Type 2 diabetes mellitus (T2DM) and essential hypertension are recognized as the leading causes of end-stage renal disease (ESRD). Because of the rising numbers and improved survival of patients with T2DM, ESRD is expected to increase considerably.1,2 Diabetic nephropathy affects 20% to 40% of T2DM patients and is responsible for 44% of new cases of ESRD.3 In addition, chronic kidney disease (CKD) in diabetic patients, even at early stages, is associated with an increased risk of death, particularly from cardiovascular disease (CVD), and patients with mild to moderate impairment of renal function—especially older individuals—are more likely to die of CVD than progress to ESRD.4,5 To improve awareness and preventive efforts about CKD, the National Kidney Foundation has recently developed the Kidney Early Evaluation Program (KEEP), which aims at offering high-risk patients older than 18 years a complete clinical and biochemical work-up, education, and support. Therefore, early detection of renal dysfunction in these patients is essential to successfully prevent progression to ESRD as well as excess CVD morbidity and mortality.
The authors concisely review the main clinical issues arising in the management of the hypertensive patient with type 2 diabetes, in whom chronic kidney disease is prevalent and heralds increased cardiovascular morbidity and mortality. Special attention is paid to the clinical meaning, relevance and limits of albumin excretion and glomerular filtration rate, the two widely used markers of reduced kidney function during the course of chronic diseases like diabetes and hypertension. The main therapeutic strategies involving blood pressure and glycemic control, treatment of dyslipidemia and improvement of lifestyle are discussed from the viewpoint of a general practitioner dealing with the clinical complexity of these patients. J Clin Hypertens (Greenwich). 2011;13:252–257. © 2011 Wiley Periodicals, Inc.
Early Markers of the Disease: Role of Albuminuria and GFR
Microalbuminuria is considered a reliable marker of early diabetic nephropathy, although its rate of progression is decreasing due to the improved treatment of diabetic patients.6 At present, 30% to 40% of T2DM patients with microabuminuria progress to macroalbuminuria within 10 years, while 30% to 50% remain microalbuminuric, and 20% to 40% are likely to return to normoalbuminuria. Biopsy studies have shown that microalbuminuria is invariably associated with significant glomerulopathy in type 1 diabetes (T1DM),7 whereas this is true only in one third of microalbuminuric T2DM patients (ie, those with typical diabetic glomerulopathy). The remaining two thirds of microalbuminuric patients have either no lesion or atypical (vascular and/or tubulointerstitial) manifestations of renal disease, which are associated with a slower rate of deterioration of renal function than the typical glomerular alterations.8
Although in the natural history of diabetic nephropathy increased albuminuria is considered to precede the reduction in glomerular filtration rate (GFR),8 mounting evidence indicates that a relevant proportion of both T1DM and T2DM patients9–11 show impaired renal function coupled with urinary albumin excretion rates (UAE) still within the normal range. Moreover, although persistent microalbuminuria is considered to be a strong predictor of subsequent GFR loss,12 decline in renal function over time is also observed in normoalbuminuric patients.13
The increased CVD risk associated with diabetic nephropathy has been related to both proteinuria and reduced GFR. Proteinuria of any degree is a powerful predictor of CVD morbidity and mortality, independent of traditional cardiovascular (CV) risk factors. This is true both in the general population and in T2DM patients. In the latter, reduction of proteinuria is associated with decreased CVD risk.14–16 Thus, as a CVD risk indicator, UAE is used as a continuous parameter. In contrast, a threshold of albumin excretion is conventionally used to mark declining renal function (or incipient nephropathy).
Regarding GFR, the relationship between estimated GFR (eGFR) (calculated by several equations such as the Cockroft-Gault formula, the simplified Modification of Diet in Renal Disease [MDRD] equation, or the more recent CKD Epidemiology Collaboration [CKD-EPI] formula)17,18 and CV morbidity and mortality has been explored in the general population and in patients at high risk to develop CVD (Table). Of note, the CKD-EPI equation reduces the bias in underestimating GFRs above 60 mL/min/1.73 m2 introduced by the MDRD formula; it lowers the number of false-positives and improves the accuracy of testing for kidney disease. For these reasons, it has become the first choice in screening programs.
