Diabetic nephropathy in patients with type 1 diabetes mellitus
Troy A. Russell
A 34-year-old Caucasian male, R.W., was seen in the nephrology clinic on the advice and referral of his primary care physician. A recent fasting lipoprotein analysis revealed a low-density lipoprotein (LDL) cholesterol level of 134 mg/dL, a high-density lipoprotein (HDL) cholesterol level of 35 mg/dL, a triglyceride level of 460 mg/dL, and a total cholesterol level of 240 mg/dL. At the time of presentation to the clinic, his blood pressure was increased (185/104 mm Hg), although there was no evidence of coronary heart disease (CHD) or peripheral vascular disease. A fasting serum glucose level drawn in the clinic revealed a level of 192 mg/dL and a glycosylated hemoglobin level of 9.5%. A urine dipstick test with Micral-Test II strips (specific for detecting microalbuminuria) showed an albumin excretion of 125 mg/1. To confirm this finding, a 24-hour urine collection was performed that revealed an albumin excretion of 90 micrograms/minute (130 g/day). Serum blood urea nitrogen (BUN) and creatinine level was checked and revealed a value of 22 mg/dL and 1.9 mg/dL, respectively. Baseline serum creatinine was found to be 0.9 mg/dL.
R.W.’s past medical history is relatively benign except for a 12-year history of type 1 insulin-dependent diabetes mellitus. He has had no previous hospitalizations. His current medications include isophane insulin suspension (NPH) (Novolin [R] N) 22 units every morning before breakfast along with the use of a regular insulin sliding scale, depending on the results of his home blood glucose monitoring.
The focus of this case study presentation will be on the treatment of R.W. in the clinic along with any planned interventions following his treatment. It must be noted that throughout this case presentation that the terms insulin-dependent diabetes mellitus (IDDM) and type 1 diabetes are used interchangeably. However, the current trend is to refer to this disorder as type 1 diabetes.
Upon physical examination (PE), R.W. appeared calm and responded appropriately to questions. His vital signs were as follows: blood pressure = 185/104 (left arm, sitting); heart rate = 73 bpm; respiratory rate = 18 breaths per minute and unlabored; temperature = 98.4 degrees Fahrenheit (orally). His height was measured to be 5′ 10″ and he weighed 210 pounds (95.5 kg). He was alert and oriented to person, place, and time.
Other pertinent positives findings in R.W.’s PE included conjunctivae that were pale with red streaking noted. The sclera was noted to have a brown patchy pigment above the iris bilaterally. Extraocular movements were intact with no nystagmus noted. Visual fields by confrontation equaled examiners. Visual acuity was determined by the use of the Rosenbaum chart and showed 20/30 in his right eye and 20/25 (+1) in his left eye. Ophthalmoscopic examination revealed a red reflex bilaterally with no evidence of arteriovenous nicking or hemorrhages noted. The patient’s respiratory rate was 18 and unlabored without the use of accessory muscles noted. The anteroposterior diameter was less than the transverse diameter. Breath sounds upon auscultation revealed crackles in the bases bilaterally that cleared upon coughing. A chest x-ray done previously at the patient’s primary care physician’s office was negative. An electrocardiogram (ECG) done in the clinic showed a normal sinus rhythm with no ST depression or signs of left ventricular hypertrophy. A previous echocardiogram of good quality showed a mildly dilated left atrium with normal wall motion and an estimated ejection fraction of 60% with no signs of vegetation. A complete blood count showed a hemoglobin of 13.2 g/dL and a calculated hematocrit of 39.6%. The patient’s pulses were of varying frequency and amplitude with no unusual findings noted. The patient’s hair distribution on his lower extremities was varied from no hair bilaterally half way up to his knee, and then normal distribution was noted with thinning evident. A monofilament test revealed deficiencies of sensation in his feet bilaterally, especially in the heel area. There was no appreciable edema.
Differential diagnoses for R.W. include the following: papillary necrosis, essential hypertension, renovascular hypertension, focal segmental glomerulosclerosis, acute renal failure, acute febrile illness, thin basement membrane disease, congestive heart failure, and nephrosclerosis. Each diagnosis will be discussed separately with the rationale as to why the disorder was ruled out or in based on the case presentation.
This disorder is characterized by a sudden onset of flank pain, hematuria, and occasionally a rising creatinine level (Hostetter, 1992). A urinalysis done in the clinic revealed no red blood cells or casts. A complete blood count showed R.W.’s creatinine level to be increased, yet this disorder was ruled out on the basis of the urinalysis and no complaints of flank pain.
In patients with essential hypertension, renal pressure is elevated and therefore maintenance of the glomerular filtration rate (GFR) is not dependent upon angiotensin II. As a result, an angiotensin-converting enzyme (ACE) inhibitor generally induces little or no change in the GFR. In light of R.W.’s recent onset of hypertension, a GFR of 72 ml/min, and the success of his ACE inhibition (discussed later), this disorder was ruled out.
There were two results which ruled out renovascular hypertension with R.W. First, the renal ultrasound showed no area of stenosis. Secondly, after the initiation of his ACE inhibition, there was a marked improvement in his GFR. Studies have shown that between one-third and one-half of patients with renal artery stenosis will have a decline in GFR after the administration of an ACE inhibitor (Mimran, Ribstein, & DuCailar, 1991).
Focal Segmental Glomerulosclerosis
The most common clinical manifestation of focal segmental glomerulosclerosis (FSGS) is proteinuria. Hematuria is common and is found in 85%-90% of patients. Protein excretion is typically in the nephrotic range (greater than 3.5 g/day). At the time of presentation, hypertension is present in 30%-50% of patients, and renal insufficiency often coexists (Zarif & Sedor, 1999). Focal segmental glomerulosclerosis was ruled out not only by a renal biopsy, but also both by a urinalysis that showed no hematuria and by the proteinuria level being in the microalbuminuric range and not the nephrotic range.
Acute Renal Failure
Diabetic nephropathy is a slowly progressive disorder over a number of years that is characterized by increases in protein excretion and the serum creatinine concentration. R.W. did not experience any of the characteristic findings of acute renal failure such as oliguria, active urine sediment, etc. which would made this diagnosis improbable.
Acute Febrile Illness
Acute febrile illness has been known to increase urinary protein excretion. This disorder is unlikely for two reasons. First, R.W.’s temperature upon assessment was 98.4 degrees Fahrenheit and, secondly, his white blood cell count was in normal range.
