- Email: [email protected]
BROWNING AND DIABETIC COMPLICATIONS
1192
BROWNING AND DIABETIC COMPLICATIONS NON-ENZYMATIC glycosylation (NEG) of many proteins in diabetes mellitus, 1,2 and the amounts of glycosylated haemoglobin and serum proteins are widely used indices of integrated glycaemic control over the preceding few weeks. It has also been suggested that NEG may play a role in the long-term tissue complications of diabetes by such mechanisms as sulphydryl oxidation and in and alterations cross-linking of proteins,3 and cellular and uptake immunogenicity,4 enzyme function,5 degradation of maèromolecules. 6,7 The initial step in NEG is formation of a Schiff base between the free aldehyde group of glucose in its open-chain form and an amino group from aminoacid residues in a protein, the N-terminal amino and e-amino groups of lysine being important binding sites. This rapid and reversible reaction contrasts with subsequent slow rearrangement of the - Schiffbase to a more stable ketoamine linkage (the Amadori rearrangement). These chemical reactions have received most attention in the study of NEG in the last few years, especially since it is the Amadori product that is measured clinically in assessment of diabetic control. Interest is now turning to a series of later dehydrations and rearrangements involving the glycosylated adducts which give rise to crosslinking and appearance of brown fluorescent pigments or melanoidins in certain proteins with a long half-life. This "browning" is the same process which has been recognised as the discoloration of stored and heated foods since 19128 (the Maillard reaction). Collagen is the best studied protein in the context of advanced NEG, partly because of the ease with which collagen can be examined in skin biopsies, but also because of its importance as a protein that is present in several tissues subject to complication in diabetes-eg, lung (reduced elasticity9), arteries (stiffening"and accelerated atheromaI2), and basement membrane (the thickening of which has long been regarded as the histological hallmark of diabetic microangiopathy13). Changes that occur in the collagen of diabetic patients closely resemble the changes associated with ageing’""—increases in NEG, in intermolecular crosslinking, in thermal stability, and in resistance to enzymatic digestion, and a decrease in solubility. Many of these changes have been reproduced by incubating collagen with glucose in vitro’7, although the effects do not relate to the Amadori product.18 Collagen isolated from postmortem specimens of dura of non-diabetic subjects also displays a yellow fluorescence, the intensity of which increases linearly with age of the subjects and has the same spectral properties as occurs
H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications Ann Intern Med 1984; 101: 527-37. 2. Kennedy L, Baynes JW. Non-enzymatic glucosylation and the chronic complications of diabetes: An overview. Diabelologia 1984; 26: 93-98 3. Monnier VM, Stevens VJ, Cerami A. Non-enzymatic glycosylation, sulphydryl oxidation, and aggregation of lens proteins in experimental sugar cataracts. J Exp Med 1979; 150: 1098-07. 4. Mangili R, Viberti GC, Vergani D. Autoantibodies to glycosylated human albumin in insulin-dependent diabetics. Diab Res Clin Pract 1985; suppl 1: 357. 5. Eble AS, Thorpe SR, Baynes JW Nonenzymatic glucosylation and glucose-dependent cross-linking of protein. J Biol Chem 1983, 258: 9506-12. 1. Brownlee M, Vlassara
b
Williams SK, Devenny JJ, Bitensky MW Micropinocytotic Ingestions of glycosylated
7
by isolated microvessels Possible role in pathogenesis of diabetic microangiopathy Proc Natl Acad Ser USA 1981, 78: 2393-97 Lorenzi M, Cagliero E, Markey B, Henriksen T, Witztum JL, Sampietro T. Interaction of human endothelial cells with elevated glucose concentrations and native and glycosylated low density lipoproteins Diabetologia 1984, 26: 218-22 albumin
8 Maillard LC Action des acides amines stir les sucres; formation des mélanoidines par voie méthodique CR Acad Sci (Paris) 1912, 154: 66-68 9 Schuyler MR, Niewoehner DE, Inkly SR, Kohn R Abnormal lung elasticity in juvenile diabetes mellitus Am Rev Resp Dis 1976; 113: 37-41 10. Rosenbloom AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M. Limited |oint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med 1981, 305: 191-94