|Stage||Description||GFR, mL/min/1.73 m2|
|1||Kidney damage with normal/increased GFR||>90|
|2||Kidney damage with mildly decreased GFR||60–89|
|3||Moderately decreased GFR||30–59|
|4||Severely decreased GFR||15–29|
|5||Kidney failure||<15 (or dialysis)|
|Estimated glomerular filtration rate (GFR) from serum creatinine|
|GFR (mL/min)=(140−age [y])×body weight (kg) [72×creatinine (mg/dL)]×0.85 (in women)|
|Levey’s formula (simplified Modification of Diet in Renal Disease equation)|
|GFR (mL/min/1.73 m2)=186×(creatinine [mg/dL])−1.154× (age [years])−0.203×0.742 (in women)×1.210 (in blacks)|
|Chronic Kidney Disease (CKD) Epidemiology Collaboration formula|
|GFR=141×min (SCr/k, 1)a×max (SCr/k, 1)−1.209× 0.993Age×1.018 (if female)×1.159 (if black)|
|where SCr=serum creatinine, k=0.7 for women and 0.9 for men, a=−0.329 for women and −0.411 for men, min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.|
As is the case for albuminuria, reduced GFR is an independent determinant of CV morbidity and mortality in the general population. Contrasting results, however, have been reported in T2DM patients. Large prospective surveys have shown a stepwise increase in probability of CVD or death with decreasing eGFR.19,20 Conversely, in an 11-year follow-up prospective cohort study in Italian T2DM patients, macroalbuminuria was the main predictor of mortality independent of both eGFR and CV risk factors, whereas eGFR signaled no further increase in CVD risk in normoalbuminuric individuals.21
An ongoing observational study in a large population of T2DM patients, the Renal Insufficiency and Cardiovascular Events (RIACE) study, aims to quantify the relationship between eGFR and CVD independent of albuminuria and traditional CVD risk factors. The baseline data show that 19% of patients with eGFR >60 mL/min/1.73 m2 have microalbuminuria or macroalbuminuria, and, conversely, that among those with CKD (19% of the whole cohort), 57% are normoalbuminuric, 31% are microalbuminuric, and 13% are macroalbuminuric. Moreover, 69% of the patients do not have retinopathy, and 43% show neither albuminuria nor retinopathy. These cross-sectional associations suggest two considerations. First, increased albuminuria and reduced GFR may represent complementary, if overlapping, manifestations of kidney impairment and CVD risk in T2DM patients.22 This distinction is based on pathophysiology. Thus, proteinuria—a manifestation of altered glomerular barrier function—is the direct consequence of dysfunction and/or loss of podocytes and thickening of the glomerular basement membrane (GBM). Impaired glomerular function, on the other hand, results from loss of glomerular units (glomerulosclerosis) and mesangial expansion. Clinically, the development of hypertension completes the triad of diabetic nephropathy or, more accurately, of the nephropathy of diabetes (Figure 1). In fact, in each category of UAE, eGFR is significantly lower in hypertensive than in normotensive patients (Figure 2). Second, the RIACE data raise the problem of insufficient performance of both UAE and eGFR as clinical indicators of early impairment of kidney function during the course of diabetes, with reduced eGFR being frequently found in normoalbuminuric patients and GFR estimation working reasonably well only with patients with eGFR <60 mL/min/1.73 m2. These issues have been recognized by the American Society of Nephrology,23 which has recently indicated as a priority the development of biomarkers and predictive algorithms to identify early-onset obesity, metabolic syndrome, and T2DM patients at risk for CKD, to allow implementation of effective preventive programs. In the search for novel biomarkers, both supervised (targeted candidate, particularly podocyte injury markers and oxidative stress pathways) and unsupervised candidate-generating (eg, microarray, proteomics, metabolomics) strategies should be pursued.
Prevention and Treatment of CKD in Type 2 Diabetes
The vast majority of T2DM patients show elevated blood pressure (BP) or abnormal circadian BP rhythms.24 Hypertension often precedes the onset of T2DM, and the coexistence of these two chronic diseases increases the risk for macrovascular complications and ESRD. Therefore, adequate treatment of hypertension is a key point in the management of diabetic complications, and improvement in BP control in T2DM patients is associated with a reduced risk of microvascular and macrovascular disease.
Compounds active on the renin-angiotensin system (RAS) are undoubtedly superior to other antihypertensive compounds in terms of nephroprotection, especially in secondary prevention.25,26 Among classes of medications with different targets—angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors—some may be more nephroprotective than others, but, so far, this has not been proven in published trials with hard end points.
Regarding chronic dual RAS blockade, although several trials have claimed efficacy for BP reduction, recent unfavorable safety data cast doubt on the suitability of such treatment in patients with vascular disease and low levels of proteinuria, dual blockade being potentially harmful for renal hemodynamic.27 This suggests a detailed phenotypical identification of patients most suitable for this treatment, reasonably those with massive proteinuria despite the use of a single RAS-active compound.
Whether the renoprotective effects of RAS inhibitors can be fully accounted for by BP reductions or whether other mechanisms are involved has not been clearly established. The most debated point is the role and real clinical relevance of ancillary mechanisms, such as the antinflammatory and antiproliferative effects exerted by RAS-active drugs, largely documented in cell and animal models28,29 but not confirmed so far by large clinical trials.
