Albuminuria is associated with hypertension (systolic and/or diastolic in men, systolic hypertension only in women) de Fine Olivarius N, Andreasen AH, Keiding N, Mogensen CE. Epidemiology of renal involvement in newly-diagnosed middle-aged and elderly diabetic patients. Cross-sectional data from the population-based study 'Diabetes care in General Practice'. Diabetologia 19-16. There is a positive correlation between albuminuria and blood pressure and/or hypertension in subjects with type 2 DM and in non diabetics Patrick AW, Leslie PJ, Clarke BF, Frier BM. The natural history and associations of microalbuminuria in type 2 diabetes during the first year after diagnosis. Diabet Med 1990;7:902-8.

Marshall SM, Alberti kgMM. Comparison of the prevalence and associated features of abnormal albumin excretion in insulin-dependent and non-insulin-dependent diabetes. Q J Med 1989;70:61-71. Fabre J, Balant LP, Dayer PG, Fox HM, Vernet AT. The kidney in maturity onset diabetes mellitus: a clinical study of 510 patients. Kidney Int 1982;21:730-8.

Metcalf P, Baker J, Scott A, Wild C, Scagg R, Dryson E. Albuminuria in people at least 40 years old: effect of obesity, hypertension and hyperlipidemia. Clin Chem 19-8. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey.

Lancet 1988;II:530-3. Torffvit O, Agardh E, Agardh CD. Albuminuria and associated medical risk factors: a cross-sectional study in 451 type II (non-insulin-dependent) diabetic patients. J Diabet Complications 1991;5:29-34.

Mattock MB, Keen H, Viberti GC, et al Coronary heart disease and urinary albumin excretion rate in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1988;31:82-7. Allawi J, Jarrett RJ. Microalbuminuria and cardiovascular risk factors in type 2 diabetes mellitus. Diabetic Med 1990;7:115-8.

Moreover, treatment of hypertension in type 1 DM decreases albuminuria Mogensen CE. Long-term antihypertensive treatment in-habiting progression of diabetic nephropathy. Br Med J 1982;285:685-8. Age itself is associated with hypertension and arteriosclerosis which can decrease glomerular filtration in aged patients Lindeman RD, Tobin JD, Shock NW.

Association between blood pressure and the rate of decline in renal function with age. Kidney Int 1984;26:861-8. Hypertension itself can lead to glomerulosclerosis and microalbuminuria, even in the absence of DM. Zuccheli P, Zuccala A. The diagnostic dilemma of hypertensive nephrosclerosis: the nephrologist’s view. Am J Kidney Dis 1993;21:87-91. Nielsen et al, showed that systolic blood pressure but not glycaemia, was correlated with decreased glomerular filtration rate (GFR) in type 2 DM patients with normoalbuminuria or microalbuminuria Nielsen S, Rehling M, Schmitz A, Mogensen CE. Systolic blood pressure relates to the rate of decline of glomerular filtration rate in type II diabetes.

Diabetes Care 19-32. A prospective Japanese study, including 22 type 2 diabetics (age range: 50 and 73 yrs) with at least a 7 yrs persistent microalbuminuria, confirmed the role of hypertension in the progression of microalbuminuria Ito Y, Utsugi T, Ohyama Y, et al. Role of blood pressure in the progression of microalbuminuria in elderly Japanese type 2 diabetic patients: a 7-year follow-up study. J Int Med Res 2001;29:280-6. However, different results were observed in other studies Nielsen S, Rehling M, Schmitz A, Mogensen CE.

Systolic blood pressure relates to the rate of decline of glomerular filtration rate in type II diabetes. Diabetes Care 19-32. Lane PH, Steffes MW, Mauer SM. Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion. Diabetes 1992;41:581-6.

Tsalamandris C, Allen TJ, Gilbert RE, et al. Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes 1994;43:649-55. In a retrospective 6-yr study including 123 type 2 diabetics aged 60 to 75 (mean age 63 yrs) Tanaka Y, Atsumi Y, Matsuoka K, Onuma T, Tohjima T, Kawamori R. Role of glycaemic control and blood pressure in the development and progression of nephropathy in elderly Japanese NIDDM patients.

Diabetes Care 1998;21:116-20. , 74 with normoalbuminuria and 49 with microalbuminuria, glycaemic control has been shown to play a more potent role on the occurrence of microalbuminuria than blood pressure. On the contrary, hypertension was the major factor for the progression from microalbuminuria to proteinuria. So it has been suggested that the cut-off for increased risk of DN was an HbA 1c over 7.8% and a mean blood pressure over 100 mmHg. Finally, it is necessary to examine the role of renal arterial lesions, particularly renal arterial stenosis and atheroma of lobar arteries. About 10% of diabetic patients with hypertension have a renal artery stenosis, and in 40% of the cases, the lesions are bilateral. Moreover the prevalence of renal artery stenosis increases with aging, and stenosis of more than 75% are 5.4 times more frequent over the age of 70 in comparison with younger subjects Anderson G, Blakeman N, Streeten D. The effect of age on prevalence of secondary forms of hypertension in 4,429 consecutively referred patients.