collagen incubated in vitro with glucose. 16 The fluorescence of collagen from diabetics corresponds to that of nondiabetics twice their age." In all probability this premature ageing of diabetic collagen is due to advanced glycosylation reactions and cross-linking, but the chemical nature of these events is unclear. Pongor and co-workers 19 proposed a structure for one of these links: after acid hydrolysis of browned polylysine and browned serum albumin, a chromophore was released and was identified as 2-(2-furoyl)-4(5)-(2-furanyl)-lH-imidazole (FFI). This novel compound suggests that protein cross-links could be formed by a precursor of FFI in which two glucose molecules (perhaps from the Amadori product) and two amino groups from lysine residues condense to form the tricyclic conjugate precursor of FFI. The relation between collagen browning and diabetic complications has now been further explored by Monnier and colleagues.20 Collagen was isolated from skin biopsies of 41 insulin-dependent diabetics and the age-corrected fluorescence was related to the severity of various complications. This measure of browning was shown to be higher in patients with worse retinopathy, arterial stiffness (aortic pulse-wave velocity), and joint stiffness than in those of similar age and duration of diabetes who had lesser degrees of or no such complications. The trend was not significant for nephropathy, but there was a correlation between collagen fluorescence and blood pressure. It is possible that arterial stiffness due to advanced NEG in diabetics may cause or exacerbate an increase in blood pressure, which is itself a risk factor for diabetic retinopathy.2I But the exact role of browning in the aetiology of diabetic complications is unknown. Is it simply a marker for the most certain of the causative factors-the duration and severity of
hyperglycaemia?21 Two features of browning that are of relevance to diabetic complications, however, are its irreversibility and the fact that soluble proteins such as albumin and IgG can be covalently trapped by browned proteins, at least in vitro.23 This binding process will presumably progress independently of the presence of glucose and may be a mechanism whereby immunoglobulins and albumin are Pillsbury HC, Hung L, Kyte MC, Freis ED. Arterial pulse waves and velocity and systolic time intervals in diabetic children. Am Heart J 1974; 87: 783-90 12. Jarrett RJ, Keen H, Chakrabarti R. Diabetes, hyperglycaemia and arterial disease In: Keen H, Jarrett J, eds. Complications of Diabetes. 2nd ed. London Edward Arnold, 11.
1982: 179-203. 13 Williamson JR, Kilo C. 14.
Capillary basement membranes in diabetes. Diabetes 1983; 32 (suppl 2): 96-100. Schneider SL, Kohn RR. Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Invest 1981, 67:
1630-35. 15 Yue DK, McLennan S, Delbridge L, Handlesman DJ, Reeve T, Turtle JR The thermal stability of collagen in diabetic rats: Correlation with severity of diabetes and non-enzymatic glycosylation. Diabetologia 1983; 24: 282-85. 16. Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci USA 1984; 81: 583-87. 17. Kohn RR, Cerami A, Monnier VM. Collagen ageing in vitro by nonenzymatic glycosylation and browning. Diabetes 1984; 33: 57-59. 18. Lyons TJ, Kennedy L Effect of in vitro non-enzymatic glycosylation of human skin collagen on susceptibility to collagenase digestion. Europ J Clin Invest. 1985, 15: 128-31. 19. Pongor S, Ulrich PC, Bencsath FA, Cerami A. Ageing of proteins Isolation and identification ofa fluorescent chromophore from the reaction of polypeptides with glucose Proc Natl Acad Sci USA 1984, 81: 2684-88. 20. Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. Relation between complications oftype 1 diabetes mellitus and collagen-linked fluorescence N Engl JMed 1986; 314: 403-08. 21. Knowler WC, Bennett PH, Ballintine EJ. Increased incidence of retinopathy in diabetics with elevated blood pressure: A six-year follow-up study in Pima Indians N Engl J Med 1980, 302: 645-50. 22. Tchobroutsky G. Relation of diabetic control to development of microvascular
complications Diabetologia 1978; 15: 143-52 Pongor S, Cerami A Covalent attachment of soluble proteins by nonenzymatically glycosylated collagen Role in the in situ formation of immuno complexes J Exp Med 1983, 138: 1739-44
23. Brownlee M,
1193
deposited in diabetic basement membrane.24 Low-density lipoprotein is also trapped by NEG products on collagen,25 and this may be important in the development of atherosclerosis in diabetes. in diabetic rats corrects NEG of haemoglobin and of liver and kidney tissue, but not the NEG of tail collagen, nor its increased thermal stability.26In human diabetes, evidence is accumulating that, on the one hand, progress of early microangiopathic complications such as background retinopathy may be at least slowed by a year or two of strict metabolic control27,28 but, conversely, advanced disease in organs such as the kidney remains largely unaltered.29 The detailed biochemistry of browning in the many long-lived body proteins, the links between this process and the pathogenesis of different diabetic complications, and the relation of browning to their reversibility, if any, are all urgent topics for research in the next few years.
