Nephrology Dialysis Transplantation 2007 22(3):703-707; doi:10.1093/ndt/gfm061
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Kidney disease in diabetology
Guntram Schernthaner
Department of Medicine I, Rudolfstiftung Hospital Vienna, Austria
Correspondence and offprint requests to: Guntram Schernthaner, MD, Professor of Medicine Liaison Editor (Diabetology), NDT, Head of the Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria. Email: guntram.schernthaner{at}wienkav.at
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Introduction
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Diabetes mellitus represents a global health problem of epidemic
proportions. Diabetic patients with insufficient glycaemic and
blood pressure control have a high risk for the development
of both cardiovascular disease (CVD) and diabetic nephropathy.
Due to the global epidemy of this disease (‘diabesity’),
diabetic patients now represent about 30–40% of all patients
with end-stage renal disease (ESRD). Moreover, CVD accounts
for at least half of all deaths in individuals with type 2 diabetes
mellitus (T2DM). Since T2DM is a major risk factor for both
CVD and ESRD, this combination can be regarded as a catastrophic
risk situation. In fact, the 5-year survival time of T2DM patients
on chronic regular haemodialysis is still less than 50% [
1].
Thus, nephrologists are confronted—even more than diabetologists—with
the most severe patients suffering from T2DM.
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Screening for chronic kidney disease in type 2 diabetes
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It was generally believed that chronic kidney disease (CKD)
among adults with T2DM follows the same clinical course as in
type 1 diabetes (T1DM) and that increased urine albumin excretion
rate (AER) is the earliest clinical evidence of kidney disease
in this population. However, increasing epidemiological evidence
suggests that population patterns of CKD among adults with T2DM
are not as uniform as those noted among adults with T1DM. In
a longitudinal follow-up of the Framingham Heart Study [
2],
7% of 2398 subjects, characterized by glucose tolerance, developed
CKD during the follow-up of 7 years. The fully adjusted odds
of developing CKD were 0.98, 1.71 and 1.93 among those with
impaired fasting glucose or impaired glucose tolerance, newly
diagnosed diabetes, or known diabetes, respectively, compared
with those who were normoglycaemic at baseline. CVD risk factors
explained much of the relationship between prediabetes and the
development of CKD. In a recent cross-sectional survey [
3],
using data from NHANES III, 33% of diabetic adults with a GFR
< 60 ml/min per 1.73 m
2 did not have evidence of either microalbuminuria,
macroalbuminuria or retinopathy. Taken together, these data
suggest that CKD in the setting of prediabetes might be thought
of as an additional complication of macrovascular atherosclerosis.
Findings obtained from T2DM patients with non-albuminuric renal
insufficiency [
4] suggest that patients with T2DM can commonly
progress to a significant degree of renal impairment while remaining
normoalbuminuric. Focusing solely on urine albumin excretion
to screen for CKD may therefore miss a substantial number of
cases in adults with T2DM. The latter consists of a more heterogeneous
group of patients, who are in general older and have more comorbid
conditions at diagnosis compared with adults with T1DM. Thus,
screening for diabetic renal disease should include an estimation
of glomerular filtration rate (GFR) in addition to measuring
AER. This will allow for the detection of subjects who follow
either an albuminuric or non-albuminuric pathway to renal impairment.
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Impact of diabetes on haemoglobin levels in renal disease
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Several small studies have suggested that renal failure secondary
to diabetes may be associated with more severe anaemia. Additional
evidence is now available from a large retrospective study [
5],
which evaluated 2052 stable ambulatory patients (336 diabetic
vs 1846 non-diabetic patients), who attended a single tertiary
referral renal unit. The impact of diabetic kidney disease (DKD)
on haemoglobin levels at all degrees of renal impairment was
studied by comparison with patients with non-diabetic kidney
disease (NDKD). Results were corrected for other commonly associated
variables that influence anaemia in patients with renal impairment,
such as ACEI use, secondary hyperparathyroidism and iron deficiency.
At CKD stages 3, 4 and 5, mean haemoglobin levels in patients
with DKD compared with those in patients with NDKD were 12.95
vs 13.69 mg/dl (
P < 0.001), 12.05
vs 12.69 mg/dl (
P <
0.001) and 10.71
vs 11.59 mg/dl (
P < 0.01), respectively.
