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Pathophysiology, Prevention and Management of Chronic Kidney Disease in the Hypertensive Patient With Diabetes Mellitus Anna Solini, MD; Ele Ferrannini, MD

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. ª2011 Wiley Periodicals, Inc.

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ype 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 From the Department of Internal Medicine, University of Pisa, Pisa, Italy Address for correspondence: Ele Ferrannini, MD, Department of Internal Medicine, University of Pisa, Via Roma 67, I-56100 Pisa, Italy E-mail: [email protected] Manuscript received January 18, 2011; revised January 26, 2011; accepted February 1, 2011

doi: 10.1111/j.1751-7176.2011.00446.x

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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. 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

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(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. 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 11year 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

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Table. Classification of CKD According to the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (K ⁄ DOQI) Stage Description 1 2 3 4 5

Kidney damage with normal ⁄ increased GFR Kidney damage with mildly decreased GFR Moderately decreased GFR Severely decreased GFR Kidney failure

GFR, mL ⁄ min ⁄ 1.73 m2 >90 60–89 30–59 15–29 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

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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.

Figure 1. The clinical triad of diabetic nephropathy. GFR indicates glomerular filtration rate; GBM, glomerular basement membrane; BP, blood pressure; T2DM, type 2 diabetes mellitus; ESRD, end-stage renal disease.

Figure 2. Estimated glomerular filtration rate (eGFR) (by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) in type 2 diabetic patients with or without hypertension by category of urinary albumin excretion. Data from the Renal Insufficiency and Cardiovascular Events (RIACE) study (ClinicalTrials.gov, NCT00715481).

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