Thin Basement Membrane Disease
The hallmark of thin basement membrane disease is microscopic hematuria, although it is usually diagnosed by a renal biopsy. Not only was R.W.’s urine sediment inactive, but his biopsy ruled this disorder out.
Congestive Heart Failure
Early signs of congestive heart failure (CHF) include not feeling well, lingering cold or cough, fatigue, frequent periods of insomnia, decreased appetite, and memory loss. Respiratory symptoms such as dyspnea and paroxysmal nocturnal dyspnea are classic indications of progressive CHF (Yontz, 1994). R.W. displayed none of these signs and symptoms upon assessment and physical examination, making this diagnosis implausible.
Renal insufficiency and proteinuria may be induced by arteriosclerotic vascular disease (nephrosclerosis) in older patients with type 2 diabetes (Gambara, Mecca, Remuzzi, & Bertani, 1993). In addition, after the administration of an ACE inhibitor, there is a rise in the plasma creatinine concentration. R.W has type 1 diabetes and showed improvement after the administration of an ACE inhibitor,making this diagnosis unlikely.
Pathophysiologic Basis of Diagnosis
Proteinuria was recognized in association with diabetes mellitus as early as the 18th century. This form of renal disease, diabetic nephropathy, was further clarified in the 1930s by Kimmelsteil and Wilson when they described the classic lesions of nodular glomerulosclerosis associated with proteinuria and hypertension (Cooper, 1998). It is now clear that diabetic nephropathy is the principal cause of ESRD in the western world. According to reports by the USRDS, in the past two decades there has been a continual increase in the incidence of ESRD among patients with diabetes (NIDDKD, 1998). However, because of the incidence of type 2 non-insulin-dependent diabetes mellitus (NIDDM) being five-fold higher than IDDM, greater than 500/0 of patients in ESRD programs have this form of diabetes (Ritz & Orth, 1999). As is the case of R.W., diabetic nephropathy with proteinuria rarely develops before 10 years duration of diabetes (Breyer, 1998).
Since it is possible to assess patients with IDDM before the onset of overt renal disease, clinical investigators have been able to characterize the development of diabetic renal disease (see Figure 1). The earliest clinical marker is the presence of low (but abnormal) levels of albumin in the urine, termed microalbuminuria. Microalbuminuria is defined as a urinary albumin excretion rate (AER) between 30 mg and 300 mg per 24 hours (equivalent to 20 to 200 micrograms/minute on a timed specimen or 30 to 300 mg/g creatinine on a random sample) (Mogensen et al., 1995). If the urinary AER is elevated in a single sample, at least two more collections should be done to rule out transient elevations due to short-term hyperglycemia, exercise, marked hypertension, heart failure and acute, febrile illness (Mogensen et al., 1995). Some clinicians advocate collecting these samples over a 3 to 6month period to confirm the diagnosis (ADA, 2004).
[FIGURE 1 OMITTED]
The cardinal and pathognomic feature of diabetes is hyperglycemia. Evidence linking hyperglycemia to diabetic end-organ damage has been in existence for many years. Recent trials, notably the Diabetes Control and Complications Trial (DCCT), have shown that the degree of hyperglycemia is a predictor of renal complications, which suggests that hyperglycemia itself may induce renal pathology (DCCT, 1993). Diabetic nephropathy is characterized by the appearance of glomerular and tubular hypertrophy, the subsequent development of glomerular and tubular basement membrane thickening associated with glomerular permeability to albumin, and the eventual accumulation of extracellular matrix (ECM) components in the mesangium and tubulointerstitium. Hyperglycemia induces proximal tubule cell hypertrophy and provokes production of type IV collagen. It also modulates mesangial cell growth and stimulates the production of fibronectin, types I and IV collagen, and laminin (Ziyadeh, Sharma, Ericksen, & Wolf, 1994). Takeuchi et al. (1995) have shown that intermittent hyperglycemia may be just as harmful because it produces a greater effect on collagen production in rat mesangial cells than sustained hyperglycemia. It has been clearly shown that it is the elevation of intracellular glucose and the consequences of an increased rate of metabolism, through enzymatic and nonenzymatic pathways, that accelerate pathological changes. In addition to increased synthesis, hyperglycemia promotes decreased ECM breakdown. For example, Leehey, Hua, Alavi, and Singh (1995) have shown that the activities and mRNA levels of ECM degrading proteinases (collagenase IV and cathepsin B) are decreased in hyperglycemia.
Changes in the glomerular basement membrane (GBM) are believed to contribute to the proteinuria seen in diabetes. The structural basis for the proteinuria remains controversial. One study looked at streptozotocin (STZ)-induced diabetes in rats and proposed a close correlation between selective proteinuria and the relative decrease in heparin sulfate proteoglycan content of the GBM (van den Born et al., 1995).
There is increasing evidence that key biochemical pathways are stimulated by hyperglycemia in renal cells that may contribute to diabetic renal disease. The polyol biochemical pathway has long been suspected as responsible for some complications such as neuropathy and retinopathy (Boel, Selmer, Flodgaard, & Jensen, 1995). Aldose reductase catalyzes the NADPH-dependent reduction of hexase or pentose sugars to their corresponding sugar alcohols, or polyols. Organ dysfunction in diabetes caused by the increased flux of glucose through the polyol pathway has been linked to the hyperglycemia-induced increase in the redox state (high NADH/NAD+ ratio). This appears to be important in de novo synthesis of diacylglycerol (DAG) and the stimulation of protein kinase C (PKC) activity (Williamson et al., 1993). In one study, mice were made to overexpress human aldose reductase in all their tissues, yet pathological changes were found in only those tissues that do not require insulin for glucose uptake (kidney, retina and lens), especially when the mice were placed on a high galactose diet. The authors concluded that their findings suggest that other factors besides the mere presence of aldose reductase are responsible for diabetic complications (Yamaoka et al., 1995).
