Patients with type 2 DM should have an initial dilated and comprehensive eye examination conducted by an ophthalmologist or optometrist shortly after the diagnosis of diabetes. An annual exam should be performed on all patients by a clinician knowledgeable in the diagnosis and management of DR. The AAO recommends that individuals who develop type 2 DM should be examined at the time of diagnosis and at least yearly thereafter.[18] Regular, ongoing screening is important given that timely laser photocoagulation therapy can prevent loss of vision in a large proportion of patients with severe NPDR and PDR and/or macular edema.[21],[22]

Nephropathy

Annual screening for microalbuminuria helps identify patients with nephropathy at an earlier and more treatable stage. Microalbuminuria, defined as persistent albuminuria in the range of 30 to 299 mg/24 h, is the earliest stage of diabetic nephropathy in type 1 DM and a marker for development of nephropathy and mortality in type 2 DM. Without specific interventions, approximately 80% of patients with type 1 DM with sustained microalbuminuria develop overt nephropathy or clinical albuminuria over 10 to 15 years.[23] Untreated, overt nephropathy results in a gradual decline in the glomerular filtration rate (GFR) over several years, resulting in ESRD in 50% of patients with type 1 DM within 10 years and in > 75% by 20 years. In patients with type 2 DM and microalbuminuria, 20% to 40% will develop overt nephropathy if the disorder is not treated. After 20 years, approximately 20% of these patients will have developed ESRD.[23]

Improving glycemic control and aggressive antihypertensive treatment slow the rate of progression of nephropathy. In addition, protein restriction and other treatment modalities, such as phosphate-lowering therapy, may benefit some patients.[24]

Microalbuminuria has been linked to an increased risk of cardiovascular disease, and patients with microalbuminuria who progress to macroalbuminuria (≥ 300 mg/24 h) are at risk of developing ESRD over a period of several years.[7] The ADA strength of recommendation grading system is shown in Table 3. ADA guidelines for screening and treatment of patients with nephropathy are shown in Table 4.

Table 3. American Diabetes Association Strength of Recommendation Grading System[7]

Grade	Description
A	Clear or supportive evidence from well-conducted, generalizable, adequately powered, randomized controlled trials, including multicenter trials or a meta-analysis incorporating quality ratings
B	Supportive evidence from well-conducted cohort studies, including prospective cohort studies or registry data, a meta-analysis of cohort studies, or a case-control study
C	Supporting evidence from poorly or uncontrolled studies or conflicting evidence with the weight of evidence supporting the recommendations
E	Expert consensus or clinical experience

 

Table 4. Guidelines for Nephropathy Screening and Treatment[24]

General recommendations To reduce the risk and/or slow the progression of nephropathy, optimize glucose control. (A) To reduce the risk and/or slow the progression of nephropathy, optimize BP control. (A) Screening Perform an annual test for the presence of microalbuminuria in 1) type 1 diabetic patients who have had DM > 5 years and 2) all type 2 diabetic patients starting at diagnosis. (E) Treatment In the treatment of albuminuria/nephropathy, both ACE inhibitors and ARBs can be used: In hypertensive type 1 DM patients with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A) In hypertensive type 2 DM patients with microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. (A) In patients with type 2 DM, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine > 1.5 mg/dL), ARBs have been shown to delay the progression of nephropathy. (A) If one class is not tolerated, the other should be substituted. (E) With regards to slowing the progression of nephropathy, the use of DCCBs as initial therapy is not more effective than placebo. Their use in nephropathy should be restricted to additional therapy to further lower BP in patients already treated with ACE inhibitors or ARBs. (B) In the setting of albuminuria or nephropathy in patients unable to tolerate ACE inhibitors and/or ARBs, consider the use of non-DCCBs, β-blockers, or diuretics for the management of BP. (E) With the onset of overt nephropathy, initiate protein restriction to ≤ 0.8 g/kg body wt/day (~ 10% of daily calories), the current adult RDA for protein. Further restriction may be useful in slowing the decline of GFR in selected patients. (B) If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of hyperkalemia. (B) Consider referral to a physician experienced in the care of diabetic renal disease when either the GFR has fallen to < 60 mL/min/1.73 m2 or difficulties have occurred in the management of hypertension or hyperkalemia. (B)

BP = blood pressure; DM = diabetes mellitus; ACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; DCCBs = dihydropyridine calcium channel blockers; RDA = recommended daily allowance; GFR = glomerular filtration rate.

Neuropathy

Screening procedures for DPN may be performed in a primary care setting, but screening for other types of neuropathy is usually conducted by specialists. All individuals with diabetes should receive an annual foot examination to identify high-risk foot conditions (Table 5).[25] The examination should include tests for protective sensation, foot structure and biomechanics, vascular status, and skin integrity. Patients with 1 or more high-risk foot conditions should be evaluated more frequently for the development of additional risk factors. People with DPN should have their feet visually inspected at every visit with a healthcare professional.

Table 5. Guidelines for Screening the Diabetic Foot[25]

All individuals with DM should receive an annual foot examination to identify high-risk foot conditions. This examination should include assessment of protective sensation, foot structure and biomechanics, vascular status, and skin integrity. People with 1 or more high-risk foot conditions should be evaluated more frequently for the development of additional risk factors. People with neuropathy should have a visual inspection of their feet at every visit with a healthcare professional. Evaluation of neurological status in the low-risk foot should include a quantitative somatosensory threshold test using the Semmes-Weinstein 5.07 (10-g) monofilament. Patients with DM and high-risk foot conditions should be educated regarding their risk factors and appropriate management. Initial screening for peripheral vascular disease should include a history for claudication and an assessment of the pedal pulses. Consider obtaining an ABI, as many patients with peripheral arterial disease are asymptomatic.

ABI = Ankle brachial index

Symptoms of DMC

The problem with microvascular complications as a whole is that each of them may remain asymptomatic until far advanced: the first symptom of retinopathy can be loss of vision, of neuropathy a painless foot ulcer, etc. Thus, DMC cannot be diagnosed on history alone; a careful examination is mandatory.

Retinopathy

The effect of DR on vision varies depending on the stage of the disease. Some common symptoms of DR are listed below and included blurred vision (often linked to blood sugar levels) and loss of central vision. However, even severe disease may be asymptomatic, so periodic professional examination is required to detect retinopathy.

