Nissen SE, Wolski K (2007). Effect of rosiglitazone on the risk of myocardial infarction an d death from cardiovascular causes. N Engl J Med 356(24):2457 \200\22371. Erratum in N Engl J Med 357(1):100. Ratner RE (1995). Rational insulin management of insulin-dependent diabetes. In Leslie RDG, Robbins DE (Eds) Diabetes: Clinical Science in Practice. Cambridge, UK: Cambridge Universi ty Press, pp. 434 \200\223449. STOP-NIDDM Trial (2003). Acabose treatment and the risk of cardiovascular disease and hyper - tension in patients with impaired glucose tolerance. JAMA 290:486 \200\223494. UK Prospective Diabetes Study (UKPDS) Group (1998). Intensive blood-glucose control with su l- fonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 352:837 \200\223853. UK Prospective Diabetes Study (UKPDS) Group (1998). Effect of intensive blood-glucose contr ol with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854 \200\223865. 104-Draznin-Chap104.indd 603 3/31/2011 4:47:46 PM CHAPTER 105 Diabetic eye disease 604 Diabetic eye disease Epidemiology Diabetic retinopathy remains the most common cause of blindness in the working population of developed countries. Currently, diabetic eye dis- ease gives a person with d iabetes a 10- to 20-fold i risk of blindness. It is suggested that 84,000 of the 7.8 millio n North American patients with dia- betics will develop proliferative retinopathy each year and another 95,000 will develop macular edema. The prevalence of diabetic retinopathy depends on the duration of diabetes, glycemic contro l, BP control, and the racial mix of the group being examined. A prevalence of 730% in a ge neral diabetic population is often quoted. In type 1 patients, <2% have any lesions of diabetic retinopathy at diag- nosis and only 8% have any features of it by 5 years (2% proliferative). But 87 \200\22398% have abnormaliti es 30 years later, 30% of these having had proliferative retinopathy. In type 2 patients, 2 0 \200\22337% can be expected to have retinopathy at diagnosis; 15 years later, 85% of thos e on insulin and 60% of those not taking insulin will have abnormalities. The 4-year incidence for proliferative retinopathy in a large North American epidemiologica l study was 10.5% in type 1 patients, 7.4% in older-onset/type 2 patients on insulin, and 2 .3% in those not on insulin. In the US, currently maculopathy is a more common and thus mor e sig- ni \201 cant sight-threatening complication of diabetes. It is suggested that 75% o f those with maculopathy have type 2 diabetes, and there is a 4-year inci- dence of 10.4% i n this group. Although type 2 patients are 10 times more likely to have maculopathy than ty pe 1 patients, 14% of type 1 patients who become blind do so because of maculopathy. Diabetic retinopathy, like many microvascular complications, is more common in ethnic minor ities than in Caucasians. Cataracts are more common in people with diabetes and are actuall y the most common eye abnormality found. These occur in up to 60% of 30- to 54-year-olds. Other abnormalities to look for include vitreous changes such as aster- oid hyalosis, which occur in about 2% of patients. These are small spheres or star-shaped opacities seen in th e vitreous that appear to sparkle when illuminated under an examining light and do not norm ally affect vision. b See Box 105.1 for classi \201 cation. 105-Draznin-Chap105.indd 604 3/31/2011 5:28:11 PM CLINICAL FEATURES AND HISTOLOGICAL FEATURES 605 Box 105.1 Classi \201 cation and features of diabetic retinopathy Background retinopathy \200 Microaneurysms \200 Hemorrhages \200 Hard exudates Preproliferative retinopathy \200 Soft exudates/cotton wool spots \200 Intraretinal abn ormalities (IRMAs) \200 Venous abnormalities (e.g., venous beading, looping, and reduplic ation) Proliferative retinopathy \200 New vessels on the disc or within 1 disc diameter of it (N VD) \200 New vessels elsewhere (NVE) \200 Rubeosis iridis ( neovascular glaucoma) Maculopathy (graded as M0 if none and M1 if present) \200 Hemorrhages and hard exudates i n the macula area \200 Reduced visual acuity with no abnormality seen Clinical features and histological features The classi \201 cation of diabetic retinopathy is based on ophthalmoscopic examination or retinal photographs. Several other changes not seen mac- roscopically may also explain some of these clinical \201 ndings. One of the \201 rst histological changes seen is thickening of the capillary basement mem brane and loss of the pericytes embedded in it. Both have been linked to hyperglycemia in e xperimental models; sorbitol accumula- tion and advanced glycation both have a role. In normal retinal capillaries there is a 1:1 relationship between endothelial cells and per icytes. Pericytes may control endothelial cell proliferation, main- tain the structural int egrity of capillaries, and regulate blood \202 ow. Altering these