J Hypertension 1994;12:609-15. However the prevalence of renal artery stenosis in diabetics is strongly underestimated due to the difficulty to perform renal artery ultrasound examination in obese patients and the limitation of renal angiography in reason of the increased risk of acute renal failure Sawicki P, Kaiser S, Heinemann L, et al. Prevalence of renal artery stenosis in diabetes mellitus: an autopsy study. J Intern Med 1991;229:489-92. Since the presence of a glomerular nephropathy in an elderly patient with DM, particularly type 2 DM, is not synonymous of DN, the problem is to define accurate diagnostic criteria. In practice, if there is no diabetic retinopathy, only 50% to 70% of the proteinuria cases occurring in aged diabetics are related to diabetes, so an important proportion of patients will have a non diabetic nephropathy (hypertension, pyelonephritis, glomerulonephritis): this fact would justify the realization of a renal biopsy Grenfell A, Bewick M, Parsons V, et al. Non-insulin dependent diabetes and renal replacement therapy.

Diabet Med 1988;5:172-6. Parving H, Gall M, Skott P. Prevalence and cause of albuminuria in non insulin dependent diabetic patients. Kidney Int 1992;41:758-62. The arguments in favour of the diabetic etiology of a nephropathy are mainly proteinuria ≥1g/day and an advanced diabetic retinopathy Iqbal Z, Meguira S, Friedman EA. Geriatric diabetic nephropathy: an analysis of renal referral in patients age 60 or older. Am J Kidney Dis 1990;16:312-6.

Marshall SM, Alberti kgMM. Comparison of the prevalence and associated features of abnormal albumin excretion in insulin-dependent and non-insulin-dependent diabetes. Q J Med 1989;70:61-71. Torffvit O, Agardh E, Agardh CD.

Albuminuria and associated medical risk factors: a cross-sectional study in 451 type II (non-insulin-dependent) diabetic patients. J Diabet Complications 1991;5:29-34. Parving H, Gall M, Skott P. Prevalence and cause of albuminuria in non insulin dependent diabetic patients. Kidney Int 1992;41:758-62. On the other hand, a recent diagnosis of diabetes, lack of retinopathy and Caucasian origin are more suggestive of a non diabetic nephropathy Amoah E, Glickman J, Malchoff C, et al. Clinical identification of nondiabetic renal disease in diabetic patients with type II and type I disease presenting with renal dysfunction.

Nephrol Dial Transplant 1988;8:204-11. With regard to renal failure in the elderly, the increase in serum creatinine is not sufficient to establish the diagnosis since serum creatinine may be in the normal range despite decreased GFR. At present, the majority of authors prefer the estimation of GFR by MDRD formula, because the evaluation by the Cockcroft and Gault’s formula can be inappropriate in the presence of edema or malnutrition.

So the percentage of aged diabetic patients with normal serum creatinine and decreased estimated GFR (eGFR) has been evaluated to be about 16% Corsonello A, Pedone, Corica F, et al; Gruppo Italiano di Farmacovigilanza nell’Anziano (GIFA). Concealed renal failure and adverse drug reactions in older patients with type 2 diabetes mellitus. J Gerontol A Biol Sci Med Sci 20-51. Indications of renal biopsy have been controversial in the past years mostly because proteinuria in diabetics was deemed to be related DN as it is the case in young type 1 diabetic patients with retinopathy. In contrast we just have seen that the probability of finding true DN in a type 2 diabetic patient is much lower. Following a National Institutes of Health (NIH) consensus conference, held in Bethesda in 1991, renal biopsy in diabetes is indicated in the following situations Glassock RJ, Hirschman GH, Striker GE. Workshop on the use of renal biopsy in research on diabetic nephropathy: a summary report.

Am J Kidney Dis 1991;18:589-92. :. overt nephropathy in type 1 diabetic patients with less than 10 years evolution;. renal involvement (proteinuria, renal failure) in type 2 diabetic patients without retinopathy;.

acute or rapidly progressive decrease in GFR or sudden nephrotic syndrome in a diabetic patient;. symptoms suggestive of a nephropathy unrelated to diabetes (active urinary sediment, haematuria, haematic cylinders, absence of proteinuria, extrarenal syndrome pointing to a systemic disease).

In elderly diabetic patients, careful attention should be paid to presentation as rapidly progressive glomerulonephritis or a nephrotic syndrome unpreceded by a history of microalbuminuria, since extracapillary glomerulonephritis, membranous nephropathy and amyloidosis have a very much higher incidence in this age range Glassock RJ, Hirschman GH, Striker GE. Workshop on the use of renal biopsy in research on diabetic nephropathy: a summary report. Am J Kidney Dis 1991;18:589-92. Several aspects are to be considered:. Can DN be prevented?. How to slow down the rate of progression of confirmed DN?. What is the treatment of renal insufficiency in aged diabetics?.

How to manage the aged diabetics in dialysis? This approach is integrated in a global care, the “renal” objective being as much as possible to slow down the progression of the nephropathy in order to delay or prevent the requirement for dialysis. However, this objective must be distinguished from late referral to dialysis, inception at a complicated stage or in emergency of a patient in poor condition.

Lastly, global care supposes the prevention of the cardiovascular and metabolic complications, as well as the prevention of nephrotoxicity. Glycaemic control plays the major role in the prevention of microalbuminuria, but blood pressure control seems determinant for the evolution from microalbuminuria to proteinuria Tanaka Y, Atsumi Y, Matsuoka K, Onuma T, Tohjima T, Kawamori R. Role of glycaemic control and blood pressure in the development and progression of nephropathy in elderly Japanese NIDDM patients.