Blurred vision

Blurred vision refers to loss of visual clarity, sharpness, or image distortion and may be caused by retinal damage, cataracts, or refractive errors. Patients with diabetes experience both retinal damage and cataracts at a greater incidence than the general population.[26] Patients with diabetes can have a variety of visual symptoms that can be classified as blurred vision. Often, blurred vision can be triggered by high levels of glucose, with symptoms resolving as glucose levels decrease. By contrast, some patients experience fluctuating visual disturbances over time.[26]

While prescription lenses can often be used to correct blurred vision due to refractive errors, blurred vision may have other causes. For example, image distortion and loss of detail vision may be brought on by DME and macular traction, while loss of contrast or detail vision, glare, and halos around point light sources may be caused by cataracts.

NPDR generally does not cause blurred vision, whereas PDR might.[27] Features of PDR include preretinal and vitreous hemorrhage, which may cause perceptual loss in either detail or shape. Retinal detachment may cause total blindness. In addition, angle-closure glaucoma secondary to neovascularization of the iris may cause gradual loss of peripheral vision, severe eye pain, or total blindness.[28]

Central vision loss

Visually intensive tasks such as reading, face recognition, and driving require central vision with good perception of color, contrast, and detail.[29] The retinal area associated with central vision is the macula, the center of which contains the fovea, the point of sharpest focus for incoming light rays in the normal eye.

Central vision loss can occur as a result of DME, NPDR, PDR, or subsequent disruption of neural structures in the retina.[30],[31],[32] Early treatment is associated with better outcomes; therefore, in addition to conducting routine clinical eye exams, clinicians should regularly ask patients about symptoms such as loss of visual acuity, fluctuations in vision, floating spots (floaters), flashes of light, apparent warping of straight lines, or double vision. Patients may also experience abnormal color and/or contrast perception, which may not be detected in a routine eye examination.[32]

Floating spots in vision

Another symptom of DR is floating spots in vision, flashes of light, or clouds crossing in front of the eye. These are often the result of tiny clumps of gel or cells inside the vitreous, causing shadows to be cast on the retina. Floating spots may be a symptom of vitreous hemorrhage, retinal detachment, or another related condition associated with DR.[33] The incidence of floating spots may increase when retinal detachment is about to occur, and such patients should undergo immediate ophthalmologic evaluation.

Peripheral vision loss

Peripheral vision impairment occurs early in the course of diabetes but may be imperceptible to the patient. Loss of contrast perception and blue-yellow color vision in the peripheral retina has been observed in children with type 1 DM who have normal central color vision and no other signs or symptoms of DR.[34] These perceptual deficits appear to be greater in microalbuminuric patients than in normoalbuminuric patients.

Glaucoma is often—but not exclusively—associated with elevated intraocular pressure. Open-angle glaucoma is a common cause of progressive loss of peripheral vision but is asymptomatic in its early stages.[26] Angle-closure glaucoma as a result of neovascularization of the iris may also cause progressive loss of peripheral vision, severe eye pain, or total blindness.

Nephropathy

During its early stages, diabetic nephropathy is generally without symptoms, while in the late stages, symptoms may result from either excretion of high amounts of protein in the urine or renal failure.

Urinary output changes

For type 1 DM, increased urine output (polyuria) and an increased GFR are often the harbingers of nephropathy. By contrast, polyuria and an elevated GFR may be absent in patients with type 2 DM. However, for both types of diabetes, controlling hyperglycemia and systemic hypertension (if present) usually improves polyuria, normalizes GFR, and slows the progression of diabetic nephropathy.[35],[36],[37]

Patients with uncontrolled diabetes can develop a number of complications resulting from nephropathy that can ultimately progress to chronic renal failure and ESRD.[38] These patients eventually experience greatly reduced urine output. In the early stages of disease, however, patients with chronic renal failure are generally asymptomatic, and by the time symptoms such as changes in urinary output are reported, as much as 90% of renal function may already be lost.[39]

Neuropathy

DPN is the most common of the neuropathies, and can develop soon after the onset of diabetes.

Numbness

Numbness, which results from sensory nerve damage, is 1 of the most prevalent symptoms of DPN. Loss of sensation is a serious symptom of DPN, as it puts the foot at risk of being damaged without the patient realizing it.

Numbness in the foot may present as a loss of feeling that can be described as the foot being “asleep” or a “bunched up socks under the toes” sensation. The numbness often starts gradually, in the toes and/or balls of the feet, and spreads upward. The symptoms may be barely noticeable or may become extreme, especially at night, and may be experienced as a burning or freezing pain, a sharp, jabbing pain, or extreme sensitivity to touch.[40],[41]

Painful sensation

In addition to numbness, pain may result from both chronic DPN and acute sensory neuropathy (ASN).[42] The painful symptoms of DPN and ASN are similar and are characterized by a burning, aching, or stabbing sensation, although these symptoms have different patterns of onset, prognosis, and accompanying signs. ASN is less common than DPN and may be more often related to loss of glycemic control.

For both DPN and ASN, pain is more likely to occur first in the feet and may be more noticeable at night.[42] In both ASN and DPN, the perception of pain triggered by a non-noxious stimulus, referred to as allodynia, can also occur. Symptom onset is rapid in ASN, but severe symptoms usually resolve within a year. By contrast, painful symptoms of DPN are generally not as severe as those associated with ASN, and they tend to develop gradually.[43] Pain due to DPN is also intermittent and may occur along with nonpainful symptoms, such as numbness or “asleep” feelings.

Tingling

A tingling or prickling sensation, with or without pain, is a common symptom of DPN and may be a presenting symptom in some patients. Tingling is more pronounced in lower limbs, similar to other symptoms of DPN.[42]

Signs of DMC

Retinopathy

Cotton wool spots

Cotton wool spots result from ischemic infarcts of the nerve fiber layer of the inner retina and are most apparent in advanced NPDR, although they may first appear in moderate NPDR. They can usually be observed with ophthalmoscopy and/or fundus photography. However, unless present in large numbers (more than 5 spots per eye), cotton wool spots are not predictive of DR progression.[44],[45]

Cotton wool spots are detected on a retinal exam as white or gray soft-edged opaque patches that block visualization of the underlying retinal vasculature. The lesions consist of clusters of degenerated and swollen nerve cells that develop when retinal capillaries become occluded, causing severe ischemia and stasis.[46]

Cotton wool spots are not usually associated with defects in vision, but they are a classic sign of capillary nonperfusion of the retina, which may ultimately cause central vision loss. They often resolve spontaneously, but new ones may develop due to ongoing blood flow problems.[46]

Exudates

Exudates are sharply defined, shiny, yellowish-white opaque bodies of variable size and may be scattered, aggregated, or ring-like (circinate), depending on the pattern of leakage from the blood vessels.[46] They are caused by increased permeability of retinal blood vessels, with subsequent leakage and deposition of serum lipids within the retina.[47] They usually accumulate gradually in the macula and may resolve spontaneously over time, or last from months to years.

