. 2008;14:3715-3722. 20. Cupisti A, Rossi M, Placidi S, et al. Response of the skin microcirculation to acetylcholine in patients with essential hypertension and normotensive patients with chronic renal failure. Nephron. 2000;85:114-119. 21. Farkas K, Nemcsik J, Kolossvary E, et al. Impairment of skin microvascular reactivity in hypertension and uremia. Nephrol Dial Transplant. 2005;20:1821-1827. 22. Sokolnicki LA, Strom NA, Roberts SK, Kingsley-Berg SA, Basu A, Charkoudian N. Skin blood flow and nitric oxide during body heating in type 2 diabetes mellitus. J Appl Physiol. 2009;106:566-570. 23. Rossi M, Carpi A, Galetta F, Franzoni F, Santoro G. Skin vasomotion investigation: a useful tool for clinical evaluation of microvascular endothelial function. Biomed Pharmacother. 2008;62:541-545. 24. De Groot K, Bahlmann FH, Sowa J, et al. Uremia causes endothelial progenitor cell deficiency. Kidney Int. 2004;66:641-646. 25. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992;339:572-575. 26. Scalera F, Borlak J, Beckmann B, et al. Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl l-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol. 2004;24:1816-1822. 27. Engelberger RP, Teta D, Henry H, et al. Haemodialysis acutely reduces the plasma levels of ADMA without reversing impaired NO-dependent vasodilation. Clin Sci. 2009;117:293-303. 28. Sun C, Liang C, Ren Y, et al. Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1 ⁄ 2 mitogenactivated protein kinase pathways. Basic Res Cardiol. 2009;104:42-49. 29. Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost. 2005;3:1646-1654. 30. Chen JZ, Zhu JH, Wang XX, et al. Effects of homocysteine on number and activity of endothelial progenitor cells from peripheral blood. J Mol Cell Cardiol. 2004;36:233-239. 31. Dou L, Bertrand E, Cerini C, et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 2004;65:442-451. 32. Tumur Z, Shimizu H, Enomoto A, Miyazaki H, Niwa T. Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stressinduced NF-kappaB activation. Am J Nephrol. 2010;31:435-444.
SKIN BLOOD FLOW IN CKD 33. Smogorzewski MJ, Zayed M, Yhang Y-B, Roe J, Massry SG. Parathyroid hormone induces a rise in cytosolic calcium of cardiac myocytes of adult rats. Am J Physiol. 1993;264:H1998-H2006. 34. Saglikes Y, Massry SG, Iseki K, Nadler JL, Campese V. Effect of PTH on blood pressure and response to vasoconstrictor agonists. Am J Physiol. 1983;248:F674-F681. 35. Isales CM, Sumpio R, Bollag RJ, et al. Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line. Am J Physiol Endocrinol Metab. 2000;279:E654-E662.
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36. Roberts CK, Barnard RJ, Jasman A, Balon TW. Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am J Physiol. 1999;277:E390-E394. 37. Zepeda RJ, Castillo R, Rodrigo R, et al. Effect of carvedilol and nebivolol on oxidative stress-related parameters and endothelial function in patients with essential hypertension. Basic Clin Pharmacol Toxicol. 2012;111:309-316. 38. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97:1129-1135.