One of the earliest mechanisms through which hyperglycemia stimulates ECM production is through activation of PKC (Xia et al., 1994). The increased activity of the polyol pathway results in a glucose-induced increase in the ratio of NADH/ NAD+ and favors this reaction. The glycolytic glyceraldehyde-3-phosphate can be converted to dihyroxyacetone phosphate that is then reduced to glycerol-3-phosphate. The latter is metabolized to phosphatidic acid, then DAG. The elevated DAG levels increase the affinity of PKC for calcium and phophatidyl serine, which allows prolonged PKC activation at baseline intracellular calcium levels (Tilton et al., 1992). PKC activation leads to increased production of the Jun/Fos (AP1) transcription factor complex. The observations that the mRNA abundance for both c-fos and c-jun are increased by hyperglycemia in mesangial cell culture and in the glomerulus of the rat support a role for PKC activation in the renal manifestations of diabetes (Sharma, Danoff, DePiero, & Ziyadeh, 1995a).
Hyperglycemia can lead to an increase in reactive oxygen species production as well as to the attenuation of free radical scavenging molecules. Williamson et al. (1993) posit that the oxidative stress produced by a high NADH/NAD+ ratio from hyperactivity of the polyol pathway may be linked to the cellular dysfunction associated with a pseudohypoxic state. They showed in vitro that hyperglycemia can cause lipid peroxidation in isolated rat glomeruli, yet further studies are needed on the pathogenic role of oxidative stress.
Urinary excretion of thromboxane B2 is increased after the onset of diabetes. In 1992, Craven, Melheim, and DeRubertis showed that this correlated with increased urinary albumin excretion, yet they were unable to identify the stimulating mechanism of thromboxane production. In another study done the same year, these authors postulated that the source of increased thromboxane production might be the diabetic glomerulus and/or infiltrating platelets. It has been shown that the addition of thromboxane analogues to mesangial cells in culture results in fibronectin production that seems to be mediated by PKC activation (Studer, Negrete, Craven, & DeRubertis, 1995). Uses of various thromboxane inhibitors are currently in clinical trials.
Transforming growth factor-beta (TGF-beta) is a central cytokine in cell growth and ECM production. TGF-beta has been implicated in many renal diseases, and there is increasing evidence implicating this cytokine in the pathology of diabetic renal disease (Sharma & Ziyadeh, 1995b). It is known that TGF-beta promotes tubuloepithelial cell hypertrophy in the kidney and regulates the glomerular production of collagens, fibronectin, tenascin, laminin, and proteoglycans. Yet, as Roberts, McCune, and Sporn (1992) have shown, it also blocks the degradation of newly synthesized ECM by up-regulating the synthesis of protease inhibitors and by down-regulating the synthesis of matrix-degrading proteases. In addition, these same authors showed that TGF-beta also stimulates the synthesis of the integrins that are the receptors for ECM molecules. The stimulation of collagen synthesis induced by hyperglycemia in mesangial cells has been linked to autocrine activation of TGF-beta, because neutralizing anti-TGF-beta antibodies reduce collagen synthesis (Ziyadeh et al., 1994). Increased TGF-beta expression in the kidney cortex is evident early after the onset of diabetes. Iwano et al. (1996) have shown that glomeruli from kidneys in patients with established diabetic nephropathy overexpress TGF-beta protein, and the increased TGF-beta mRNA levels have a positive correlation with the degree of hyperglycemia. A study by Sharma et al. (1995) showed that nondiabetic patients exhibit a net renal extraction of circulating TGF-beta, whereas diabetic patients exhibit a net renal production of TGF-beta, even before established kidney disease. All the previous data mentioned strongly support the idea that elevated levels and/or activity of TGF-beta in the kidney is the final mediator of diabetic renal hypertrophy and ECM expansion in diabetic nephropathy.
Hyperglycemia and blood pressure are the most important things to control with R.W. Several studies, including the one conducted by the DCCT have indicated that intensified (strict) glycemic control retards the rate of development of both microalbuminuria and overt proteinuria in patients with IDDM (“The Effect of Intensive Diabetes Therapy,” 1995). Previously, it was thought that intensified glycemic control played no part in slowing the progression of proteinuria, yet studies have shown it plays a pivotal role in patients with IDDM, particularly if blood pressure is well controlled (Alaveras, Thomas, Sagriotis, & Viberti, 1997). In addition, the Epidemiology of Diabetes Interventions and Complications (EDIC) study (2003) showed that intensive therapy of glycemic control has the benefit of reducing the onset or progression of diabetic nephropathy that can persist for years compared to less intensive therapy. Patients who progress to ESRD are more likely to have higher hemoglobin Alc values and a higher blood pressure than those who do not progress. One retrospective study measured both albumin excretion and glycemic control in patients with T1DM (Krolewski, Laffel, Krolewski., Quinn, & Warram, 1995). The authors concluded that the risk of having microalbuminuria increases greatly at a Alc value above 8.1%. In contrast, Barzilay et. al. (1992), deduced from their study that the risk is greatest when the Alc level is greater than 12%.
While a 24-hour urine collection is the gold standard for the detection of microalbuminuria, it can be avoided entirely by calculation of the albumin-to-creatinine ratio in an untimed urine specimen. A value above 30 mg/g (or 0.3 mg/mg) suggests that albumin excretion is above 30 mg/day and that microalbuminuria is present (Mogensen et al., 1995). A study done by Nathan, Rosenbaum, and Protasowicki (1987) compared 24-hour urine collections and random, single-void urine specimens. The authors concluded that a random albumin-to-creatinine ratio above 30 mg/g had a sensitivity of 100% for the detection of microalbuminuria. Since most patients simply do not collect 24-hour urine samples correctly (even after proper instruction), the decision was made to use the albumin-to-creatinine ratio. In addition, besides knowing the sensitivity rate of these collections, it was also selected because it is inexpensive to perform. While the urine dipstick method is also relatively inexpensive to perform, it is an insensitive marker for initial increases in protein excretion, not becoming positive until protein excretion exceeds 300 to 500 mg/day (upper limit of normal less than 150 mg) (Russo, Bakris, & Comper, 2002).
Depending on the results of R.W.’s referral to the ophthalmologist, a renal biopsy will be scheduled if the results show a normal fundoscopy. In those patients with a normal fundoscopy, a renal biopsy is the only way to rule out nondiabetic renal disease as a possible cause of urinary abnormalities (Ruggenenti & Remuzzi, 1997). In addition to GBM thickening, other distinctive lesions include nodular (Kimmelstiel-Wilson) and diffuse forms of intracapillary glomerulosclerosis, the capsular drop lesion, the fibrin cap, and mesangial matrix expansion. These changes, along with afferent and efferent arteriolar hyalinosis and increased renal extracellular membrane albumin and immunoglobin G (IgG) localization in the glomeruli, are diagnostic of diabetic nephropathy (Breyer, 1998).
