Course Authors

Eli A. Friedman, M.D.

Within the past three years, Dr. Friedman has received grant/research support from Alteon.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Discuss how renal failure in a person with diabetes may result from causes other than diabetic nephropathy

• Discuss the occurrence of causes of renal disease other than diabetic nephropathy in diabetic persons and enumerate the varied therapeutic options open to the uremic diabetic patient

• Describe early perturbations in diabetic nephropathy

• Discuss the significance of renal functional changes in early (incipient) diabetic nephropathy

• Evaluate the comparative risk/benefit of pancreas transplants as a therapeutic option for uremic individuals with type 1 diabetes.

 

This Cyberounds^® presentation starts not with educational objectives but, instead, with five cases. After each case, we will focus on the educational objective and its discussion. Hopefully, in this way, the presentation will be more of a learning experience.

Case #1: Assessing Synthesis

A 56-year-old African-American man with known hypertension for 14 years entered the emergency room complaining of anxiety, persistent dyspnea at rest and increasing leg swelling for two weeks. He had been treated intermittently with a variety of antihypertensive medications but had not seen a physician for seven months. Approximately three years ago, after a "routine" employment evaluation, the patient was advised that he had diabetes but neither hypoglycemic treatment nor a dietary regimen had been prescribed. Other than reliance on corrective lenses for myopia, the patient had no complaints referable to vision impairment. His mother died of "diabetic complications" at the age of 53 and a 51-year-old sister was under treatment with insulin for diabetes diagnosed at the age of 47.

The patient's vital signs were:

On initial evaluation, the patient was restless and in respiratory distress. The neck veins were distended and there was 3+ pitting edema up to the knees bilaterally. Funduscopic examination after pupillary dilation discerned marked arteriolar narrowing without hemorrhages or exudates. Examination of the chest disclosed flatness to percussion in both lung bases with moist rales up to the 4^th rib bilaterally. The heart was enlarged to the left anterior axillary line with regular rhythm and no murmurs.

Laboratory studies:

Chest roentgenogram showed diffuse cardiomegaly with left ventricular predominance and bilateral pleural effusions. An electrocardiogram documented left ventricular hypertrophy without evidence of ischemia.

Discussion

Although approximately 40% of all new cases of end stage renal disease (ESRD) in the United States occur in people with diabetes, the high prevalence of diabetes means that all forms of kidney disease may occur as unrelated coincident disorders. This patient has two key findings that are highly atypical in patients with ESRD secondary to diabetes: 1) absence of diabetic retinopathy and 2) normal serum albumin concentration.

Though cursory examination of the optic fundi may miss early diabetic retinopathy, approximately 96% of individuals whose ESRD is caused by diabetes will have advanced retinopathy and/or vision loss at onset of uremia. Suspicion of an alternative cause of renal malfunction should be stimulated by the absence of a history of laser photocoagulation.

Diabetic nephropathy follows a characteristic sequence of urinary perturbations that begins with macroalbuminuria and is followed by proteinuria, azotemia and ultimately, ESRD. Recent longitudinal observational studies of populations of diabetic individuals indicate that these stages occur in both type 1 and type 2 diabetes. At presentation of renal failure caused by diabetic nephropathy, a nephrotic syndrome (proteinuria >3.5 g/day and hypoalbuminemia) is usual. A normal serum albumin concentration is reason to doubt the diagnosis of ESRD attributable to diabetes.

With the hematocrit at 24%, there is no reason to suspect acute renal failure because profound anemia usually takes three weeks to decrease the hematocrit below 25%. Prerenal azotemia only rarely increases the serum creatinine concentration above 3 mg/dl and is not associated with anemia. Intravascular volume contraction in diabetic patients with heart failure is frequent but is the result of excessive use of diuretics such as furosemide or metolazone. Diabetic cystopathy, an unlikely explanation for the patient's findings, does produce a functional urinary outflow obstruction but is generally a late complication of diabetes and is associated with other components of autonomic neuropathy.

Nephrosclerosis (pathologic changes of atherosclerosis in renal arteries and glomeruli) is a common finding in hypertensive individuals who progress to ESRD. Vascular occlusion caused by atherosclerosis is noted in medium and small size renal arteries. Glomeruli underperfused by atherosclerotic renal vessels undergo obliteration as years of hypertension continue. Proof that hypertension, per se, causes renal failure is incomplete. In the present patient, however, long standing hypertension, left ventricular hypertrophy, hypercholesterolemia and inadequate treatment are the hallmarks of renal functional deterioration with the vascular findings termed nephrosclerosis.

Case #2: Assessing Judgment

A 57-year-old Caucasian woman with known type 2 diabetes for 17 years is admitted for complaints of progressive fatigue, anorexia, nausea and weight loss, diminished ability to concentrate and insomnia. The patient had declined fingerstick glucose monitoring and had consistently had a hemoglobin A1c above 10%. Her physician had detected proteinuria two years earlier. An eye doctor, one year previously, reported that she had "blood in the eyes" but the patient declined follow up testing.