Control of
glycaemia
ULTRAFILTRATION AND HAEMOFILTRATION FOR REFRACTORY CONGESTIVE CARDIAC FAILURE with congestive heart failure and heart disease respond to treatment with diuretics, vasodilators, inotropic agents, angiotensin-converting-enzyme inhibitors, bedrest, and diet. Symptoms are relieved and life may be prolonged.1 However, some patients with pulmonary and peripheral oedema are resistant to conventional - therapy and physical methods for the removal of oedema fluid may be considered. This is not a new idea. Southey’s tubes, venesection, and both thoracocentesis and pericardiocentesis have been used in the past. The value of peritoneal dialysis with hypertonic solutions was described in 1968, and appeared to initiate clinical improvement.2 Nevertheless, although the technique is simple and cheap, it was never widely used because efficiency of fluid removal is poor, diaphragmatic splinting is deleterious in the presence of impaired ventilatory function, and there is a real risk of peritonitis. Haemodialysis to remove larger volumes of extracellular fluid may relieve symptoms, but is often limited by adverse haemodynamic effects. Use of ultrafiltration and haemofiltration has now been advocated as a method of managing refractory heart failure. The terminology of these techniques is confusing, and they may be employed together. Haemodialysis equipment with a semipermeable membrane is used for ultrafiltration; diffusion of solutes into the dialysate is modified by application of hydrostatic pressure. Hydrostatic pressure is also used for haemofiltration, but in this technique a compact, highly permeable membrane produces an ultrafiltrate of blood MOST
severe
patients underlying
24. Miller K, Michael AF Immunopathology of renal extracellular membranes in diabetes: Specificity of tubular basement membrane immunofluorescence. Diabetes 1976; 25: 701-08. 25. Brownlee M, Vlassara H, Cerami A. Non-enzymatic glycosylation products on collagen covalently trap low-density lipoprotein. Diabetes 1985; 34: 938-41. 26 McLennan S, Yue DK, Marsh M, et al The prevention and reversibility of tissue nonenzymatic glycosylation in diabetes. Diab Med 1986, 3: 141-46 27. Lauritzen T, Frost-Larsen K, Larsen H-W, Deckert T, and the Steno Study Group. Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Diabetes 1985; 34 (suppl 3). 74-79. 28 Kroc Collaborative Study Group. The Kroc study patients at two years: A report on further retinal changes. Diabetes 1985, 34 (suppl 1). 37A. 29 Viberti GC, Bilous RW, Mackintosh D, Bending JJ, Keen H. Long-term correction of hyperglycaemia and progression of renal failure in insulin-dependent diabetes. Br Med J1983; 286: 598-602. 1.
Yusuf S. Effect of vasodilators on survival in chronic congestive heart failure. Am J Cardiol 1985; 55: 1110-13.