Diabetes Care 1998;21:116-20. However no clinical data are available on the beneficial effects of glycaemic control in frail older persons in whom less stringent treatment goals may be appropriate given the limited life expectancy and multiple comorbidities Constans T. Plasma glucose goals and therapeutic management in elderly diabetic patients. Diabetes Metab 2005;31:5S58-5S61. In younger subjects, improved glycaemic control has been shown to reduce the risk of diabetic nephropathy, retinopathy and neuropathy.

In the absence of clinical trial in older patients with DM, extrapolation of data obtained in younger subjects is reasonable in attempt to reduce the burden of disease and improve the quality of life. Treatment of frail older persons requires a careful balance between the treatment goals proposed in the guidelines and an individualized approach of drug therapy to avoid potential adverse events such as hypoglycaemia. RENAAL (Reduction of End-points in NIDDM with Angiotensin II Antagonist Losartan) included 1,513 type 2 diabetic patients with nephropathy (mean age: 60±7 yrs), randomized to receive in addition to a conventional antihypertensive treatment, either losartan (50-100 mg/day) or placebo, for an average follow-up period of two yrs Brenner BM, M.D., Cooper ME, de Zeeuw D, et al. Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. N Engl J Med 2001;345:861-9. The primary efficacy measure was the time to a composite endpoint of doubling serum creatinine, ESRF, or both. For a similar BP reduction, losartan significantly reduced by 20% the risk of the primary endpoint, by 28% the incidence of ESRF and by 25% the risk of doubling serum creatinine.

The IDNT study (Irbesartan Diabetic Nephropathy Trial) included 1,715 patients with type 2 diabetes and DN (mean age: 59±8 years), who were randomized in three groups to receive in addition to their conventional antihypertensive treatment, either irbesartan 300 mg/day or amlodipine 10 mg/day, or a placebo; mean follow-up was 2.6 years Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to Type 2 Diabetes. N Engl J Med 2001;345:851-60.

The main outcome was a composite of time to doubling plasma creatinine, ESRF and all cause mortality. For a slightly better BP control (approximately –2 mmHg) with irbesartan and amlodipine compared to placebo, irbesartan significantly increased the delay to the primary endpoint by 20% as compared to placebo and by 23% as compared to amlodipine; time to doubling plasma creatinine was increased by 33% as compared to placebo and by 37% as compared to amlodipine and finally, irbesartan increased the delay to ESRF by 23% as compared to placebo or amlodipine. The post hoc analyses of RENAAL and IDNT indicate that the mechanisms of the nephroprotective effect are strongly related to the reduction of proteinuria. BP targets were. A direct comparison between the two therapeutic classes has been carried out in the DETAIL study (Diabetics Exposed to Telmisartan and Enalapril) Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting– enzyme inhibition in type 2 diabetes and nephropathy.

N Engl J Med 2004;351:1952-61. This double blind study compared the effects of telmisartan 80 mg/day and enalapril 20 mg/day, in 250 type 2 diabetic patients (mean age: 61±9 yrs) with an early stage nephropathy (UAER: 11-999 µg/day). The main endpoint was the 5-year change in GFR. The fall in GFR in the enalapril and the telmisartan groups were identical. Secondary endpoints including the annual change in GFR, UAER, plasma creatinine, blood pressure, incidence of clinical events and all cause mortality, were not significantly different between groups. The authors concluded that telmisartan was not inferior to enalapril on the renal protection of type 2 diabetic patients with early stage nephropathy.

This study, suggest that moderate doses of ACEI are at least as effective as the usual doses of A2A. To date, there is no study comparing ACEI and A2A on the mortality rate in type 2 diabetic patients with microalbuminuria or a more advanced DN. The systematic review by Strippoli et al Strippoli FM, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004;329:828. compared the renal outcomes and mortality rate observed in 43 randomized studies of at least 6-month duration.

Altogether, these studies suggest that ACEI and A2A have similar beneficial renoprotective effects, but that ACEI in contrast with A2A might improve survival. It should be noted that these findings on mortality are driven for 90% by the results of HOPE study, performed in very high risk patients with symptomatic CAD or past myocardial infarction. It is also important to stress that these conclusions are based on indirect comparisons made from rather heterogeneous populations and not from head to head comparisons between ACEI and A2A. The STENO 2 study had initially shown the dramatic efficacy of a multifactorial approach in type 2 diabetic patients, by combining diet, exercise, cessation of smoking, aspirin, BP reduction and treatment with ACEI and statins. A 57% risk reduction in cardiovascular events and a 61% risk reduction in developing nephropathy have been observed in patients (mean age: 63 yrs) in the intensive group, suggesting that this approach is feasible and highly effective in older patients Gaede P, Vedelle P, Marsen N, et al. Multifactorial interventions and cardiovascular disease in patients with type 2 diabetes.

N Engl J Med 2003;348:383-93. In very old frail patients, the benefit of a strict glycaemic and BP control is however more uncertain and the therapeutic targets must take into account the increased iatrogenic risk, and integrate the social context of the patient.

Elderly diabetic patients with renal disease require a multidisciplinary collaboration in order to provide optimal care. Reduced GFR, limits the use of oral antidiabetic agents and often leads to their replacement by insulin treatment. An extended geriatric evaluation of cognitive functions and autonomy for daily life activity is determinant for the assessment of the possibilities for the patient of coping with his, often complex, treatment. A nutritional evaluation is necessary also, as denutrition is common in these patients and frequently associated with comorbidities. Finally, it has been shown that early referral to the nephrologist of patients with type 2DM and DN is associated with better outcomes during later renal replacement therapy Frimat L, Loos-Ayav C, Panescu V, et al.