Exudates signify the presence of DME, which may coexist with DR of any degree or severity. Exudates that form away from the center of the macula are associated with mild DME, a condition that does not immediately threaten vision. By contrast, exudates that extend into the macula (or within 500 µm of the center) are associated with clinically significant macular edema (CSME), a condition that can damage central vision.[48]

Intraretinal microvascular abnormalities

Intraretinal microvascular abnormalities (IRMA) are associated with severe NPDR, although the severity of IRMA is strongly correlated to the risk of progression to PDR.[44] IRMA can appear as irregular loops of vessels within the retina adjacent to areas of capillary bed closure. In contrast to neovascularization on the retina or iris that occurs in PDR, IRMA may present as shunt vessels and intraretinal new vessels that can straddle normal vessels.[44]

Ocular hemorrhages

Several types of ocular hemorrhage may occur in DR, including intraretinal, “blot” or “flame,” preretinal, vitreous, and “dot” hemorrhages. Hemorrhages may be precipitated by exertion or coughing and sneezing, or they may develop spontaneously. Intraretinal hemorrhage refers to leakage of blood between the layers of the retina. “Blot” or “flame” hemorrhages are long, narrow lesions in the superficial nerve-fiber layer of the retina. Intraretinal hemorrhages are associated with NPDR, while preretinal and vitreous hemorrhages are associated with PDR.[44]

“Dot” hemorrhages are bigger than microaneurysms and appear as small, round lesions deep within the retina. Preretinal hemorrhage refers to leakage of blood from the retinal vasculature into the space between the retina and the posterior vitreous surface, while leakage of blood into the vitreous body is called a vitreous hemorrhage.[44]

Often, hemorrhages present without symptoms; however, they may also cause sudden visual loss. Hemorrhages may or may not be accompanied by eye pain. While hemorrhages may resolve spontaneously without sequelae, prompt identification and treatment with laser photocoagulation or vitrectomy, as appropriate, increase the chance of maintaining vision. Untreated intraretinal hemorrhages may cause permanent damage to the neural retina, and large hemorrhages can cause fibrotic scarring.[44]

Ocular neovascularization

Neovascularization, or the abnormal growth of new, fragile blood vessels in structures of the eye, is the hallmark of PDR and can occur on the optic disc, retina, or iris. It presents in the form of finely tangled net-like projections from capillaries overlying the retina.

These fragile vessels are prone to bleeding, causing vitreous hemorrhage, and can grow over other retinal structures or undergo fibrosis and contraction. In combination with other fibrous proliferation, neovascularization may result in epiretinal membrane formation, vitreoretinal traction, retinal tears, and retinal detachment.[49]

Plasma leakage

Plasma leakage, which results from a breakdown of the blood-retinal barrier, occurs early in the progression of DR.[50] Usually asymptomatic until it has reached an advanced stage, it is the hallmark sign of DME. Endothelial cells that form the blood-retinal barrier become damaged in patients with DR, leading to increased vascular permeability and plasma leakage.

Retinal microaneurysms

Retinal microaneurysms are areas of localized weakening of retinal capillary walls that cause outpouchings of microcapillary walls. On dilated ophthalmoscopy, these lesions may be observed as small, round, red dots not associated with any visible blood vessels.[51]

Retinal thickening and DME

Retinal thickening, characterized by an increase in hydrostatic pressure along the vascular network of the retina, can develop at any stage of DR. This increase in pressure causes a buildup of fluid and macromolecules in the retinal interstitium. As a result, the vessels around the retina dilate and swelling occurs. Retinal thickening that occurs within 500 µm of the center of the macula constitutes CSME, which can result in vision loss.[30]

Venous beading

Another sign of DR is venous beading, which is the extension of retinal capillaries into major veins that may induce changes in the vein wall.[44] This abnormality may resemble beads on a necklace and is distinct from the generalized vasodilation of early DR. The presence of venous beading is strongly indicative of hypoxia and imminent neovascularization associated with the initiation of PDR. In fact, the presence of venous beading is a more powerful predictor of subsequent development of PDR than the presence of any other abnormality, and PDR may already be present in more than 50% of eyes affected by venous beading.[49]

Nephropathy

Changes in GFR

Elevated GFR is an early sign of diabetic nephropathy and may be associated with increased urination. GFR can be measured directly with timed urine creatinine collection or estimated from serum creatinine (SC) level and other patient data.[36]

Chronic kidney disease, including diabetic nephropathy, can be staged using measurements of GFR, as shown in Table 6.[52]

Table 6. Stages of Kidney Disease by Glomerular Filtration Rate (GFR)[52]

Stage	GFR
1	Kidney damage with normal or increased GFR, GFR ≥ 90 mL/min/1.73 m2
2	Kidney damage with mild decrease in GFR, GFR = 60-89 mL/min/1.73 m2
3	Moderate decrease in GFR, GFR = 30-59 mL/min/1.73 m2
4	Severe decrease in GFR, GFR = 15-29 mL/min/1.73 m2
5	Kidney failure, GFR < 15 mL/min/1.73 m2 or dialysis

The preliminary increase in GFR is thought to result from increases in multiple pathologic factors, including glomerular capillary luminal volume, filtration surface area, intraglomerular BP, and vascular permeability.[36] Glomerular function is affected by changes in the mesangial area more than by changes in the basement membrane thickness. As the relative volume of the mesangial glomeruli progressively increases, the capillary filtering surface area eventually decreases, leading to a reduction in GFR.[53] The reduction in GFR may be highly variable in patients with both type 1 and type 2 DM; however, those patients with rapidly declining GFR usually have advanced glomerulopathy and poorly controlled metabolic parameters.

Hypertension

Hypertension and diabetes are interrelated disorders. Systemic hypertension is a risk factor for progression of diabetic nephropathy and DR, whereas diabetic nephropathy is itself a risk factor for escalating systemic hypertension.[54] Systemic hypertension may not occur until microalbuminuria develops, but glomerular hypertension appears to occur early in the course of diabetic nephropathy. At normal glomerular capillary pressures, a minimal amount of albumin filters from the capillary lumen into the urinary space (ie, normoalbuminuria). By contrast, elevated intraglomerular pressure is associated with both microalbuminuria and macroalbuminuria. Intensive BP control has been found to reduce the risk of diabetic nephropathy, DR, stroke, and diabetes-related death.[35]

Increased kidney size

Renal, glomerular, and even mitochondrial hypertrophy have all been observed in patients with diabetes.[55] Increased kidney volume is considered an early sign of both type 1 and type 2 DM, whereas reduction in kidney size may be interpreted as a sign of clinical improvement. However, kidney size may remain unchanged while other markers of kidney function improve.[56]

Microalbuminuria

Microalbuminuria is the earliest clinical sign of diabetic nephropathy in patients with diabetes, characterized by the presence of low but abnormal levels of urinary albumin (≥ 30 mg/day or ≥ 20 µg/min).[57] Approximately 7% of patients have microalbuminuria when type 2 DM is diagnosed; as such, patients with suspected type 2 DM should always be screened for microalbuminuria.