Skin Blood Flow and Vascular Endothelium Function in Uremia Miroslaw J. Smogorzewski, MD, PhD Prevalence of dermatological disorder in patients with end-stage kidney disease is estimated as 50% to 100% in various studies. Some of the skin lesions are specific for the diseases causing chronic kidney disease (CKD), some are associated with CKD, and still others are the dermatological manifestation of uremia. Microangiopathy was also found in both arterioles and venule in the skin biopsy of ‘‘normal looking’’ skin in patients with end-stage kidney disease. In a cross-sectional study in patients on dialysis, we measured skin blood flow (SBF) using laser Doppler device in a standardized way at various areas of lower extremities at 2 different local skin temperatures: 35 C and 44 C. Local heating increases skin perfusion by mechanisms dependent on nitric oxide (NO). SBF was impaired in CKD patients Stage 5 on HD, particularly in those with diabetes mellitus as a cause of CKD. The reduced response in the SBF to the heat in our patients may be due to decreased generation of NO in uremia. Endothelium-dependent vasodilatation in patients on dialysis and the response of the skin microcirculation to acetylcholine was diminished in hypertensive patients on dialysis. Similarly, patients with diabetes mellitus had decreased SBF during intradermal microdialysis with a NO synthase inhibitor. Multiple uremic toxins have been studied in vitro and show to cause various degree of endothelial cell dysfunction. Unfortunately, no clear benefit has been described in CKD patients to different intervention aimed to reduce uremic toxin effect on endothelium. There are no long-term data on the factors which can modify endothelium function in uremia, but non pharmacologic interventions, diet, and several pharmacologic approaches could be beneficial. Measurement of SBF can be useful in evaluation of vasculopathy in CKD population and can potentially be used for assessment of vascular response during specific clinical intervention. Ó 2017 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
Introduction
H
ISTORICALLY, THE BRITISH dermatologist, Dyce Duckworth in the year 1900, noticed that in a uremic patient, the skin irritation was ‘‘due to toxic matters resulting from disordered renal metabolism,’’ suggesting a role of uremic toxins in skin pathology in these patients.1 Skin diseases are very common in patients during progression of chronic kidney diseases (CKD) and eventually close to 100% of end-stage renal disease (ESRD) patients are affected by at least 1 dermatological disorder.2-4 The skin pathology findings are 5 to 10 times more common than in the general age-matched population.5-6 There are some differences in the type of skin pathology depending on the cause of renal failure. Cross-sectional study of 220 patients from our dialysis unit show that of 96 patients with diabetes mellitus (DM) as a cause of CKD Stage 5, 60% had diabetic dermatopathy, 11% scleredema, 20% skin pebbling, and 25% Division of Nephrology and Hypertension, Department of Medicine at Keck School of Medicine, University of Southern California, Los Angeles, California. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Miroslaw J. Smogorzewski, MD, PhD, Division of Nephrology and Hypertension, Department of Medicine, LAC/USC Medical Center, 2020 Zonal Avene IRD # 805, Los Angeles, CA 90033. E-mail:
[email protected] Ó 2017 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2017.04.012
Journal of Renal Nutrition, Vol 27, No 6 (November), 2017: pp 465-469
acanthosis nigricans, whereas patients with diagnosis of hypertensive nephropathy (n 5 39) and those with non-DM CKD Stage 5 (n 5 85) had high rate of xerosis (55% and 43%, respectively) and skin hyperpigmentation (36% and 27%, respectively).7 Skin disorders were associated with excessive morbidity, and skin pathology affects the quality of life and general appearance of CKD patients. Our epidemiologic findings also suggested that diabetic patients with renal diseases experience significant metabolic differences compared with non-DM CKD patients. Diabetic patients with normal kidney function, without evidence of cutaneous disease in the skin, have abnormal skin blood flow (SBF) as a manifestation of diabetic microangiopathy. Their SBF at basal body temperature was not different from that in healthy subjects, but there was a 40% to 50% reduction in heat stimulated flow in diabetic patients compared with the nondiabetic control population.8 Significant microangiopathy was also found in both arterioles and venules in skin biopsy of ‘‘normal looking’’ skin in patients with end-stage kidney disease.9,10 Australian observational study did compare the arterial and venous size of the retinal vasculature in CKD Stages 1 to 2 versus CKD Stages 3 to 5 (n 5 126 in each group). They found, after proper adjustment, that central retinal artery and vein equivalent were smaller in more advance renal failure11 and the higher diameter of retinal arteries predicts better renal event-free survival.12 We hypothesized that diabetic patients with ESRD on dialysis might have different and perhaps more severe decrement 465
466
SMOGORZEWSKI
in SBF and skin abnormalities than patients with CKD due to other causes.