The evidence for a better effect of ACE inhibitors and ARBs in preventing macrovascular complications as compared with other drug classes is not strong, mainly for cerebrovascular disease, where calcium channel blockers, for any given BP level, seem to confer some advantage.30,31
It should also be pointed out that, unlike glucose control, relative risk reductions obtained by tight BP control do not persist when BP differences are no longer maintained.32 Therefore, irrespective of the drug class, optimal BP control is a must in nephropathic T2DM. Of note, the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) study has recently shown the beneficial affect of combining optimal glucose and BP levels in preventing both the development of microalbuminuria (−25%) and its worsening to macroalbuminuria (−54%) in T2DM.33
Treatment of hypertension in T2DM is a daunting task, and to reach goal BP often requires aggressive treatment with ≥2 drugs. Just how aggressive this antihypertensive treatment should be is still under debate. Aiming at a systolic level <120 mm Hg appears to reduce the risk of stroke, but the effects on other CV outcomes are uncertain,34,35 and this is even true for kidney function.36
Tight metabolic control is a cornerstone in the prevention and treatment of diabetic nephropathy. Reversal of established lesions with long-term euglycemia obtained by pancreas transplant has been documented in T1DM,37 and, recently, simultaneous kidney and pancreas transplant has also been recommended for T2DM and ESRD patients.38
Besides insulin, whose safety makes it a first-choice drug for any degree of renal impairment, some of the available oral agents should be used with caution in patients with GFRs <60 mL/min because they expose the patient to the risk of hypoglycemia.39 This is especially true of sulphonylureas with a long duration of action. With regard to metformin, its contraindication in CKD patients has been recently revised40 and limited to GFRs <30 mL/min,41 with the suggestion to discontinue it before the administration of a contrast medium for radiologic examinations.40 Thiazolidinediones, which sensitize tissues to insulin action mostly through activation of the transcription factor peroxisome proliferator-activated receptor γ, may have beneficial effects on CKD by decreasing both microalbuminuria and macroalbuminuria.42 Data on the long-term safety of glinides for kidney function are lacking. Similarly, the renal effects of incretin mimetics (dipeptidylpeptidase IV inhibitors, and glucagon-like peptide 1 receptor agonists) as well as amylin on microvascular complications of diabetes have yet to be determined.
Regarding the ability of good metabolic control to prevent kidney damage, it should be considered that the legacy effect of normoglycemia, if reached and maintained since the very beginning of the natural history of the disease, can provide long-term benefits in terms of reduced incidence of microvascular complications, including nephropathy.43
Dyslipidemia has been linked to the development of CKD. Patients with CKD are more likely to have reduced high-density lipoprotein (HDL) cholesterol and elevated triglycerides as compared with individuals with normal renal function. Moreover, they are frequently characterized by small and dense low-density lipoprotein (LDL) particles, known to be strongly atherogenic.44 In the UK Prospective Diabetes Study (UKPDS), high levels of triglycerides were an independent risk factor of microalbuminuria and macroalbuminuria, and low serum HDL cholesterol was also associated with doubling of serum creatinine.11 Despite the fact that the National Cholesterol Education Program Adult Treatment Panel III guidelines emphasize the importance of LDL cholesterol correction to prevent coronary heart disease events, only 75% of patients with CKD on statin therapy reach total cholesterol levels <200 mg/dL, and only 63% have levels <100 mg/dL.45 Recent data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study show that fenofibrate therapy reduced CVD events as well as the progression of albuminuria.46 For reduction in LDL cholesterol, statins are first-choice agents in addition to lifestyle changes. These drugs are typically well tolerated and have been demonstrated to reduce CVD events and mortality in CKD as well as to attenuate the decline in renal function and the increase in proteinuria.45 The combination of these outcomes makes statin therapy invaluable to patients with CKD.
In addition to its deleterious effects on the CV system, smoking is also an independent risk factor for CKD, as among CKD patients an increased mortality has been observed in smokers.47 In T2DM, several epidemiologic and pathophysiologic studies support the concept that smoking favors the onset and/or the progression of renal insufficiency toward renal failure, and there is evidence that this risk is independent of age, sex, duration of diabetes, and degree of metabolic control.48 Moreover, smoking cessation has been shown to reduce progressive kidney damage in comparison with continued smoking in T2DM.49 Smoking prevention and cessation programs should be strongly promoted not only to reduce CVD, but also to avoid the deterioration of renal function in diabetic patients.
CKD is associated with an increased risk of CVD, and an accelerated course of CVD in T2DM patients with nephropathy is likely related to common underlying mechanisms in the renal and CV system and sharing of risk factors. In fact, virtually all the comorbidities frequently found in T2DM patients are known to induce microvascular dysfunction. Conversely, T2DM is associated with early, diffuse, and severe atherosclerosis. The kidney in T2DM is therefore the target of at least a double hit of pathogenic mechanisms (Figure 3).
Because of the asymptomatic nature of the disease, CKD is often not detected until its later stages, thus delaying the opportunity for prevention with antihypertensives, better glycemic control, statins, and lifestyle intervention. This picture calls for a multidimensional approach to the detection of CKD in the general population and of early kidney damage in hypertensive T2DM individuals. A coordinated therapeutic effort in these high-risk patients is likely to favorably influence their outcome. Furthermore, strategies to improve the management of patients with CKD might offer an efficient use of health service resources, focusing on earlier detection and disease prevention rather than late treatment.
Acknowledgments and disclosures: The RIACE study is supported in part through a grant from the Italian Society of Diabetology. The authors have no financial interest to disclose in relation to this manuscript.