Diabetes and the Kidney – Treatment Strategies for Success

Chronic kidney disease (CKD) affects an estimated 10% to 13% adults in the United States and Europe.^[1,2] Patients with CKD are at increased risk not only for end-stage renal disease (ESRD), but for cardiovascular disease and death. Type 2 diabetes is the main driver of CKD in the Western world, accounting for 50% or more of new cases. With the publication of the 2002 National Kidney Foundation Disease Outcomes Quality Initiative (KDOQI) CKD guidelines,^[3] awareness and diagnosis of CKD has improved significantly. This is important because kidney disease is often diagnosed late in its course.

The symptoms of CKD develop slowly. As a consequence, it remains largely asymptomatic. Laboratory testing using either creatinine-based estimating formulae or the presence of albumin or protein in the urine have been recommended screening measures. However, traditional urinary dipstick measures — which are concentration-dependent — often do not identify lower levels of albumin or protein in the urine. Furthermore, changes in serum creatinine between 0.7 and 1.3 mg/dL indicate normality on many laboratory tests, even though a greater loss of renal function occurs between serum creatinine of 0.7 and 1.3 mg/dL compared with 1.3 to 2.0 mg/dL.

Unfortunately, current guidelines classify CKD based on estimated glomerular filtration rate (eGFR) and do not include proteinuria to estimate the risk of progression or associated cardiovascular or renal events. More recent epidemiological evidence indicates that proteinuric patients with minimal changes in eGFR may have greater risk for progressive loss of renal function than patients with more advanced reductions in eGFR who have little or no proteinuria.^[4,5]

Several investigators have suggested that the definitions and staging of CKD be revised to incorporate albuminuria or proteinuria. Two large studies have provided the impetus for revising the staging of kidney disease. Hemmelgarn and colleagues^[4] used a province-wide laboratory registry from Ontario, Canada with a cohort of more than 900,000 adults who were not on renal replacement therapy and who had simultaneous measures of serum creatinine and urinary protein measurement using a urine dipstick or albumin-to-creatinine ratio. They evaluated their subsequent clinical course based on administrative data files. During a mean follow-up of 35 months, 2514 adults (0.4%) had a doubling of serum creatinine and 771 (0.08%) reached ESRD. The risk for either cardiovascular or kidney disease progression was noted to increase significantly with the severity of proteinuria at a given eGFR.

A collaborative meta-analysis conducted by the Chronic Kidney Disease Prognosis Consortium examined the independent and combined association of estimated GFR and albuminuria with all-cause and cardiovascular mortality, and cardiovascular mortality and ESRD.^[6] The meta-analysis used data from 21 studies and included more than 1 million patients from the general population, populations at high risk, and those with CKD. As shown in Figure 1, a greater relative risk for adverse renal and cardiovascular outcomes was associated with lower GFR categories and higher levels of albuminuria.

Figure 1. Relationship between estimated GFR, ACR, and adjusted hazard ratio for progressive CKD, ESRD, and cardiovascular mortality.These data are derived from a continuous meta-analysis of general population cohorts. The 3 lines represent ACR <30 mg/g or dipstick negative and trace (green), urine ACR 30 to 299 mg/g or dipstick positive (gray), and ACR ≥300 mg/g or dipstick ≥2 + positive (blue).
From Levey AS, et al. Kidney Int. 2011;80:17-28. Republished with permission.^[5]
ACR = albuminuria-to-creatinine ratio, ESRD = end-stage renal disease, GFR = glomerular filtration rate.

Importantly, an albumin-to-creatinine ratio greater than 30 mg/g was associated with a statistically significant increased risk of adverse kidney outcomes, even in people with estimated GFR greater than 60 mL/min per 1.73 m². Thus, these 2 studies^[4,6] provide important evidence that there is an increased risk of adverse renal and cardiovascular outcomes with estimated GFR below 60 mL/min per 1.73 m², independent of proteinuria, and that the risk is more substantial for those with estimated GFR levels in the 30 to 44 mL/min per 1.73 m² range compared with those with estimated GFR levels of 45 to 59 mL/min per 1.73 m². Thus, it seems reasonable to incorporate both estimated GFR and levels of proteinuria or albuminuria in staging CKD as outlined in the Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference report (Figure 2).

Figure 2. Composite ranking for relative risks by GFR and albuminuria from KDIGO controversies conference report.
From Levey AS, et al. Kidney Int. 2011;80:17-28. Republished with permission.^[5]

Although the staging considerations have helped increased awareness, the late diagnosis may limit some of our opportunities to preserve GFR and reduce cardiovascular morbidity and mortality. The aging of our population, increasing obesity, and increased prevalence of hypertension and type 2 diabetes raise important concerns about a widening epidemic of CKD. Lifestyle modifications such as proper diet, weight control, and exercise may help attenuate some of the CKD burden. Most of our current clinical approach is focused on secondary prevention of cardiovascular disease after CKD is diagnosed.

Most treatment strategies focus on controlling blood pressure and blood glucose. However, CKD is not a single process that can be reversed by improved blood pressure and glycemia control. A variety of therapies will be required to target the many facets of the various disease progression processes, whether they be inflammatory, immune, toxic, or final common pathophysiological pathways such as glomerular capillary hypertension.

Future treatment strategies should improve our ability to delay progression of CKD. Perhaps even more importantly, future strategies should focus on ways to increase awareness and improve our opportunity to provide primary prevention, as opposed to the more traditional later-stage interventional processes that are currently utilized. Putting a price tag on renal disease replacement therapy is not realistic, as most patients with CKD die before they reach the requirement for renal replacement therapy. Medicare statistics in the United States indicate that individuals with CKD are 5 to 10 times more likely to die than to reach dialysis.^[7] Thus, the enormity of the burden of CKD is not best measured simply by healthcare resource utilization.

Matthew R. Weir, MD