DIABETIC NEPHROPATHY

Diabetic nephropathy is the most common cause of endstage renal disease (ESRD) in adults. In
the United States, almost half of patients entering ESRD programs are diabetic, and most of
them (≥80%) have type 2 diabetes. The mortality rate of patients with diabetic nephropathy is
high, with a marked increase in cardiovascular risk accounting for more than half of the
increased mortality risk among these patients. After overt diabetic nephropathy is present,
ESRD can often be postponed, but in most instances not prevented, by effective
antihypertensive treatment and careful glycemic control. Accordingly, there has been intensive
research into early pathophysiologic mechanisms of diabetic kidney injury, predictors of risk
for diabetic nephropathy, and early intervention strategies

Fisiopatología

Although other important modulating factors may exist, diabetic nephropathy is a result of the
long-term metabolic aberrations caused by hyperglycemia. Studies in both type 1 and type 2
diabetes have shown that improved glycemic control can reduce the risk of diabetic
nephropathy. Moreover, the development of the earliest diabetic kidney lesions can be slowed
or prevented by strict glycemic control, as was demonstrated in a randomized trial in type 1
diabetic kidney transplant recipients. Similarly, intensive insulin treatment decreased the
progression rates of glomerular lesions in a controlled trial in microalbuminuric type 1 diabetic
patients. Finally, established diabetic glomerular lesions in the native kidneys of type 1 diabetic
patients regressed with prolonged normalization of glycemic levels after successful pancreas
transplantation. In sum, these studies strongly suggest that hyperglycemia is necessary for the
development and maintenance of diabetic nephropathy, as correction of hyperglycemia allows
expression of reparative mechanisms that facilitate healing of the original diabetic glomerular
injury

Although hemodynamic mechanisms may be also involved in the pathogenesis of diabetic

nephropathy, patients with other causes of hyperfiltration (such as unilateral nephrectomy) do
not develop diabetic lesions. Therefore, glomerular hyperfiltration alone cannot fully explain
the genesis of the early lesions of diabetic nephropathy; however, clinical observations do
suggest that hemodynamic factors may be important in modulating the rate of progression of
diabetic lesions that are already well established. It is worth noting that the presence of
reduced glomerular filtration rate (GFR) in normoalbuminuric patients with type 1 diabetes has
been associated with more severe glomerular lesions, and these patients may be at increased
risk of progression to overt diabetic nephropathy. Systemic blood-pressure levels and a lack of
normal nocturnal blood-pressure dipping both may be implicated in the progression and
genesis of diabetic nephropathy. Supporting this hypothesis is the association between
intensive blood-pressure control and decreased rates of progression from normoalbuminuria
to microalbuminuria and from microalbuminuria to proteinuria in both normotensive and
hypertensive type 2 diabetic patients

Genetic predisposition to diabetic nephropathy has been strongly suggested in multiple cross-
sectional studies in type 1 and type 2 diabetic siblings concordant for diabetes. Importantly,
diabetic sibling pairs, known to be concordant for diabetic nephropathy risk, are also highly
concordant for diabetic glomerulopathy lesions, and this risk is in part independent of
glycemia. Accordingly, there are ongoing searches for genetic loci related to diabetic
nephropathy susceptibility through genomic scanning and candidate gene approaches
The kidney lesions of diabetic nephropathy appear to be mainly related to extracellular matrix
(ECM) accumulation in both the glomerular basement membrane (GBM) and the tubular
basement membrane (TBM); this ECM accumulation, which reflects an imbalance between
ECM synthesis and degradation, is the principal cause of mesangial expansion and a
contributor to expansion of the interstitium late in the disease. Many regulatory mechanisms
have been proposed to explain the link between a high ambient glucose concentration and
ECM accumulation. These include increased levels of TGFβ; activation of protein kinase C,
which stimulates ECM production through the cyclic adenosine monophosphate pathway;
increased advanced glycation end products; and increased activity of aldose reductase, leading
to accumulation of sorbitol. There is also growing evidence that oxidative stress is increased in
diabetes and is related to diabetic nephropathy, mediated through altered nitric oxide
production and action, and endothelial dysfunction

Pathology

TYPE 1 DIABETES

In patients with type 1 diabetes, glomerular lesions can appear within a few years after
diabetes onset. The same time frame is present when a normal kidney is transplanted into a
diabetic patient. The changes in kidney structure caused by diabetes are specific, creating a
pattern not seen in any other disease, and the severity of these diabetic lesions is related to
the functional disturbances of the clinical kidney disease as well as to diabetes duration,
glycemic control, and genetic factors. However, the relationship between the duration of type
1 diabetes and extent of glomerular pathology is not precise. This is consistent with the
marked variability in susceptibility to this disorder, such that some patients may develop
kidney failure after having diabetes for 15 years whereas others escape kidney complications
despite having type 1 diabetes for decades

LIGHT MICROSCOPY

Kidney hypertrophy is the earliest structural change in type 1 diabetes but is not reflected in
any specific light microscopic changes. In many patients, glomerular structure remains normal
or near normal even after decades of diabetes, whereas others develop progressive diffuse
mesangial expansion seen mainly as increased periodic acid–Schiff (PAS)-positive ECM
mesangial material. In about 40% to 50% of patients developing proteinuria, there are areas of
extreme mesangial expansion called Kimmelstiel-Wilson nodules (nodular mesangial
expansion). Mesangial cell nuclei in these nodules are palisaded around masses of mesangial
matrix material with compression of surrounding capillary lumina. Nodules are thought to
result from earlier glomerular capillary microaneurysm formation. Notably, about half of
patients with severe diabetic nephropathy do not have these nodular lesions; therefore,
although Kimmelstiel-Wilson nodules are diagnostic of diabetic nephropathy, they are not
necessary for severe kidney disease to develop.