Although a quick assessment using the Cockrofft-Gault formula showed R.W. to have a declining glomerular filtration rate, it was felt this needed to be confirmed with an iothalamate-125 test (the gold standard for determining an accurate GFR). The first renal functional changes in IDDM are an increase in albumin excretion and an elevated GFR (greater than 120 ml/min -1 x 1.73 [m.sup.-2]). Yet, as may be the case with R.W., after 5 to 10 years of diabetes, some patients progress to a stage in which albumin excretion rises further and microalbuminuria develops with little or no change in the GFR (Messent et al., 1992).
It has been shown that hyperglycemia is a major determinant of progression of diabetic nephropathy. Several studies, most notably the DCCT, have indicated that intensified glycemic control retards the development of both microalbuminuria and overt proteinuria in patients with IDDM. However, the role of intensified glycemic control remains controversial. While there is no question that improved glycemic control is beneficial, controversy exists over the glycemic threshold of diabetic nephropathy and whether there is a benefit in patients with a decreased GFR. It appears, from most studies, that fight glycemic control must be instituted early (i.e., before the onset of overt proteinuria) to halt the progression effectively (DCCT, 1993; Bangstad et al., 1994; Rudberg & Dahlquist, 1996). The DCCT of 1995 showed that fight glycemic control was achieved with multiple daily insulin injections and was associated with a 40%-50% decrease in the incidence of proteinuria (Schelling, 1999).
Based on this and other data, R.W.’s insulin prescription was changed to NPH insulin 25 units subcutaneously every morning along with 5 units of regular insulin subcutaneously before breakfast. In addition, every night before the evening meal, R.W. is to inject ultralente insulin 28 units subcutaneously and 5 units of regular insulin. He is to continue to check his glucose levels at home, and based on the results, administer the recommended sliding scale doses of insulin. His primary care physician has already prescribed a glucagon emergency kit for him.
Overall, the benefits of improved glycemic control outweigh the risk of hypoglycemia and increase the quality of life of these patients substantially. It should be remembered that improved glycemic control not only decreases the rates of development and progression of nephropathy but also those of retinopathy, neuropathy, and possibly vascular disease (DCCT, 1993). In lieu of this, the American Diabetes Association (ADA) has put forward glycemic goals of therapy for all patients with diabetes. These include a preprandial glucose of 80-120 mg/dL, bedtime glucose between 100-140 mg/dL, and an Alc of less than 7% (ADA, 2004).
Blood Pressure Control
The next problem to address pharmacologically is R.W.’s hypertension. An increase in blood pressure (BP) has been shown to predict and accompany the development of diabetic nephropathy from the early stages. Studies have shown that a close correlation exists between the onset and degree of microalbuminuria and the onset and degree of hypertension (Barzilay et al., 1992). Mogensen (1982) showed the beneficial effects of conventional antihypertensive therapy in reducing urinary albumin excretion and slowing the decline in GFR in IDDM patients with established nephropathy. ACE inhibitors have been shown to be more effective than other antihypertensive drugs in reducing protein excretion, diminishing the frequency of progression from microalbuminuria to overt proteinuria, and slowing the rate of decline in the GFR (Lewis, Hunsicker, Bain, & Rohde, 1993). The effect of ACE inhibitors on renal function in the hypertensive patient is related both to the glomerular actions of angiotensin II and to the mechanism of autoregulation of the GFR (Braam & Koomans, 1996). Angiotensin II constricts both the afferent and efferent arterioles, but preferentially increases efferent resistance. The net effect of the increase in efferent tone is that the intraglomerular pressure is stable or increased, thereby maintaining or increasing the GFR. In addition to the arteriolar actions, angiotensin II constricts the mesangial cell that tends to lower the GFR by decreasing the surface area for filtration (Denton, Fennessy, Alcorn, & Anderson, 1992).
Once the renal perfusion pressure is lowered, the kidney is initially able to maintain both blood flow and GFR by autoregulation. The first part of the autoregulatory response is decreased afferent arteriolar tone, which allows more of the systemic pressure to be transmitted to the glomerulus. The afferent dilatation is mediated by both the tubuloglomerular feedback and by a direct myogenic response. With continued reduction in renal perfusion pressure, renin release is stimulated. The ensuing increase in angiotensin II production maintains both the intraglomerular pressure and the GFR, increasing the resistance at the efferent arteriole. The net effect is that the GFR and renal blood flow do not begin to decrease until these autoregulatory changes in arteriolar resistance are maximized (Ito, Arima, Ren, Juncas, & Carretero, 1993).
In considering the course of treatment for R.W., it is important to consider the effects of certain antihypertensives on protein excretion. Sympathetic blockers such as methyldopa and guanfacine have little effect on protein excretion (Gansevoort, Sluiter, Hemmsmelder, de Zeeuw, & de Jong, 1995). Betablockers, diuretics, and the alpha-1-blockers (such as prazosin) usually have a lesser antiproteinuric effect. The dihydropyridine calcium channel blockers (e.g., nifedipine and nitrendipine), have a variable effect on proteinuria ranging from an increase to no effect to a fall in protein excretion (Ruggenenti, Perna, Benini, & Remuzzi, 1998). Diltiazem and verapamil are the only drugs that appear to consistently have an antiproteinuric effect as compared to an ACE inhibitor, at least in diabetic nephropathy (Gansevoort et al., 1995). Given their different mechanisms of protection, and, in patients with diabetes, their additive antiproteinuric effects, combination therapy with an ACE inhibitor and a calcium channel blocker will be more effective than either drug alone (Stefanski, Amann, & Ritz, 1995).
R.W. was started on captopril 25 mg by mouth three times a day and verapamil hydrochloride SR 180 mg by mouth every morning. R.W. will be treated with a blood pressure goal of less than 130/85 mm Hg as suggested by the guidelines in the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (ADA, 2004).
The fall in protein excretion induced by ACE inhibitors (and some other antihypertensive agents) may have an additional benefit of lowering plasma lipid levels, which may reduce both the risk of systemic atherosclerosis and the rate of progression of the renal disease. Keilani, Schleuter, Levin, and Baffle (1993) showed that less proteinuria is associated with a 10% to 15% reduction in the plasma levels of total and LDL-cholesterol and lipoprotein (a). While R.W. does not have a family history of CHD and shows no clinical signs of coronary artery disease (CAD), it would be prudent to treat his hyperlipidemia to reduce his chances of CHD and morbidity.