Furberg CD,
(a solution of water, electrolytes, and molecules up to MW6000) without contact with dialysate. Arterial-tovenous communication may be used, but with a blood pump venous-to-venous link is practical. The efficacy of these methods for removal of excess fluid has been shown in oedematous patients3-5 and during cardiac
surgery.6 In six patients with refractory congestive heart failure, considerable amelioration of cardiac symptoms was observed during two courses of ultrafiltration which resulted in loss of an average 7-7 litres of fluid and 7-3 kg bodyweight.7 Nine similar patients lost an average of 12.7 litres (range 3-7-23) with up to five courses of ultrafiltration;8 during and following the five courses, measurements of heart rate, blood pressure, cardiac output, and left ventricular function were unchanged, but ventricular filling pressure was reduced transiently and serum sodium was increased. Treatment was limited by development of muscle cramps or hypotension.8 Haemofiltration appears to have a similar beneficial effect; loss of fluid and weight is achieved without haemodynamic deterioration.9-11 After physical removal of fluid, weight reduction appears to be maintained for some weeks and treatment may be repeated frequently (one patient had thirty courses over three months with loss of 122 litres of fluid7). In addition, patients become more responsive to standard heart-failure therapy. The poor prognosis of patients with refractory heart failure is well known, and in one series only two of nine patients survived for a year.8 Although most patients who have been treated by these techniques were unsuitable for operative intervention, in a few cases condition ultrafiltration stabilised the patient’s sufficiently for valve surgery or cardiac transplantation to be carried ouC. Physical removal of fluid will affect only the secondary features of heart failure and not the primary pathophysiological disorder, therefore there was no evidence of improvement in cardiac function or output or of a persistent effect on filling pressure. Ultrafiltration and to a lesser extent haemofiltration
complex and expensive, requiring special equipment highly trained medical, technical, and nursing personnel. In many countries, including the UK, these facilities are under-provided. Since the techniques do not alter prognosis, they should be used for palliation only when definitive treatment, such as cardiac surgery or transplantation, is contemplated.
are
with
2. Cairns
KB, Porter GA, Kloster FE, Bristow JD, Grinwold HE. Clinical and hemodynamic results of peritoneal dialysis for severe cardiac failure. Am Heart J 1968; 76: 227-34. 3. Silverstein ME, Ford CA, Lysaght MJ, Henderson LW. Treatment of severe fluid overload by ultrafiltration. N Engl J Med 1974; 291: 747-51. 4. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. Arteriovenous haemofiltration: A new and simple method for treatment of overhydrated patients resistant to diuretics. Klin Wschr 1977; 55: 1121-22. 5. Editorial: Haemofiltration. Lancet 1983; i: 1196-97. 6. Magilligan DJ. Indications for ultrafiltration in the cardiac surgical patient. J Thorac Cardiovasc Surg 1985; 89: 183-89. 7. Fauchald P, Forfang K, Amlie J. An evaluation of ultrafiltration as treatment of therapy-resistant cardiac edema. Acta Med Scand 1986; 219: 47-51. 8. Simpson IA, Rae AP, Gribben J, Boulton-Jones JM, Allison ME, Hutton I. Ultrafiltration in the management of refractory congestive heart failure. Br Heart J 1986; 55: 344-47. 9. Blanke H, Kreuzer H, Wigger W, Scheler F. Die Behandlung der akuten Linksherzinsuffizenz anurischer patienten mit der Hamofiltration. Dtsch Med
Wschr 1977; 102: 1804-47. AW, Flendrig JA, Fiersen H. Hemofiltratie bij ernstige, chronilsche decompensatio cordis: Cen nieuw therapentisch perspectief. Ned Tijdschr Geneeskd 1983; 127: 1755-59. 11. Page E, Machecourt J, Dechelette E, Wolf JE, Bourlard P, Denis B. Traitement des ilnsuffisances cardiaques avec oedemes refractaires par ultrafiltration extracorporelle. Arch Mal Coer 1984; 77: 1040-45.