SBF in Patients with Stage 5 CKD on Hemodialysis We studied 24 nondiabetic and 25 diabetic subjects with ESRD on dialysis. Control group consisted of 10 healthy subjects. The SBF studies were performed under the same standardized conditions before hemodialysis procedure at room temperature of 20 C using a Vasamedic Model 403B laser Doppler device (Vasamedics Inc., St. Paul, Minnesota) as described previously.13 The measurements of SBF were performed at (1) the plantar surface of the tip of the index finger (finger pulp); (2) the dorsal surface of the distal phalange of the index finger, immediately proximal to the nail bed (finger dorsum); (3) the plantar surface of the tip of the great toe (toe pulp); (4) the extensor surface of the distal phalange of the great toe, immediately proximal to the nail bed (toe dorsum); and (5) the pretibial surface of the leg. At all sites tested at the probe temperature of 35 C, the SBF was lower in the diabetic patients on dialysis compared with healthy subjects and nondiabetic dialysis patients. However, the SBFs at 35 C of non-DM patients were not different from control subjects. Decrease in SBF in DM patients on dialysis was more severe than previously reported in DM patients without renal diseases,14 suggesting that diabetic skin vasculopathy can be exaggerated by uremia. All subject groups increased SBF in response to increased temperature of the probe to 44 C but there was Figure 1. Skin blood flow measured at temperature of 44 C at unaffected skin in nondiabetic and diabetic patients on hemodialysis and in control subjects. The columns represent mean values and the brackets one standard deviation.
significantly lower (70%-80%) response in patients with diabetes compared with healthy subjects and nondiabetic patients (Fig. 1). Although, non-DM CKD patients showed similar to control group SBF at 35 C, they had impaired response in blood flow at 44 C compared with the response in control subjects.13 Thus, renal failure may cause additional injury to SBF noted in DM. Since local warming causes vasodilatation that is mainly dependent on nitric oxide (NO) generation,15 the reduced response in SBF to the heat in our patients may be due to decreased generation of NO in diabetes as well as in ESRD. In summary, SBF in normal looking skin is impaired in CKD patient’s Stage 5 on HD, particularly 1 with DM as a cause of CKD. These derangements are likely related to impaired vasodilatory response of small vessels in patients with end-stage renal failure and diabetes on dialysis.
Endothelium Function in CKD and Uremia The endothelial cells that are covering the lumens of blood vessels and lymphatic tree participate in the magnitude of physiological function. Their whole body mass is equal to the liver cell mass. The endothelial cells are interacting with surrounding cellular and acellular environment. They are regulating vascular tone and permeability, hemostatic response, angiogenesis, vascular proliferation, inflammatory, and many other metabolic processes. In the following part of this review, I will focus on the role of endothelial dysregulation in CKD and uremia.
SKIN BLOOD FLOW MEASURED at VARIOUS AREAS at 44°C
Skin Blood Flow (ml/min/100g tissue)
100
80 NONDIABETIC DIABETIC CONTROL
60
40
20
0
FINGER
TOE
PRETIBIAL
SKIN BLOOD FLOW IN CKD
acetylcholine was diminished in hypertensive patients on dialysis.20,21 Similarly, patients with DM show decrease in SBF to intradermal microdialysis with L-NAME, a NO synthase inhibitor.22 The blunted response in blood flow to skin warming was severely impaired in DM patients on HD suggests greater impairment in NO generation in these patients than in non-DM dialysis patients.23 In our study, ESRD, non-DM patients on dialysis had also impaired vasodilatory response in SBF during skin warming.13 Uremic plasma inhibits endothelial progenitor cells differentiation and migration in vitro and endothelial cell repair.24 Some uremic toxins in vitro are causing endothelial cells and endothelial progenitor cells dysfunction as well. Asymmetrical dimethyl arginine (ADMA) was identified as endogenous inhibitor of NO synthase and increases vascular resistance in humans. ADMA in renal failure binds to protein and accumulates in patients with CKD.25 ADMA accelerates endothelial cell senescence and its capacity for repair and impairs NO synthesis and bioavailability.26 Hemodialysis, although significantly and transiently, decreased the plasma levels of both L-arginine and ADMA, had no acute effect on impaired NOdependent vasodilatory response in the skin microcirculation assessed by SBF.27 Advanced glycation end products (AGEs) derive from modification of proteins by carbohydrates and also accumulate in CKD patients. Endothelial cells exposed in vitro to AGEs display decreased capacity of migration and enhanced apoptosis.28 AGE extract from CKD patients decreases eNOS in human aortic endothelial cells. Homocysteine is a protein-bound uremic toxin. It inhibits endothelium-dependent vasodilatation in patients with DM and in hypertensive patients. Homocysteine impairs endothelial progenitors function and accelerates oxidative inactivation of NO.29,30 Other uremic toxin,