roles, along with the i blood viscosity, abnormal \201 brinolytic activity, and reduced red cell deformity also seen in diabetes, may lead to capillary occlusion, tissue hypoxia, and the stimulus for new vessel formation. Exactly how locally produced growth factors, altered protein kinase C, alterations in oxida tive stress responses, and alterations in the autoregu- lation of retinal blood \202 ow c ombine to cause this remains unclear. The natural progression is from background to preproliferative then to pro- liferative reti nopathy/maculopathy and, ultimately, sight-threatening disease. Background retinopathy Capillary microaneurysms are the earliest feature seen clinically, a s red dots. Small intraretinal hemorrhages, or \200\234blots, \200\235 also occur, as can hemorrhage 105-Draznin-Chap105.indd 605 3/31/2011 5:28:11 PM CHAPTER 105 Diabetic eye disease 606 into the nerve \201 ber layer, which are often more \202 ame shaped. With i capil- lary leakage, hard exudates, which are lipid deposits, can also be seen. Preproliferative retinopathy A cotton wool spot is an infarct in the nerve \201 ber layer that alters axoplas- mic transportation in ganglion cell neurons, giving an edematous infa rct seen as a pale gray, fuzzy-edged lesion, which gives it its name. IRMAs are tortu- ous dilated hypercellular capillaries in the retina that occur in response to retinal ischemia. A further change seen is alternating dilatation and constriction of veins (venous beading) as well as other venous alterations such as duplication and loop formation. Overall, there are large areas of capillary non-per- fusion occurring in the absence of new vessels. The Early Treatment of Diabetic Retinopathy Study (ETDRS) suggested that certain of these features matter and suggested a 4 \200\2232 \200\2231 rule: \200 4 quadrants of severe hemorrhages or microaneurysms \200 2 quadrants of IRMAs \200 1 quad rant with venous beading If the patient has one of these features, there is a 15% risk of d eveloping sight-threatening retinopathy within the next year; if two are present, the risk rises to 45%. Proliferative retinopathy New vessels are formed from the retina and can grow along, into, or out from it. A scaffolding for \201 brosis then forms. There are two forms of new vess els: those on the disc or within 1 disc diameter of the disc (NVD) and new vessels elsewher e (NVE). Both give no symptoms but can cause the problems of advanced retin- opathy, such as hemorrh age, scar tissue formation, traction on the retina, and retinal detachment, which actually results in loss of vision. Thus pan- retinal photocoagulation, which can result in the regr ession of these new vessels, is used when such problems are seen. Diabetic maculopathy Edema in the macula area can distort central vision and reduce visual acu- ity. Any of the above changes can coexist with maculopathy. The changes seen can be as follows: \200 Edematous \200\224clinically it may just be dif \201 cult to focus on th e macula with a hand-held ophthalmoscope. Exudative \200\224with hemorrhages, hard exudates, and circinate exudates \200 Ischemic \200\224capillary loss occurs but clinically the macula may look normal on direct ophthalmoscopy but the unperfused area will show up on \202 uorescein an giography. Any combination of these A ring or circinate pattern of lipid deposits suggest a focal defe ct that may be treated with focal laser therapy, whereas more diffuse problems may require more extensive treatment with a macula grid of laser. 105-Draznin-Chap105.indd 606 3/31/2011 5:28:11 PM EYE SCREENING 607 Eye screening Because so many patients can expect to develop eye complications, some of whi ch are sight threatening but with treatment can be reduced, a suit- able screening program is advisable. Patients with diabetes should undergo ophthalmic examination at least once a year. A full examination should include the elements discussed below. Visual acuity Use a standard chart for distance and check each eye separately. Let the pati ent wear their glasses for the test. If vision is worse than 20/30, also check with a pinho le as this will correct for any refractive (glasses) error. If vison does not correct to 20 /30 or better, consider more careful review; some maculopathy changes cannot be seen easily with a hand-held ophthalmoscope and an ophthalmology review may be needed. Cataracts are a more likely cause, so look carefully at the red re \202 ex. If vision gets worse with a p inhole, assume maculopathy until proven otherwise. High blood glucose readings can give myopia (dif \201 culty in distance vision) and low bl ood glucose can produce hypermetropia (dif \201 culty in reading), although this is not un iversal. Eye examination Dilate the pupil before looking into the eye. \200 Use tropicamide 1% in most cases, as it dilates the pupil adequately in 15 \200\22320 minutes and lasts only 2 \200\2233 hours. In those with a dark iris, you may also need phenylephrine (2.5%) added soon after the tropicamide to give adequate views. The main reasons not to dilate are closed-angle glaucoma and recent eye surgery, although a s such patients are usually under an eye clinic already, most people are suitable for dilat ation. 