The vital signs were:

Physical examination found the patient alert, well-developed, cooperative and mildly depressed. There was evidence of muscle wasting in the temporal muscles, arms, legs and hands. Bilateral 3+ pitting edema was present in the ankles and calves. Visual acuity was 20/100 in both eyes. Both fundi had microcapillary aneurysms, punctate and flame hemorrhages, and wooly exudates. Patella and ankle reflexes were absent and there was diminished sensation in a glove stocking distribution.

Laboratory studies:

Chest and abdominal roentgenograms are normal. An electrocardiogram showed a constant RR interval without respiratory variation but was otherwise unremarkable.

Discussion

Debate in the literature suggests that the proportion of renal biopsies with renal findings other than diabetic nephropathy obtained in diabetic patients ranges from under 5% to as high as 40%.

The diagnosis of diabetic nephropathy explains the renal failure. Consistent with this diagnosis are the decreased serum albumin resulting from years of proteinuria and the finding of diabetic retinopathy which is present in 96% of diabetic individuals who progress to renal failure secondary to diabetic nephropathy. The high total cholesterol and hypoalbuminemia suggest that proteinuria in excess of 3.5 g/day is continuing. A renal biopsy is not needed for diagnosis in typical cases such as this.

Urgent hemodialysis or peritoneal dialysis is applied to patients at risk of serious complications of uremia such as hyperkalemia, pericardial hemorrhage and tamponade, neuromuscular irritability presaging seizures or an uncontrolled bleeding tendency. The patient's serum potassium was normal and the electrocardiogram did not disclose changes as the result of hyperkalemia.

Surgery to create an arteriovenous limb fistula prejudges and forecloses the patient's choices. At the time of detailed discussion of the admission findings, the patient may be advised of the possibility of preemptive (no intervening dialytic therapy) kidney transplantation from a suitable intrafamilial or other potential live donor as well as the relative merits of peritoneal dialysis and hemodialysis. While the patient is clearly suffering from advanced kidney failure, there is time to think and plan incorporating the patient, family members, and others in the formulation of a long-term strategy.

Case #3: Recall

A 23-year-old man with type 1 diabetes with onset at age 14 is found at initial evaluation to have a urinary albumin excretion of 56 mg/24 hr and an endogenous creatinine clearance of 159 ml/min. His height is 5'8" and his weight 157 lbs.

The vital signs were:

Physical examination found the patient alert, well developed, slender and cooperative. There were no abnormal physical findings. Reflexes were brisk and normal bilaterally. The fundi were well visualized and normal.

Laboratory studies:

Discussion

Healthy people excrete less than about 25 milligrams of albumin in their urine each day. Microalbuminuria, defined as an albumin excretion rate of 30 to 300 mg per day, occurs in about 4-15% of adult individuals with diabetes, typically in those who have had the disease for at least five years.

Hyperfiltration is defined as a higher than normal glomerular filtration rate (GFR). Nondiabetic individuals fed a high protein meal may raise their GFR to its reserve capacity and thereby exhibit hyperfiltration until the meal is digested. Diabetic individuals who are hyperglycemic may manifest hyperfiltration until morphologic damage to the glomerulus prevents GFR increase to the reserve level. After weeks of careful metabolic regulation, hyperfiltration in people with type 1 diabetes disappears, while the nephromegaly typical of early diabetes reverts to normal.

The finding of hyperfiltration has not been linked to any specific renal pathologic change and is not predictive of progressive nephropathy. Either hyperfiltration or normal glomerular filtration may be present with microalbuminuria.

The importance of early discovery of microalbuminuria lies in the predictive value of its detection -- in both type I and type II diabetes -- those with microalbuminuria are many times more likely to progress to the later stages of kidney disease. Furthermore, people with microalbuminuria may slow the course of nephropathy for many years by normalizing blood pressure plus good blood glucose control.

To find microalbuminuria, a specific laboratory test must be requested because the usual urine dipsticks or clinic tests for protein are not sufficiently sensitive. Introduction of dipsticks for microalbuminuria (Microalb^®) permit rapid screening. The first morning specimen of urine has been found most reliable. If positive, a 24-hr urine specimen should be checked for total albumin content which can then be compared after treatment.

While hyperfiltration is silent (no signs or symptoms), changes in biopsies of the kidney in those with hyperfiltration may document alterations in small blood vessels and in the anatomy of glomeruli that are unique to diabetes. The key importance of finding microalbuminuria is that it signals the need for treatment with an angiotensin converting enzyme (ACE) inhibitor, which has been shown to both reduce the amount of urinary albumin and slow the loss of glomerular filtration rate.