10. Mulder
BROWNING AND DIABETIC COMPLICATIONS NON-ENZYMATIC glycosylation (NEG) of many proteins in diabetes mellitus, 1,2 and the amounts of glycosylated haemoglobin and serum proteins are widely used indices of integrated glycaemic control over the preceding few weeks. It has also been suggested that NEG may play a role in the long-term tissue complications of diabetes by such mechanisms as sulphydryl oxidation and in and alterations cross-linking of proteins,3 and cellular and uptake immunogenicity,4 enzyme function,5 degradation of maèromolecules. 6,7 The initial step in NEG is formation of a Schiff base between the free aldehyde group of glucose in its open-chain form and an amino group from aminoacid residues in a protein, the N-terminal amino and e-amino groups of lysine being important binding sites. This rapid and reversible reaction contrasts with subsequent slow rearrangement of the - Schiffbase to a more stable ketoamine linkage (the Amadori rearrangement). These chemical reactions have received most attention in the study of NEG in the last few years, especially since it is the Amadori product that is measured clinically in assessment of diabetic control. Interest is now turning to a series of later dehydrations and rearrangements involving the glycosylated adducts which give rise to crosslinking and appearance of brown fluorescent pigments or melanoidins in certain proteins with a long half-life. This "browning" is the same process which has been recognised as the discoloration of stored and heated foods since 19128 (the Maillard reaction). Collagen is the best studied protein in the context of advanced NEG, partly because of the ease with which collagen can be examined in skin biopsies, but also because of its importance as a protein that is present in several tissues subject to complication in diabetes-eg, lung (reduced elasticity9), arteries (stiffening"and accelerated atheromaI2), and basement membrane (the thickening of which has long been regarded as the histological hallmark of diabetic microangiopathy13). Changes that occur in the collagen of diabetic patients closely resemble the changes associated with ageing’""—increases in NEG, in intermolecular crosslinking, in thermal stability, and in resistance to enzymatic digestion, and a decrease in solubility. Many of these changes have been reproduced by incubating collagen with glucose in vitro’7, although the effects do not relate to the Amadori product.18 Collagen isolated from postmortem specimens of dura of non-diabetic subjects also displays a yellow fluorescence, the intensity of which increases linearly with age of the subjects and has the same spectral properties as occurs
H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications Ann Intern Med 1984; 101: 527-37. 2. Kennedy L, Baynes JW. Non-enzymatic glucosylation and the chronic complications of diabetes: An overview. Diabelologia 1984; 26: 93-98 3. Monnier VM, Stevens VJ, Cerami A. Non-enzymatic glycosylation, sulphydryl oxidation, and aggregation of lens proteins in experimental sugar cataracts. J Exp Med 1979; 150: 1098-07. 4. Mangili R, Viberti GC, Vergani D. Autoantibodies to glycosylated human albumin in insulin-dependent diabetics. Diab Res Clin Pract 1985; suppl 1: 357. 5. Eble AS, Thorpe SR, Baynes JW Nonenzymatic glucosylation and glucose-dependent cross-linking of protein. J Biol Chem 1983, 258: 9506-12. 1. Brownlee M, Vlassara
b
Williams SK, Devenny JJ, Bitensky MW Micropinocytotic Ingestions of glycosylated
7
by isolated microvessels Possible role in pathogenesis of diabetic microangiopathy Proc Natl Acad Ser USA 1981, 78: 2393-97 Lorenzi M, Cagliero E, Markey B, Henriksen T, Witztum JL, Sampietro T. Interaction of human endothelial cells with elevated glucose concentrations and native and glycosylated low density lipoproteins Diabetologia 1984, 26: 218-22 albumin
8 Maillard LC Action des acides amines stir les sucres; formation des mélanoidines par voie méthodique CR Acad Sci (Paris) 1912, 154: 66-68 9 Schuyler MR, Niewoehner DE, Inkly SR, Kohn R Abnormal lung elasticity in juvenile diabetes mellitus Am Rev Resp Dis 1976; 113: 37-41 10. Rosenbloom AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M. Limited |oint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med 1981, 305: 191-94