Early changes often include arteriolar hyalinosis lesions involving replacement of the smooth
muscle cells of afferent and efferent arterioles with PAS-positive waxy, homogenous material
(Fig. 25.1). The severity of these lesions is directly related to the frequency of global
glomerulosclerosis, perhaps as the result of glomerular ischemia. GBM and TBM thickening
may be seen with light microscopy, although they are more easily seen with electron
microscopy. In addition, atubular glomeruli and glomerulotubular junction abnormalities are
present in proteinuric type 1 diabetic patients and may be important in the progressive loss of
GFR in diabetic nephropathy. Finally, usually quite late in the disease, tubular atrophy and
interstitial fibrosis occur.

IMMUNOFLUORESCENCE

Diabetes is characterized by increased linear staining of the GBM, TBM, and Bowman capsule,
especially for immunoglobulin G (mainly IgG4) and albumin. Although this staining is removed
only by strong acid conditions, consistent with strong ionic binding, the intensity of staining is
not related to the severity of the underlying lesions. Care is needed to avoid confusing these
findings with anti–basement membrane antibody disorders

ELECTRON MICROSCOPY

The first measurable change observed in diabetic nephropathy is thickening of the GBM,
which can be detected as early as 1.5 to 2.5 years after onset of type 1 diabetes (Fig. 25.2).
TBM thickening is also seen and parallels GBM thickening. An increase in the relative area of
the mesangium becomes measurable by 4 to 5 years, with the proportion of the volume of the
glomerulus that is mesangium increasing from about 20% (normal) to about 40% when
proteinuria begins and to 60% to 80% in patients with stage 3 chronic kidney disease (CKD).
Immunohistochemical studies indicate that these changes in mesangium, GBM, and TBM
represent expansion of the intrinsic ECM components at these sites, most likely including types
IV and VI collagen, laminin, and fibronectin

Qualitative and quantitative changes in the renal interstitium are observed in patients with
various kidney diseases. Interstitial fibrosis is characterized by an increase in ECM proteins and
cellularity. Preliminary studies suggest that the pathogenesis of interstitial changes in diabetic
nephropathy is different from the changes that occur in the mesangial matrix, GBM, and TBM
in diabetic nephropathy. Whereas, for all but the later stages of diabetic nephropathy, GBM,
TBM, and mesangial matrix changes represent the accumulation of basement membrane ECM
material, early interstitial expansion is largely a result of cellular alterations and only later,
when GFR is already compromised, is interstitial expansion associated with increased
interstitium fibrillar collagen and peritubular capillary loss. Consistent with most kidney
diseases affecting the glomeruli, the fraction of GBM covered by intact, nondetached foot
processes is lower in proteinuric patients with diabetes when compared with either control
subjects or individuals with type 1 diabetes with low levels of albuminuria. Moreover, the
fraction of the glomerular capillary luminal surface covered by fenestrated endothelium is
reduced in all stages of diabetic nephropathy, with increasing severity in normoalbuminuric,
microalbuminuric, and overtly proteinuric type 1 diabetics, respectively, as compared with
controls.17

TYPE 2 DIABETES

Glomerular structure in type 2 diabetes is less well studied but overall seems more
heterogeneous than in type 1. Between 30% and 50% of type 2 diabetes patients with clinical
features of diabetic nephropathy have typical changes of diabetic nephropathy, including
diffuse and nodular mesangial expansion and arteriolar hyalinosis (Fig. 25.3). Notably, some
patients, despite the presence of microalbuminuria or even overt proteinuria, have absent or
only mild diabetic glomerulopathy, whereas others have disproportionately severe tubular and
interstitial abnormalities and/or vascular lesions and/or an increased number of globally
sclerosed glomeruli. Type 2 diabetic patients with microalbuminuria more frequently have
morphometric glomerular structural measures in the normal range on electron microscopy and
less severe lesions than type 1 diabetic patients with microalbuminuria or overt proteinuria.
Interestingly, Pima Indians with type 2 diabetes, a high-risk population for ESRD, have lesions
more typical of those seen in type 1 diabetes

It is currently unclear why some studies show more structural heterogeneity in type 2 than in
type 1 diabetes whereas others do not. Regardless, the rate of kidney-disease progression in
type 2 diabetes is related, at least in part, to the severity of the classic changes of diabetic
glomerulopathy. Although there are reports that patients with type 2 diabetes have an
increased incidence of nondiabetic lesions, such as proliferative glomerulonephritis and
membranous nephropathy, this likely reflects biopsies more often being performed in patients
with atypical clinical features. When biopsies are performed for research purposes, the
incidence of other definable kidney diseases is very low (<5%).

STRUCTURAL–FUNCTIONAL RELATIONSHIPS IN DIABETIC NEPHROPATHY

Kidney disease progression rates vary greatly among individuals with diabetes. Patients with
type 1 diabetes and patients with proteinuria who are biopsied for research purposes rather
than for diagnosis of atypical clinical characteristics always have advanced glomerular lesions
and usually have vascular, tubular, and interstitial lesions as well. Similarly, patients with
microalbuminuria biopsied for research purposes usually have well-established lesions, which
vary widely in severity. However, there is considerable overlap in glomerular structural
changes between long-standing normoalbuminuric and microalbuminuric patients, as some
normoalbuminuric patients with longstanding type 1 diabetes can have quite advanced kidney
lesions, whereas many patients with longstanding diabetes and normoalbuminuria have
structural measurements within the normal range.