The presence of diabetic nephropathy is associated with higher levels of plasma LDL cholesterol and lower levels of HGL2 cholesterol (Garg, 1994). In experimental animal models, hyperlipidemia has been implicated in causing direct renal injury. It is postulated that the mechanism of this lipid injury includes an accumulation of intraglomerular macrophages; alterations in renal cortical tissue lipids; alterations in membrane fluidity and function induced by alterations in available fatty acid concentrations; and alterations in glomerular hemodynamics (Garg, 1994). In patients with diabetes and proteinuric renal disease, treatment with an 3-hydroxyl-3-methyglutaryl-coenzyme A (HMGCoA) reductase inhibitor can lead to stabilization or improvement in renal function (Rabelink, Hene, Erkelens, Joles, & Koomans, 1990). Because lipidemia is closely related to the progression of cardiovascular disease, a highly prevalent problem in patients with IDDM, lipid-lowering agents are recommended.
R.W. was started on lovastatin 20 mg by mouth with his evening meal and it was reinforced to continue his diabetic diet throughout his therapy. Lovastatin is used as an adjunct to dietary therapy to decrease elevated serum total and LDL cholesterol concentrations. Lovastatin acts by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis (Truong, 2003).
It is well established that high dietary protein intake augments GFR and renal plasma flow, causes intraglomerular hypertension, and accelerates the deterioration of renal function in animal models of renal disease including diabetes (Rodby, Firth, & Lewis, 1996). In clinical studies of humans, most notably the Modification of Diet in Renal Disease Study (MDRD), lower protein diets have been shown to reduce glomerular hyperfiltration, decrease urinary albumin excretion, and slow the rate of decline in renal function. Interestingly, the recommended dietary allowance (RDA) of protein is 0.8 g/kg/day, which is substantially lower than the protein content of the average American diet, which often exceeds 1.5 g/kg/day (Breyer, 1998). Controlled trials have demonstrated that protein restriction (0.6 g/kg/day) slowed the rate of decline in GFR by 60% to 75% from approximately 12 ml/min per year to 3 ml/min per year (Zeller, Whittaker, Sullivan, Raskin, & Jacobson, 1991).
R.W. was placed on a modest protein restriction of 0.6 mg/kg/day (total = 57.3 g/day). A consult was placed to the renal dietitian who provided sample diet plans and discussed any concerns the patient might have. In addition, he was instructed to keep a food diary that would be evaluated when he returned to the clinic.
Patient teaching is a critical component to achieve desired goals as it allows patients to assume increased responsibility for their own care, enhancing therapy and its effectiveness (Rich, 1999). It must be stressed that R.W. has been newly diagnosed with diabetic nephropathy and that his teaching will be continuous throughout his clinic visits to ensure the patient’s adherence to his prescribed regimen. R.W.’s wife will be included, as appropriate, in all teaching to enhance further compliance. The teaching plan will include the effects of exercise in diabetes mellitus, smoking and cardiovascular risks, side effects of his new medications, and necessary information for any specific procedures to be performed.
Although R.W. stated that he is in active military duty, upon further questioning, it was learned that he has a desk job that requires little or no physical activity. Upon calculation, his body surface area (BSA) was found to be 2.17 [m.sup.2] and his body mass index (BMI) was 44 kg/[m.sup.2], which places him at high risk for cardiovascular complications. Also, as mentioned previously, he is very knowledgeable regarding his diabetic diet, but readily admits that he has trouble following this diet. His diabetic diet was reinforced and an explanation of the benefits of exercise was given to R.W.
Exercise has both short and long-term effects on carbohydrate metabolism in patients with diabetes. Koivisto, Fyhrquist, Sane, and Pelkonen (1992) showed that patients with T1DM can tolerate vigorous exercise, including participation in competitive triathlons. R.W. will be scheduled for an exercise stress test prior to starting an exercise program because it is now well established that sudden exercise in sedentary subjects can precipitate a myocardial infarction (Curfman, 1993; Willich et al., 1993). To enhance adherence, the clinician should help the patient choose a type of exercise that he will enjoy, and offer encouragement and suggestions for overcoming barriers to exercise (Calfas et al., 1996).
R.W.’s initial prescribed regimen consisted of 10 minutes of stretching and warm-up, followed by 20 minutes of aerobic exercise such as walking or cycling. He was instructed to perform the exercises at least three times per week and preferably at the same time in relation to his meals and insulin injections. Lastly, he was instructed to gradually increase the duration and intensity of exercise as tolerated.
In regards to his insulin regimen, R.W. was instructed to measure his blood glucose before, during, and after exercise so that any changes in blood glucose can be documented and then predicted for further exercise sessions (McNiven, Temple, Bar-Or, & Riddell, 1995). He is to inject the insulin in a site other than the muscles to be exercised to prevent increased insulin absorption. For example, the arm is a preferred site for cycling. On the other hand, the abdomen is suitable with tennis or racquetball where the exercise involves both the arms and legs. Although absorption of insulin from the abdomen is faster than that from the arm or leg in the resting state, McNiven et al. (1995) showed that this difference is reversed with exercise.
R.W. was instructed to time the insulin injection 60 to 90 minutes before exercise to help minimize the problem of increased absorption. Lastly, R.W. was instructed that 15 to 30 grams of quickly absorbed carbohydrate (such as hard candies or juice) should be taken 15 to 30 minutes before and approximately every 30 minutes during exercise. He is also at risk of developing late hypoglycemia due to the replenishment of depleted glycogen stores; however, this can be avoided by having him ingest slowly absorbed carbohydrates (dried fruit, granola bars, or trail mix) immediately after exercise (Soo et al., 1996). R.W. will be encouraged and supported to participate in regular physical activity to improve his cardiovascular risk factors and prevent any untoward cardiovascular events.