Peripheral edema

Another sign of diabetic nephropathy is peripheral edema, which may result from hypoalbuminemia and/or the inability of the kidneys to remove salt and may indicate severe chronic renal insufficiency and ESRD.[58] Peripheral edema may be referred to as “pitting edema” if pressure on the affected area results in a depression that remains for some time after the pressure is removed. Pitting edema is more commonly observed than nonpitting edema when systemic diseases affecting the kidneys, heart, and liver are present.

DPN

Abnormal pressure distribution

Patients with diabetes may experience alterations in pressure distribution associated with early to mild DPN, usually on the soles of the feet.[59] Increased plantar pressure can occur early in the natural history of DPN and is also a risk factor for ulcer formation. Screening for high-pressure regions on the sole of the foot can be accomplished using a variety of plantar pressure-measurement devices described below.[60]

Decreased proprioception

Another symptom of DPN is decreased proprioception, or the perception of movements and position of the body independent of vision. Proprioception results from 2 primary inputs: 1) the sensory nerve terminals in muscles and tendons (muscle spindles) and the fibrous capsule of joints, and 2) the vestibular (balance) system.[41]

Impaired lower-limb proprioception and absent tendon reflexes are associated with increased incidence of recurrent or accidental falls, although postural instability is usually not obvious if the impairment is restricted to the lower limb. Unsteadiness appears to be related to involvement of medium-sized myelinated afferent fiber damage in more-advanced DPN.[61]

Decreased tendon reflexes

Patients with DPN may experience decreases in deep-tendon reflexes, even in asymptomatic early-stage disease. The legs should be relaxed and symmetrical for reflex testing, so that reflex amplitude is not influenced. If no reflex is present, reinforcement techniques can be used (eg, the patient can gently contract the muscle by raising the limb slightly or concentrate on contracting a different muscle group).

Decreased thermal sensitivity

DPN may also be indicated by the presence of deficits in thermal sensitivity as well as other sensory deficiencies. Thermal sensitivity can be measured using a variety of techniques that assess warm and cold sensations, including computer-controlled devices to generate and record responses to varying thermal stimuli. Such testing may be useful in the early detection of DPN in patients without other clinical signs or symptoms of the disease.[41]

Decreased vibration perception

The inability to detect vibration is associated with damage to sensory nerve fibers. Vibration perception may be deficient in patients with moderate to severe DPN, although this deficiency may also be experienced by patients with mild DPN.[62]

Loss of light touch

DPN can cause nerve damage which results in loss of light touch sensation. The degree of loss reflects the extent of damage: mild DPN is associated with decreased light touch sensation, while severe DPN may be associated with an absence of such sensation. Sensory deficits associated with DPN typically begin in the distal extremities, affecting the feet and lower legs before the hands. They are often seen to occur in a “glove and stocking” pattern.[63]

Loss of sharp/dull differentiation

Sensory nerve damage resulting from DPN can lead to an inability to distinguish between sharp and dull objects, and patients who experience this are at increased risk for foot injuries and amputation.[64]

Muscle weakness

Loss of motor nerve fibers due to DPN can cause muscle weakness that typically results in ankle and knee weakness, although it may be a more difficult sign to recognize than signs and symptoms of sensory DPN, and reports of this symptom are rare. Despite the limited number of reports, some studies have indicated that the degree of ankle and knee weakness correlates with DPN severity.[65] In addition, patients with diabetes have been reported to have abnormal muscle strength scores, and muscle wasting may be seen in advanced cases of DPN.

Diagnostic Methods for DMC

Retinopathy

DR can be assessed using many techniques, including stereo slit-lamp biomicroscopy, fluorescein angiography, stereoscopic digital and color film–based fundus photography, direct and indirect ophthalmoscopy, and mydriatic or nonmydriatic digital color or monochromatic single-field photography. Grading of stereoscopic color fundus photographs in 7 standard fields—as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) group—is a recognized standard for the detection of DR, although it is costly and labor intensive.[66] A group of 31 individuals from 16 countries, representing comprehensive ophthalmology, retina subspecialty, endocrinology, and epidemiology expertise, have developed a consensus regarding a simpler, alternative classification system for clinical diabetic retinopathy (Table 7).[67]

Table 7. International Clinical Diabetic Retinopathy Disease Severity Scale[18]

Dilated Ophthalmoscopy Findings	Proposed Disease Severity Level
No abnormalities	No apparent DR
Microaneurysms only	Mild NPDR
More than “mild” but less than “severe”	Moderate NPDR
Any of the following:   20 or more intraretinal hemorrhages in 4 quadrants    Definite venous beading in 2 or more quadrants    Prominent IRMA in 1 or more quadrants and no neovascularization	Severe NPDR
1 or more of the following:    Definite neovascularization    Preretinal or vitreous hemorrhage	PDR

DR = diabetic retinopathy; NPDR = nonproliferative diabetic retinopathy; IRMA = intraretinal microvascular abnormalities; PDR = proliferative diabetic retinopathy.

Stereo slit-lamp biomicroscopy

Stereo slit-lamp biomicroscopy involves the use of a low-power microscope combined with a high-intensity light source to evaluate eye structures, including the cornea, iris, vitreous, and retina. This is the standard clinical exam method used in the United States and the foundation of the ETDRS protocol.[68]

Fluorescein angiography

Fluorescein angiography can be used to assess the structure and function of the retinal vasculature in patients with suspected or confirmed DR. The steps of fluorescein angiography are listed in Table 8. This diagnostic technique is not routinely included in eye exams for patients with diabetes, but it is usually used for the evaluation of DME.[32]

Table 8. Steps in Performing Fluorescein Angiography

Mydriatic (dilating) eye drops are instilled prior to the procedure. Fluorescein dye emits green light when stimulated by blue light. A blue filter is used to excite the dye, while a green filter allows only green light to reach the photographic film. The fluorescein dye is injected antecubitally, and the choroidal filling phase occurs within 10 seconds of the injection, revealing the lobular choroidal architecture. The retinal arteriole filling phase and laminar venous flow phase occur about 10 seconds after injection, and reveal the arterial circulation. The postlaminar venous flow and recirculation phases occur about 20 seconds postinjection, and reveals the venous circulation.