Ultimately expansion of the mesangium, mainly resulting from ECM accumulation, reduces or
even obliterates the glomerular capillary luminal space, decreasing the glomerular filtration
surface and therefore decreasing the GFR. Accordingly, the fraction of the glomerulus occupied
by mesangium correlates with both GFR and albuminuria in patients with type 1 diabetes,
reflecting in part the inverse relationship between mesangial expansion and total peripheral
GBM filtration surface per glomerulus. GBM thickness is also directly related to the albumin
excretion rate. Finally, the extent of global glomerulosclerosis and interstitial expansion are
correlated with the clinical manifestations of diabetic nephropathy (proteinuria, hypertension,
and declining GFR)

In patients with type 1 diabetes, glomerular, tubular, interstitial, and vascular lesions tend to
progress more or less in parallel, whereas in type 2 diabetic patients this often is not the case.
Current evidence suggests that, among type 2 diabetes patients with microalbuminuria, those
patients with typical diabetic glomerulopathy have a higher risk of progressive GFR loss than
those with lesser degrees of glomerular changes. A remarkably high frequency of glomerular
tubular junction abnormalities can be observed in proteinuric type 1 diabetic patients. Most of
these abnormalities are associated with tuft adhesions to Bowman capsule at or near the
glomerular tubular junction (tip lesions). The frequency and severity of these lesions (as well as
the presence of completely atubular glomeruli) predict GFR loss.

The data on structural–functional relationships in type 2 diabetes based on quantitative

morphometric analysis are less abundant. In several small studies, morphometric measures of
diabetic glomerulopathy correlated with kidney function parameters similar to those observed
in type 1 diabetes, although there seems to be a subset of patients who have normal
glomerular structure despite persistent albuminuria. Overall, the relationships between kidney
function and glomerular structural variables, although significant, are less precise than in
patients with type 1 diabetes. Importantly the rate of GFR decline significantly correlates with
the severity of diabetic glomerulopathy lesions. Thus, kidney lesions different from those
typical of diabetic glomerulopathy should be considered when investigating the nature of
abnormal levels of albuminuria in type 2 diabetes. These lesions include changes in the
structure of renal tubules, interstitium, arterioles, and podocytes. For example, Pima Indians
with type 2 diabetes and proteinuria have fewer podocytes per glomerulus than those without
nephropathy, and, in this population, a lower number of podocytes per glomerulus at baseline
was the strongest predictor of greater increases in albuminuria and of progression to overt
nephropathy in microalbuminuric patients. Similar findings were noted in another type 2
diabetes cohort, where the density of podocytes per glomerulus was significantly decreased in
all diabetic patients compared with controls and was lower in patients with microalbuminuria
and overt proteinuria than in patients with normoalbuminuria. In addition, microalbuminuric
and proteinuric patients had increased foot process width compared with normoalbuminuric
patients, and foot process width was directly related to the level of albuminuria. In sum, these
results suggest that changes in podocyte structure and density occur early in diabetic
nephropathy and might contribute to increasing albuminuria in these patients.

REVERSAL OF DIABETIC NEPHROPATHY LESIONS

The lesions of diabetic nephropathy have long been considered irreversible. Theoretically, if
reversal were possible, this would happen in the setting of long-term normoglycemia.
Interestingly, in recipients of successful pancreas transplantation alone, the lesions of diabetic
nephropathy were unaffected after 5 years of normoglycemia, whereas, by 10 years after
pancreas transplant, reversal of diabetic glomerular and tubular lesions was apparent in all
patients, with a remarkable amelioration of glomerular structure abnormalities evident by light
microscopy, including total disappearance of Kimmelstiel-Wilson nodular lesions. Although the
reasons for the long delay in the reversal of diabetic nephropathy lesions are unknown, the
long time necessary for these diabetic lesions to disappear is consistent with their slow rate of
development. The understanding of the molecular and cellular mechanisms involved in these
repair processes could provide new directions for the treatment of diabetic nephropathy.
Other therapeutic approaches, such as antihypertensive agents, have not been described as
leading to amelioration or reversal of diabetic kidney lesions.

MEDICAL MANAGEMENT OF DIABETES

Both kidney and cardiovascular morbidity and mortality are increased in patients with type 2
diabetes, particularly in those with nephropathy. Accordingly, treatment goals in these
individuals focus on slowing the rate of GFR decline and delaying the onset of kidney failure as
well as primary and secondary prevention of cardiovascular disease. This is mainly done by
targeting multiple kidney and cardiovascular risk factors, such as hyperglycemia, hypertension,
and dyslipidemia. Targeting albuminuria appears of specific interest for kidney protection

In the next section, traditional therapeutic options to decrease the risk of kidney and
cardiovascular morbidity and mortality are discussed. In addition to traditional risk factors,
novel risk factors for diabetic nephropathy are identified, which provide insight into new drug
targets and possibilities for new therapeutic interventions. An overview is provided of novel
therapeutic avenues that target these novel risk markers.