1% pilocarpine drops can be used (although not routinely) if acuity is >20/40 after dilatat ion. They may speed up reversal and allow driving sooner. Once the pupil is dilated, look at the red re \202 ex to check for lens opacities. Examine the anterior chamber; although rare, rubeosis iridis is important to pick up. The vitreous is examined before examining the retina. When examining the retina, use the optic disc as a landmark, follow all four arcades of ves sels out from it, examine the periphery, and, at the end, examine the macula. This examinat ion can be uncomfortably bright through a dilated pupil and if done at the start makes it d if \201 cult for anyone to keep their eye still enough to complete it adequately. Retinal photographs Although consultant diabetologists are more accurate than general prac- titioners, they still miss some cases of retinopathy, compared to the gold standard of an ophthalmologist. One way to reduce the false-negative rate for a screening program is to use retinal photogr aphy and ophthalmoscopy. More than 90% of people 105-Draznin-Chap105.indd 607 3/31/2011 5:28:11 PM CHAPTER 105 Diabetic eye disease 608 can have good-quality photos performed. This was often performed using 35 mm slide \201 l m, although digital images are now of suf \201 ciently good qual- ity, require a less inte nse \202 ash, and avoid the delay of having to develop the \201 lm. A digital image should be used with a minimum of 27 pixels per degree and a 45 \201 eld of vision for each of the two images taken per eye (one centered on the macula the other o n the optic disc). The images obtained should then be graded and assessed by a trained observer with a quality assurance system to maintain consistency of grading. When to refer The physician performing eye screening will need consultation with an experie nced ophthalmologist (see Box 105.2 ). Box 105.2 Reasons for and timing of referral to an ophthalmologist Immediate referral \200 R3/proliferative retinopathy, as untreated NVD carries a 40% risk of blindness in <2 years and laser treatment reduces this Rubeosis iridis/neovascular glaucoma \200 Vitreous hemorrhage \200 Advanced retinopathy with \201 brous tissue or retinal detachments Early referral (<6 weeks) \200 R2/preproliferative changes \200 M1/maculopathy, for non proliferative retinopathy involving the macula or for any hemorrhages/hard exudates within 1 disc diameter of the fovea Fall of >2 lines on a Snellen chart (regardless of what fundoscopy shows) Routine referral \200 Cataracts \200 Nonproliferative retinopathy with large circinate exudates not threatening the macula/fovea Other categories \200 R0/no retinopathy \200\224annual screening \200 R1/background ret inopathy \200\224annual screening and inform diabetes care team 105-Draznin-Chap105.indd 608 3/31/2011 5:28:11 PM TREATMENT 609 Treatment Glycemic control There is good epidemiological evidence for an association between poor gly cemic control and worsening of retinopathy (see Box 105.3 ). The Diabetes Control and Complications Trial (DCCT) looked at inten- sive glycemic control in type 1 patients over age 6.5 years and showed a 76% reduction in risk of initially devel oping retinopathy in the tightly man- aged group compared to the control group. The rate of progression of existing retinopathy was slowed by 54% and the risk of developing severe no nproliferative or proliferative retinopathy was reduced by 47%. The UKPDS looked at type 2 patients over a 9-year period and showed a 21% reduction in prog ression of retinopathy and 29% reduction in the need for laser therapy in those with good g lycemic control. The long-term bene \201 ts of improved glycemic control are therefore cle ar. However, the DCCT, the UKPDS, and several previous studies also showed an initial worsening of retinopathy in the \201 rst 2 years in the groups with tight or improved glycemic con trol. Thus all patients need careful moni- toring over this period. The long-term bene \201 ts outweigh this initial risk. Blood pressure control/therapy There is good evidence for an association between both systo lic and diastolic hypertension and retinopathy in type 1 patients, but the link may only be with systolic hypertension in type 2 patients. The UKPDS looked at BP control in type 2 patients and showed that the treatment group, with a mean BP of 144/82 mmHg, compared to the control group, which had a mean of 154/87 mmHg, had a 35% reduction in the need for laser therapy. Adequate BP control, e.g., <140/80 in ty pe 2 patients, is