Eearly referral to a nephrologist is associated with better outcomes in type 2 diabetes patients with end-stage renal disease. Diabetes Metab 2004;30:67-74. Renal impairment modifies the elimination rate of many antidiabetic drugs and reduces the catabolism of insulin. Elderly patients have an increased risk of severe hypoglycaemia and are more likely to experience sequela after a severe hypoglycaemic episode. Furthermore, elderly patients have frequently multiple therapies which can lead to drug-drug interactions.

Available data on the pharmacokinetics of the antidiabetic drugs in elderly patients with renal insufficiency are very scarce and generally concern only small groups of severely affected patients. Repaglinide is presently the only meglitinide analogue available in France. The drug has not been studied in patients aged over 75, but its pharmacokinetic profile suggests a relative safety in elderly patients Hatorp V, Huang WC, Strange P. Repaglinide pharmacokinetics in healthy young adult and elderly subjects. Clin Ther 1999;21:702-10. Repaglinide is almost completely metabolized via CYP 450 3A4 in several inactive derivatives, eliminated in the bile and for only 8% in the urine.

Pharmacokinetics of repaglinide remains unchanged as long as creatinine clearance is  15 ml/min Marbury TC, Ruckle JL, Hatorp V, et al. Pharmacokinetics of repaglinide in subjects with renal impairment. Clin Pharmacol Ther 2000;67:7-15. Schumacher S, Abbasi I, Weise D, et al.

Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur J Clin Pharmacol 2001;57:147-52. In hemodialyzed patients however, the AUC concentration is doubled and the elimination half-life increased. Repaglinide can be used in patients with severe renal failure and in dialyzed patients at the starting dose of 0.5 mg before the main meals, and then progressively adapted according to tolerance and blood glucose levels. Metformin is an hydrophilic substance, which circulates almost completely unbound in the plasma and is eliminated in unchanged form by the kidney (70-90%) and partly by the liver.

The elimination of metformin is slowed in chronic or acute renal insufficiency and the accumulation of the drug favors the occurrence of lactic acidosis, which remains a complication with a high mortality rate Sambol NC, Chiang J, Lin ET, et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol 19-102.

However, metformin associated lactic acidosis can also occur in the absence of metformin accumulation. This occurs generally in patients with less severe renal insufficiency Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995;18:779-84. Old age and even moderate renal insufficiency are usually considered as contraindications to its use, and so, creatinine levels must be determined before the prescription and regularly monitored during treatment. However, considering the rarity of metformine-associated lactic acidosis and the risks of the alternative therapeutics, some authors now propose its cautious use in patients with mild renal impairment, arguing that there is no increase in plasma lactate levels in these patients in comparison with patients with normal serum creatinine Chan NN Brain HPS, Feher MD.

Metformin-associated lactic acidosis: a rare or very rare clinical entity? Diabet Med 1999;16:273-81. Connolly V, Kesson CM. Metformin treatment in NIDDM patients with mild renal impairment. Postgrad Med J 1996;72:352-4.

However, due to the risk of a rapid deterioration of the GFR, the drug should be withdrawn in the case of intercurrent illness or initiation of a treatment susceptible to deteriorate renal function. Consequently, eGFR should be regularly assessed in these patients.

Rosiglitazone and pioglitazone are insulinsensitisers. Rosiglitazone is almost completely protein bound and is metabolized in the liver via CYP 2C8 and 2C9. The biological activity of its major metabolite is debated.

Two thirds of the dose is eliminated by the kidney as metabolites. The pharmacokinetics of rosiglitazone remains unchanged in renal insufficiency, even in end stage disease and in hemodialysis Thompson-Culkin K, Zussman B, Miller AK, Freed MI.

Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res 2002;30:391-9.

Chapelsky MC, Thompson-Culkin K, Miller AK, et al. Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol 2003;43:252-9. Pioglitazone is also strongly protein bound, metabolized in the liver by CYP 3A4 and 2C9.

Two of its metabolites exert significant biological activity. The drug is eliminated by the kidney for 45% and the liver for 55%. The AUC of pioglitazone and of its major metabolites slightly decrease with increasing renal impairment, probably due to reduced protein binding and increased hepatic clearance Edwards G, Eckland DJA. Pharmacokinetics of pioglitazone in patients with renal impairment. Diabetologia 1999;42 (Suppl 1):A230 Abstract.

The free concentrations of the drug remain normal even with a 45 mg daily dose. No adverse effects have been observed in haemodialyzed patients with a 30 mg daily dose. So, thiazolidinediones can be theoretically used in patients with renal failure without dose adjustment. However, the cardiac function of these elderly patients with frequently long lasting diabetes and hypertension will often represent a contra-indication to their use. Although acarbose is not absorbed, the molecule is partly cleaved by bacterial and digestive enzymes Lebovitz HE.glucosidase inhibitors as agents in the treatment of diabetes.

Diabetes Rev 1998;6:132-45. These inactive metabolites are absorbed and excreted by the kidney. They are probably involved in the rare cases of hepatotoxicity described with high doses of acarbose Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000;26:73-85.