R.W. has made it clear that he is not ready to quit smoking, but this is not an indication to circumvent teaching on the adverse effects of smoking. The health hazards of cigarette smoking are well known. Smoking is an independent risk factor for all-cause mortality, due in large part to cardiovascular disease. Smoking is associated with increases in the plasma concentrations of total cholesterol and VLDL, a reduction in the HDL-cholesterol level, and a greater degree of insulin resistance (Facchini, Hollenbeck, Jeppesen, Chen, & Reaven, 1992). Smokers, through an uncertain mechanism, have poor glycemic control. In patients with type 1 diabetes, smoking is independently associated with an increase in urinary albumin excretion and nonproliferative retinopathy. The degree of albuminuria has been shown to fall to the level of nonsmokers once smoking is discontinued (Chaturvedi, Stephenson, & Fuller, 1995). Mitchell, Hawthorne, and Vinik (1990) showed that smokers with either type 1 or type 2 diabetes are at an increased risk for neuropathy, an effect that persists even after adjusting for glycemic control.
Smoking has been associated with an increased risk of ESRD and with decreased survival rates once dialysis is started (Biesenbach & Zazgornik, 1996). A meta-analysis done by Yudkin (1993) of the cardiovascular risk reduction trials showed that stopping smoking had a greater benefit on survival than most other nonpharmacological interventions. Unfortunately, the magnitude of smoking is often underappreciated. A recent survey by Ford, Malarcher, Herman, and Aubert (1994) found that the prevalence of cigarette smoking was higher among people with diabetes than those without, and that over 25% of people newly diagnosed diabetes were smokers. Moreover, the authors suggested that long-term contact with health care professionals had little impact on smoking status.
At every visit to the clinic, R.W. will be advised, in a brief, clear, and unambiguous manner about the importance of stopping smoking. When he starts to show interest, the staff will assist R.W. by offering self-help material, offering referral to a local support group, and considering nicotine replacement therapy, if needed. Once R.W. has quit smoking, follow-up will be done and positive reinforcement given during the first year after he quits smoking.
R.W. was started on captopril 25 mg by mouth three times a day for management of his diabetic nephropathy. This medication has an added benefit of being an antihypertensive too. As with any new medication, R.W. was instructed to take this medication exactly as prescribed and to not discontinue it without first consulting the clinic. He is to take all doses on an empty stomach (1 hour before or 2 hours after meals) to prevent decreased absorption. Although the risk is less than 1%, hyperkalemia is a reported side effect of captopril. For this reason, R.W. was instructed to not use potassium supplements or salt substitutes containing potassium without first consulting the clinic. It was stressed that this drug does not eliminate the need for the prescribed diet and exercise regimen. The patient was advised to avoid sudden position changes to minimize orthostatic hypotension. R.W. is to immediately call the clinic if he experiences any chest pain or palpitations; mouth sores; fever or chills; swelling of extremities, face, mouth or tongue; skin rash; numbness; tingling, or pain in muscles; difficulty in breathing or unusual cough; or other persistent adverse reactions (Truong, 2003).
Although R.W. is aware of the side effects of insulin therapy, it was reinforced to him that this medication is used to control his diabetes and it is not a cure. He was reminded again to follow his prescribed diet and exercise regimen. The patient was asked to contact the clinic immediately should he experience a hypoglycemic reaction. He was reminded to carry a quick source of sugar at all times. In addition, R.W. was asked to report any adverse effects (Truong, 2003). Lastly, R.W. was reminded of the importance of rotating sites of injections to avoid atrophy, along with the importance of daily monitoring of his blood glucose levels.
R.W. was prescribed the sustained release form of verapamil. It is important that R.W. know not to crush or chew the extended release form. The patient was instructed to report any signs of heart failure, such as swelling of the hands and feet or shortness of breath. In addition, the importance of good oral hygiene was relayed to the patient due to the possibility of verapamil-induced gingival hyperplasia (Truong, 2003).
The last new drug R.W. was started on was lovastatin to help decrease his signs of hyperlipidemia. His liver function profile was shown to be normal before initiation of therapy. R.W. was instructed to take this medication with his evening meal because the highest rate of cholesterol synthesis occurs from midnight to morning. However, if he should experience any sleep disturbances, he can take the medication earlier in the day. The patient was reminded of the importance of regular ophthalmic examinations to check for cataracts. He was instructed to notify the clinic if he experienced severe gastrointestinal disturbances (mild disturbances are common) or if he experienced severe muscle pain or tenderness accompanied with malaise, chest pain or blurred vision (Truong, 2003). R.W. was urged to adhere to a cholesterol-lowering diet and he and his wife were given a handout of foods high in cholesterol.
When having R.W. return to the clinic for random albumin-to-creatine ratio measurements, two important caveats must be relayed to him to maximize the reliability of the test.
First, vigorous exercise can cause a transient increase in albumin excretion. Therefore, he should refrain from vigorous exercise for at least 24 hours before the test. Lastly, the slope of the relationship between the spot urine and the 24-hour collection varies throughout the day. The correlation is best if samples are taken in the mid-morning, although mid-afternoon specimens have been shown to be relatively accurate (Jefferson et al., 1985).
Although fundoscopy revealed normal findings without any signs of retinopathy in the clinic, it would be prudent to refer the patient to an ophthalmologist who is better trained and equipped to make this diagnosis. Direct ophthalmoscopy by well-trained personnel is an accurate and cost-effective method of screening for diabetic retinopathy (Javitt et al., 1994). ADA guidelines currently recommend annual screening for patients with diabetes by a trained ophthalmologist (ADA, 2004).
The social worker was consulted to help obtain a home blood pressure monitor for R.W. Records of home blood pressures help the clinician to monitor the patient’s response to medications more accurately (Schoenberger & Krakoff, 1997). The social worker also gave R.W. information on exercise rehabilitation programs as well as smoking cessation clinics in his area.
R.W. was referred to the diabetic foot clinic for measurement of his feet to obtain proper fitting shoes for exercise and everyday life. He was instructed on proper foot care and the importance of wearing the shoes to prevent the complications of diabetic neuropathy. Foot problems due to vascular and neurologic disease are a common and important source of morbidity in patients with diabetes (Del Aguila, Reiber, & Koepsell, 1994).
R.W.’s diet regimen is very complex, so a dietitian was consulted to incorporate his current diabetic diet with his new restriction on cholesterol and protein. Sample diets were given to R.W. and his wife to take home. Constant education, reinforcement, and encouragement by all of the clinic staff are essential for maintaining adherence to this complex prescribed regimen.