Trials in progress are assessing the relative value of ACE inhibitors, calcium blockers and other antihypertensive drugs in retarding progression of diabetic nephropathy. Recently reported, The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) were conducted in patients in advanced stages of diabetic nephropathy. Two other studies -- the Irbesartan Microalbuminuria Study (IRMA)-2 and the Microalbuminuria Reduction with Valsartan study (MARVAL) -- were trials conducted in patients with type 2 diabetes with microalbuminuria.(7),(8),(9),(10),(11),(12),(13),(14),(15),(16),(17),(18),(19),(20)

These trials bear a common theme: does an angiotensin receptor blocker (ARB) interfere with the natural history of diabetic nephropathy in a blood pressure-independent fashion? Results clearly substantiate that ARBs forestall deterioration in renal function, which is otherwise inevitable in untreated diabetic nephropathy. Added to the broad evidence supporting angiotensin-converting enzyme (ACE) inhibitor use in nephropathy associated with type 1 diabetes, it may be concluded that diabetic nephropathy should be managed with a drug that interrupts the renin-angiotensin system. 

Unresolved, however, is the question as to whether an ACE inhibitor or an ARB is preferable. An evidence-based therapeutic approach from completed trials suggests that ARBs be the foundation of therapy in the patient with type 2 diabetes and nephropathy.

This patient meets the definition of both microalbuminuria and hyperfiltration and thus has incipient diabetic nephropathy. The abnormally high hemoglobin A1c is reason to strive for better metabolic control, reducing the level to the desired <7%.

Case #3: More Recall

Discussion

Defined as a urinary albumin excretion of 30 to 300 mg/day, microalbuminuria is a marker for that subset of both type 1 and type 2 individuals with diabetes who are likely to progress to overt proteinuria (>500 mg/day), a nephrotic syndrome (3.6 g/day) and, ultimately, renal failure. While microalbuminuria has been reported in essential hypertension and various kidney disorders other than diabetic nephropathy, its discovery clearly identifies those diabetic individuals at risk for renal deterioration. Additionally, microalbuminuria in type 1 diabetes has been linked to the likelihood of subsequent progressive proliferative retinopathy.

Clinical trials with captopril, enalapril and lisinopril in hypertensive patients with type 1 and type 2 diabetes show that treatment with an angiotensin converting enzyme inhibitor reduces proteinuria and slows renal functional deterioration (GFR decrease). Consensus statements from the American Diabetes Association and others urge that hypertensive diabetic people with microalbuminuria be started on treatment with an angiotensin converting enzyme inhibitor.(21) A recent multicenter trial of the value of treating nonhypertensive type 1 diabetic people with an angiotensin converting enzyme inhibitor found that preservation of glomerular filtration rate and a reduced rate of proteinuria resulted. It is now a standard of practice to test for microalbuminuria in all diabetic people who have a negative screening test for proteinuria whether or not they are hypertensive.

Microalbuminuria precedes and does not follow the nephrotic syndrome. The cause of microalbuminuria, though still speculative, is a change in permeability in injured glomerular mesangial cells and surrounding glomerular basement membrane and is not a consequence of reduced glomerular filtration rate.

Case #4: Final Judgment

A 43-year-old woman with uremia attributed to nephropathy in type 1 diabetes is weighing the risks and benefits of a pancreas plus kidney transplant from a cadaver donor versus a proffered intrafamilial kidney from her healthy 41-year-old nondiabetic brother. Should she opt to receive her brother's kidney, no intervening dialytic therapy would be necessary. By contrast, the decision to wait for a cadaver organ donor will necessitate initiating dialytic therapy. Following panretinal photocoagulation in both eyes three years earlier, proliferative retinopathy regressed and vision stabilized at 20/40 bilaterally. A dobutamine stress test one month ago showed no evidence of cardiac dysfunction.

The vital signs were:

Height 5'4", weight 137 lbs. Physical examination noted the patient to be slightly obese, alert, well-developed and cooperative. Examination of the chest and abdomen was negative. The heart was unremarkable. There was 1+ ankle edema bilaterally. Reflexes were absent below the knees bilaterally. Neither dorsalis pedis nor posterior tibial pulses were felt.

Laboratory studies:

Discussion

Although outcome has greatly improved over the past five years, combined pancreas plus kidney allograft recipients have about a 10% greater first-year mortality than do recipients of a solitary cadaver donor kidney. When compared with recipients of intrafamilial live donor kidney transplants, the disparity is even greater. Continuing patient and graft loss over the first three years are greater for dual organ recipients than for solitary kidney recipients.

Longer hospital stays, repeated surgical re-exploration and at least double the cost are other drawbacks of pancreas transplants as currently practiced. The risk of excess surgical morbidity is sufficient to restrict pancreas transplants to recipients younger than age 45 with organs obtained from donors younger than age 45. On the positive side, life quality with a functioning pancreas, i.e., de facto cure of diabetes so long as the pancreas normalizes glucose, is regarded as so advantageous to recipients that they endorse the rigors and risks of the procedure.

Hemodialysis or peritoneal dialysis before a kidney transplant afford no advantage. Indeed, mortality of diabetic patients during maintenance dialysis of either type is at least double that of age-matched renal allograft recipients. Reports based on small series of patients suggest that diabetic neuropathy improves after a pancreas transplant.(22) Reversal of nodular and diffuse intercapillary glomerular sclerosis in native kidneys has been noted in several nonuremic diabetic type 1 pancreas recipients after a decade.