TRADITIONAL THERAPEUTIC STRATEGIES FOR DIABETIC NEPHROPATHY

GLYCEMIC CONTROL

RATIONALE

Inadequate glycemic control, as reflected by higher hemoglobin A1c (HbA1c) levels, is

associated with markedly worse kidney and cardiovascular outcomes in observational studies
of patients with diabetes, and targeting HbA1c values lower than 7% may delay the
progression of diabetic kidney disease, including development of microalbuminuria and overt
nephropathy. In type 1 diabetics, the benefit of intensive glucose control in the prevention of
microvascular complications (i.e., the development of retinopathy or microalbuminuria) was
demonstrated in the diabetes control and complications trial (DCCT), where long-term follow-
up showed a significant reduction in the risk of developing reduced GFR among individuals
who were treated intensively earlier in the course of diabetes. In type 2 diabetes, the United
Kingdom prospective diabetes study (UKPDS) documented benefit of intensive glucose
targeting on microvascular complications. Of note, although most studies of type 2 diabetes
have shown a benefit in kidney outcomes, multiple trials failed to show a benefit of intensive
glycemia therapy on mortality and cardiovascular disease, with some trials actually showing
increased mortality with intensive control. Accordingly, a careful individualized approach is
required when assigning glycemic targets in individuals with diabetes and kidney disease

MEDICATIONS OF CHOICE

In principle one uses the same drugs for glycemic control in diabetic patients with and without
kidney disease until late stage 3 CKD (Table 25.1). There is some controversy regarding
metformin use in advanced CKD, with current suggested use limited to those with serum
creatinine ≤1.5 mg/dl (133 µmol/L) in men and 1.4 mg/dl (124 µmol/L) in women because of
an increased risk for life-threatening lactic acidosis, although in practice many patients with an
estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2 receive metformin
without any problem. Although it is unlikely to occur, a randomized controlled trial assessing
the efficacy and safety of metformin in patients with more advanced CKD is warranted, as
metformin is an excellent glucose-lowering agent for many patients. Of note, metformin
should be temporarily discontinued before surgery or administration of contrast media.
Reduction in the doses of other oral hypoglycemic agents in later stages of CKD may also be
necessary, especially for some sulfonylurea compounds that are metabolized by the kidney.
Similarly, as insulin is degraded by the kidney, dose reduction may be needed to prevent
hypoglycemia. Finally, thiazolidinediones, such as rosiglitazone or pioglitazone, may affect
kidney water and sodium handling, thereby aggravating edema and congestive heart failure. In
non-CKD populations, rosiglitazone use is associated with increased risk of heart failure and
myocardial infarction compared with placebo, prompting regulatory agencies in Europe to
suspend its marketing.

BLOOD-PRESSURE CONTROL

Rationale

Treatment of high blood pressure is of paramount importance for preventing and delaying the
progression of diabetic nephropathy. Blood-pressure–lowering therapy is vital during any stage
of CKD and is the mainstay of renoprotective therapy in diabetes and nondiabetic kidney
diseases. In the UKPDS trial, where average blood-pressure levels of 144/82 mm Hg were
achieved, there was no threshold below which further blood-pressure reduction did not
reduce risk of progressive diabetic nephropathy and cardiovascular morbidity. However,
recent data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed
that intensive (average 119 mm Hg) versus standard blood pressure (average 134 mm Hg)
control conferred no benefit on kidney outcomes in type 2 diabetes patients. Critically,
patients with more than 1 g of proteinuria per day were excluded from this trial, leaving the
benefits of a lower blood-pressure target (<120 mmHg systolic) for patients with type 2
diabetes and nephropathy untested. Surprisingly little evidence from randomized controlled
trials demonstrates that a lower target blood pressure actually reduces kidney or
cardiovascular risk in people with diabetes and CKD. Accordingly, at present, a target of less
than 140/90 mm Hg appears to be best supported by evidence.

Drugs of Choice

Any antihypertensive agent can be effectively used in the diabetic population, with agents that
block the renin-angiotensin-aldosterone system (RAAS) being the first choice in those with
diabetes and hypertension as well as those with (normotensive) diabetes with
microalbuminuria or macroalbuminuria. Medication choice is further tailored to the need of
the individual patient and the tolerability of the individual drugs. Patients with diabetic
nephropathy are often volume overloaded; accordingly diuretic therapy is indicated. Increasing
doses of loop diuretics, rather than thiazide diuretics, may become necessary to control fluid
retention and accompanying hypertension if GFR declines. Multiple experimental and clinical
studies conclusively demonstrate that RAAS blocking agents lead to additional cardiovascular
and renoprotection benefits beyond those expected with blood-pressure reduction alone. This
has led many medical societies, such as the National Kidney Foundation and American
Diabetes Association, to advocate the use of angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARB) as first choice antihypertensive therapy to achieve
renoprotection. The beneficial effects of ACE inhibitors and ARB appear to be attributable not
only to their blood-pressure–lowering effect but also to their antialbuminuric effect, with the
degree of the reduction in albuminuria induced by RAAS intervention in the first months of
therapy linearly associated with the magnitude of long-term renoprotection both in early and
in late stages of diabetic nephropathy.

ACE Inhibitors

The captopril trial by the Collaborative Study Group was the first large trial to show definitively
the benefit of ACE inhibitor therapy in delaying progression of overt nephropathy in patients
with type 1 diabetes throughout a 4-year period of follow-up, with a nearly 50% reduction in
the risk of doubling of serum creatinine concentration or in the combined endpoints of death,
dialysis, and kidney transplantation despite similar achieved blood pressure between the
captopril and noncaptopril groups. ACE inhibitors should be used in type 1 diabetic patients as
soon as persistent microalbuminuria is documented, even if blood pressure is not elevated, to
delay and/or prevent the development of overt nephropathy. In type 2 diabetes and
normoalbuminuria, ACE inhibitors have consistently reduced the risk of development of
microalbuminuria and reduced the rate of kidney function decline. RAAS-blocking drugs can be
prescribed for cardioprotective indications in all diabetic patients, regardless of the presence
or absence of kidney disease; for example, the subgroup of diabetic patients who received the
ramipril in the Heart and Outcome Protection Evaluation (HOPE) trial had significantly fewer
cardiovascular events.