In the absence of specific data, acarbose should not be used when creatinine clearance is below 25 ml/min. Miglitol is absorbed by active transport, circulates free in plasma and is eliminated by the kidney Lebovitz HE.glucosidase inhibitors as agents in the treatment of diabetes. Diabetes Rev 1998;6:132-45. Scott LJ, Spencer CM. Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus. Drugs 2000;59:521-49. Age has only a minor influence on its elimination half-life, but as expected, renal insufficiency leads to a drug accumulation proportional to the severity of the disease.

However, since it acts locally in the digestive tract and its intracellular penetration is very low, miglitol has no known adverse effect Scott LJ, Spencer CM. Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus. Drugs 2000;59:521-49. Because of the lack of specific data, miglitol should not be used when creatinine clearance is below 25 ml/min Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure.

Diabetes Metab 2000;26:73-85. Several factors explain the reduced insulin needs and the susceptibility to hypoglycaemia in advanced chronic renal failure: the reduction of the renal catabolism of insulin (the kidney plays a major role in the elimination of insulin after the first hepatic pass) and of the peripheral degradation of the hormone due to accumulation of nitrogen derivatives Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000;26:73-85. Moreover, renal neoglucogenesis can be impaired and anorexia frequently occurs in ESRF Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure.

Diabetes Metab 2000;26:73-85. On the other hand, insulin resistance tends to increase and this can explain the interindividual variability of the reduction of insulin needs Schmitz O, Alberti KG, Orskov H. Insulin resistance in uraemic insulin-dependent diabetics. Effect of dialysis therapy as assessed by the artificial endocrine pancreas.

Acta Endocrinol 1984;105:371-8. Reduced insulin degradation in kidney failure alters the pharmacokinetics of insulin, with as a general rule, an increase of their duration of action. As a consequence, long acting insulins are generally not recommended in renal insufficiency Snyder RW, Berns JS. Use of insulin and oral hypoglycaemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial 2004;17:365-70. However, limited data suggest that age and kidney function have only a minor effect on the pharmacokinetics of insulin Detemir and even insulin glargine can be used at low dose as basal insulin in addition to preprandial injection of rapid analogs, which remains faster absorbed than regular insulin, even in hemodialysis patients Jacobsen LV, Popescu G, Plumm A. Pharmacokinetics of insulin detemir in subjects with renal or hepatic impairment.

Diabetologia 2002;45 (suppl 2):A259-60 abstract 806. Pscherer S, Schreyer-Zell G, Gottsmann M. Experience with insulin glargine in patients with end-stage renal disease. Diabetes 2002;51 (Suppl 2):A53 abstract 216 OR. Aisenpreis U, Pfutzner A, Giehl M, Keller F, Jehle PM. Pharmacokinetics and pharmacodynamics of insulin Lispro compared with regular insulin in haemodialysis patients with diabetes mellitus. Nephrol Dial Transplant 1999;14 (Suppl 4):5-6.

Czock D, Alsenpreis U, Rasche FM, Jehle PM. Pharmacokinetics and pharmacodynamics of lispro-insulin in hemodialysis patients with diabetes mellitus. Inter J Clin Pharmacol Ther 2003;41:492-7. In elderly diabetic patients with severe renal failure who are not adequately controlled by diet alone (with or without repaglinide), the following therapeutic regimens could be considered: 1°) one injection bed time NPH+repaglinide t.i.d.; 2°) two or three injections of premix insulin when it is possible in aged patients; 3°) basal insulin+three preprandial injections of a rapid analog.

A prospective formal evaluation of these therapeutic schemes in terms of glycaemic control and occurrence of hypoglycaemia should however be undertaken, since repaglinide is presently not recommended in patients older than 75 yrs. Two main therapeutic drug classes with nephrotoxic potential are more and more widely used in aged and/or diabetic patients. Non steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors are largely used in the treatment of many painful or rheumatologic diseases, frequent in elderly subjects. By inhibiting the synthesis of the renal vasodilatory prostaglandins, these drugs interfere with renal circulatory autoregulation, especially in the setting of nephron reduction (renal failure) or renal hypoperfusion (dehydration, diuretics, nephrotic syndrome). These drugs can induce acute functional renal failure, particularly when co-prescribed with blockers of the RAS and/or in case of dehydration, notably if GFR is below 60 ml/mn/1.73 m 2. Moreover, NSAIDs reduce sodium and potassium renal excretion, favoring edema, poor blood pressure control, hyperkalemia and heart failure. The iodinated contrast media are still among the first suppliers of acute renal failure, especially in hospitalized patients and despite a better knowledge of the risk factors and progress in prevention.

Indeed, radiological procedures, particularly angiographies and CT-scan are used more and more frequently in elderly and frail patients. Numerous risk factors of acute renal failure after contrast media have been identified: diabetes, age above 75 yrs, hypovolemia or renal hypoperfusion, intra-arterial infusion of iodinated contrast media, use of NSAIDs, but the two most important are preexistent renal disease, and the amount of contrast media. The global incidence of acute renal failure post-contrast media is low, ranging from 0.5 to 1% of all procedures, but increases up to one third of the patients when several risk factors are present, notably underlying renal failure. In addition to the risk of requiring dialysis treatment, acute renal failure post-contrast media in the hospital setting is associated with prolonged hospitalization stay and increased mortality both during the hospitalization and on the long term. This worse prognosis is partially explained by the coexistence of other risk factors, particularly diffuse atheromatosis.

