Laboratory Evaluation of Chronic Medical Conditions for Dental Treatment—Part II. Diabetes and renal function.

Diabetes mellitus is a multifaceted disease that must be carefully managed to reduce complications in many systems of the body. The problem in the United States is growing, affecting about 8% of the population, or about 24 million. One quarter of these affected Americans are not aware of their disease, and dental healthcare providers may be able to help identify these patients due to oral manifestations, such as rapidly progressing periodontal disease, poor healing after oral surgery, candidiasis, rampant caries, burning mouth syndrome, and ketone breath. These signs and symptoms may also be present when diabetes is poorly controlled, and the patient should be referred to a physician.

A patient with well-controlled diabetes can tolerate any dental treatment and will have fewer complications systemically.¹ Dental healthcare providers should reinforce excellent glycemic control and lifestyle when these patients receive oral care. Two blood tests are commonly used to monitor glycemic levels: glycated hemoglobin (A1C or HbA1c) and blood glucose (random or fasting). Most patients are encouraged to perform self-monitoring of blood glucose testing, especially those using insulin injections.²

A1_C is a measure of long-term blood glucose control. Red blood cells (RBCs) are analyzed to determine the percentage of hemoglobin that has been altered by high blood glucose. As RBCs mature and leave the bone marrow, the level of blood glucose alters the hemoglobin to the glycated state. This is a permanent change but does not compromise the oxygen-carrying capacity of RBCs. Because RBCs survive approximately 120 days, this test shows the patient’s blood glucose levels for about the past 4 months. The American Diabetes Association recommends that the goal should be a value less than 7% and the A1C test be performed every 3 to 6 months.² The A1C value appears to help predict microvascular and neuropathic complications of diabetes for most patients and is somewhat indicative of macrovascular complications.²

Blood glucose levels change throughout the day and should be measured so that the patient can alter food intake or medication dose accordingly. A small, electronic glucometer measures blood glucose as milligrams per deciliter of blood. The patient is instructed by the physician to consider a target range, eg, 90 mg/dL to 130 mg/dL.² Patients who are taking insulin through injections or a pump may need to self-test three or more times daily. In patients who are not using insulin, recent studies in 2007³ and 2008⁴ have characterized this self-monitored blood glucose testing as providing a limited clinical benefit, and the American Diabetes Association has no specific guidelines for daily testing.² However, the American Association of Clinical Endocrinologists recommends daily blood glucose testing for patients not using insulin treatment.⁵

The dental healthcare provider should be familiar with the patient’s diabetes history, including any complications or medical emergencies. In preparation for elective treatment, reviewing the A1_C may help with formulating specific treatment plans. When initiating dental care, the blood glucose should be tested chairside, especially for extensive and lengthy procedures. If the blood glucose is less than 70 mg/dL to 90 mg/dL, the patient should be allowed to eat. If the value is more than 200 mg/dL, the patient may need hypoglycemic medications or insulin, or the treatment may need to be deferred.⁶ If the patient receives any dental treatment that alters the ability to eat, medication doses will need to be changed as appropriate. If the A1_C is greater than 9%, perioperative antibiotics should be prescribed with any signs of infection (Table 1). Dental management of a patient with diabetes may also include considering other complications of diabetes, such as renal or heart disease.

Kidney Disease
Chronic kidney disease (CKD) is characterized by the kidneys’ inability to adequately eliminate metabolic (nitrogenous) waste via the urine, regulate acid-base and electrolyte balance and bodily fluid volume, reabsorb protein, secrete the hormones renin and angiotensin (which are responsible for the maintenance of blood pressure), and synthesize erythropoietin and the active forms of vitamin D. The National Kidney Foundation (NKF)’s Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines define CKD as either kidney damage or glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 for 3 or more months (Table 2).⁷ Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test results or imaging studies. The NKF KDOQI Guidelines also include a system for staging chronic kidney disease based on GFR (Table 2). The complex signs and symptoms that occur in patients with untreated, severe persistent renal failure are known collectively as uremic syndrome or uremia.

Systemic Manifestations
Because of the numerous specialized functions of the kidney, patients with CKD can have an extensive range of both systemic and oral clinical manifestations that directly affect their dental treatment and management. The pathogenesis and resultant systemic clinical manifestations of CKD have been well elucidated in the literature^8,9 and can be summarized according to the effects on the various organ systems.