Angiotensin Receptor Blockers

The merits of angiotensin receptor blockers (ARB) to protect the kidney and heart beyond
blood-pressure control have been demonstrated in numerous randomized placebo controlled
trials, including the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA2)
and the Incipient to Overt; Angiotensin II Blocker Telmisartan Investigation on Type 2 Diabetic
Nephropathy (INNOVATION) trials, where ARB-based regimens significantly reduced the
number of patients with microalbuminuria who progressed to macroalbuminuria. Similarly,
large-scale trials in patients with type 2 diabetes and overt nephropathy, including the
Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) and
Irbesartan Diabetic Nephropathy Trial (IDNT) trials, have shown that ARBbased therapy
reduces the risk of a composite endpoint consisting of doubling of serum creatinine, ESRD, and
all cause mortality. IDNT also established the superiority of irbesartan over the calcium
channel blocker (CCB) amlodipine in this setting. Apart from kidney protection, ARBs also
afford cardiovascular protection in diabetic patients as demonstrated in the Losartan
Intervention for Endpoint Reduction in Hypertension (LIFE) trial.

Comparing ACE Inhibitors to ARBs

Data comparing the benefits of ACE inhibitors and ARB for cardiovascular and/or kidney
protection in patients with type 2 diabetic nephropathy are scarce but potentially interesting.
One small study directly compared the effects of telmisartan and enalapril on kidney function
in type 2 diabetes and reported no difference between the two drugs. Similar results were
noted in the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET),
where, in people at cardiovascular risk, there was no difference in the incidence of kidney or
cardiovascular outcome in subjects treated with ACE inhibitor- or ARB-based regimens in
either the overall population or in the third of participants with diabetes. Accordingly, there is
no efficacy basis for recommending an ACE inhibitor over an ARB in patients with type 2
diabetes, although the not infrequent occurrence of cough with an ACE inhibitor has increased
the popularity of an ARB-based antihypertensive regimen despite the increased cost.

COMBINATIONS OF BLOOD-PRESSURE– LOWERING DRUGS

Rationale

More than one medication is usually required to control blood pressure, with patients with
overt diabetic nephropathy usually requiring three or four different antihypertensive drugs,
including a diuretic. In addition, synergistic combinations may have the advantage that one can
reduce the dose of individual components of the antihypertensive regimen, potentially
retaining efficacy while reducing side effects

Combinations of Choice

Logical combinations can be used just as in uncomplicated hypertensive patients. Since RAAS
blockade typically will be the first line agent, clinicians should use other agents, in conjunction
with RAAS blockade, that have proven efficacy for preventing both surrogate and hard clinical
outcomes.

Diuretic Plus ACE-inhibitor or ARB. This combination effectively reduces both blood pressure
and proteinuria in diabetic and non-diabetic patients; however, no studies with hard outcomes
have been done to compare this combination with single therapies. The ADVANCE trial showed
that the combination of an ACE inhibitor (perindopril) with a diuretic (indapamide) significantly
reduces blood pressure and the risk of kidney and cardiovascular complications as compared
with placebo therapy in a broad range of patients with type 2 diabetes.

Calcium Channel Blocker Plus ACE Inhibitor or ARB. The combination of a CCB and an ACE
inhibitor has been investigated in two large trials. The BENEDICT trial compared the
combination of the nondihydropyridine CCB verapamil and the ACE inhibitor trandolapril
versus the single use of these agents in preventing the onset of microalbuminuria in type 2
diabetes, demonstrating that the combination of verapamil and trandolapril provided no
advantage over trandolapril alone, whereas trandolapril was superior compared with
verapamil. The ACCOMPLISH trial compared benazepril plus hydrochlorothiazide versus
benazepril plus amlodipine in high cardiovascular risk patients and reported that the
combination of benazepril and amlodipine was superior in preventing cardiovascular and
kidney outcomes. Although a prespecified analysis in the diabetic population in ACCOMPLISH
(60% of the overall population) showed results similar to the main study, the small number of
kidney events in ACCOMPLISH renders the interpretation of this outcome difficult.

COMBINATIONS OF RAAS-INTERVENTIONS

ACE inhibitor+ARB

The recognition of the importance of the RAAS in kidney and cardiovascular health has led to
the idea that more stringent RAAS blockade by means of combination of ACE inhibitor and ARB
therapy would afford additional protection. Indeed, combination therapy with ACE inhibitors
and ARBs does result in additional blood pressure and albuminuria reduction, but the effect of
dual therapy on major kidney or cardiovascular events in people with diabetic nephropathy
has not been adequately assessed to date. Notably, in early 2013, the VA VA NEPHRON-D trial,
which compared ARB alone to combination therapy had medications terminated early per
recommendations of the Data Monitoring Committee, based on a greater number of observed
acute kidney injury events and hyperkalemia in the combination therapy group. Similarly, the
ONTARGET demonstrated that, despite additional blood-pressure reduction and less
progression of albuminuria, dual RAAS blockade did not reduce kidney or cardiovascular
events in a lower kidney risk population.