With regard to prevention, the European Society of Urologic Radiology and the American College of Radiology recommend the evaluation of risk factors, in particular dehydration, heart failure, age above 70 yrs and use of potentially nephrotoxic drugs. Measurement of plasma creatinine and estimation of GFR by either MDRD or Cockcroft and Gault’s formulas should be made before intra-arterial use of the contrast media and in patients with a history of kidney disease, proteinuria, renal surgery, diabetes, hypertension or gout Barret BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med 2006;354:379-86. When at least two risk factors are present or when eGFR is below 50 ml/min/1.73 m 2, the use of iodinated contrast media should be limited to those situations where there are no alternative imaging methods (doppler-echography, MRI). It is also necessary to stop potentially nephrotoxic drugs and diuretics. In type 2 diabetics treated with metformin, this agent should be withhold the day of the procedure and reintroduced only 48 h after the procedure if eGFR remains greater than 40 ml/min, in order to avoid lactic acidosis in the case of occurrence of contrast-media-induced acute renal failure.

Iodinated contrast media can be classified by osmolarity (high osmolar contrast media such as sodium ditrizoate, low-osmolar media such as iohexol and iso-osmolar media such as iodixanol). When necessary, low-osmolar and even iso-osmolar media in limited doses are usually recommended in diabetic patients, especially when there is preexistent renal disease; there is however no definite proof that this strategy can reduce the need for dialysis. Multiple infusions of contrast media within a short period of time and the use of mannitol or diuretics are to be avoided.

Maintaining adequate hydration and administration of additional fluids are also recommended, but the details of the regimens are not defined. Intravenous infusions of isotonic or semi-isotonic saline 9‰ at 1 ml/kg/hour during the 12 h preceding the procedure and 12 h afterwards are among the best validated procedures. The use of N-acetylcystein remains controversial, and its effectiveness, if any, seems overall marginal. Most guidelines do not recommend systematic use of N-acetylcystein and, if used, it should accompany, not replace, validated prophylactic procedures Barret BJ, Parfrey PS. Preventing nephropathy induced by contrast medium.

N Engl J Med 2006;354:379-86. Anemia is a very frequent complication of advanced chronic renal failure. Its prevalence increases in parallel with the degree of GFR reduction.

Ckd Pneumatic Cylinders

More than half of aged patients beginning dialysis have a hematocrit lower than 30%, whereas only 15% are treated with erythropoietin (EPO) Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2002;162:1401-8. Xue JL, St Peter WL, Ebben JP, Everson SE, Collins AJ. Anemia treatment in the pre-ESRD period and associated mortality in elderly patients. Am J Kidney Dis 20-61. In the absence of more specific data in this population of patients, it can be reasonably assumed that old diabetic patients are not more frequently anemic than non diabetic dialysed patients. Diabetes is significantly associated with anemia as early as stages 2 (eGFR 30-60 ml/min) and 3 (eGFR 15-30 ml/min) of chronic renal failure but not significantly more at stage 4 (eGFR.

Hyperparathyroidism and mineral metabolism disorders are very frequent complications of the ESRF and are associated with an increased morbi-mortality Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 20-18. Hyperparathyroidism is the consequence of phosphate retention, calcitriol deficiency and the resulting absorptive hypocalcemia. The consequence is a high bone turnover with demineralization and accelerated vascular and soft tissues calcifications.

However, uremic bone is resistant to parathormone (PTH) effects, and so, the goal is not to normalize PTH levels but to maintain them in the 150-300 pg/ml range K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42 (Suppl 3):S1-201. Lower PTH levels are associated with a low bone turnover, loss of buffering function and a higher risk of metastatic calcifications.

In the whole population of dialysis patients, elderly and diabetics have the lowest rates of PTH Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis 1997;29:862-5. In the same way, hyperparathyroidism requiring parathyroidectomy is rather rare among elderly and patients with DN Kestenbaum B, Seliger SL, Gillen DL, et al. Parathyroidectomy rates among United States dialysis patients:1990-1999. Kidney Int 2004;65:282-8.

This may be due in part to a shorter life expectancy of these patients in dialysis and to a shorter duration of renal failure before dialysis. Moreover, advanced age and diabetes represent a cause of high circulating levels of advanced glycation end products which have an inhibiting effect on PTH secretion Sugimoto T, Ritter C, Morrissey J, Hayes C, Slatopolsky E. Effects of high concentrations of glucose on PTH secretion in parathyroid cells. Kidney Int 19-7. Yamamoto T, Ozono K, Miyauchi A, et al. Role of advanced glycation end products in adynamic bone disease in patients with diabetic nephropathy.

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Am J Kidney Dis 2001;38 (Suppl 1):S161-4. Elderly diabetics are thus more at risk to develop adynamic bone disease. Consequently, treatment calls less often for calcitriol and due to the frequent anorexia of the elderly, the use of phosphate binders is seldom necessary Young EW, Albert JM, Satayathum S, et al. Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study. Kidney Int 20-87. The calcium load has to be moderate in order to avoid peaks of hypercalcemia leading to ectopic calcifications. For patients with a PTH over 300 pg/ml, the therapeutic strategy is standardized, including, vitamin D if phosphatemia is normal or low, with the help of phosphate binders when necessary.

