The kidney may be damaged by diabetes in three main ways:
1 Glomerular damage
2 Ischaemia due to hypertrophy of afferent and efferent arterioles
3 Ascending infection
Clinical nephropathy secondary to glomerular disease usually manifests 15-25 years after diagnosis and affects 30-40% of patients diagnosed under the age of 30 years. It is the leading cause of premature death in young diabetic patients. Older patients may also develop nephropathy, but the proportion affected is much smaller. The earliest functional abnormality in the diabetic kidney is renal hypertrophy associated with a raised glomerular filtration rate; this appears soon after diagnosis and is related to poor glycaemic control. The initial structural lesion in the glomerulus is thickening of the basement membrane. Associated changes may result in disruption of the protein cross-linkages that make the membrane an effective filter. In consequence, a progressive leak of protein into the urine occurs. The earliest evidence of this is ‘micro albuminuria’ (i.e. amounts of urinary albumin so small as to be undetectable by dipsticks), which in turn may, after some years, progress to intermittent albuminuria followed by persistent proteinuria. Light-microscopic changes of glomerulosclerosis become manifest; both diffuse and nodular glomerulosclerosis can occur. The latter is sometimes known as the Kimmelstiel-Wilson lesion. At a later stage still, the glomerulus is replaced by hyaline material. At the stage of persistent proteinuria, the plasma creatinine is normal but the average patient is only some 8-10 years from end-stage renal failure. The proteinuria may become so heavy as to induce a transient nephrotic syndrome, with peripheral oedema and hypoalbuminaernia. Patients with nephropathy typically show a normochromic normocytic anaemia and a raised erythrocyte sedimentation rate (ESR). Hypertension is a common development and may itself damage the kidney still further. A rise in plasma creatinine is a late feature that progresses inevitably to renal failure, although the rate of progression may vary widely between individuals. The natural history of this process. A curious feature is that almost all patients with long-established diabetes have abnormalities on renal biopsy but only a proportion develop the features of a progressive renal disease.
Arteriolar lesions, with hypertrophy and hyalinization of the vessels, affect both afferent and efferent arterioles. The appearances are similar to those of hypertensive disease but are not necessarily related to the blood pressure in patients with diabetes.
Urinary tract infections are more common in women but not men with diabetes. Ascending infection may occur because of bladder stasis due to autonomic neuropathy, and infections more easily become established in damaged renal tissue. Autopsy material frequently reveals interstitial changes suggestive of infection, but ischaemia may produce similar changes and the true frequency of pyelonephritis in diabetes remains uncertain. Untreated infections in diabetics can result in renal papillary necrosis, in which renal papillae are shed in the urine, but this complication is rare.
Diagnosis and management of diabetic nephropathy The urine of all diabetic patients should be checked regularly for the presence of protein. Many centres also screen for microalbuminuria since there is some evidence that meticulous glycaemic control or early antihypertensive treatment at this stage may delay the onset of frank proteinuria. Once proteinuria is present, other possible causes for this should be considered (see below), but once these are excluded, a presumptive diagnosis of diabetic nephropathy can be made. For practical purposes this implies inevitable progression to end-stage renal failure, although the time course can be very markedly slowed by early aggressive antihypertensive therapy. Clinical suspicion may be provoked by an atypical history, the absence of diabetic retinopathy (usually but not invariably present with diabetic nephropathy) and the presence of haematuria. Renal biopsy should be considered in such cases, but in practice is rarely necessary or helpful. The risk of intravenous urography is increased in diabetes, especially if patients are allowed to become dehydrated prior to the procedure, and a renal ultrasound is preferable. Other investigations include repeated microscopy and culture of the urine, 24-hour urine collections to quantify protein loss and to measure creatinine clearance, and regular measurement of the plasma creatinine level. Management of diabetic nephropathy is similar to that of other causes of renal failure, with the following
AGGRESSIVE TREATMENT OF BLOOD PRESSURE with a target below 140190 mmHg has been shown to slow the rate of deterioration of renal failure considerably. Angiotensin-converting enzyme inhibitors are the drugs of choice.