ACE inhibitor/ARB and Direct Renin Inhibition

Blockade of the RAAS by renin inhibition was considered an attractive target to prevent kidney
and cardiovascular outcomes. The direct renin inhibitor aliskiren is a potent inhibitor of renin,
and short-term studies demonstrated its efficacy as well as its safety. However, the large hard
outcome ALTITUDE trial, which tested the combination of the direct renin-inhibitor aliskiren
plus ACE inhibitor or ARB treatment, demonstrated that aliskiren was associated with adverse
kidney and cardiovascular effects in patients with type 2 diabetes at cardiovascular risk,
leading to premature termination of the trial and recommendations from drug regulatory
agencies that aliskiren is contraindicated in patients with diabetes and moderate or severe
CKD who are taking ACE inhibitors or ARBs

ACE inhibitor/ARB and Mineralocorticoid Receptor Blockers

Adding aldosterone blockers to ACE inhibitors or ARBs is another strategy to block the
deleterious effect of the RAAS in diabetic nephropathy. Because aldosterone promotes tissue
fibrosis, and to counteract aldosterone breakthrough, a phenomenon defined by elevations of
plasma aldosterone levels during chronic ACE inhibitor or ARB treatment that occurs in
approximately 40% of patients receiving these agents, mineralocorticoid receptor blocking
agents may be beneficial as add-on therapy to ACE inhibitors or ARBs. Targeting aldosterone in
these patients is particularly effective on the surrogate marker albuminuria. However, the risk
of hyperkalemia and the lack of long-term efficacy and safety data (in particular given the
results of ONTARGET and ALTITUDE) warrant caution when combining mineralocorticoid
receptor blocking agents with an ACE inhibitor or ARB.

LIPID MANAGEMENT

RATIONALE

Cholesterol lowering has contributed to improved cardiovascular outcomes in a range of

patient populations. However, whether lipid management delays the progression of
nephropathy and decreases the risk of ESRD has been subject to debate. Metaanalyses have
reported that statin therapy may reduce proteinuria in CKD patients, but the lack of well-
designed long-term trials fueled uncertainty as to whether improved lipid management
reduces kidney risk. The results of the Study of Heart and Renal Protection (SHARP) trial
provided much needed insight into the longterm efficacy and safety of lipid management
among kidney disease patients. The SHARP results, which are reviewed in greater detail in
Chapter 56, showed that the combination of simvastatin and ezetimibe as compared to
placebo treatment reduced the risk of major vascular events by 16% in individuals with
advanced CKD. Of note, a recent metaanalysis of all statin trials in CKD, including SHARP,
showed that the cardiovascular protective effect of statins is attenuated at lower eGFR levels,
and, unfortunately, the combination of simvastatin and ezetimibe in SHARP did not decrease
the risk of progression to kidney failure.

Choice of Lipid-Lowering Therapy

Choosing among lipid-lowering strategies in CKD patients is challenging given a lack of

adequate data, with most studies focusing on statins. Several studies have assessed the
comparative effects of statins on kidney or cardiovascular outcome, with the results of the
Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive
Renal Disease Trial (PLANET) suggesting a benefit for atorvastatin over rosuvastatin on kidney
function. Further studies are needed to evaluate the long-term effects of lipid-lowering
therapies on kidney function.

TREATMENT OF TYPE 2 DIABETES IN DIALYSIS PATIENTS

When a diabetic patient approaches kidney failure, the various options for kidney replacement
therapies should be offered: peritoneal dialysis, hemodialysis, or kidney transplantation.
Survival with any kidney replacement modality is generally worse for patients with diabetes
compared with nondiabetic patients, and cardiovascular complications markedly contribute to
premature deaths. In fact, more than 70% of deaths in the diabetic ESRD population are
attributed to a cardiovascular cause.

Control of Hyperglycemia

Appropriate glycemic control in dialysis patients is important because (severe) hyperglycemia

not only increases cardiovascular risk but also causes thirst and high fluid intake. The
assessment of glycemic control in dialysis patients is complicated, because interpretation of
the commonly used assays for HbA1c is confounded by interference with uremic toxins. In
addition, altered red blood cell survival, blood transfusion, and use of erythropoietin all impact
the accuracy of HbA1c measurement.

The pharmacologic management of hyperglycemia in dialysis patients must take into account
that dialysis reverses insulin resistance so that the insulin requirement is generally lower than
before dialysis. The glucose concentration in dialysate typically is 100 mg/dl (6.1 mmol/L) to
avoid the risk of hypoglycemic and hypotensive episodes

Blood-Pressure Control

Previous trials have shown that blood-pressure lowering consistently reduces cardiovascular
morbidity and mortality in a broad range of patients, and that the magnitude of bloodpressure
reduction is an important driver of protection. However, as most blood-pressure trials have
systematically excluded dialysis patients, the benefits and harms of blood-pressure– lowering
therapies in this population remains uncertain. Two metaanalyses of small randomized
controlled trials suggest that blood-pressure–lowering therapies (including volume control) are
associated with a nearly 30% risk reduction for cardiovascular events and 25% risk reduction
for cardiovascular death compared with control treatment. Large outcome trials are urgently
needed to evaluate this further.

Lipid Control

Based on 4D (Die Deutsche Diabetes Dialysis Study) and the AURORA (A Study to Evaluate the
Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and
Cardiovascular Event) trial, patients treated with hemodialysis should not be started on a
statin. Although the SHARP trial noted a benefit in a mixed CKD/ESRD population,
metaanalyses of these studies have not demonstrated a substantial benefit in dialysis.
Accordingly, we recommend not initiating a statin in patients treated with hemodialysis but
often do continue statin treatment in those that are already receiving these agents at dialysis
initiation.