The retrospective nature of the study did not allow for identification
of the underlying mechanisms responsible for the more severe
anaemia in patients with DKD. Future prospective studies are
necessary to clarify which of the discussed abnormalities contribute
to the lower haemoglobin in diabetic patients. These may include
a relative deficiency of erythropoietin, autonomic neuropathy
interfering with anaemia-sensing by the erythropoietin-producing
cells in the kidney, damage to the erythropoietin-producing
peritubular fibroblasts or chronic inflammation contributing
to erythropoietin hypo-responsiveness.
Increasing evidence indicates that anaemia in patients with renal impairment contributes to considerable cardiovascular morbidity and mortality and may accelerate the progression to end-stage renal failure in diabetic patients. Since effective treatment for anaemia associated with renal impairment is now widely available, prospective trials of early erythropoietin intervention in patients with DKD are urgently required, to clarify whether this intervention is of benefit or is harmful. Earlier correction of anaemia in patients with DKD may slow progression of renal impairment and could reduce cardiovascular morbidity and improve patient survival in these patients.
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Strategies to improve prognosis and survival of T2DM patients with CKD
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What can be done for these patients and what have we learned
from the current studies and trials? Several studies have shown
that glycaemic control at initiation of haemodialysis had an
important impact on the prognosis of patients with T2DM, although
interventional studies were not available. Recently, a group
from Osaka reported clinically significant data analysing mean
HbA1c values during a 4-year follow study in 114 diabetic patients
(mean age: 60.8 years) on haemodialysis [
1]. Remarkably, 63.0%
of all patients died during the 5-year survey, but cumulative
survival rates of patients with poor glycaemic control (HbA1c
> 8.0%) were significantly lower than those of patients with
better diabetes control: 28, 9%
vs 53%. In a multivariate Cox
proportional hazard model, both the high HbA1c group (hazard
ratio 2.89,
P = 0 0.01) and the mean HbA1c group (1.26 per 1.0%,
P = 0.003) were significant predictors of survival. These findings
indicate the importance of careful management of glycaemic control,
even after initiation of haemodialysis.
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Blood pressure lowering with ARB: different effects on kidneys and the heart?
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CVD is a major risk in patients with decreased renal function
of nearly any degree. Strict control of blood pressure is one
of the key strategies to reduce both CVD and renal failure in
T2DM patients. Angiotensin II plays a key pathophysiological
role in the progression of diabetic renal disease, and blockade
of the renin–angiotensin system (RAS) with angiotensin-converting
enzyme inhibitors (ACEi) or angiotensin II antagonists (ARB)
has therefore become an important therapeutic strategy to reduce
renal and cardiovascular events in diabetic patients. Several
studies have demonstrated the effects of ARB on the reduction
of albuminuria and the progression of renal disease from microalbuminuria
to macroalbuminuria [
6]. More importantly, several trials (IDNT,
RENAAL) have shown that the antiproteinuric effects of losartan
and irbesartan translate into renoprotective benefits beyond
blood pressure lowering, thereby delaying by several years the
need for dialysis or kidney transplantation. However, in T2DM
patients with diabetic nephropathy no benefits were found for
CVD outcomes in the RENAAL and IDNT trials associated with ARB
treatment, with the exception of heart failure for losartan.
In the IDNT study [
7], progressive lowering of systolic blood
pressure (SBP) to 120 mmHg was associated with improved renal
and patient survival, whereas below this threshold, all-cause
mortality increased.
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Insulin resistance syndrome: relevant for widespread atherosclerosis in diabetes
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The main aetiology for the high rate of CHD in T2DM patients
is atherosclerosis, known to occur earlier and being more severe
and more generalized in T2DM patients than in non-diabetic individuals.
Atherosclerosis is considered to be a chronic inflammatory disease
that involves accumulation of lipids with subsequent foam cell
formation, mononuclear cells, migration and proliferation of
smooth muscle cells, and formation of fibrous tissue. This process
starts with endothelial dysfunction and is influenced by both
traditional and non-traditional risk factors. There is increasing
evidence that insulin resistance (IR) is not only an underlying
feature in most cases of T2DM, but is also associated, through
the Insulin Resistance Syndrome (IRS), with cardiovascular risk
factors that promote atherothrombosis through diverse mechanisms.