Evaluation and Follow-up
R.W’s referral to the ophthalmologist revealed a normal fundoscopy as suspected in the clinic. In order to confirm the diagnosis of diabetic nephropathy, R.W. was scheduled for a renal biopsy. The findings, by immunofluorescence microscopy, were diagnostic of diabetic nephropathy. In addition, on the day R.W returned for his biopsy, another spot urine done in the clinic was consistent with previous findings. R.W.’s biopsy showed a thickened GBM, epithelial foot-process fusion and ECM expansion. There was no evidence of tubular atrophy or interstitial fibrosis that is observed in advanced disease (Schelling, 1999). The results of R.W.’s exercise (treadmill) test showed no changes in his electrocardiogram pattern and he experienced no hypotension while performing the test.
Patients with diabetes are prone to develop hyperkalemia with the institution of ACE inhibitors, so R.W. was instructed to return to the clinic in 1 week to check his BUN, serum creatinine, and potassium level at which point any adjustments could be made to his therapy. Other labs to monitor with the use of ACE inhibitors include urine dipstick for protein and complete leukocyte count as captopril may cause agranulocytosis (Lewis et al., 1993).
Lovastatin may elevate the aminotransferases and can also cause myalgia and rhabdomyolysis. R.W. was instructed to return to the clinic in 4 weeks to monitor his liver function profile. He is to return every 4 to 6 weeks thereafter for the first 12 to 15 months of therapy and periodically thereafter (Lewis et al., 1993). R.W. was instructed on the side effects of his antihypertensive medications and was supplied with a home blood pressure monitor. He was given a diary to record his blood pressure measurements at home that will be checked every time he returns to the clinic.
Anticipated Physiologic Outcomes/Complications
Atherosclerosis is accelerated in patients with diabetes, and cardiovascular events account for most of the mortality in these patients. Patients with diabetes have an increased risk of atherosclerosis because of the presence of diabetes and other risk factors, including obesity, hypertension, dyslipidemia, and smoking. Stopping smoking (by far the greatest benefit), and aggressive treatment of hypertension and the commonly associated lipid abnormalities could achieve a substantial reduction in cardiovascular mortality. Therefore, implementation of the American Diabetes Association guidelines for nutrition and the pharmacological management of dyslipidemia should be implemented (ADA, 1994 a). R.W’s probability of developing coronary artery disease over the next 12 years was estimated from risk factors according to data obtained from the Framingham Heart Study (Anderson, Wilson, Odell, & Kannel, 1991). The results showed a 6.9% probability in the next 4 years that increases to 22.0% by the 12th year.
Congestive Heart Failure
The Framingham Study firmly established the link between diabetes and congestive heart failure (Anderson et al., 1991). The presence of congestive heart failure is associated with decreased survival, and the risk is even greater in patients with diabetes. A report by the Studies of Left Ventricular Dysfunction (SOLVD) showed that patients with diabetes, when compared to those who did not have diabetes, were admitted more often for congestive heart failure and had a higher rate of all-cause mortality, cardiovascular mortality, and mortality related to pump failure (Shindler et al., 1996).
Autonomic neuropathy is a common complication in diabetes. It carries a high risk of cardiovascular morbidity and mortality. The effect of near-normal glucose control in patients with diabetic peripheral neuropathy has been demonstrated by the DCCT, yet autonomic function is resistant to the return of normoglycemia with studies showing only a slower deterioration over time rather than an improvement in autonomic function (Burger, Weinrauch, D’Elia, & Aronson, 1999). Unfortunately, there is no effective treatment for diabetic neuropathy, and with the patents soon ending for most of the current ACE inhibitors, it is likely that this goal will not be attained (Malik, 2000).
Retinopathy is the most common microvascular disease in patients with diabetes. The DCCT has demonstrated that intensive insulin therapy is beneficial in the primary prevention of diabetic retinopathy, yet strict glycemic control is of little or no benefit in advanced retinopathy (Wang et al., 1994). As mentioned previously, patients with established retinopathy should be closely followed by an ophthalmologist that is experienced in the management of diabetic retinopathy.
The key to preventing this painful complication is strict glycemic control. The first evidence to support this came from a report of nine patients with painful neuropathy in which intensive therapy led to symptomatic improvement in all of the patients treated (Boulton, Drury, Clarke, & Ward, 1982). Since that time, several subsequent studies, notably the one conducted by the DCCT, have confirmed the ability of strict glycemic control in relieving symptoms and improving neurologic function (DCCT, 1993).
Unless R.W. adheres to the prescribed regimen, there is little hope for therapeutic success. He has been given a lot of new information, and it is difficult to modify life-long habits and make the necessary changes needed in one’s current lifestyle patterns. Among the characteristics of patients at greatest risk for noncompliance are those with a complicated regimen and those who experience adverse reactions to their medications. R.W., along with his wife, will require continued reinforcement and education with each clinic visit. This step is critical in preventing complications (Sehoenberger & Krakoff, 1997).
Morbidity and Mortality
Diabetes and hypertension are both independent risk factors for cardiovascular disease and, when coexistent, increases the risk two to eight fold for cardiovascular morbidity and more than doubles it for cardiovascular mortality (Sowers & Epstein, 1995). Although it is difficult to predict the course of R.W.’s disease, a multidisciplinary approach will be used in an effort to prevent the sometimes-devastating complications of his disease.
Potential future benefits of pancreas transplantation. In the United States, more than 900 pancreas transplantations are done each year. Ninety percent are performed in conjunction with a kidney transplantation in patients with type 1 diabetes and renal failure (Gruessner & Sutherland, 1997). Unfortunately, few studies have been done that show the effects of pancreas transplantation on diabetic nephropathy in patients without uremia. However, one recent study has suggested that successful pancreas transplantation can reverse diabetic nephropathy in native kidneys (Fioretto, Steffes, Sutherland, Goetz, & Mauer, 1998). The clinicians looked at patients with type 1 diabetes without uremia who had a pancreas transplant. At 5 years post-transplant, the patients showed no improvement in urinary AER and glomerular mesangial volume; however, after 10 years, both of these parameters had decreased substantially. Since R.W. is showing improvement in his clinical status, it was felt that the potential risks of surgery and immunosuppression outweighed the benefits of this procedure. However, should uremia leading to ESRD become imminent in the future, this would be another option to consider for treatment of his diabetic nephropathy. In addition, consideration for this procedure would be made should R.W. develop hypoglycemic unawareness (Fioretto et al., 1998).