If phosphatemia is high, therapeutic options include calcimimetics and nowadays seldom parathyroidectomy. The risk of this surgery should be taken into account due to the high burden of comorbidities in these patients Kestenbaum B, Andress DL, Schwartz SM, et al. Survival following parathyroidectomy among United States dialysis patients. Kidney Int 20-6.

Dialysis techniques have made real progress with a much better tolerance of dialysis sessions. Acetate free dialysate, ultrafiltration controllers and the newer tools as blood temperature and blood volume monitoring all have improved considerably the comfort and the hemodynamic tolerance of the hemodialysis procedure. Moreover, older patients draw the same benefits from dialysis than younger patients and thus ageing is no more considered as a contraindication for starting maintenance dialysis Rotellar E, Lubelza RA, Rotellar C, Martinez-Camps E, Alea MV, Valls R. Must patients over 65 be haemodialysed?

Nephron 1985;41:152-6. However, dialysis may be difficult in patients with cognitive dysfunction. Indeed, these patients can touch or withdraw their hemodialysis or peritoneal dialysis catheters and can withdraw their needles during the hemodialysis on fistula.

The infectious or hemorrhagic consequences can be severe. In such situations, dialysis should be reserved to the symptomatic patients, in particular to those with a refractory fluid overload. Moreover patients with impaired cognitive functions will probably not benefit from dialysis in terms of quality of life as long as they are asymptomatic. It should be recalled that uremia can be responsible for degradation of the cognitive functions and in such situations, it is licit to start dialysis with a temporary catheter and to reevaluate the cognitive functions after correction of uremia Hart R, Pederson J, Czerwinski A, Adams R. Chronic renal failure, dialysis, and neuropsychological function. J Clin Neuropsychol 1983;5:301-12. According to European guidelines, the diabetic patients should start dialysis earlier than non-diabetic patients, when eGFR is lower than 15 ml/min/1.73 m 2 European Best Practice Guidelines for Haemodialysis. Section I: Measurement of renal function, when to refer and when to start dialysis.

Nephrol Dial Transplant 2002;17 (Suppl 7):7-15. This point out those patients should be referred timely to the nephrologists, so that psychological and technical preparation to dialysis can be planned smoothly. This is even more important for elderly diabetics in whom the creation of the vascular access can be a technical challenge and in whom uremic symptoms and poor general condition may obviate surgery. Moreover, atherosclerotic and calcified vessels account for a slower development of the vascular access so that it is advisable to anticipate vascular access surgery at least 3 to 6 months before the start of extra-renal purification Astor BC, Eustace JA, Powe NR, et al. Timing of nephrologist referral and arteriovenous access use: the CHOICE Study.

Am J Kidney Dis 2001;38:494-501. Friedman EA. Management choices in diabetic end-stage renal disease. Nephrol Dial Transplant 1995;10 (Suppl 7):61-9.

For elderly diabetic patients, kidney transplantation is no more an option because of comorbidities and the risks related to the immunosuppressant. The therapeutic options are narrowed to two main techniques of dialysis: haemodialysis or peritoneal dialysis. To date, there is no randomized study comparing these two techniques in term of quality of life or morbi-mortality.

Only epidemiological data issued from registers with major bias related to the lack of randomization are available. The results of these studies are conflicting and it cannot be concluded on the superiority of one technique as compared to the other. In practical terms the decision takes into account the choice of the well-informed patient, the distance to the dialysis facility or the existence of absolute or relative contraindications, to one or the other techniques.

Among these contraindications, for the old diabetic patient, the creation of a vascular access should be underscored. Indeed, vascular calcifications make the surgery very challenging and the arterial stenosis may compromise the development of the vascular access. The creation of a vascular access in every elderly diabetic should be thoroughly considered and should be preceded by an arterial doppler examination, or even an arteriography in the difficult cases. Peritoneal dialysis should be preferred whenever a high risk of amputation or repeated surgical failures can be anticipated. In addition, among patients with a previous history of heart failure or coronary artery disease, hemodialysis procedure can induce deleterious hypovolemia and arterial pressure drop. Peritoneal dialysis, as a continuous technique devoiced of volemic variation, may offer a better hemodynamic tolerance. The choice of the site for the vascular access should take into account the technical possibilities, but also the risks of ischemic steal syndrome which could be prejudicial for the limb extremity Tzamaloukas AH, Murata GH, Hardford AM, et al.

Hand gangrene in diabetic patients on chronic dialysis. ASAIO Trans 1991;37:638-43. The forearm vascular accesses have to be preferred because of a lower risk of distal ischemia and heart failure, but are more difficult to realize due to the small caliber of the vessels, often atherosclerotic and calcified. For this type of fistula, age and diabetes are not independent risk factors of primary failure, but the association of age and diabetes significantly reduces the success rates Lin SL, Huang CH, Chen HS, Hsu WA, Yen CJ, Yen TS. Effects of age and diabetes on blood flow rate and primary outcome of newly created hemodialysis arteriovenous fistulas. Am J Nephrol 1998;18:96-100. To avoid repeated surgical interventions and anesthesia in these high-risk patients, an arterial and venous preoperative mapping should be made by sonography or even by CO 2 venography Allon M, Lockhart ME, Lilly RZ, et al.

Effect of preoperative sonographic mapping on vascular access outcomes in hemodialysis patients. Kidney Int 20-20.