ORAL HYPOGLYCAEMIC AGENTS partially excreted via the kidney (e.g. chlorpropamide) must be avoided.
INSULIN SENSITIVITY INCREASES and drastic reductions in dosage may be needed.
DIABETIC RETINOPATHY tends to progress rapidly and frequent ophthalmic supervision is essential. Management of end-stage disease is made more difficult by the fact that patients often have other complications of diabetes such as blindness, autonomic neuropathy or peripheral vascular disease. Vascular shunts tend to calcify rapidly and hence chronic ambulatory peritoneal dialysis may be preferable to haemodialysis. The failure rate of renal transplants is somewhat higher than in non-diabetic patients. A segmental pancreatic graft is sometimes performed at the same time as a renal graft. Although pancreatic grafts have a limited viability, owing to progressive fibrosis within the graft, they may give the patient a year or so of freedom from insulin injections. Diabetic nephropathy is becoming less common as diabetic care improves.
Diabetes can damage peripheral nervous tissue in a number of ways. The vascular hypothesis postulates occlusion of the vasa nervorum as the prime cause. This seems likely in isolated mononeuropathies but the diffuse symmetrical nature of the common forms of neuropathy implies a metabolic cause. Since hyperglycaemia leads to increased formation of sorbitol and fructose in Schwarm cells, accumulation of these sugars may disrupt function and structure.
The earliest functional change in diabetic nerves is delayed nerve conduction velocity; the earliest histological change is segmental demyelination, due to damage to Schwarm cells. In the early stages axons are preserved, implying prospects of recovery, but at a later stage irreversible axonal degeneration develops.
The following varieties of neuropathy may occur :
1 Symmetrical mainly sensory polyneuropathy (distal) 2 Acute painful neuropathy
3 Mononeuropathy and multiple mononeuropathy:
(a) Cranial nerve lesions
(b) Isolated peripheral nerve lesions
4 Diabetic amyotrophy
5 Autonomic neuropathy
Symmetrical mainly sensory polyneuropathy
This is often unrecognized by the patient in its early stages. Early clinical signs are loss of vibration sense, pain sensation (deep before superficial) and temperature sensation in the feet. At later stages patients may complain of a feeling of ‘walking on cotton wool’ and can lose their balance when washing the face or walking in the dark owing to impaired proprioception. Involvement of the hands is less common and results in a ‘stocking and glove’ sensory loss. Complications include unrecognized trauma, beginning as blistering due to an ill-fitting shoes. or a hot water bottle, and leading to ulceration.
SEQUELAE OF NEUROPATHY. Involvement of motor nerves to the small muscles of the feet gives rise to interosseous wasting. Unbalanced traction by the long flexor muscles leads to a characteristic shape of the foot, with a high arch and clawing of the toes, which in turn leads to abnormal distribution of pressure on walking, resulting in callus formation under the first metatarsal head or on the tips of the toes and perforating neuropathic ulceration.
Neuropathic arthropathy (Charcot’s joints) may sometimes develop in the ankle. The hands show small-muscle wasting as well as sensory changes but it is important to differentiate these signs and symptoms from those of the carpal tunnel syndrome, which occurs with increased frequency in diabetes and may be amenable to surgery.
Acute painful neuropathy
A diffuse, painful neuropathy is rare. The patient describes burning or crawling pains in the feet, shins and anterior thighs. These symptoms are typically worse at night, and pressure from bedclothes may be intolerable. It may present at diagnosis or develop after sudden improvement in glycaemic control (e.g. when insulin is started). It usually remits spontaneously after 3-12 months if good control is maintained. A more chronic form, developing later in the course of the disease, is sometimes resistant to almost all forms of therapy. Neurological assessment is difficult because of the hyperaesthesia experienced by the patient, but muscle wasting is not a feature and objective signs can be minimal. Mononeuropathy and multiple mononeuropathy
CRANIAL NERVE LESIONS. Isolated or multiple palsies of nerves to the external eye muscles, especially the third and sixth nerves, are more common in diabetes. A characteristic feature of diabetic third nerve lesions is that pupillary reflexes are retained owing to sparing of pupillomotor fibres. Full spontaneous recovery is the rule.