The hematologic/immunologic systems can exhibit normochromic, normocytic anemia due to insufficient production of erythropoietin by the kidneys; iron and/or folate deficiency anemias are also possible. Thrombocytopathy due to abnormal platelet aggregation and adhesiveness can occur, and are marked by decreased activity of platelet factor 3 and impaired prothrombin consumption. Mild-to-moderate thrombocytopenia can occur due to decreased platelet production. Host defenses can be compromised, increasing the risk of infections due to lymphopenia, and impaired cell-mediated immunity can result from the acceleration of apoptosis of lymphocytes, monocytes, and neutrophils, in addition to reduced chemotactic, phagocytic, and bacteriocidal activity by neutrophils.¹⁰

Cardiovascular disease is the leading cause of morbidity and mortality in patients with CKD at all stages.^11,12 Hypertension is already present or develops in about 90% of these individuals due to sodium overload, extracellular fluid volume expansion, activation of the renin-angiotensin-aldosterone system, and the sympathetic nervous system. Patients with chronic renal failure tend toward a high cardiac output state. They often have extracellular fluid volume overload and anemia. In addition to hypertension, these abnormalities cause increased myocardial work and oxygen demand with resultant left ventricular hypertrophy, cardiomyopathy, and congestive heart failure (CHF). Uremic pericarditis may develop when blood urea nitrogen (BUN) concentration exceeds 100 mg/dL. Pericarditis may exacerbate (or precipitate) CHF. Atherosclerosis may be accelerated with an increased risk of occlusive coronary disease, cerebrovascular disease (stroke), and peripheral vascular disease. Hyperkalemia associated with CKD can increase the risk for cardiac arrhythmias.

In the respiratory system, pulmonary edema (“uremic lung”) secondary to left-sided heart failure can cause dyspnea and orthopnea. Gastrointestinally, anorexia nervosa, nausea, vomiting, diarrhea, and occult gastrointestinal tract bleeding can all be exhibited in patients with CKD.

Neurologically, there can be development of symmetric peripheral polyneuropathy, typically with sensory deficits and/or restless leg syndrome. Patients may exhibit neuromuscular irritability characterized by hiccups, muscle cramps, and involuntary muscle contractions or twitching. Mild uremia can produce memory disturbances, impaired concentration, and insomnia; severe uremia can result in “uremic delirium” characterized by impaired cognitive function, confusion, disorientation, lethargy, seizures, and coma.

In the endocrine/skeletal systems, hypothalamic-pituitary axis dysfunction can be characterized by amenorrhea, menorrhagia, impotence, oligospermia, and hyperprolactinemia. Renal osteodystrophy is a group of bone disorders caused by the kidneys’ decreased capacity to synthesize 1,25-dihydroxycholecalciferol (also called 1,25-dihydroxyvitamin D, or calcitriol) and to excrete phosphate. Decreased serum calcium (due to increased serum phosphate), the impairment of calcium absorption in the intestine, and the loss of the feedback inhibitory effect of 1,25-dihydroxycholecalciferol on parathyroid hormone (PTH) production creates severe secondary hyperparathyroidism. The clinical manifestations of renal osteodystrophy include osteitis cystica fibrosa (increased bone resorption, bone marrow fibrosis, and fibrotic cystic bone lesions with hemorrhagic elements [central giant cell granulomas or “brown tumors”] in the long bones and jaw); osteomalacia (increased unmineralized bone matrix); and osteosclerosis (increased bone density). Clinical manifestations of renal osteodystrophy include vague, ill-defined, and deep-seated bone pain; bone fragility with a tendency for spontaneous fractures of bone and slow healing; aseptic hip necrosis; vascular calcifications (eg, Mönckeberg’s sclerosis), heterotopic tissue calcification (eg, eyes, myocardium, lungs), calciphylaxis (characterized by vascular calcification in the tunica media of peripheral arteries, thrombosis, and skin necrosis), and tumoral calcinosis (soft-tissue calcification that usually involves the periarticular tissues).¹³

Dermatologically, patients may be pale because of anemia or have pigmented skin due to the accumulation of retained, carotene-like, yellow-brown metabolites (“urochromes”) in the skin. They may exhibit easy bruising with multiple petechia and ecchymoses (secondary to hemostatic defects). Uncomfortable pruritus is common.