Even in the absence of hyperglycaemia, IR is associated with
a 2–3-fold increase in the risk of CVD. IR contributes
to the development of hyperglycaemia as well as to a cluster
of characteristic CVD risk factors, including an atherogenic
lipid profile, hypertension, and a prothrombotic, pro-inflammatory
vascular environment.
Thiazolidinediones (TZDs) represent a relatively new class of compounds currently used for the treatment of T2DM that exert their hypoglycaemic properties through reduction of IR. These agents act by stimulating a type of nuclear receptor, called peroxisome proliferator-activated receptor gamma (PPAR
). Such receptors are abundant not only in adipose tissue cells, but are also present in various other cell types, such as vascular smooth muscle cells, macrophages, vascular endothelial cells, as well as renal glomerular and tubular cells. Through transcriptional regulation of various genes, PPAR receptors play an important role in adipocyte differentiation and lipid and carbohydrate metabolism. Apart from improving glycaemic control in patients with T2DM, several lines of evidence indicate that TZDs have beneficial effects on other components of the IRS, such as blood pressure lowering, triglyceride reduction, HDL-cholesterol elevation, redistribution of body fat away from the central compartment, and decrease many biomarkers of chronic vascular inflammation (e.g. C-reactive protein, Interleukin 6, MCP-1, sCD40L) and plasma PAI-1 levels. Several studies have shown that TZDs significantly increase protective levels of adiponectin in patients with T2DM as well as in non-diabetic patients with metabolic syndrome. Remarkably, improvements of atherogenic biomarkers during TZDs treatment were accompanied by a substantial reduction in carotid intima-media thickness [8], an important predictor of first and recurrent stroke, as well as of myocardial infarction.
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PPAR agonists and microalbuminuria
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About one-third of all patients with T2DM develop microalbuminuria.
Notably, recently published data showed a strong, independent
relationship between the severity of IR and microalbuminuria
in patients with T2DM [
9]. Moreover, the risk of CVD mortality
is three-fold increased in T2DM patients with microalbuminuria
when compared with those diabetics without evidence of renal
disease. Thus, microalbuminuria is a major risk factor for renal
and CVD events, and therefore early identification and treatment
of patients at increased risk for microalbuminuria is mandatory
to limit the excess renal and CVD associated with T2DM.
Data from several animal and human studies support the concept that TZDs reduce urine albumin excretion (UAE) and may prevent development of renal injury. In various animal models of diabetes and IR, the reduction of UAE with TZDs was accompanied by a reduction of glomerular hyperfiltration, prevention of intrarenal arteriolosclerosis, and prevention of glomerulosclerosis and tubulointerstitial fibrosis. This beneficial effect of TZDs on UAE was recently demonstrated in three European multicenter, randomized, double-blind trials [10–12]. These trials compared the efficacy and safety of pioglitazone (PIO) in comparison with other oral antidiabetic agents (metformin or gliclazide) in a large number of patients with T2DM (n = 2444). In drug-naive patients with T2DM, PIO significantly reduced ACR by 19%, whereas metformin had no effect after 1 year of treatment [10]. When PIO or metformin was administered to patients already receiving sulfonylureas, the two regimens resulted in a similar glycaemic control after 1 year; however, albumin–creatinine ratio (ACR) was reduced by 15% under PIO, but increased by 2% with metformin [11]. Similarily, when PIO was added to patients who had previously received metformin therapy, ACR decreased by 10%, whereas the addition of gliclazide was associated with an increase of 6% [12]. A recent study [13] confirmed that rosiglitazone, combined with metformin, provides a greater reduction in microalbuminuria and blood pressure than the widely used combination therapy of metformin and glyburide at comparable levels of glycaemic control. In that study [13], 389 T2DM patients were followed for 32 weeks by using a double-blind, parallel-group design. Thus, TZDs provide a promising approach for the prevention of nephropathy in diabetic patients. However, the renoprotective effect of TZDs should be explored by future studies that examine the effects of TZDs in patients with proteinuria and on harder renal outcomes, like progressive decline in renal function.