NOVEL STRATEGIES AND AGENTS FOR DIABETIC NEPHROPATHY

Optimizing glucose, blood pressure, and lipid control in CKD patients with diabetes has
undoubtedly improved their prognosis; however, a considerable proportion of patients
continue to develop diabetic nephropathy and progress to kidney failure. An overview of novel
agents that target wellestablished or novel pathophysiologic pathways is provided in the next
section. Many of these novel agents not only affect the target for which they are developed
(on-target risk factor) but impact multiple other risk markers as well (off-target risk factors)
(Table 25.2). Optimizing drug regimens to impact multiple parameters may lead to better drug
use in the future.

NEWER GLYCEMIC CONTROL AGENTS

Glycagon-like Peptide-1 and Dipeptidyl Peptidase Inhibitors

Glycagon-like peptide-1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion in
a glucose-dependent manner. Several GLP-1 agonists as well as dipeptidylpeptidase 4 (DPP-4)
inhibitors, which block the GLP-1 degrading enzyme DPP-4, have been developed to treat
patients with type 2 diabetes (see Table 25.1). DPP-4 inhibitors seem to exert similar effects on
HbA1c as alternative agents, with decreases in the range of 0.5% to 1.0%. However, the
pharmacokinetic properties vary among the different agents, which could render a specific
agent particularly useful for a certain subpopulation. For example, linagliptin is mainly
metabolized and eliminated by the liver, making it particularly useful for patients with lower
GFR (see Table 25.1). Long-term effects on kidney and cardiovascular outcomes appear
promising.

Sodium-Glucose Cotransporter-2 Inhibition

The role of the kidney in maintaining glucose homeostasis has been increasingly appreciated in
the last few decades. Plasma glucose is filtered in the glomerulus and reclaimed by tubular
reabsorption along with two positively charged sodium ions per glucose molecule. This process
involves the sodium-glucose cotransporter-2 (SGLT-2) system, which is located in the proximal
tubule. The SGLT-2 transporter accounts for the reabsorption of approximately 90% of all
filtered glucose, whereas the SGLT-1 transporter, located in the more distal proximal tubule,
reabsorbs the remaining 10%. SGLT-2 inhibitors reversibly inhibit the SGLT-2 transporter,
leading to enhanced glucose and sodium excretion and, in turn, to reductions in plasma
glucose and HbA1c of up to 0.8% (see Table 25.1). The role of SGLT-2 inhibitors in diabetes
management remains uncertain, and their use in patients with lower GFR is likely limited by
their mechanism of action

SGLT-2 inhibitors may have more kidney and cardiovascular protective potential than the
protection that is only due to its effects on glucose homeostasis. In addition to the beneficial
effects on glycemic control, trends toward increases in sodium excretion and hemoglobin and
decreases in body weight and blood pressure have been observed with SGLT-2 inhibition (Fig.
25.5). These bloodpressure–lowering effects could result from enhanced natriuresis and
diuresis, whereas the weight loss may reflect caloric losses. Potential kidney benefits are being
evaluated in long-term hard outcome trials.

NOVEL BLOOD-PRESSURE AND LIPID-LOWERING AGENTS

Mineralocorticoid Receptor Blockers

Mineralocorticoid receptor blockers (MRBs) are potent drugs for lowering risk factors such as
blood pressure and proteinuria; however, there is concern that these drugs may not improve
clinical outcomes in CKD patients because of their tendency to increase serum potassium. To
avoid the latter, several new compounds are being tested, including MRBs that may have less
effect on potassium homeostasis while retaining the blood-pressure and albuminuria-lowering
effect. Today no clinical trials with such drugs are available. Another approach is to use
mineralocorticoid synthase inhibitors, which are effective in reducing serum aldosterone and
have blood-pressure–lowering capacity. Whether this approach will effectively decrease the
incidence of hyperkalemia in patients with diabetes and nephropathy is still unknown. A third
approach is using classical MRBs together with agents that prevent or attenuate hyperkalemia.
Whether the benefits of this approach will outweigh possible risks of hyperkalemia as well as
safety concerns associated with potassium-binding resins remains unknown, although novel
potassium-binding resins are in development

Endothelin Antagonists

Endothelin receptor blockers are promising given potent effects on both blood-pressure and
proteinuria reduction; however, the hard outcome study on one of the first agents in this class
(avosentan) demonstrated an increased incidence of edema and hospitalization for heart
failure with avosentan, leading to the premature discontinuation of the trial. The high risk of
heart failure was most likely caused by the drug’s sodium retaining effects. Atrasentan, a more
specific inhibitor of the endothelin-1A receptor than avosentan, was recently shown to lower
albuminuria with fewer side effects (Fig. 25.6). The albuminuria-lowering effects of atrasentan
currently are being tested in the Reducing residual Albuminuria in subjects with type 2
Diabetes and nephropathy with AtRasentan (RADAR; NCT01356849) study.

High-Density Lipoprotein-Increasing Drugs

Patients with diabetes are often diagnosed with mixed dyslipidemia, characterized by low
levels of high-density lipoprotein (HDL) cholesterol and high levels of triglycerides. Various
agents are currently in development for increasing HDL by modulating cholesterol ester
transfer protein (CETP), including dalcetrapib; notably, the first-in-class agent, torcetrapib, was
abandoned after a hard outcome trial showed an increased risk of cardiovascular events with
its use.