Because fluorescein angiography cannot normally pass through the tight junctions between retinal capillary endothelial cells, this procedure is useful in detecting early alterations of the blood-retinal barrier, capillary closure, and microaneurysm formation.[51] It can also be used to determine whether loss of visual acuity is due to macular capillary nonperfusion, DME, or both. Fluorescein angiography requires a specially equipped camera that takes a series of images of the fundus to capture different phases of the retinal and choroid plexus, as the dye circulates through blood vessels in the retina. The resulting angiograms locate leaking vessels and can be used to guide laser photocoagulation treatment.[32]

Fundus photography

Fundus photography is conducted with a specialized low-power microscope attached to a camera. Both standard and nonmydriatic fundus cameras permit high-quality stereo 35-mm or digital photography of the retinal fundus, although nonmydriatic fundus cameras tend to offer lower resolution, a smaller field, and a higher rate of ungradable images. Stereo images are superior to 2-D images for diagnosing DME and other retinal lesions, but both techniques require dilation of the pupils prior to the procedure.[69]
An advantage of digital imaging is the ability to electronically transmit images to a centralized reading center.[70] This technology has led to the development of a number of telemedicine screening programs for DR, such as those provided by the Joslin Vision Network™ and commercially by providers such as Inoveon™ and EyeTel Imaging.[71],[72]

Ophthalmoscopy

Ophthalmoscopy is useful for screening components of the fundus, including the blood vessels, choroid, retina, and optic disc. Two types of ophthalmoscopic tests are available: direct and indirect.

A handheld direct ophthalmoscope can magnify the viewing field approximately 15 times and is most useful for examining the central retina. By contrast, an indirect ophthalmoscope provides a wider, stereo (3-D) view. While direct ophthalmoscopy is commonly used, studies suggest that a wide variation exists in the device’s sensitivity and specificity to detect diabetic eye disease.[73[ At best, the results are less accurate than those seen with biomicroscopy with a handheld lens or stereo fundus photography.[69],[73],[74],[75]

Optical coherence tomography (OCT)

OCT is a diagnostic imaging procedure that provides cross-sectional images of the retina. It can be used to image and analyze macular thickness, the retinal nerve fiber layer, and the optic disc.[76], [77] OCT is convenient for monitoring the progression or response to treatment of DME but, as with any optical procedure, cataract and vitreous hemorrhage may prevent visualization of the fundus.

OCT relies on an optical technique known as low-coherence interferometry to generate images. The light source is a diode, not a laser or x-ray. The principle of operation is similar to ultrasound, except that light is used instead of sound. OCT permits tissue detail resolution < 15 µm versus a resolution of approximately 300 to 600 µm with conventional ultrasound.

Ultrasonography

Ocular ultrasonography is an established adjunctive technique for evaluating the retina. It is especially useful when visualization of the posterior eye structures is limited in patients with vitreous hemorrhage from PDR or dense cataracts.[78]“B-scan” ultrasound capability is required for posterior segment imaging, whereas “A-scan” ultrasound is most often used to measure the axial length of the eye prior to cataract surgery. Ultrasonography may also be used to check for retinal detachment when the retina cannot be visualized due to vitreous hemorrhage or dense cataracts.[78]

Nephropathy

Albumin:creatinine ratio

Microalbuminuria can be easily detected by measuring the urinary albumin-to-creatinine ratio from a single random specimen (Table 9).[79] Although a 24-hour urine collection may be more accurate than measuring the albumin:creatinine ratio, since the amount of albumin in the urine varies throughout the day, it is less convenient as it relies on patient compliance and/or the use of a catheter. Timed urine collections (eg, 4 hour or overnight) can also be used to measure for albuminuria, although untimed (random) spot urine collection is widely recommended.

The albumin:creatinine ratio is used along with a spot collection to correct for variations in urinary albumin, since urinary creatinine levels are relatively stable. This technique yields a result that is nearly as accurate as the 24-hour test but without the difficulties associated with 24-hour urine collection (Table 9).[79]

Table 9. Tests of Urinary Albumin Excretion[79]

Category	Spot collection (µg/mg creatinine)	24-h collection (mg/24 h)	Timed collection (µg/min)
Normal	< 30	< 30	< 20
Microalbuminuria	30-299	30-299	20-199
Clinical albuminuria	≥ 300	≥ 300	≥ 200

Because of variability in urinary albumin excretion, 2 of 3 specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed 1 of these diagnostic thresholds. Several factors may increase albumin excretion over baseline values, including exercise within the previous 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, pyuria, and hematuria.[24]

Creatinine clearance

Creatinine is a by-product of muscle metabolism and is usually excreted at a constant rate. Creatinine clearance can therefore be used as a surrogate marker of the GFR to measure renal function.

Laboratory measurement of creatinine clearance can be determined from timed or 24-hour urine collections, although these methods are subject to collection errors. As an alternative, measurement of SC is typically used to avoid the inconvenience and errors associated with urine collection. The Cockcroft-Gault equation can then be used to predict creatinine clearance from knowledge of SC, age, weight, and gender (Figure 2).

Figure 2. Cockcroft-Gault equation
 
Men:
Creatinine clearance = (140-age) x weight in kg
                                   --------------------------------
                                    (72 x serum creatinine)
Women:
Creatinine clearance = (140-age) x weight in kg
                                     ------------------------------- x 0.85
                                    (72 x serum creatinine)

GFR estimation

Since only the kidneys remove creatinine from the body, the measurement of SC is useful in evaluating renal function in patients with diabetes. Creatinine levels are usually consistent because muscle mass changes little from day to day, although minor elevations in SC may be consistent with a substantial change in the GFR.[80]

The use of SC for measuring GFR was validated by the Modification of Diet in Renal Disease (MDRD) Study, which used SC and other variables such as sex, age, and race to estimate GFR, as shown in Figure 3.[81] This MDRD method has been shown to be more accurate than either a 24-hour urine collection or the Cockcroft-Gault equation for estimating creatinine clearance.[82]


Figure 3. MDRD equation[81]

GFR = 170 x [SC] ^–0.999 x [age] ^0.176 x [SUN] ^–0.170 x [SA]^+0.318

Multiply this GFR by 0.762 if patient is female.

Multiply this GFR by 1.180 if patient is black.

SC = serum creatinine, mg/dL; SUN = serum urea nitrogen, mg/dL; SA = serum albumin, g/dL; age = age in years.

SC concentration generally does not reflect modest changes in GFR and may not detect early changes in kidney function. Increased SC concentration can indicate a variety of conditions other than diabetic nephropathy and should be interpreted in the context of patient history, including use of other medications.[24]

DPN

DPN is clinically diagnosed by confirming a neurological deficit and excluding nondiabetic causes. Rarely are quantitative sensory testing (QST), electrophysiological testing, or other expensive tests required in day-to-day clinical practice.