Oral Manifestations
In most instances, the oral signs and symptoms of CKD represent focal expressions of the systemic consequences of the disease process and can include: pallor of the oral mucosa (secondary to anemia); diminished salivary flow and xerostomia, which predisposes the patient to caries, gingivitis, oral candidiasis, and parotid infections; uremic fetor, an ammonia/urine-like odor on the breath caused by the breakdown of urea to ammonia in saliva, that is often associated with dysgeusia and/or complaints of an unpleasant and/or metallic taste; and tooth erosion from persistent vomiting.

In addition to these classic oral symptoms, petechiae and/or ecchymoses may be evident on the labial and buccal mucosa, soft palate, and borders of the tongue secondary to the hemostatic defects associated with advanced CKD. Uremic stomatitis (US) is a relatively uncommon intraoral complication most frequently seen in undiagnosed or untreated Stage V CKD (kidney failure).^14,15 US is correlated with significantly elevated (usually > 55 mg/dL) BUN levels. While the pathogenesis of US remains uncertain, it is postulated to be due to irritation and chemical injury of the oral mucosa by ammonia or ammonium compounds formed by the hydrolysis of urea in saliva by urease.¹⁶ Four clinical presentations of US have been described clinically: erythemopultaceous, ulcerative, hemorrhagic, and hyperkeratotic.^17-19

Classic oral manifestations of renal osteodystrophy include a triad of thinning or loss of lamina dura, demineralized bone (with a “ground-glass” or “chalky”” appearance), and localized osteolytic radiolucent jaw lesions (central giant cell granulomas).^20,21 Other osseous findings associated with renal osteodystrophy include widened trabeculations, cortical bone resorption/thinning (eg, borders of the mandible, mandibular canal, alveolar crest, maxillary sinus walls), widening of the periodontal ligament, abnormally calcified extraction sites (“socket sclerosis”), pulpal calcifications, pulpal chamber narrowing, root resorption, and heterotopic soft-tissue calcifications.^20,22

The dental treatment and management of the patient with CKD can be extremely challenging not only because of the numerous possible complications associated with CKD but also because of complications due to its treatment (eg, hemodialysis, peritoneal dialysis) and causative and/or comorbidities (eg, diabetes, hypertension, CHF). Detailed information regarding the dental management of patients with CKD is beyond the scope of this article; however, this subject has been adequately discussed in several publications.^21-27

The primary laboratory tests that can provide an indication of renal function and consistent results include decreased GFR, decreased creatinine clearance in the urine, increased blood urea nitrogen, and increased serum (plasma) creatinine (Table 3). Additional laboratory test results that would be considered supportive in the confirmation of advanced CKD typically include decreased serum calcium with increased serum phosphate/inorganic phosphorus, increased serum potassium, decreased serum chloride, decreased serum sodium, increased serum uric acid, increased serum alkaline phosphatase, decreased serum bicarbonate, and decreased venous blood total carbon dioxide.28 The principal test used to measure renal function and to gauge CKD severity is GFR, which provides an excellent indication of the filtering capacity of the kidneys.²⁸ A low or decreasing GFR is a good indicator of CKD. GFR cannot be determined directly and is traditionally measured as the renal clearance of a particular substance, or marker, from plasma. Inulin is a fructose polymer, and inulin clearance was once widely regarded as the “gold standard” for measuring GFR. Inulin clearance measurements in healthy, hydrated young adults (adjusted to a standard body surface area of 1.73 m²) have mean values of 127 mL/min/1.73 m² in men and 118 mL/min/1.73 m² in women with a standard deviation of approximately 20 mL/min/1.73 m².²⁹ GFR declines with age. After 20 to 30 years of age, GFR decreases by approximately 1 mL/min/1.73 m² per year with considerable variation between “healthy” adults.³⁰

A review of laboratory test results for creatinine clearance, serum creatinine, BUN, and (estimated) GFR for a patient with CKD would provide the dental healthcare provider with an indication of the severity of CKD and amount of remaining renal function. As renal function and GFR decrease, there is an increase in the risk for the many systemic and oral complications of CKD as previously described. Stage I (GFR ≥ 90 mL/min/1.73 m²) and Stage II (GFR 60 mL/min/1.73 m² to 89 mL/min/1.73 m²) CKD are usually not associated with any signs or symptoms attributable to renal failure. However, there may be signs or symptoms from the underlying renal disease itself (eg, hypertension in patients with polycystic kidney disease, or some forms of glomerulonephritis) or from diseases contributory or causative of CKD (eg, diabetes).