LIFESTYLE MODIFICATION

Dietary sodium restriction enhances the blood-pressure and albuminuria-lowering effects of

ACE inhibitors and ARBs, with both RENAAL and IDNT showing that the effects of ARBs on hard
kidney and cardiovascular outcomes in type 2 diabetic patients are greater in patients with
moderately low dietary sodium intake. Prospective studies are needed to definitively confirm
or refute these data. Dietary protein restriction has been shown in a metaanalysis of nine
randomized controlled trials (seven in type 1 diabetic patients and three in type 2 diabetic
patients) to have a small, statistically nonsignificant, long-term beneficial effect in slowing the
rate of decline in GFR without demonstrable evidence of malnutrition. Currently, the ADA
recommends 0.8 g/kg/ day of protein restriction for diabetic patients with increased
albuminuria, which is a manageable and safe recommendation for most patients with
challenging dietary prescriptions related to their diabetes and CKD. Dietary counseling by a
nutritionist may be useful to assist CKD patients in safely implementing dietary changes
(Chapter 54).

NOVEL TARGETS

ANEMIA

A lower hemoglobin level is a risk marker for adverse cardiovascular outcomes, and the
interaction between CKD and diabetes amplifies that risk. This observation formed the
rationale for the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT), which
investigated whether raising hemoglobin targets with darbepoetin-α versus placebo improved
kidney and cardiovascular outcomes in patients with diabetic nephropathy. Unfortunately,
there was no benefit with darbepoetin, and perhaps a suggestion of increased stroke risk.
Accordingly, current erythropoiesis-stimulating agents cannot be recommended for
cardiovascular or kidney risk reduction in patients with diabetic nephropathy.

Inflammation

In the past years, increasing evidence has indicated an important role for underlying, low-
grade inflammatory processes in the pathogenesis of diabetic nephropathy. Consequently,
research in antiinflammatory strategies may open a therapeutic window to halt the
progression of disease
Pyridoxamine Dihydrochloride. Pyridoxamine dihydrochloride (Pyridorin, NephroGenex)
inhibits formation of advanced glycation end products and scavenges reactive oxygen species
and toxic carbonyls. Whether these effects translate into kidney protection is unknown,
although a year-long study of the effects of pyridoxamine dihydrochloride in patients with type
2 diabetes and proteinuria failed to show a difference in kidney function decline with
pyridoxamine dihydrochloride in daily doses of 300 or 600 mg versus placebo treatment

Pentoxifylline. Pentoxifylline is a methylxanthine phosphodiesterase inhibitor with favorable

antiinflammatory effects and immunoregulatory properties. Despite this theoretical benefit,
pentoxifylline offers at best a small beneficial effect on kidney function and reduction in
albuminuria and proteinuria with no apparent serious adverse effects. Importantly, most
studies of this agent were poorly reported, small, and methodologically flawed. The results of
the PREDIAN study (Pentoxifylline for Renoprotection in Diabetic Nephropathy) will likely shed
some further light on the potential use of pentoxifylline for kidney protection in patients with
diabetes. Until then, current evidence does not support the use of pentoxifylline in this patient
population

Monocyte Chemoattractant Protein-1 Inhibitors. An increasing body of evidence demonstrates

that monocyte chemoattractant protein-1 (MCP-1), a potent cytokine, plays a very important
role in initiating and sustaining chronic inflammation in the kidney. MCP-1 is secreted in
response to high glucose concentrations. MCP-1 in turn attracts blood monocytes and
macrophages and facilitates inflammation. A prospective randomized placebo controlled study
showed that inhibition of MCP-1 synthesis further reduced albuminuria when used in addition
to ACE inhibitor or ARB therapy in subjects who had macroalbuminuria, although there was no
significant effect in individuals with lower levels of albuminuria. To our knowledge there are no
hard kidney outcome trials ongoing.

Bardoxolone Methyl. Bardoxolone methyl is an antiinflammatory drug that activates the Nrf2-
Keap1 pathway, resulting in inhibition of the proinflammatory cytokine Nf-κB. In a previous
nonrandomized 8-week trial, treatment with bardoxolone methyl resulted in a significant
increase in estimated GFR. A subsequent 52-week follow-up study showed that the early
bardoxolone-methyl–induced rise in eGFR was sustained throughout the 52-week follow-up
period (Fig. 25.7). Unfortunately, a longer-term hard outcome study (Bardoxolone Methyl
Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes [BEACON], NCT
01351675) was terminated early for safety concerns because of excess serious adverse events
and mortality in the bardoxolone methyl arm

Vitamin Supplements

Vitamin-D Receptor Activation. Emerging data suggest an important role for the vitamin-D axis
in kidney and cardiovascular health. The vitamin-D receptor is expressed in numerous tissues,
and small studies have shown that activators of this receptor may inhibit the RAAS by
suppressing renin synthesis, causing a reduction in albuminuria and inflammatory markers. The
Vitamin-D Receptor Activator for Albuminuria Lowering (VITAL) study, designed to investigate
the antialbuminuric effect of the vitamin-D receptor activator paricalcitol, showed that 24-
weeks of treatment with paricalcitol at 2 mcg/day caused a significant fall in albuminuria over
time and was well tolerated (see Fig. 25.6). Larger studies with longer follow-up are pending.

CONCLUSION
Despite the successful use of glycemic, lipid, and bloodpressure control, including ACE inhibitor
and ARB therapy, kidney risk in patients with diabetes remains very high, leaving the diabetic
population with a clear unmet need. As outlined in this section, various novel treatment
options are in development that may offer additional renoprotection and have the potential to
reduce the high morbidity and mortality rates typically seen in patients with diabetes