Endothelial cells and smooth muscle cells interaction in control of vascular tone is schematically depicted in Figure 2. Endothelial cells are responding to the changes in pressure, mechanical forces of blood flow (shear stress), circulating agents (norepinephrine, adenosine triphosphate [ATP], angiotensin, and acetylcholine) by generating various cellular signaling molecules. These vasoactive factors include relaxing such as adenosine, NO, prostacyclin and contracting factors (reactive oxygen species, endothelin-1, and angiotensin II).16,17 These chemicals are released from endothelial cells and exert their action on adjacent vascular smooth muscle. Lately, a new mechanism of endothelial cell–smooth muscle interaction was identified as endothelium-derived hyperpolarizing factor (EDHF); EDHF causes hyperpolarization of smooth muscle and its relaxation.18 The endothelial monolayer propagates an electrical signal along the blood vessel by means of myoendothelial gap junctions. These responses involve an increase in the endothelial intracellular calcium concentration. EDHF-mediated response is not a totally separate pathway but it also stimulates endothelial nitric oxide synthase (eNOS) and augments other responses. Endothelium can be evaluated in vivo by assessment of blood flow in an easy accessible area such as skin by laser Doppler flowmetry under specific conditions. The vasodilatory response of the vessels can be measured after application of either endothelial dependent (acetylcholine by iontophoresis or localize heating of the skin) or independent (sodium nitroprusside) stimuli.13 Flow-mediated dilation of the brachial artery by ultrasounds is also frequently used for vascular test to assess endothelium-dependent vasodilation. Other methods include measurement of microcirculatory reactive hyperemia by forearm venous plethysmography.19 Endothelium-dependent vasodilatation in patients on dialysis and the response of the skin microcirculation to
Agonists : Ach, NE, ATP
Shear stress ANG1
Endothelial cell
ANGII
2+
Ca
Arginine ET-1
Endothelium – Derived
EDHF Hyperpolarization Factors PGI2 2+ Ca
NOS
K VSMS 2+
Ca
Constriction
+
Hyperpolarization
VSMS
NO
cAMP
cGMP
Hyperpolarization Relaxation
Relaxation
K
+
467
Figure 2. Schematic presentation of endothelial cell–vascular smooth muscle interaction. Acetylcholine (Ach) interaction with endothelial cell activates nitric oxide synthase (NOS) and generates nitric oxide (NO). NO exerts its action on vascular smooth muscle (VSMS) through cGMP generation and is causing VSMS relaxation. Also endotheliumderived hyperpolarization factor (EDHF) and prostacyclin (PGI2) released from endothelial cell are causing VSMS relaxation. Angiotensin II (ANGII) and endothelin 1 (ET-1) are rising cytosolic calcium in VSMS and causing VSMS constriction. ATP, adenosine triphosphate.
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indoxyl sulfate, a degradation product of the tryptophan, also accumulates in CKD and causes in vitro endothelial cell dysfunction. It impairs endothelial repair and induces oxidative stress in human umbilical endothelial cells.31,32 Parathyroid hormone, well recognized and documented uremic toxin, is known to have direct effect on cardiac myocytes33 and vascular constriction and relaxation.34 In human umbilical vein endothelial cell line, parathyroid hormone increases intracellular calcium and cyclic adenosine monophosphate content and stimulated endothelin-1 secretion.35
Therapeutic Options for Amelioration of Endothelial Dysfunction in Uremia There is no long-term data on the factors which can modify endothelium function in uremia, and unfortunately no mortality benefit has been described to different intervention aimed to reduced uremic toxin levels. But a nonpharmacologic and dietary approaches, and several pharmacologic approaches were studied in general population with positive outcome and could potentially improve or even reverse endothelial dysfunction also in CKD patients. Moderate-intensity exercise was shown to increase eNOS activity and to reduce angiotensin II type 1 receptor expression on endothelial cells lowering oxidative stress and increasing NO bioavailability.36 Bioflavonoids contained in fruits and cocoa have also been found to reduce oxidative stress and inflammation and improve endothelial function. Some beta blockers such as Nebivolol and carvedilol could potentiate NO production and reduces endothelin1 expression in endothelial cells.37 Angiotensin converting enzyme (ACE) inhibitors also increase endothelial cell NO and prostacyclin synthesis. Statin therapy increases eNOS activity, decreases oxidative stress by oxidized low-density lipoprotein and other reactive oxygen species and improves vascular smooth muscle migration and proliferation.38
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