Heye S, Maleux G, Marchal GJ. Upper-extremity venography: CO 2 versus iodinated contrast material. Radiology 2006;241:291-7. Sedlacek M, Teodorescu V, Falk A, Vassalotti JA, Uribarri J. Hemodialysis access placement with preoperative noninvasive vascular mapping: comparison between patients with and without diabetes. Am J Kidney Dis 2001;38:560-4.

In some cases, it may be preferable to create an upper-arm fistula as a first access, to gain a rapidly functional vascular access. At the ultimate stage, a long duration catheter should be considered when dialysis has to be started quickly, when there is a doubt about the benefit of dialysis in a patient in poor condition or when there is a risk of amputation with an arteriovenous access Garcia Cortes MJ, Viedma G, Sanchez Perales MC, et al. Fistulae or catheter for elderly who start hemodialysis without permanent vascular access? Nefrologia 2005;25:307-14. The cardiovascular dysautonomy of the diabetic patients is usually worsened in ESRF and dialysis Giordano M, Manzella D, Paolisso G, Caliendo A, Varricchio M, Giordano C. Differences in heart rate variability parameters during the post-dialytic period in type II diabetic and non-diabetic ESRD patients. Nephrol Dial Transplant 2001;16:566-73. , exposing the dialysed diabetic patients to an increased mortality due to arrhythmia and sudden death.

These neurovegetative abnormalities are worsened with the duration of uremia and diabetes, so that older patients are even more exposed to these disorders. The dysautonomy also contributes to poor hemodynamic tolerance of the hemodialysis sessions, particularly in undernourished hypoalbuminemic patients, and is associated with an increased morbi-mortality Desmet C, Beguin C, Swine C, Jadoul M. Falls in hemodialysis patients: prospective study of incidence, risk factors, and complications. Am J Kidney Dis 2005;45:148-53. Hemodynamic tolerance can be improved by increasing dialysis time, by achieving a better glycaemic control and by monitoring the thermal balance and plasma volume during the sessions Maggiore Q, Pizzarelli F, Santoro A, et al.

The effects of control of thermal balance on vascular stability in hemodialysis patients: results of the European randomized clinical trial. Am J Kidney Dis 2002;40:280-90. Perdialytic hypotensions are serious complications in elderly diabetics in whom cerebral and coronary vascular diseases are more frequent than in the general population Xue JL, Frazier ET, Herzog CA, Collins AJ. Association of heart disease with diabetes and hypertension in patients with ESRD. Am J Kidney Dis 2005;45:316-23. It is unknown whether systematic assessment and correction of these coronary and cerebrovascular lesions do improve prognosis.

So far, drug interventions with high dose of statin have been disappointing. These hemodynamic changes are not observed in peritoneal dialysis as ultrafiltration is carried out in a continuous way throughout the day. Peritoneal dialysis may thus be a technique of choice for patients with poor cardiac status. Dialysis has an impact on glycaemic control and inversely glycaemic control has an impact on the tolerance of hemodialysis sessions. Hyperglycaemia triggers thirst and increases interdialytic weight gain Miles AM, Friedman EA. Dialytic therapy for diabetic patients with terminal renal failure.

Curr Opin Nephrol Hypertens 1993;2:868-75. This overweight requires aggressive ultrafiltration rate increasing the risk of hypotension and cramps during the dialysis course, but also of tiredness after the session. Moreover, hemodialysis sessions can influence glycaemic control in several ways.

Firstly, schedules of the meals are modified by the sessions and transport times; secondly, the dialysate which contains 1 g/l glucose can drop plasma glucose in patient with severe hyperglycaemia at the beginning of the dialysis. However, thanks to the physiological concentration of glucose in dialysate, hypoglycaemic episodes during sessions have become rare, provided that the insulin doses are correctly adapted. With regard to peritoneal dialysis, standard dialysate usually contains glucose as an osmotic agent.

Dialysate contributes to an additional glucose load of about 150 to 300 g/day with consequently, higher insulin requirements, weight gain and hypertriglyceridemia. Insulin can be administered intraperitonealy, which is thought to be more physiologic because insulin goes through the portal way. In the past years, polymers of glucose have been used more widely as osmotic agents, reducing the glucose load. On the other hand, these polymers are absorbed and transformed in maltose which can be detected by some blood glucose meters mimicking hyperglycaemia. Beside these polymers-based solutions, there are aminoacid enriched solutions which may improve the nutritional state, particularly in elderly diabetic patients.

Main characteristics of diabetic nephropathy in the elderly are an increased burden of comorbidities, higher risk patients and higher benefit from rigorous interventions on metabolic and hemodynamic status. There are some important differences in diabetic nephropathy between aged and younger patients, notably more prevalent hypertension and arteriosclerosis in aged diabetics, which interfere on its evolution and partly explain its heterogeneity. Therefore prevention of DN in the elderly requires a multifactorial approach, including mainly strict glycaemic and blood pressure control.

It is necessary to highlight the importance of an early management of aged diabetics affected with diabetic nephropathy. Too many aged patients with diabetic nephropathy, even at an advanced stage, are non recognized, and inadequately treated Patel UD, Young EW, Akinlolu OO, Hayward RA. Pathogenesis and treatment of kidney disease and hypertension. CKD progression and mortality among older patients with diabetes. Am J Kidney Dis 2205;46:406-14. It appears important to optimize the collaboration between general practitioners, diabetologists and nephrologists to slow down the evolution toward end stage renal failure.

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