collagen incubated in vitro with glucose. 16 The fluorescence of collagen from diabetics corresponds to that of nondiabetics twice their age." In all probability this premature ageing of diabetic collagen is due to advanced glycosylation reactions and cross-linking, but the chemical nature of these events is unclear. Pongor and co-workers 19 proposed a structure for one of these links: after acid hydrolysis of browned polylysine and browned serum albumin, a chromophore was released and was identified as 2-(2-furoyl)-4(5)-(2-furanyl)-lH-imidazole (FFI). This novel compound suggests that protein cross-links could be formed by a precursor of FFI in which two glucose molecules (perhaps from the Amadori product) and two amino groups from lysine residues condense to form the tricyclic conjugate precursor of FFI. The relation between collagen browning and diabetic complications has now been further explored by Monnier and colleagues.20 Collagen was isolated from skin biopsies of 41 insulin-dependent diabetics and the age-corrected fluorescence was related to the severity of various complications. This measure of browning was shown to be higher in patients with worse retinopathy, arterial stiffness (aortic pulse-wave velocity), and joint stiffness than in those of similar age and duration of diabetes who had lesser degrees of or no such complications. The trend was not significant for nephropathy, but there was a correlation between collagen fluorescence and blood pressure. It is possible that arterial stiffness due to advanced NEG in diabetics may cause or exacerbate an increase in blood pressure, which is itself a risk factor for diabetic retinopathy.2I But the exact role of browning in the aetiology of diabetic complications is unknown. Is it simply a marker for the most certain of the causative factors-the duration and severity of
hyperglycaemia?21 Two features of browning that are of relevance to diabetic complications, however, are its irreversibility and the fact that soluble proteins such as albumin and IgG can be covalently trapped by browned proteins, at least in vitro.23 This binding process will presumably progress independently of the presence of glucose and may be a mechanism whereby immunoglobulins and albumin are Pillsbury HC, Hung L, Kyte MC, Freis ED. Arterial pulse waves and velocity and systolic time intervals in diabetic children. Am Heart J 1974; 87: 783-90 12. Jarrett RJ, Keen H, Chakrabarti R. Diabetes, hyperglycaemia and arterial disease In: Keen H, Jarrett J, eds. Complications of Diabetes. 2nd ed. London Edward Arnold, 11.
1982: 179-203. 13 Williamson JR, Kilo C. 14.
Capillary basement membranes in diabetes. Diabetes 1983; 32 (suppl 2): 96-100. Schneider SL, Kohn RR. Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Invest 1981, 67:
1630-35. 15 Yue DK, McLennan S, Delbridge L, Handlesman DJ, Reeve T, Turtle JR The thermal stability of collagen in diabetic rats: Correlation with severity of diabetes and non-enzymatic glycosylation. Diabetologia 1983; 24: 282-85. 16. Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci USA 1984; 81: 583-87. 17. Kohn RR, Cerami A, Monnier VM. Collagen ageing in vitro by nonenzymatic glycosylation and browning. Diabetes 1984; 33: 57-59. 18. Lyons TJ, Kennedy L Effect of in vitro non-enzymatic glycosylation of human skin collagen on susceptibility to collagenase digestion. Europ J Clin Invest. 1985, 15: 128-31. 19. Pongor S, Ulrich PC, Bencsath FA, Cerami A. Ageing of proteins Isolation and identification ofa fluorescent chromophore from the reaction of polypeptides with glucose Proc Natl Acad Sci USA 1984, 81: 2684-88. 20. Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. Relation between complications oftype 1 diabetes mellitus and collagen-linked fluorescence N Engl JMed 1986; 314: 403-08. 21. Knowler WC, Bennett PH, Ballintine EJ. Increased incidence of retinopathy in diabetics with elevated blood pressure: A six-year follow-up study in Pima Indians N Engl J Med 1980, 302: 645-50. 22. Tchobroutsky G. Relation of diabetic control to development of microvascular
complications Diabetologia 1978; 15: 143-52 Pongor S, Cerami A Covalent attachment of soluble proteins by nonenzymatically glycosylated collagen Role in the in situ formation of immuno complexes J Exp Med 1983, 138: 1739-44
23. Brownlee M,
1193
deposited in diabetic basement membrane.24 Low-density lipoprotein is also trapped by NEG products on collagen,25 and this may be important in the development of atherosclerosis in diabetes. in diabetic rats corrects NEG of haemoglobin and of liver and kidney tissue, but not the NEG of tail collagen, nor its increased thermal stability.26In human diabetes, evidence is accumulating that, on the one hand, progress of early microangiopathic complications such as background retinopathy may be at least slowed by a year or two of strict metabolic control27,28 but, conversely, advanced disease in organs such as the kidney remains largely unaltered.29 The detailed biochemistry of browning in the many long-lived body proteins, the links between this process and the pathogenesis of different diabetic complications, and the relation of browning to their reversibility, if any, are all urgent topics for research in the next few years.