Protective sensation

Monofilament

Loss of protective sensation in more severe DPN can be measured with a Semmes-Weinstein 5.07 (10-g) monofilament and can be used to identify a high risk of foot ulceration.[83] Many sites on the foot can be evaluated with the monofilament, and although no clinical consensus exists for how many anatomic sites should be tested, some authorities recommend testing 8 to 10 per foot. Although evaluating multiple dermatomes of the foot may improve the sensitivity and specificity of the monofilament test compared with testing only a single location, testing just 4 plantar sites on the forefoot (great toe and base of first, third, and fifth metatarsals) may identify as many as 90% of patients with an imperceptible site.[83] Consistent with this finding, the National Diabetes Education Program recommends the 5 plantar testing sites illustrated in Figure 4.[83] There is a wide variability in the performance of commercially available monofilaments, so care should be taken to ensure that the monofilament is accurate enough to provide clinically useful information.[84]

Instructions for Using a Semmes-Weinstein Monofilament The examiner should place the monofilament perpendicular to the skin and apply pressure until the monofilament buckles. The monofilament should be held in place for approximately 1 second, then released. Two negative responses at any particular site on the bottom of the foot indicate a loss of protective sensation at that site. Four or more imperceptible sites (out of 10 sites tested) are often considered to be a clinically significant loss of protective sensation. A patient who has difficulty detecting the monofilament is prone to foot ulceration.

Tuning fork

Decreased vibration perception can be measured using a simple test with a 128-Hz tuning fork, as well as electronic quantitative sensory devices that generate vibrations of increasing amplitude until they are felt by the patient (Table 10).[59]

Table 10. Instructions for Using a Tuning Fork

The examiner should place the tuning fork on the dorsal portion of the great toe, adjacent to the bed of the nail or over the lateral malleolus. It is important that the patient not be aware of where the tuning fork is applied. Application should be conducted at least twice in every location. The patient should be asked whether he or she feels the tuning fork and to indicate when the vibration stops. When the patient indicates that he or she can no longer detect vibration, the examiner should test the tuning fork to see if it is still vibrating. If the examiner detects the vibration longer than the patient, vibration perception is decreased.

Pinprick

A pinprick test is used to evaluate deficits in pain perception (Table 11). A diminished response to the pinprick test suggests the presence of mild to moderate DPN. Sterile, single-use pins that eliminate the risk of infection are commercially available.[86]

Table 11. Instructions for Administering a Pinprick Test

The examiner should ensure that the patient’s foot is out of his or her field of view. The examiner should then place the pin somewhere on the bottom of the patient’s foot. Following the placement of the pin, the examiner should assess the degree of patient response (eg, verbal response, jerk of the foot, or other movement). If the patient fails to react, pain perception is diminished. This process should be repeated using several different locations on the bottom of the foot.

Cotton wool swab

A cotton wool swab or soft brush can be used to assess a patient’s ability to perceive light touch (Table 12). Decreased light touch sensation may be observed in patients with mild to moderate DPN. Failure to detect light touch may indicate severe DPN.[86]

Table 12. Instructions for Using a Cotton Wool Swab

The patient should be instructed to close his or her eyes before testing. The examiner should gently wipe the cotton wool swab/soft brush on several different locations on the bottom of the patient’s foot to evaluate loss of light touch perception. The patient should be asked to indicate the site of each cotton wool swab/soft brush application. Failure to describe the location of the cotton wool swab/soft brush on his or her foot and/or failure to react with movement (eg, jerking of the foot) may indicate DPN.

Quantitative sensory testing (temperature)

Quantitative sensory testing (QST) is a method of estimating the magnitude of sensory deficits associated with DPN. Computer-controlled devices are used to generate and record a patient’s response to repeatable thermal stimuli (eg, warmth, cold, heat-induced pain, or cold-induced pain). Some of the devices available for measuring responsiveness to thermal stimuli include the CASE IV™ System (WR Medical Electronics Co) and the TSA-II NeuroSensory Analyzer (Medoc Advanced Medical Systems US). Both of these devices measure vibration perception as well.[86]

Temperature QST tools can be used to evaluate sensory nerve impairment in clinical practice. Such testing may be of value in the detection of early DPN, even in patients without overt symptoms of neuropathy, and for monitoring sensory changes in patients with previously diagnosed DPN. A reusable thermal device is placed on the patient’s skin (eg, foot) to heat or cool the skin as needed. The patient is asked to respond to these temperature stimuli by pushing a response button. A sensory threshold (ie, a recognizable change in temperature) is recorded and compared with an age-matched normal population value by the computer. A deviation from the normal range can indicate the existence of peripheral nerve dysfunction, although it does not diagnose its cause.

Quantitative sensory testing (vibration)

A number of electronic devices have been developed to detect vibration perception threshold (VPT) (ie, patient sensitivity to vibration), and these noninvasive QST tools may be used in identifying patients at high risk for foot ulceration, including those without symptoms of DPN.

Many of these devices detect nerve damage by placing an electromechanical probe to a specific site on the finger, toe, or ankle. The amplitude of vibration varies directly with the voltage setting of the meter, which is increased until the patient perceives the vibration. Thresholds ≥ 25 V are associated with a 6-fold increased risk of foot ulceration in patients with type 1 or type 2 DM. Some currently available devices include the Bio-Thesiometer (Bio-Medical Instrument Company), the VSA-3000 Vibratory Sensory Analyzer (Medoc Advanced Medical Systems US), and the VPT Meter^® (Xilas Medical, Inc).

Electromyography

Electromyography (EMG) instrumentation is used to measure nerve conduction velocity (NCV) and other electrophysiological neuromuscular parameters (Table 13). Such tests are used to identify entrapment and proximal demyelinating conditions associated with DPN[86] and may identify patients with diabetes at high risk for foot ulceration, including those who are asymptomatic. Changes in NCV cannot be detected with any of the other tools commonly used to assess DPN.

EMG instrumentation is available from many manufacturers. Units range from simple devices dedicated to NCV measurement to sophisticated, computer-based, general-purpose signal generation and detection devices used in a research setting.

Table 13. Guidelines for Using Electromyography

Most EMG instruments permit the use of different types of electrodes (eg, disposable surface, reusable surface, needle). Regardless of electrode type, the proper skin-preparation technique must be followed to ensure clear and accurate signal recording. Electrodes are applied to the skin over the distribution of the nerve to be studied. For DPN, this will typically be somewhere on the foot, leg, or ankle. Patient motion or muscle tension at the wrong time can cause measurement errors. Therefore, patients should be made comfortable in a warm room with their limbs heated and asked to remain still. Following site selection, skin preparation, and electrode application, an electrical stimulus is applied that allows for the detection of signals produced at the sensing electrodes. Expert interpretation of the signal tracings, usually by a neurologist, is required to assess the degree and type of damage to sensory and motor nerves or nerve fibers.

