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to the reported efficacy of ACE inhibitor drugs in reducing microalbuminuria in normotensive patients 2 Progressive diabetic nephropathy Progressive diabetic nephropathy consists of proteinuria of varying severity occasionally leading to nephrotic syndrome with hypoalbuminemia, edema, and an increase in circulating LDL cholesterol as well as progressive azotemia In contrast to all other renal disorders, the proteinuria associated with diabetic nephropathy does not diminish with progressive renal failure (patients continue to excrete 10 11 g daily as creatinine clearance diminishes) As renal failure progresses, there is an elevation in the renal threshold at which glycosuria appears Hypertension develops with progressive renal involvement, and coronary and cerebral atherosclerosis seems to be accelerated Approximately two-thirds of adult patients with diabetes have hypertension Once diabetic nephropathy has progressed to the stage of hypertension, proteinuria, or early renal failure, glycemic control is not beneficial in influencing its course In this circumstance, antihypertensive medications, including ACE inhibitors, and restriction of dietary protein to 08 g/kg body weight per day are recommended ACE inhibitors have been shown to protect against deterioration in renal function in type 1 diabetic patients with clinical nephropathy This beneficial effect appears to be due to improved glomerular hemodynamics that cannot be explained only by the antihypertensive action of these drugs Captopril (25 mg three times daily) has shown a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation in type 1 subjects with diabetic nephropathy and clinical proteinuria During initiation of ACE inhibitor therapy, an increment in serum creatinine greater than 2 mg/dL due to a rapid fall in intraglomerular pressure or the occurrence of persistent hyperkalemia (above 6 mEq/L) due to hyporeninemic hypoaldosteronism is an indication to stop this medication Dialysis has been of limited value in the long-term treatment of renal failure due to diabetic nephropathy At present, experience in renal transplantation especially from related donors is more promising and is the treatment of choice in cases where there are no contraindications such as severe cardiovascular disease
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C Diabetic Neuropathy
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Diabetic neuropathies are the most common complications of diabetes affecting up to 50% of older patients with type 2 diabetes 1 Peripheral neuropathy a Distal symmetric polyneuropathy This is the most common form of diabetic peripheral neuropathy where loss of function appears in a stocking-glove pattern and is due to an axonal neuropathic process Longer nerves are especially vulnerable, hence the impact on the foot Both motor and sensory nerve conduction is delayed in the peripheral nerves, and ankle jerks may be absent Sensory involvement usually occurs first and is generally bilateral, symmetric, and associated with dulled perception of vibration, pain, and temperature The pain can range from mild discomfort to severe incapacitating symptoms (see
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abling Amitriptyline, 25 75 mg at bedtime, has been recommended for pain associated with diabetic neuropathy Dramatic relief has often resulted within 48 72 hours This rapid response is in contrast to the 2 or 3 weeks required for an antidepressive effect Patients often attribute the benefit to having a full night s sleep Mild to moderate morning drowsiness is a side effect that generally improves with time or can be lessened by giving the medication several hours before bedtime This drug should not be continued if improvement has not occurred after 5 days of therapy If amitriptyline s anticholinergic effects are too troublesome, then nortriptyline can be used Desipramine in doses of 25 150 mg/d seems to have the same efficacy as amitriptyline Tricyclic antidepressants in combination with the phenothiazine, fluphenazine have been shown in two studies to be efficacious in painful neuropathy, with benefits unrelated to relief of depression Gabapentin (900 1800 mg/d in three divided doses) has also been shown to be effective in the treatment of painful neuropathy and should be tried if the tricyclic drugs prove ineffective Pregabalin, a congener of gabapentin, has been shown in an 8week study to be more effective than placebo in treating painful diabetic peripheral neuropathy However, this drug was not compared with an active control Also, because of its abuse potential, it has been categorized as a schedule V controlled substance Duloxetine, a serotonin and norepinephrine reuptake inhibitor, has been approved for the treatment of painful diabetic neuropathy In clinical trials, this drug reduced the pain sensitivity score by 40 50% Capsaicin, a topical irritant, has been found to be effective in reducing local nerve pain; it is dispensed as a cream (Zostrix 