Control of
glycaemia
ULTRAFILTRATION AND HAEMOFILTRATION FOR REFRACTORY CONGESTIVE CARDIAC FAILURE with congestive heart failure and heart disease respond to treatment with diuretics, vasodilators, inotropic agents, angiotensin-converting-enzyme inhibitors, bedrest, and diet. Symptoms are relieved and life may be prolonged.1 However, some patients with pulmonary and peripheral oedema are resistant to conventional - therapy and physical methods for the removal of oedema fluid may be considered. This is not a new idea. Southey’s tubes, venesection, and both thoracocentesis and pericardiocentesis have been used in the past. The value of peritoneal dialysis with hypertonic solutions was described in 1968, and appeared to initiate clinical improvement.2 Nevertheless, although the technique is simple and cheap, it was never widely used because efficiency of fluid removal is poor, diaphragmatic splinting is deleterious in the presence of impaired ventilatory function, and there is a real risk of peritonitis. Haemodialysis to remove larger volumes of extracellular fluid may relieve symptoms, but is often limited by adverse haemodynamic effects. Use of ultrafiltration and haemofiltration has now been advocated as a method of managing refractory heart failure. The terminology of these techniques is confusing, and they may be employed together. Haemodialysis equipment with a semipermeable membrane is used for ultrafiltration; diffusion of solutes into the dialysate is modified by application of hydrostatic pressure. Hydrostatic pressure is also used for haemofiltration, but in this technique a compact, highly permeable membrane produces an ultrafiltrate of blood MOST
severe
patients underlying
24. Miller K, Michael AF Immunopathology of renal extracellular membranes in diabetes: Specificity of tubular basement membrane immunofluorescence. Diabetes 1976; 25: 701-08. 25. Brownlee M, Vlassara H, Cerami A. Non-enzymatic glycosylation products on collagen covalently trap low-density lipoprotein. Diabetes 1985; 34: 938-41. 26 McLennan S, Yue DK, Marsh M, et al The prevention and reversibility of tissue nonenzymatic glycosylation in diabetes. Diab Med 1986, 3: 141-46 27. Lauritzen T, Frost-Larsen K, Larsen H-W, Deckert T, and the Steno Study Group. Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Diabetes 1985; 34 (suppl 3). 74-79. 28 Kroc Collaborative Study Group. The Kroc study patients at two years: A report on further retinal changes. Diabetes 1985, 34 (suppl 1). 37A. 29 Viberti GC, Bilous RW, Mackintosh D, Bending JJ, Keen H. Long-term correction of hyperglycaemia and progression of renal failure in insulin-dependent diabetes. Br Med J1983; 286: 598-602. 1.
Yusuf S. Effect of vasodilators on survival in chronic congestive heart failure. Am J Cardiol 1985; 55: 1110-13.