Foot structure and biomechanics

Plantar pressure

Changes in plantar pressure are often associated with DPN. Screening for high-pressure regions on the sole of the foot can help to identify areas of excessive pressure that are predictive of foot ulceration. A number of devices are available to measure plantar pressure. One methodology uses a mat to measure barefoot plantar load distribution. Some devices, such as the MatScan^® (Tekscan) and emed^® (Novel) systems, are software-based and provide quantitative measurements of foot pressure. Other systems, such as the Podotrack^® (Masterpiece Solutions Inc), PressureStat^® ( the Harris Mat Test (Orthoprint™), identify and quantify plantar pressure by comparing the impression made by a patient’s foot to a calibration card. All of these measurements are inexpensive to assess and quick to perform. Systems such as the Novel and Tekscan devices are expensive and are generally used in the research setting.

Alternatively, shoe inserts containing sensors can also be used to record foot pressure. This methodology allows the measurement of plantar pressures and forces without interfering with normal gait pattern. Commercially available, shoe-based foot-pressure measurement devices include the pedar^® (Novel), the F-Scan^® (Tekscan), and the footscan^® insole (RSscan International).

Plantar pressure testing is recommended as a follow-up test for patients who fail VPT tests. Many patients may be unable to feel local areas of high pressure (eg, from ill-fitting shoes) and therefore may be at an especially increased risk for developing a foot ulcer at that site.

Reflex hammer

A reflex hammer can be used to detect deep-tendon reflexes in the ankle, as the ankle reflex may be diminished even among asymptomatic patients who have very early-stage DPN (Tables 7 and 14).

Table 14. Instructions for Administering a Reflex Hammer Test

The patient’s legs should be relaxed and symmetrical for reflex testing so that reflex amplitude is not influenced. The examiner should test reflexes on both sides of the leg so that any asymmetries can be detected. The examiner should use the reflex hammer 2 or 3 times in 1 particular spot on a deep tendon, such as the Achilles. If no reflex is present, the examiner can use reinforcement techniques: Have the patient gently contract the muscle. Have the patient concentrate on contracting a different muscle at the moment when the testing is being conducted.

Toe flexion/extension

A simple test can determine whether a patient is sensitive to changes in foot position, and it can serve as a measure of proprioception. Such deficits are generally found among individuals with moderate to severe DPN (Table 15).

Table 15. Instructions for Toe Flexion/Extension Test

The examiner should hold the patient’s great toe by its sides and out of his or her view (the patient is asked to close his or her eyes). The examiner should then move the great toe up and down. The patient should be asked to indicate the position of the toe in space. If the patient is unable to determine the toe position, significant neuropathy is present.

 

Flowcharts for Screening and Treatment

Table 16 summarizes screening guidelines and recommended treatments for retinopathy, nephropathy, and neuropathy, as well as underlying risk factors. Tables 17-19 give additional detail on screening for all 3 DMC, including the strength of evidence (Table 3) for each recommendation. Figure 5 shows the screening algorithm for microalbuminuria.

Table 16. Summary of Prevention and Treatment of Diabetic Microvascular Complications and Underlying Risk Factors[1]

Complication or Comorbidity	Goal	Monitoring/Treatment	Action If Goal Not Met
Hyperglycemiaa	A1C < 7.0%b Preprandial plasma glucose 90-130 mg/dL (5-7.2 mmol/L) Peak postprandial plasma glucose < 180 mg/dL (10 mmol/L)	Measure A1C every 6 months if meeting treatment goals; every 3 months in those not meeting goals	Intensify/change treatment regimen; identify barriers to adherence; provide culturally appropriate and enhanced diabetes self-management education; initiate/increase glucose self-monitoring; increase frequency of office visits; comanage with diabetes team; refer to endocrinologist.
Retinopathy	Prevent vision loss	Optimize glycemic and BP control. Perform annual comprehensive eye exam.c	Laser treatment
Neuropathy	Prevent foot complications	Perform annual foot examd and visual inspection at every visit.	Refer high-risk patients to a foot care specialist.
Nephropathy	Prevent renal failure	Optimize glucose and BP control. Perform annual urinary protein determination (see below). Spot albumin: creatinine testing preferred. Continue surveillance even if treated with an ACE or ARB.	See notese for treatment details; consider nephrology referral.
Hypertension	Adult: BP ≤ 130/80f mm Hg	Measure BP at every routine diabetes visit.g	If ACEs or adrenergic receptor binders are used, monitor renal function and potassium levels.
Hyperlipidemia	LDL < 100 mg/dLh TG < 150 mg/dL HDL > 40 mg/dL	Perform annual determination, and more frequently to achieve goals. If low risk (LDL < 100, HDL > 60, TG < 150), assess every 2 years. Routine monitoring of liver and muscle enzymes in asymptomatic patients is not recommended unless patient has baseline enzyme abnormalities or is taking drugs that interact with statins.	Advise patient to lose weight, increase physical activity, start nutrition therapy; follow National Cholesterol Education Program recommendations for pharmacologic treatment.
Macrovascular disease	Prevent limb ischemia, stroke, and MI	1. Use aspirin therapy (75-162 mg/day) as primary prevention for all patients ≥ 40 years or those with ≥ 1 cardiovascular risk factor. 2. Advise patient to stop smoking. 3. Manage hyperlipidemia and hypertension as above. 4. Assess for peripheral arterial disease with pedal pulses ± ankle brachial pressure index via Doppler. 5. Consider ACE inhibitor if age > 55 years, with or without hypertension, if cardiovascular risk factor is present.	Use aspirin as secondary prevention if patient has history of myocardial infarction, vascular bypass procedure, stroke or transient ischemic attack, peripheral vascular disease, claudication, and/or angina.

^a Less intensive glycemic goals if severe or frequent hypoglycemia.

^b Postprandial glucose may be targeted if A1C goals are not met despite meeting preprandial goals.

^c Dilated eye exam or 7-field, 30-degree fundus photography by ophthalmologist or optometrist. In setting of normal eye exam, less frequent screening can be considered by eye specialist.

^d Includes evaluation of protective sensation (monofilament test and tuning fork), vascular status, and inspection for foot deformities or ulcers.