R.W. continued to be seen in the clinic as scheduled. His treatment with captopril showed a marked improvement in his GFR. The GFR increased by 23 ml/minute making it 95 ml/minute. His urinary AER began to decline and his lipid profile began to improve. His blood pressure was eventually lowered to 142/89 mm Hg (a substantial improvement from baseline), yet it was decided to continue his regimen to achieve the target goal of less than 130/85 mm Hg. The patient admits to increasing his level of activity, but he also admits to occasionally cheating on his diet, attributing the cheating to too many restrictions. The neuropathy in his feet has remained stable with no further progression. He continues to keep his appointments with the ophthalmologist and has no signs of retinopathy. His serum creatinine and BUN have decreased to an acceptable range, which will hopefully avoid any need for future dialysis. R.W. continues to smoke one pack of cigarettes per day, yet his education on this subject will continue with every visit to the clinic.
There are many patients with diabetes, like R.W., who progress to diabetic nephropathy which is often not discovered until overt nephropathy is present. There is a lot of debate whether care provided by primary care physicians differs from that provided by specialists. The majority of patients with diabetes (greater than 90%) receive their care from primary care physicians, yet specialists have been found to be more knowledgeable about efficacious interventions and tend to adopt new approaches more quickly (Markson, Cosler, & Turner, 1994). Whatever approach is used, organized, planned, proactive, population-based programs should substantially improve outcomes and reduce costs for diabetic patients (Wagner, 1995). Many of the complications of diabetes could be minimized if patients received a comprehensive health maintenance program that includes vigorous cardiac risk reduction; routine eye examinations; routine foot examination; screening and treatment for microalbuminuria; optimal hypertension management, and improved glycemic control. In the case of R.W., examination of his urine revealed microalbuminuria along with an elevated serum BUN and creatinine that prompted a quick referral to the nephrology clinic, which has proven efficacious in R.W.’s treatment. Hence, the key is not only prudent screening of these patients, but referral as well.
[FIGURE 2 OMITTED]
This Offering for 2.5 contact hours is being provided by the American Nephrology Nurses’ Association(ANNA). ANNA is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. ANNA is a provider approved by the California Board of Registered Nursing; provider number CEP 00910.
The Nephrology Nursing Certification Commission (NNCC) requires 60 contact hours for each recertification period for all nephrology nurses. Forty-five of these 60 hours must be specific to nephrology nursing practice. This CE article may be applied to the 45 required contact hours in nephrology nursing.
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Troy A. Russell, MSN, RN, APRN, BC, CNN, is a Nephrology Nurse Practitioner, The VA Medical Center, Nashville, TN. He is Chairperson, Certification Committee, and Chairperson, CNN Test Committee, for the Nephrology Nursing Certification Commission (NNCC). He is a member of the Music City Chapter of ANNA.
Diabetic Nephropathy in Patients with Type 1 Diabetes Mellitus
Posttest-2.5 Contact Hours Posttest Questions
(See posttest instructions on the answer form, on page 30.)
1. In the case presentation, which differential diagnosis(ses) were eliminated based on R.W.s glomerular filtration rate (GFR) increase with the initiation of an angiotensin-converting enzyme (ACE) inhibitor?
A. Essential hypertension only.
B. Essential hypertension and renal vascular hypertension only.
C. Essential hypertension, renal vascular hypertension, and nephrosclerosis only.
D. Essential hypertension, renal vascular hypertension, nephrosclerosis, and focal segmental glomerulosclerosis.
2. The earliest clinical marker of kidney disease in diabetes mellitus type 1 is
3. Which statement is true concerning the pathophysiology of diabetic nephropathy?
A. Diabetic nephropathy is characterized by nodular glomerulosclerosis.
B. Hyperglycemia has little effect on renal pathology.
C. Hypertension is the key contributor to glomerular basement membrane changes.
D. Extracellular components in the mesangium contribute to the development of microalbuminuria.
4. What are the most important thing(s) to control with R.W. in slowing progression of kidney disease?
A. Blood glucose only.
B. Blood glucose and blood pressure only.
C. Blood glucose, blood pressure, and cholesterol only.
D. Blood glucose, blood pressure, cholesterol and smoking cessation.
5. You are testing R.W.’s level of microalbuminuria. You would
A. Measure a 24-hour urine only.
B. Measure a 24-hour urine or calculate microalbumin-to-creatinine ratio in a random urine specimen only.
C. Measure a 24-hour urine or calculate microalbumin-to-creatinine ratio in a random urine specimen or, perform a urine dipstick only.
D. Measure a 24-hour urine or calculate microalbumin-to-creatinine ratio in a random urine specimen or, perform a urine dipstick or perform a urinalysis.
6. An ACE inhibitor was used to treat R.W.’s hypertension because it is more effective than other antihypertensives in
A. reducing protein excretion only.
B. reducing protein excretion and slowing rate of decline of GFR only.
C. reducing protein excretion, slowing rate of decline of GFR, and improving glycemic control only.
D. reducing protein excretion, slowing rate of decline of GFR, improving glycemic control, and slowing progression of retinopathy.
7. You are talking with R.W. about his insulin regime and beginning and exercise program, which will include walking on the treadmill. You instruct R.W. to
A. “Take your insulin injection immediately prior to beginning exercise.”
B. “Eat a candy bar immediately prior to beginning exercise.”
C. “Inject your insulin in your leg to promote faster absorption.”
D. “Ingest trail mix or granola bar immediately after exercise.”
8. R.W. continues to smoke. Your discussion with him about the adverse effects of smoking include:
A. increased mortality only.
B. increased mortality and increased total cholesterol only.
C. increased mortality, increased total cholesterol, and poorer glycemic control only.
D. increased mortality, increased total cholesterol, and poorer glycemic control, and increased risk of neuropathy.
9. What statement is true about the anticipated physiologic outcomes or complications of diabetes mellitus?
A. Atheroscelrosis is accelerated in patients with diabetes mellitus.
B. There is no increased risk of development of congestive heart failure in patients with diabetes mellitus.
C. Autonomic neuropathy improves with tight glycemic control.
D. Peripheral vascular disease is the most common microvascular disease in patients with diabetes mellitus.
10. R.W.’s compliance with his treatment regime might improve more if you
A. Give him a list of his complicated medication regime.
B. Closely monitor him for medication reactions.
C. Reinforce education annually.
D. Refer him to a dietician to discuss the many dietary restrictions.
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