ISOLATED PERIPHERAL NERVE LESIONS. Manifestations may be sensory, motor, or mixed, and multiple nerves may be involved (‘mononeuritis multiplex’). The onset is usually abrupt and sometimes painful; recovery is typically slow and incomplete. Lesions are more likely to occur at common sites for external pressure palsies or nerve entrapment, e.g. the median nerve in the carpal tunnel.
This condition is usually seen in older men with diabetes. Presentation is with painful wasting, usually asymmetrical,
of the quadriceps muscles. The wasting may be very marked and knee reflexes are diminished or absent. The affected area is often extremely tender. Extensor plantar responses sometimes develop and CSF protein content is elevated. Diabetic amyotrophy is usually associated with periods of poor glycaemic control and may be present at diagnosis. It often resolves in time with careful control of the blood glucose.
Asymptomatic autonomic disturbances can be demonstrated on laboratory testing in many patients, but symptomatic autonomic neuropathy is rare. It affects both the sympathetic and parasympathetic nervous system and can be disabling.
THE CARDIOVASCULAR SYSTEM. Vagal neuropathy results in tachycardia at rest and loss of sinus arrhythmia. At a later stage the heart may become denervated (resembling a transplanted heart). Cardiovascular reflexes such as the Valsalva manoeuvre are impaired. Postural hypotension occurs owing to loss of sympathetic tone to peripheral arterioles. A warm foot with a bounding pulse is sometimes seen in a polyneuropathy as a result of peripheral vasodilatation.
GASTROINTESTINAL TRACT. Vagal damage can lead to gastroparesis, often asymptomatic, but sometimes leading to intractable vomiting. Diarrhoea often occurs at night accompanied by urgency and incontinence. Diarrhoea and steatorrhoea may occur owing to bacterial overgrowth and treatment is with antibiotics.
BLADDER INVOLVEMENT. Loss of tone, incomplete emptying, and stasis (predisposing to infection) can occur, and may ultimately result in an atonic, painless, distended bladder.
IMPOTENCE. This is common. The first manifestation is incomplete erection which may in time progress to total impotence; retrograde ejaculation also occurs. However, impotence in diabetes is not always due to autonomic neuropathy. Other causes include anxiety, depression, alcohol excess, drugs, primary or secondary gonadal failure and inadequate vascular supply due to atheroma in pudendal arteries. Treatment should ideally include sympathetic counselling of both partners. Some patients may benefit from intracavernous injection of papaverine or the use of vacuum devices to produce an erection which is then maintained by slipping a tight rubber band over the base of the penis until intercourse is complete.
The diabetic foot
Many amputations in diabetes could be delayed or prevented by more effective patient education and medical supervision. Ischaemia, infection and neuropathy combine to produce tissue necrosis. Although these factors may coexist, it is important to distinguish between the ischaemic and the neuropathic foot.
Management of the diabetic foot
Many diabetic foot problems are avoidable, so patients need to learn the principles of foot care and should be advised concerning appropriate footwear and the risks of smoking. Older patients should visit a chiropodist regularly and should not cut their own toe-nails. Once tissue damage has occurred in the form of ulceration
or gangrene, the aim is preservation of viable tissue. The two main threats are:
INFECTION. This rapidly takes hold in a diabetic foot, and early effective antibiotic treatment is essential. Collections of pus are drained and excision of infected bone is needed if osteomyelitis develops and does not respond to appropriate antibiotic therapy. Regular Xrays of the foot are needed to check on progress.
ISCHAEMIA. The blood flow to the feet is assessed clinically or with the Doppler ultrasound stethoscope. Femoral arteriography may be performed, since localized areas of occlusion may be amenable to bypass surgery or angioplasty.
Foot problems are the major cause of hospital bed occupancy by diabetic patients. Good liaison between surgeon and physician is essential if this period in hospital is to be used efficiently. When irreversible arterial insufficiency is present, it is often quicker and kinder to opt for an early major amputation rather than subject the patient to a debilitating sequence of conservative procedures.