For patients in Stage III (GFR 30 mL/min/1.73 m² to 59 mL/min/1.73 m²) and Stage IV (GFR 15 mL/min/1.73 m² to 29 mL/min/1.73 m²), the clinical manifestations of kidney failure are clearly evident. Virtually all organ systems are affected, and there are abnormalities in serum calcium, phosphorus, sodium, and potassium levels; mineral-regulating hormones (calcitriol and PTH); and acid-base homeostasis. Patients may complain of decreasing appetite and show progressive malnutrition. Anemia is observed as early as Stage III CKD and occurs in almost all patients with Stage IV CKD with associated easy fatigability. Subtle clinical manifestations of uremic neuromuscular disease usually become evident at Stage III CKD, while peripheral neuropathy usually becomes clinically evident in Stage IV.⁸

For patients in Stage V (GFR < 15 mL/min/1.73 m²), toxic nitrogenous waste accumulates to such a degree that a marked disturbance in daily living, well-being, and nutritional status occurs, necessitating renal replacement therapy (dialysis or transplantation). Gastrointestinal ulceration and bleeding is common, with uremic stomatitis occurring in patients particularly when BUN > 55 mg/dL. Signs and symptoms of impending uremia, such as anorexia, nausea, vomiting, lassitude, impaired cognitive function, and pruritus may be present. Between 30% and 45% of patients in Stage V already have advanced cardiovascular complications (eg, CHF, hypertension, pericarditis), and dependent edema is frequently seen. Hemostatic complications may also be evident, eg, a BUN elevation over 100 mg/dL will begin to cause qualitative platelet dysfunction and possible impaired hemostasis that should be considered before any surgery.²⁶

Modifications of Medications in CKD
Another important application of laboratory tests used to assess renal function in the management of patients with CKD is in providing guidance to the dental healthcare provider in the selection and correct dosage of drugs. Some drugs should not be administered to patients with CKD, while many others must be prescribed in smaller doses or over longer intervals than what would be usually be used.

Most drugs administered or prescribed in dentistry are eliminated from the body via renal excretion. This process may involve filtration, secretion, and reabsorption depending on the specific medication. In addition to modulating such rates, the kidney accumulates certain drugs. For medications normally eliminated in an unchanged form, reduced glomerular filtration and tubular secretion associated with renal insufficiency or failure may lead to toxic plasma drug levels with normally safe dosages (particularly if the drug does not undergo hepatic metabolism or has a low [narrow] therapeutic index or a long half-life). The kidney is also capable of metabolizing certain medications. Renal insufficiency may affect the metabolism of drugs not only by decreasing the rates of excretion in the urine but also by a number of non-renal mechanisms.²⁴

For medications commonly used in dentistry, tables containing schedules for dose modification are available for use in patients with CKD and provide a helpful guide.^21,31,32 These tables employ the patient’s GFR as the basis for determining the necessity and method of modification of dose regimens in patients with CKD. Generally, two methods are used to adjust drug regimens in these individuals.³¹

In the first method, the amount of drug administered is reduced, but the dosing interval is held constant. For example, in an adult with a GFR > 50 mL/min, a normal dose of codeine (eg, 30 mg) may be given every 4 hours. If the patient’s GFR is 10 mL/min to 50 mL/min, then the dose of codeine should be reduced to 75% of the normal dose (eg, 22.5 mg) administered every 4 hours. If GFR is < 10 mL/min, then the dose of codeine should be reduced to 50% of the normal dose (eg, 15 mg) administered every 4 hours. In the second method, the amount of drug administered per dose is held constant, but the dosing interval is lengthened. For example, in an adult with a GFR > 50 mL/min, a dose of amoxicillin (eg, 500 mg) may be administered every 8 hours (which is the normal dose interval). If the patient’s GFR is 10 mL/min to 50 mL/min, then the dose interval of amoxicillin should be lengthened to every 8 to 12 hours. If the GFR is < 10 mL/min, then the dose of amoxicillin should be administered every 24 hours.

Some drugs, particularly those that are potentially nephrotoxic, should not be used in patients with CKD. For example, tetracycline antibiotics (with the exceptions of doxycycline and perhaps minocycline) can exacerbate renal impairment in patients with pre-existing kidney disease, and clinicians should not administer these drugs to patients with renal impairment.³³

Conclusion
The laboratory assessment of the dental patient to assess the medical stability of CKD is a vital component of risk assessment prior to invasive dental care. The information obtained by preoperative laboratory tests allows the clinician to make informed decisions regarding the provision of dental care and facilitates treatment modifications to minimize complications.

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