^e Microalbuminuria treatment: if type 1, use ACE inhibitor; if type 2 and hypertensive, use ACE or ARB. Clinical albuminuria treatment: (1) achieve BP < 130/80 mm Hg; (2) use ACE inhibitor or ARB; (3) maintain tight glycemic control; and (4) decrease protein to 10% of dietary intake, especially in patients progressing despite optimal glucose and BP control. Refer to nephrologist if estimated glomerular filtration rate < 30 mg/min, creatinine > 2.0 mg/dL, or when management of hypertension or hyperkalemia is difficult.

^f The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial showed no difference in cardiovascular and renal outcomes in diabetes patients treated with diuretics or ACE (or ARB) (JAMA. 2002;288:2981). Diuretics should be first line in black patients (Ann Intern Med. 2003;138:587).

^g ACP recommends tight BP control (systolic BP < 135, diastolic BP < 80).

^h LDL < 70 mg/dL, using a high-dose statin, is an option in high-risk patients with diabetes mellitus and overt cardiovascular disease.

BP = blood pressure; ACE = angiotensin-converting enzyme; ARB = angiotension receptor blocker; LDL = low-density lipoprotein; TG = triglycerides; HDL = high-density lipoprotein; MI = myocardial infarction.

Source: Adapted from American Diabetes Association position statement, “2007 Clinical Practice Recommendations.”[7] Available at: http://www.diabetes.org/for-health-professionals-and-scientists/cpr.jspFor recommended quality improvement and public reporting measures, see “National Diabetes Quality Improvement Alliance Performance Measurement Set for Adult Diabetes” (2005). Available at: http://www.nationaldiabetesalliance.org.

Table 17. American Diabetes Association Recommendations for Screening and Treatment of Retinopathy[7]

Recommendations General recommendations Optimal glycemic control can substantially reduce the risk and progression of DR. (A) Optimal BP control can reduce the risk and progression of DR. (A) Aspirin therapy does not prevent DR or increase the risks of hemorrhage. (A) Screening Adults and adolescents with type 1 DM should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 3 to 5 years after the onset of diabetes. (B) Patients with type 2 DM should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes. (B) Subsequent examinations for type 1 and type 2 DM patients should be repeated annually by an ophthalmologist or optometrist. Less frequent exams (every 2 to 3 years) may be considered in the setting of a normal eye exam. Examinations will be required more frequently if retinopathy is progressing. (B) Women who are planning to or who have become pregnant should have a comprehensive eye examination and should be counseled on the risk of development and/or progression of DR. Eye examination should occur in the first trimester, with close follow-up throughout the pregnancy and for 1 year postpartum. This guideline does not apply to women who develop GDM because such individuals are not at increased risk for DR. (B) Treatment Laser therapy can reduce the risk of vision loss in patients with high-risk characteristics. (A) Promptly refer patients with any level of macular edema, severe nonproliferative DR, or any proliferative DR to an ophthalmologist who is knowledgeable and experienced in the management and treatment of DR. (A) DR = diabetic retinopathy; BP = blood pressure; DM = diabetes mellitus; GDM = gestational diabetes mellitus. Table 18 American Diabetes Association Recommendations for Screening and Treatment of Nephropathy[7] Recommendations General recommendations To reduce the risk and/or slow the progression of nephropathy; optimize glucose control. (A) To reduce the risk and/or slow the progression of nephropathy; optimize BP control. (A) Screening Perform an annual test for the presence of microalbuminuria in type 1 DM patients with diabetes duration of ≥ 5 years and in all type 2 DM patients, starting at diagnosis and during pregnancy. (E) SC should be measured at least annually for the estimation of GFR in all adults with diabetes regardless of the degree of urine albumin excretion. The SC alone should not be used as a measure of kidney function but used instead to estimate GFR and to stage the level of CKD. (E) Treatment In the treatment of both micro- and macroalbuminuria, either ACE inhibitors or ARBs should be used except during pregnancy. (A) While there are no adequate head-to-head comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements: In patients with type 1 DM, hypertension, and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A) In patients with type 2 DM, hypertension, and microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. (A) In patients with type 2 DM, hypertension, macroalbuminuria, and renal insufficiency (SC > 1.5 mg/dL), ARBs have been shown to delay the progression of nephropathy. (A) If one class is not tolerated, the other should be substituted. (E) Reduction of protein intake to 0.8 to 1.0 g · kg body wt-1 · day-1 in individuals with DM and the earlier stages of CKD and to 0.8 g · kg body wt-1 · day-1 in the later stages of CKD may improve measures of renal function (urine albumin excretion rate, GFR) and is recommended. (B) To slow the progression of nephropathy, the use of DCCBs as initial therapy is not more effective than placebo. Their use in nephropathy should be restricted to additional therapy to further lower BP in patients already treated with ACE inhibitors or ARBs. (B) In the setting of albuminuria or nephropathy in patients unable to tolerate ACE inhibitors and/or ARBs, consider the use of non-DCCBs, β-blockers, or diuretics for the management of BP. Use of non-DCCBs may reduce albuminuria in patients with diabetes, including during pregnancy. (E) If ACE inhibitors, ARBs, or diuretics are used, monitor serum potassium levels for the development of hyperkalemia. (B) Continued surveillance of microalbuminuria/proteinuria to assess both response to therapy and progression of disease is recommended. (E) Consider referral to a physician experienced in the care of diabetic renal disease when the estimated GFR has fallen to < 60 mL/min per 1.73 m2 or if difficulties occur in the management of hypertension or hyperkalemia. (B) BP = blood pressure; DM = diabetes mellitus; SC = serum creatinine; GFR = glomerular filtration rate; CKD = chronic kidney disease; ACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; DCCBs =dihydropyridine calcium channel blockers. Figure 5. Flowchart for microalbuminuria screening[24]   Table 19. American Diabetes Association Recommendations for Screening and Treatment of Neuropathy[7] Recommendations All patients should be screened for DSP at diagnosis and at least annually thereafter, using simple clinical tests. (A) Electrophysiological testing is rarely ever needed, except in situations where the clinical features are atypical. (E) Once the diagnosis of DSP is established, special foot care is appropriate for insensate feet to decrease the risk of amputation. (B) Simple inspection of insensate feet should be performed at 3- to 6-month intervals. An abnormality should trigger referral for special footwear, a preventive specialist, or podiatric care. (B) Screening for autonomic neuropathy should be instituted at diagnosis of type 2 DM and 5 years after diagnosis of type 1 DM. Special electrophysiological testing for autonomic neuropathy is rarely needed since it may not affect management and outcomes. (E) Education of patients about self-care of the feet and referral for special shoes/inserts are vital components of patient management. (B) A wide variety of medications is available for the relief of specific symptoms related to autonomic neuropathy. These treatments are recommended, as they improve the patient’s quality of life. (E) DSP = distal symmetric polyneuropathy; DM = diabetes mellitus. 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