therefore advocated. Use of angiotensin-converting enzyme (ACE) inhibitors as \201 rst-line therapy should be considered with caution in those with pre-existing renal Box 105.3 Risk factors for development or worsening of diabetic retinopathy \200 Duration of diabetes \200 Type of diabetes (proliferative disease is more common in type 1 and maculopathy in type 2) Poor diabetic control \200 Hypertension \200 Diabetic nephropathy \200 Recent catarac t surgery \200 Pregnancy \200 Alcohol (variable results, which may be related to the ty pe of alcohol involved, e.g., worse in Scotland than Italy) Smoking (variable results, but appears worse in young people with exudates and older women with proliferative disease) 105-Draznin-Chap105.indd 609 3/31/2011 5:28:11 PM CHAPTER 105 Diabetic eye disease 610 disease, as these agents may cause hyperkalemia and may worsen renal function in those with undiagnosed renal artery stenosis. Experimental evidence suggests these agents may have antiangiogenic effects by altering loc al growth factor levels and reducing blood pressure. Studies using enalapril and lisinopril have both shown a reduction in the progression of retinopathy in type 1 patients. Lipid control/therapy Experimental evidence suggests that oxidized low-density lipoprotein (LDL) cholesterol may be cytotoxic for endothelial cells. Epidemiological data also suggest an association between higher LDL cholesterol and worse diabetic retinopathy, especially m aculopathy with exudates. A total cholesterol of >270 mg/dL gives a 4-fold greater risk of prolifera- tive retinopath y than a total cholesterol of <200 mg/dL. A worse outcome from laser therapy in those treat ed for maculopathy has also been seen if hyperlipidemia is present. Aggressive lipid loweri ng is therefore advo- cated, especially in patients with maculopathy. Antiplatelet therapy In view of the altered rheological properties of diabetic patients, th ese agents have been tried, but the results are variable. No evidence that they make things worse has been shown, and some studies suggest that aspirin and ticlopidine may slow the p rogression of retinopathy, although the bene \201 t was small. Lifestyle advice Although stopping smoking reduces macrovascular risk, its effect on retin- opathy is less clear. Alcohol consumption and physical activity also show no consistent ef fect. Other therapies The use of agents such as protein kinase-C inhibitors and vascular endothe- lial growth factor (VEGF) inhibitors (e.g., bevacizumab) are currently being investigated to see if they can delay the progression of diabetic retinopa- thy. Initial studies are enc ouraging. Surgical treatment Laser treatment Up to 1500 \200\2237000 separate burns of 100 \200\223500 micron diameter, each taking about 0.1 seconds to apply, are needed for panretinal or \200\234scatter \200 \235 laser photocoagulation. For edematous/exudative maculopathy, a macula grid may use onl y 100 \200\223200 burns of 100 \200\223200 micron diameter separated by 200 \200\223400 mic ron gaps, avoiding the fovea. Laser therapy is usually performed as 3 \200\2234 sessions of outpatient treat- ment on con scious patients. Topical local anesthetic drops allow a contact lens to be placed on the co rnea and are often all that is needed. 105-Draznin-Chap105.indd 610 3/31/2011 5:28:11 PM SURGICAL TREATMENT 611 In some patients, however, this procedure may be slightly uncomfort- able. A retro-orbital injection (performed through the inside of the lower eyelid) can be given to anesthetize th e eye. The laser energy is absorbed by the choroid and the pigment epithe- lium, which lie below t he neurosensory layer. This also absorbs the energy and heat and is destroyed. In patients with severe proliferative retinopathy, panretinal photoco- agulation reduces vi sual loss by >80%, wheras a macula grid reduces visual loss in maculopathy by >50%. The aim of laser treatment is to prevent further visual loss, especially in maculopathy, no t to restore vision, and this distinction must be empha- sized to all patients requiring tr eatment. The bene \201 ts from laser therapy currently outweigh the risks, which include a ccidental burns to the fovea if the eye moves during therapy, a reduction in night vision, and, in a small number of patients, interference with visual \201 eld severe enough to af fect the ability to drive. Vitrectomy If the vitreous contains scar tissue, hemorrhage, or any opacity, a vitrec- tomy to remove it may help restore vision and allows the possibility of intraoperative laser tr eatment or a better view for postoperative laser therapy. It can also help reduce retinal t raction and allows retinal reat- tachment to be performed. A success rate at restoring vision of 70% is seen, but the risk of worsen- ing vision, deta ching the retina, or worsening lens opacities should also be considered. Cataract