Information on the use of TZDs in patients with overt diabetic nephropathy is relatively limited. As discussed earlier, glycaemic control is important for the prognosis of T2DM patients on haemodialysis. However, the choice of oral hypoglycaemia agents is limited in these patients and, very often, a high dose of insulin is required because of the uraemia-associated insulin-resistant state. TZDs can improve insulin resistance, and excretion of these drugs does not rely on renal function. In a recent study [14], the efficacy and safety of the use of rosiglitazone was evaluated in 78 diabetic haemodialysis patients, whereby about one-third had also chronic viral hepatitis. During the follow-up period of 15 months, high-dose rosiglitazone (8 mg/day), decreased HbA1c, triglycerides and C-reactive protein levels and increased serum adiponectin levels, as expected from previous studies. After rosiglitazone, interdialytic weight gain (2.07 kg vs 3.2 kg; P < 0.01) and mean cardiothoracic ratio (48.2% vs 50.4%; P = 0.02) of the individuals significantly increased. Interestingly, liver enzyme levels did not show a tendency to increase in patients with viral hepatitis B or C infections. Thus, among regular haemodialysis diabetic patients with chronic viral hepatitis infections, rosiglitazone may be safely used for glycaemic control. Since chronic heart failure (CHF) is common in patients with CKD, patients with CHF have to be carefully excluded from treatment with TZDs due to the water retention effects of these drugs.
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Vascular protection by PPAR agonists: lessons from PROactive
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Because of the favourable actions of TZDs, the PROactive study
(PROspective pioglitAzone Clinical Trial) was initiated to assess
the effects of pioglitazone (PIO) on the secondary prevention
of macrovascular events in T2DM patients. PROactive was a randomized,
double blind, placebo-controlled study [
15] in 5238 patients
with T2DM (age: 35–75 years) who had a history of macrovascular
disease; 50% had myocardial infarction (MI), 20% suffered from
stroke and 20% from peripheral arterial disease. Almost 50%
of all patients presented with increased UAR when tested by
the MICRAL test strip (Roche). The patients were randomized
to receive placebo or PIO titrated to 45 mg/day. Because study
patients had preexisting CVD and diabetes of long duration (average
8 years), almost all subjects at the time of enrolment were
taking glucose-lowering drugs and agents reducing the risk of
CVD events. The addition of 45 mg PIO to conventional therapy
for 3 years reduced the primary endpoint (many adverse macrovascular
outcomes including procedure-related endpoints like coronary
and or leg revascularization) by 10% (
P = 0.095), whereas the
disease-related endpoints (consisting of all-cause mortality,
non-fatal MI and stroke) were reduced by 16% (
P = 0.027) compared
with placebo. In patients with T2DM and a previous MI (
n = 2.445),
PIO significantly reduced the risk [
16] of recurrent fatal/non-fatal
MI by 28% (HR 0.72;
P = 0.045) and the risk of acute coronary
syndrome by 37% (HR 0.63;
P = 0.035). In the patients with previous
stroke [
17], PIO reduced a recurrent fatal or non-fatal stroke
by 47% (HR = 0.53;
P = 0.008), whereas no effect was seen in
patients without a prior stroke. However, 6% of the patients
in the PIO and 4% of the placebo group were hospitalized with
heart failure; mortality rates from heart failure did not differ
between the groups. There was a 3.6 kg increase in mean body
weight in the PIO group and a 0.4 kg decrease in the placebo
group. Since diabetic patients with kidney disease have a very
high risk for the development of stroke, MI and acute coronary
syndrome, future studies should evaluate the risks and benefits
of the use of TDZs in this large group of patients.
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Conclusion
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Diabetes continues to be the most common cause for ESRD in the
Western world. Remarkably, the proportions of patients in Asia
who need haemodialysis because of diabetes are now similar to
those in Western countries and most patients in this region
who have end-stage renal disease have type 2 diabetes [
18].
The increasing incidence of diabetes and improved longevity
due to better management of such patients is likely to further
increase the workload of nephrologists and diabetologists. Patients
with diabetic kidney disease continue to have a poor prognosis,
with mortality being 70–100 times that of a matched population.
The excess cardiovascular mortality associated with diabetes
and chronic renal failure is well-recognized. Carefully planned
and large controlled studies are needed to clarify whether aggressive
multifactorial intervention strategies aimed at controlling
glycaemia, anaemia, lipid and blood pressure values as well
as insulin risk factor associated abnormalities can improve
the catastrophic prognosis of these patients.
Conflict of interest statement. None declared.
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Introduction
Screening for chronic kidney...