Furberg CD,
(a solution of water, electrolytes, and molecules up to MW6000) without contact with dialysate. Arterial-tovenous communication may be used, but with a blood pump venous-to-venous link is practical. The efficacy of these methods for removal of excess fluid has been shown in oedematous patients3-5 and during cardiac
surgery.6 In six patients with refractory congestive heart failure, considerable amelioration of cardiac symptoms was observed during two courses of ultrafiltration which resulted in loss of an average 7-7 litres of fluid and 7-3 kg bodyweight.7 Nine similar patients lost an average of 12.7 litres (range 3-7-23) with up to five courses of ultrafiltration;8 during and following the five courses, measurements of heart rate, blood pressure, cardiac output, and left ventricular function were unchanged, but ventricular filling pressure was reduced transiently and serum sodium was increased. Treatment was limited by development of muscle cramps or hypotension.8 Haemofiltration appears to have a similar beneficial effect; loss of fluid and weight is achieved without haemodynamic deterioration.9-11 After physical removal of fluid, weight reduction appears to be maintained for some weeks and treatment may be repeated frequently (one patient had thirty courses over three months with loss of 122 litres of fluid7). In addition, patients become more responsive to standard heart-failure therapy. The poor prognosis of patients with refractory heart failure is well known, and in one series only two of nine patients survived for a year.8 Although most patients who have been treated by these techniques were unsuitable for operative intervention, in a few cases condition ultrafiltration stabilised the patient’s sufficiently for valve surgery or cardiac transplantation to be carried ouC. Physical removal of fluid will affect only the secondary features of heart failure and not the primary pathophysiological disorder, therefore there was no evidence of improvement in cardiac function or output or of a persistent effect on filling pressure. Ultrafiltration and to a lesser extent haemofiltration
complex and expensive, requiring special equipment highly trained medical, technical, and nursing personnel. In many countries, including the UK, these facilities are under-provided. Since the techniques do not alter prognosis, they should be used for palliation only when definitive treatment, such as cardiac surgery or transplantation, is contemplated.
are
with
2. Cairns
KB, Porter GA, Kloster FE, Bristow JD, Grinwold HE. Clinical and hemodynamic results of peritoneal dialysis for severe cardiac failure. Am Heart J 1968; 76: 227-34. 3. Silverstein ME, Ford CA, Lysaght MJ, Henderson LW. Treatment of severe fluid overload by ultrafiltration. N Engl J Med 1974; 291: 747-51. 4. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. Arteriovenous haemofiltration: A new and simple method for treatment of overhydrated patients resistant to diuretics. Klin Wschr 1977; 55: 1121-22. 5. Editorial: Haemofiltration. Lancet 1983; i: 1196-97. 6. Magilligan DJ. Indications for ultrafiltration in the cardiac surgical patient. J Thorac Cardiovasc Surg 1985; 89: 183-89. 7. Fauchald P, Forfang K, Amlie J. An evaluation of ultrafiltration as treatment of therapy-resistant cardiac edema. Acta Med Scand 1986; 219: 47-51. 8. Simpson IA, Rae AP, Gribben J, Boulton-Jones JM, Allison ME, Hutton I. Ultrafiltration in the management of refractory congestive heart failure. Br Heart J 1986; 55: 344-47. 9. Blanke H, Kreuzer H, Wigger W, Scheler F. Die Behandlung der akuten Linksherzinsuffizenz anurischer patienten mit der Hamofiltration. Dtsch Med
Wschr 1977; 102: 1804-47. AW, Flendrig JA, Fiersen H. Hemofiltratie bij ernstige, chronilsche decompensatio cordis: Cen nieuw therapentisch perspectief. Ned Tijdschr Geneeskd 1983; 127: 1755-59. 11. Page E, Machecourt J, Dechelette E, Wolf JE, Bourlard P, Denis B. Traitement des ilnsuffisances cardiaques avec oedemes refractaires par ultrafiltration extracorporelle. Arch Mal Coer 1984; 77: 1040-45.
10. Mulder