extraction This is a common procedure with a slightly higher complication rate tha n that in the nondiabetic population. Approximately 15% of patients under- going a cataract extraction can be expected to have diabetes. A large lens implant should be considered, especially if laser therapy is going to be neede d subsequently. Worsening of maculopathy after cata- ract extraction is also a risk that ne eds careful monitoring. Further reading British Multi-Center Study Group (1983). Photocoagulation for diabetic macu lopathy: a randomized controlled clinical trial using xenon. Diabetes 32:1010 \200\2231016. Early Treatment Diabetic Retinopathy Study Research Group (1985). Photocoagulation for diab etic macular edema. Arch Ophthalmol 103:1796 \200\2231806. Scottish Intercollegiate Guidelines Network (2001). Management of diabetes. http://www.sign . ac.uk/guidelines/fulltext/55/index.html 105-Draznin-Chap105.indd 611 3/31/2011 5:28:11 PM CHAPTER 106 Diabetic renal disease 612 Diabetic renal disease Background Diabetic nephropathy is now a major cause of premature death in patients with al l types of diabetes. Approximately 1/6 patients entering most renal replacement programs in developed countries have diabetes, at least 50% with type 2 diabetes. De \201 nition Diabetic nephropathy is de \201 ned as albuminuria (albumin excretion rate >300 mg/24 hours, which equates to 24-hour urinary protein >0.5 g) and declining renal fun ction in a patient with known diabetes who does not have a urinary tract infection, heart f ailure, or any other renal disease. This is usually associated with systemic hypertension, diabetic retin- opathy, or neuropath y. In the absence of these, the diagnosis needs to be carefully evaluated. b See Box 106.1. Box 106.1 Investigations of lipid abnormalities \200 Proteinuria \200\224urinary protein >0.5 g/24 hours \200 Albuminuria \200\224urinary albumin excretion rate >300 mg/24 hour s or >200mcg/min Microalbuminuria \200\224urinary albumin excretion rate 30 \200\223300 mg/day or 20 \200\223200 mcg/min 106-Draznin-Chap106.indd 612 3/31/2011 5:28:39 PM MAKING THE DIAGNOSIS 613 Epidemiology Microalbuminuria has a prevalence of 6 \200\22360% of patients with type 1 dia be- tes after 5 \200\22315 years \200\231 duration of diabetes. Diabetic nephropathy occurs in up to 35% of patients with type 1 diabetes, more commonly in males and in those diagnos ed <15 years of age, with a peak incidence approaching 3%/year 16 \200\22320 years after th e onset of diabetes. Of those type 1 patients who develop proteinuria, 2/3 will subse- quently develop renal fai lure. In the UK, 15% of all deaths in diabetic patients <50 years old are due to nephropath y. In type 2 patients there are more obvious racial differences, with up to 25% of Caucasians and 50% of Asians expected to develop neph- ropathy, giving a prevalence in a general clini c of 4 \200\22333%. The duration of diabetes before development of clinical nephropathy is also often shorter in type 2 than in type 1 patients. This may be due to an initial delay i n diagnosis of type 2 diabetes. Making the diagnosis A urine positive on dip testing for protein (i.e., >0.5 mg/L protein o r >300 mg/L albumin) suggests diabetic nephropathy. A timed urine collection either overnig ht or over 24 hours will con \201 rm proteinuria or albuminu- ria, but other causes of pro teinuria must be excluded before labeling this diabetic nephropathy. Proteinuria from nondiabetic renal disease occurs in up to 10% of type 1 and 30% of type 2 patients. Urinary tract infections, acute illness, heavy exercise, and cardiac failure are the most common causes to exclude (Box 106.2). The absence of hypertension or diabetic reti nopa- thy would also put the diagnosis in question; con \201 rmation from a renal biopsy m ay be required. If the urine is standard dip test negative for albumin, microalbuminu- ria should be looked for. The implementation group for the St. Vincent Declaration recommends that all patients with negative protein on con- ventional urinalysis be annually screened for microalbuminur ia. A urinary albumin/creatinine ratio >2.5 mg/mmol in males and >3.5mg/ mmol in females or a p ositive urine dip test (urine albumin >20 mcg) should be followed by a timed urine collecti on repeated 3 \227 with at least two being abnormal. Box 106.2 False positives for microalbuminuria \200 Exercise \200 Urinary tract infecti on \200 Menstruation \200 Semen 106-Draznin-Chap106.indd 613 3/31/2011 5:28:39 PM CHAPTER 106 Diabetic renal disease 614 Pathology Although macroscopically there is an increase in kidney size, microscopi- cally t here is thickening of the glomerular basement membrane, expansion of glomerular supporting tissues (the mesangium), and \201 brotic changes in both efferent and afferent arterioles . If localized, this is termed nodular glomerular sclerosis (Kimmelsteil \200\223Wilson nod ules) and if more widespread, diffuse glomerular sclerosis . The thickened basement membrane initially results in alteration in its electrical charge bu t not in pore size, which allows i passage of albumin into the glomerular ultra \201 ltrat e, seen clinically as microalbuminuria. Pathogenesis Hyperglycemia As with all microvascular diabetic complications, hyperglycemia has been impl icated in the pathogenesis of diabetic nephropathy via metabolic altera- tions. The DCCT sh owed a reduction in the development of microalbu- minuria in patients with better glycemic control, which would support this. The UKPDS showed similar improvements. These metabolic a lterations may be due to sorbitol accumulation from the polyol pathway, which in turn is th e result of the accumulation of advanced glycation end-products (AGE) or an as-yet unknown mechanism. AGE have been linked to the extracellular matrix accumulation known to occur in nephropathy . The use of aminoguanidine to block renal AGE accumulation and an associated slowing in th e progression of albuminuria and mesangial expansion would support their role in the pathog enesis of nephropathy. The evidence for the polyol pathway \200\231s importance comes from aldose reductase inhibi tor trials, the results of which are more variable. Ongoing studies (e.g., Action 1 and Act ion 2 for aminoguanidine) will examine whether any agents are useful clinically. Hemodynamic alterations Increased intraglomerular pressures can be associated with elevatio ns in systemic blood pressure (85% of type 1 patients with nephropathy are hypertensive), i vasoactive hormones (e.g., angiotensin-II, endothelin), or altered levels of speci \201 c growth factors (e.g., TGF-B, IGF-I, and VEGF). Hormonal and growth factor alterations have been suggested as impor- tant in the initial hy per \201 ltration phase seen in type 1 patients who progress to nephropathy. A role for an giotensin-II in the accumulation of extracellu- lar matrix has also been postulated. Whethe r these changes are secondary to or independent of hyperglycemia is not certain. Genetic predisposition There is an increase in red blood cell sodium \200\223lithium counte rtransport activity in nephropathic patients and their parents in some populations, 106-Draznin-Chap106.indd 614 3/31/2011 5:28:39 PM NATURAL HISTORY 615 and an i incidence of hypertension in the relatives of diabetic patients with nephropathy. An association between nephropathy and polymorphisms of the ACE gene has also been noted. Smoking A consistent link between cigarette smoking and nephropathy has been known for some time, but an etiological mechanism is not yet known. Natural history In 20 \200\22340% of type 1 diabetic patients there is initially a period o f glomeru- lar hyper \201 ltration. The \201 rst sign of nephropathy, however, is microa lbu- minuria, usually occurring 5 \200\22315 years after the onset of type 1 diabetes but p ossibly present at the time of diagnosis in those with type 2 diabetes. Associated with thi s is often the development of hypertension, a reduc- tion in high-density lipoprotein (HDL) cholesterol, and an increase in LDL cholesterol and triglycerides. This progresses to the next stage of frank proteinuria or albuminuria, which has a peak inc idence 717 years after the diagnosis of type 1 diabetes. This is the start of overt nephrop athy; in both type 1 and type 2 patients an approximate 10 mL/min \200\2231 1.73 m \200 \2232 reduction in glomerular \201 ltration rate (GFR) occurs each year once the albumin excretion rate has reached 300 mg/day, although in some patients the deterioration may be m ore rapid, and treatment may reduce it. Once serum creatinine concentration reaches 200 mol/L, a fall of 1 mL/min per month in GF R is expected. This leads to end-stage renal failure (ESRF) with uremia and potentially dea th 7 \200\22310 years after onset of albuminuria. A plot of the reciprocal of creatinine ag ainst time is a relatively straight line showing the projected rate of deterioration. Patients with diabetes and persistent proteinuria/albuminuria have a high mortality rate, d ue to cardiovascular disease in 40% of cases. Nephropathy carries a 20 \200\223100 \227 gr eater mortality than that in age-matched diabetic patients without proteinuria. See Box 106 .3. Box 106.3 Risk factors for development of microalbuminuria \200 Duration of diabetes \200 Poor long-term glycemic control \200 Hypertension \200 Dyslipidemia \200 Hyper \201 ltration \200 Parents with renal disease 106-Draznin-Chap106.indd 615 3/31/2011 5:28:39 PM CHAPTER 106 Diabetic renal disease 616 Treatment Treatment options for ESRF are either renal dialysis (hemodialysis or ambulatory peritoneal dialysis) or renal transplantation, but life expect- ancy with either is no bett er than that of some common malignancies. Several other therapies