0025%, Zostrix-HP 0075%) to be rubbed into the skin over the painful region two to four times daily Gloves should be used for application since hand contamination could result in discomfort if the cream comes in contact with eyes or sensitive areas such as the genitalia Diabetic neuropathic cachexia is a syndrome characterized by a symmetric peripheral neuropathy associated with profound weight loss (up to 60% of total body weight) and painful dysesthesias affecting the proximal lower limbs, the hands, or the lower trunk Treatment is usually with insulin and analgesics The prognosis is generally good, and patients typically recover their baseline weight with resolution of the painful sensory symptoms within 1 year 2 Autonomic neuropathy With autonomic neuropathy, there is evidence of postural hypotension, decreased cardiovascular response to Valsalva s maneuver, gastroparesis, alternating bouts of diarrhea (particularly nocturnal) and constipation, inability to empty the bladder, and impotence Gastroparesis should be considered in type 1 diabetic patients in whom unexpected fluctuations and variability in their blood glucose levels develops after meals Impotence due to neuropathy differs from psychogenic impotence in that the latter may be intermittent (erections occur under special circumstances), whereas diabetic impotence is usually persistent; aortoiliac occlusive disease may contribute to this problem a Management of autonomic neuropathy There is no consistently effective treatment for diabetic autonomic neuropathy Metoclopramide has been of some help in treat-
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below) The sensory deficit may eventually be of sufficient degree to prevent patients from feeling pain Patients who have a sensory neuropathy should therefore be examined with a 507 Semmes Weinstein filament and those who cannot feel the filament must be considered at risk for unperceived neuropathic injury The denervation of the small muscles of the foot result in clawing of the toes and displacement of the submetatarsal fat pads anteriorly These changes, together with the joint and connective tissue changes, alter the biomechanics of the foot and increase plantar pressures This combination of decreased pain threshold, abnormally high foot pressures, and repetitive stress (such as from walking) can lead to calluses and ulcerations in the high-pressure areas such as over the metatarsal heads Peripheral neuropathy, autonomic neuropathy, and trauma also predisposes to the development of Charcot s arthropathy An acute case of Charcot s foot arthropathy presents with pain and swelling, and if left untreated, leads to a rocker bottom deformity and ulceration The early radiologic changes show joint subluxation and periarticular fractures As the process progresses, there is frank osteoclastic destruction leading to deranged and unstable joints particularly in the midfoot Not surprisingly, the key issue for the healing of neuropathic ulcers in a foot with good vascular supply is mechanical unloading In addition, any infection should be treated with debridement and appropriate antibiotics; healing duration of 8 10 weeks is typical Occasionally, when healing appears refractory, platelet-derived growth factor (Regranex) should be considered for local application Once ulcers are healed, therapeutic footwear is key to preventing recurrences Custom molded shoes are reserved for patients with significant foot deformities Other patients with neuropathy may require accommodative insoles that distribute the load over as wide an area as possible Patients with foot deformities and loss of their protective threshold should get regular care from a podiatrist Patients should be educated on appropriate footwear and those with loss of their protective threshold should be instructed to inspect their feet daily for reddened areas, blisters, abrasions, or lacerations b Isolated peripheral neuropathy Involvement of the distribution of only one nerve ( mononeuropathy ) or of several nerves ( mononeuropathy multiplex ) is characterized by sudden onset with subsequent recovery of all or most of the function This neuropathology has been attributed to vascular ischemia or traumatic damage Cranial and femoral nerves are commonly involved, and motor abnormalities predominate The patient with cranial nerve involvement usually has diplopia and single third, fourth, or sixth nerve weakness on examination but the pupil is spared A full recovery of function occurs in 6 12 weeks Diabetic amyotrophy presents with onset of severe pain in the front of the thigh Within a few days or weeks of the onset of pain, weakness and wasting of the quadriceps develops As the weakness appears, the pain tends to improve Management includes analgesia and improved diabetes controls The symptoms improve over 6 18 months c Painful diabetic neuropathy Hypersensitivity to light touch and occasionally severe burning pain, particularly at night, can become physically and emotionally dis-
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