Diabetic Nephropathy
- Misreading the Tea Leaves?
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
One
of the most feared complications of diabetes is kidney disease,
also called diabetic nephropathy (DN). DN is the leading cause
of end-stage renal disease in the U.S., and the incidence of
DN is poised to double over the next ten years due to the rapid
rise in the number of cases of diabetes, particularly type 2
diabetes. The expected cost of this problem is expected to top
$28 billion. Keep in mind that this is not the cost of treating
diabetes per se, but only this single complication. This is
a BIG issue.
Most of what we know about DN
comes from observations made in patients with type 1 diabetes,
and we have tended to extrapolate what we have learned from
that condition to type 2 diabetes. As we will see, this may
not have been a completely valid approach. At any rate, the
course of DN is believed to begin with the spillage of small
amounts of a blood protein called albumin into the urine. The
kidney contains millions of structures called glomeruli; you
can think of each glomerulus as a filter, similar to the fuel
or air filters in your car. Water, salt, and other small molecules
can pass freely into the urine, but larger things, like red
blood cells and proteins, are kept in the bloodstream. In diabetes,
the filtering function of the glomeruli fails, and albumin begins
to show up in the urine. At this stage, the problem is called
microalbuminuria. Over time (usually years), if things go untreated,
progressively more protein will get through the filters until
a level is reached called macroalbuminuria, or overt nephropathy.
Despite the leaky filters, up
to this point the kidneys are still functioning fine, in that
they are clearing the blood of toxins that build up during metabolism.
Once you reach a state of overt nephropathy, however, things
tend to go south, and many folks (but not all) will experience
a progressive loss of kidney function until end-stage renal
disease occurs. From that point on, patients will require dialysis
or kidney transplantation to survive.
In the clinic, we screen for
the appearance of DN and monitor its progression by measuring
albumin levels in the urine, using either “spot”
urines (collected in a cup at the time of the visit), or more
accurately, timed collections that range from 4 to 24 hours.
We do this because (a) monitoring the course of DN can help
patients and physicians prepare for the possibility of end-stage
renal disease, (b) cardiovascular complications of diabetes
are more common and more severe in patients with DN, and (c)
there are things you can do to prevent DN from showing up, or,
if already present, from getting any worse. For example, it
has been shown that tight blood glucose control can prevent
the onset of DN or delay its progression. Similarly, careful
attention to blood pressure control is also important, as are
two specific classes of antihypertensive agents called ACE inhibitors
(ACE-I) and angiotensin receptor blockers (ARBs). Interestingly,
these drugs appear to be useful in DN even if the patient does
not have high blood pressure. Finally, there is some evidence
that eating a protein-restricted diet can reduce the progression
of DN, although this is less well supported than the other strategies.
In the last few weeks, two new
studies have appeared that question some of the most basic assumptions
that we have had about DN. There is good news and bad news,
and because I prefer getting bad news out of the way first,
we’ll start with a study just published in the Journal
of the American Medical Association (JAMA). This report looked
at a little over a thousand adults with type 2 diabetes, and
asked what percentage of them had a serious loss of kidney function
without showing the telltale signs of protein in the urine that
define DN. Thirteen percent of these folks had a serious reduction
of kidney function. What was amazing, however, was that roughly
a third of those unlucky 13% had no evidence of albumin in their
urine, which means that they would have been missed by our current
screening approaches. Furthermore, in type 1 diabetes, the presence
of DN is almost invariably associated with diabetic retinopathy,
or eye disease. In these patients with type 2 diabetes, however,
that was not the case, with only 28% of the patients with kidney
damage showing signs of retinopathy. The authors interpret these
results to indicate that the classic pathological mechanisms
that cause DN in type 1 diabetes may not explain what’s
going on type 2 diabetes. Other insults that might be contributing
to the loss of kidney function in type 2 diabetes could include
age-related changes, atherosclerosis of the arteries leading
to kidneys, or possibly cholesterol emboli. This latter condition
occurs when little fragments of cholesterol-laden plaques inside
blood vessels break off and clog small arteries in the kidney
(or elsewhere), leading to lack of proper blood flow and the
death of large parts of the affected kidney. Regardless of what’s
going on, the suggestion here is that physicians should not
rely solely on urine protein levels and the presence of diabetic
eye disease to diagnose kidney disease in people with diabetes.
Instead, a blood test and subsequent calculation that allows
physicians to estimate the creatinine clearance, a measure of
renal function, should also be used.
Now for the good news. A study
in the New England Journal of Medicine shows that close to 60%
of type 1 diabetes patients who have been given the diagnosis
of microalbuminuria can display regression of the levels of
protein in their urine. This is in sharp contrast to what has
traditionally been felt to be the strictly progressive nature
of DN. As mentioned earlier, we knew that interventions like
good glucose and blood pressure control could prevent the onset
or delay the progression of DN, but it was widely believed that
once you have it, the horse is out of the barn, and not much
could be done to make it go away. The people who were the most
likely to see regression of their albuminuria were those who
had not had DN for very long, and who had hemoglobin A1c levels
less than 8% and good blood pressure and cholesterol levels.
These two papers show us that
we have lots to learn still about even the most basic and timeworn
questions in diabetes care. DN has been studied extensively
for years, yet we can still find out remarkable things that
will definitely change the way we treat people with this condition.
We will need to include measures of renal function outside of
simple urine protein determinations in our screening tests,
for one thing. The thought that we may have been missing up
to a third of all cases of poor renal function in our diabetic
patients is mortifying, and we simply must do better on that
front. But we have also learned that, in type 1 patients at
least, there are things that can push back the clock on DN,
and patients can still heed the clarion call for better glucose
and blood pressure control even after the diagnosis is made.
References:
Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency
in the absence of albuminuria and retinopathy among adults with
type 2 diabetes mellitus. Journal of the American Medical Association.
2003 Jun 25;289(24):3273-7.
Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram
JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes.
New England Journal of Medicine. 2003 Jun 5;348(23):2285-93
Written by Evan D. Rosen, M.D.,
Ph.D.
Content created 7/11/03
Content last reviewed July 7, 2003
Print
This Page
Dr.
Rosen's Archives