can, however, delay the p rogression to this stage. Blood pressure Controlling hypertension reduces the progression to microalbuminuria and fro m this to albuminuria and subsequent progression to ESRF. BP should be reduced to <130/85 m mHg, with avoidance of hypotension, although if proteinuria is >1 g/day, a better target is <120/75 mmHg. Weight loss, alcohol restriction, and reduced salt intake help, but drugs ar e usually needed to achieve this. Studies show bene \201 ts from B-blockers, furosemide, hydralazine, and calcium channel bl ockers, but the ACE inhibitors are currently the pre- ferred \201 rst-line agent in both microalbuminuric and albuminuric patients as they also have an effect on kidney function in dependent of their hypo- tensive action. Several studies suggest, however, that more than o ne agent will be required to control BP adequately. Large studies with several ACE inhibitors have con \201 rmed their bene \201 t in hyperte nsive patients. These agents delay the progression of microalbu- minuria to albuminuria and then to ESRF. There is no documented bene \201 t in treating normotensive patients withou t microalbuminuria. Captopril (50 mg 2 \227 day) for 2 years in type 1 patients with micro- albuminuria reduced progression to albuminuria by 68%. Enalapril (10 mg daily) given to type 2 patients with microalbuminuria for 5 years reduced progression to albuminuria by 67%. When used for 4 years in type 1 patients with nephropath y, captopril (50 mg 2 \227 day) reduced the risk of death, dialysis, and transplantation b y 50% and slowed the reduction in creatinine clearance. The EUCLID study looked at treating normotensive microalbuminuric type 1 patients. In this study, lisinopril reduced the albumin excretion rate by nearly 20% compared to placebo, but there was a 3 mmHg lower BP in the treatment group. From this result it was suggested that normotensive type 1 patients be treated with ACE inhibitors. An enalapril study in nor- mo tensive type 2 patients showed similar results. Angiotensin II receptor antagonists can also reduce progression of microalbuminuria and ESR F from trials with losartan (RENAAL) and irbe- sartan (IDNT, IRMA-II). Glycemic control Correction of hyperglycemia can reverse glomerular basement membrane thick ening and mesangial changes. Studies looking at progression to micro- albuminuria and subse quent progression to frank albuminuria (e.g., the Steno 1 and II Studies, the KROC Study) a lso suggest a clinical bene \201 t from improving glycemic control. In the DCCT, tight gly cemic control of type 1 patients was shown to reduce progression to microalbuminuria by 30% and subsequent progression to albuminuria by 54%. 106-Draznin-Chap106.indd 616 3/31/2011 5:28:39 PM TREATMENT 617 Not all trials con \201 rm this \201 nding (e.g., the Microalbuminuria Collaborative Stu dy Group Trial), and not all patients with good control in the above trials gained bene \201 t. Even so, the current treatment aim is to normalize or signi \201 cantly reduce HbA 1c (< 7.2%) while avoiding any weight gain or hypoglycemia associated with the increased us e of both oral agents and insulin needed to do so. Dietary protein restriction High dietary protein can damage the kidney by increasing renal blood \202 ow and intraglomerular pressures in experimental situations. For microalbu- mi nuric type 1 patients, in small studies, reducing dietary animal protein intake appears to reduce both hyper \201 ltration and micralbuminuria, and the bene \201 t in more severe r enal impairment is more evident. In type 2 patients, the UKPDS showed an initial reduction in microalbu- minuria with dietar y modi \201 cation, which may in part be related to protein reduction. A dietary protein c ontent <0.8 g/kg is suggested. Lipid lowering Although diabetic nephropathy is not shown to reduce the progression of micr oalbuminuria to albuminuria or renal failure, these patients have a signi \201 cant dyslip idemia and a high cardiovascular mortality. They require careful lipid monitoring and aggre ssive treatment. The use of aspirin for similar reasons is also advisable. Further reading Ahmad J, Siddiqui MA, Ahmad H (1997). Effective postponement of diabetic ne phropathy in normo- tensive type 2 diabetic patients with microalbuminuria. Diabet Care 20: 1576 \200\2231581. Diabetes Control and Complications Trial Research Group (1993). The effect of intensive tre at- ment of diabetes on the development of microvascular complications of DM. N Engl J Med 329:304 \200\223309. Diabetes Control and Complications Trial Research Group (1995). Effect of intensive therapy on the development and progression of diabetic nephropathy in the DCCT. Kidney Int 42:1703 \200\2231720. EUCLID Study Group (1997). Randomized placebo-controlled trial of lisinopril in normotensiv e patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 349:1787 \200\2231792. Laffel LMB, McGill JB, Dans DJ, for the North American Microalbuminuria Studsy Group (1995) . The bene \201 cial effect of angiotensin converting enzyme inhibition with captopril on diabetic neph- ropathy in normotensive IDDM patients with microalbuminuria. Am J Med 99:497 \200\223504. Lewis EJ, Hunsicker LG, Bain RP, et al. (1993). The effect of angiotensin converting enzyme inhibi- tion on diabetic nephropathy. N Engl J Med 329:1456 \200\2231462. Microalbuminuria Captopril Study Group (1996). Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia 39:587 \200\223593. NICE (2002). Type 2 diabetes \200\224renal disease. Clinical guidelines. http://www.nice.or g.uk NICE (2002). Type 2 diabetes \200\224management of blood pressure and blood lipids. Clinica l guidelines. http://www.nice.org.uk Ravid M, Brosch D, Levi Z, et al. (1998). Use of enalapril to attenuate decline in renal fu nction in normotensive, normalbuminuric patients with type 2 DM. Ann Intern Med 128:982 \200\223988. 106-Draznin-Chap106.indd 617 3/31/2011 5:28:39 PM CHAPTER 106 Diabetic renal disease 618 UK Prospective Diabetes Study Group (1998). Intensive blood glucose control with sulphonylu reas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837 \200\223853. UK Prospective Diabetes Study Group (1998). Tight blood pressure control and risk of macrov as- cular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:703 \200 \223713. UK Prospective Diabetes Study Group (1998). Ef \201 cacy of atenolol and captopril in redu cing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BM J 317:713 \200\223720. 106-Draznin-Chap106.indd 618 3/31/2011 5:28:39 PM PATHOLOGY 619 Diabetic neuropathy De \201 nition Involvement of cranial, peripheral, and autonomic nerves may be found in pa tients with diabetes and is termed diabetic neuropathy . This usually sug- gests a diffuse, predominantly sensory peripheral neuropathy. The effects on nerve function can be acute or chronic as well as transient or perma- nent. The consequences of neuropathy include the fo llowing: \200 Neuropathic ulcers, usually on the feet \200 Charcot arthropathy \200 A ltered sensation (both pain and i sensitivity to normal sensation) \200 Impotence (with a utonomic neuropathy) b See box 107.1 for classi \201 cation. Box 107.1 Classi \201 cation of diabetic neuropathies \200 Sensory neuropathy Acute \200 Chronic Autonomic neuropathy \200 Mononeuropathy Entrapment neuropathy \200 External pressure palsies \200 Spontaneous mononeuropathy Proximal motor neuropathy (diabetic amyotrophy) Pathology Diabetic neuropathy is one of the microvascular complications of diabe- tes. Path ologically, distal axonal loss occurs with focal demyelination and attempts at nerve regene ration. The vasa nervorum often shows basement membrane thickening, endothelial cell changes, and s ome occlusion of its lumen. This results in slowing of nerve conduction velocities or a com plete loss of nerve function. Both metabolic and vascular changes have been implicated in i ts etiology. 107-Draznin-Chap107.indd 619 3/31/2011 9:36:50 PM CHAPTER 107 Diabetic neuropathy 620 Pathogenesis Hyperglycemia is probably the underlying cause of the histological and functio nal changes. Several possible mechanisms have been suggested: \200 Overloading of the nor mal pathways for glucose metabolism resulting in i use of the polyol pathway, which leads t o i levels of sorbitol and fructose and d levels of myoinositol and glutathione. This may r esult in more free radical damage and lowers nitric oxide levels, thus altering nerve blood \202 ow. Experimental models using aldose reductase inhibitors, which can improve some a spects of diabetic neuropathy, add some weight to this theory. Possible accumulation of AGE (via nonenzymatic glycation) may also have a role to play, as could the hypercoagulable state and altered blood rheology known to occur in all patients w ith diabetes. When used in animal studies, aminoguanidine, which blocks AGE formation, can increase nerve conduction velocities and nerve blood \202 ow in diabetic subjects, streng thening the role of AGE accumulation in this process. In the more acute neuropathies, acute ischemia of the nerves due to vascular abnormalities has been suggested as the cause, but again the underlying reason for this is still unclear. Insulin-induced neuritis may occur when insulin therapy is started and blood glucose level s fall. Other potential etiological factors include changes in local growth factor production and o xidative stress. Further work is needed to clarify the exact role of each of the above mechanisms. In the me antime, studies showing improvements in neuropa- thy associated with good diabetic control strengthen the argument for the role of hyperglycemia and offer us a treatment option while we await other therapies. 107-Draznin-Chap107.indd 620 3/31/2011 9:36:51 PM