Salama, Alan D. MBBS, PhD
Diabetes is already a global epidemic, and it's predicted to grow only more common over the next twenty years as a result of obesity-related type 2 diabetes.
Alan D. Salama, MBBS...Image Tools
Approximately one-third of diabetic patients will develop diabetic nephropathy, and a significant majority of these individuals will reach end-stage renal disease (ESRD) and require renal replacement therapy (RRT). Diabetic nephropathy is the most common cause of ESRD, accounting for approximately 40% of our RRT populations—and even more among certain higher risk groups.
Our current strategies to identify those at greatest risk of nephropathy progression are disappointing, as are our current treatments for these patients. While glycemic control, blood pressure control, and use of renin-angiotensin pathway blockade form the mainstay of treatment, these strategies only delay progression; they are not sufficient to prevent it.
So what else can be done to stave off this inevitable decline in renal function, and which pathways should we be tackling? Evidence for a significant inflammatory contribution to diabetic nephropathy is growing, stimulating a new look at what alternative therapeutic regimens we could utilize to try and prevent the condition from progressing.
Role of RAGE
Diabetic nephropathy is a complex, multifactorial process that occurs in genetically susceptible individuals. An interaction between metabolic abnormalities, hemodynamic changes, and immune activation ultimately leads to the destructive glomerulosclerosis, tubulointerstitial fibrosis, and hyalinosis that underlie the decline in kidney function.
Kidney biopsies are frequently taken in more advanced cases of diabetes or in patients who may have some atypical features, such as a rapid development of nephrotic-range proteinuria or significant hematuria, meaning that we know less about the early changes in “typical” diabetic kidneys.
As such, we have relied on animal studies using various models, many of which do not precisely mimic the human condition. This work has led to certain discoveries and avenues of research but clearly needs to be properly validated in patients.
In the diabetic kidney, the activation of cells by hyperglycemia and the interaction of advanced glycation end products (AGE) with their receptors (RAGE) on renal cells, including podocytes, mesangial cells, glomerular endothelial cells, and tubular cells, leads to the induction of a number of inflammatory cytokines and chemokines.1
These cytokines stimulate recruitment and activation of various leukocytes, with macrophages and T lymphocytes predominating. Furthermore, since certain leukocytes also express RAGE, as well as particular S100 proinflammatory proteins, which are RAGE ligands, a positive cycle of inflammation and leukocyte recruitment and activation ensues, resulting in tissue damage.
RAGE is therefore an important mediator of progression in diabetic nephropathy. Blockade or deficiency of RAGE leads to attenuated disease in animal models of type 1 and type 2 diabetic nephropathy.2,3
Additionally, there appears to be an intriguing link between RAGE and angiotensin that may be of considerable importance in the development of diabetic nephropathy: angiotensin II signalling through the type 2 (AT2) receptor can promote RAGE expression, and RAGE deficiency results in augmented AT2 expression.2 Whether this means that combination therapy targeting RAGE and AT2 receptor signalling would be of benefit in diabetic patients remains to be seen.
Before and After
Recruitment of inflammatory cells into the kidney occurs in different renal compartments at different stages of diabetes.
While macrophages infiltrate the glomeruli early on in the disease, possibly as a result of podocyte-mediated chemokine release, their numbers do not appear related to progressive renal decline. The impact they have on disrupting the filtration barrier and damaging podocytes, mediating albuminuria, is not completely clear.
The number and activation state of the interstitial macrophages, on the other hand, correlate with subsequent decline of glomerular filtration rate (GFR) in both human biopsy series and experimental animal models of diabetes,4,5 demonstrating that ongoing inflammation plays an important role in chronic kidney disease progression.
So is there a benefit to targeting these cells in subjects with early or established renal damage? As yet, there are limited clinical data addressing this issue. However, animal models have demonstrated that a decrease in renal macrophage infiltration is accompanied by an improvement in clinical parameters of diabetic nephropathy, such as a reduction in albuminuria when pentoxifylline is administered for a prolonged time period to diabetic rats.6
More specific therapies that target macrophage recruitment by blocking key chemokines such as monocyte chemoattractant protein (MCP)-1, its receptor CCR2, or the colony-stimulating factor (CSF)-1 receptor (c-fms) all demonstrate a reduction in infiltrating macrophages that is accompanied by an improvement in disease parameters in diabetic rodent models.7
Translating these findings to patients is the next step. Early-phase trials of CCR2 antagonists in patients with diabetes are already under way, as are numerous trials investigating the effects of established interventions on macrophage phenotypes and MCP-1 production in diabetes. (See www.clinicaltrials.gov.)
In addition to macrophages, lymphocytes are recruited early into the diabetic kidney and may also contribute to inflammatory-mediated damage through production of cytokines; activation of other cell types, including macrophages; and RAGE-mediated signalling. However, animals deficient in lymphocytes are equally susceptible to diabetic nephropathy but have altered phenotypes, with lower levels of albuminuria and macrophage activation.7
It is of interest that even with routine angiotensin blockade we are still seeing progression of diabetic nephropathy—but in some cases without significant proteinuria. Whether alterations in infiltrating leukocytes underlie some of these discrepancies is unknown but may be worthy of future study.
Both resident and infiltrating cells are capable of cytokine production, and a number of cytokines appear to play important roles in some of the damage seen in diabetic nephropathy. Among these, interleukins 1 and 6 are elevated in experimental and human diabetic nephropathy and mediate proliferation of intrinsic renal cells, as well as the release of certain profibrotic factors. Whether these cytokines, which can be inhibited by novel biologics in routine use for other inflammatory conditions, can be usefully targeted in early- or late-stage diabetic nephropathy is an idea currently being investigated in numerous clinical trials.
Finally, many of the effects of cell activation and cytokine release, as well as hyperglycemia itself, are mediated by intracellular signalling pathways—especially the stress-activated protein kinases, which include various isoforms of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK).
These molecules have been shown to be upregulated within glomeruli and the tubulointerstitium in diabetic nephropathy, and they have been demonstrated to be important in experimental models of diabetic nephropathy. While these kinases can be targeted by small-molecule inhibitors, the challenge of manipulating these pathways is to find non-redundant isoforms, which can be antagonized without major adverse effects in other systems.
Biopsies, Better Markers
Targeting cell recruitment and cytokine effectors will be most effective if carried out at a time when these factors are inducing the most damage. Should we be using them in patients at early stages of diabetic nephropathy—perhaps even before the earliest signs of microalbuminuria, although not all patients will go on to develop nephropathy—or later when disease is established and the risk-benefit ratio is more in favor of treatment?
Clearly, we need to understand more about the dynamic changes that occur in these pathways in patients and not animal models. This may mean capturing many sequential biologic samples, including serum and urine, as well as performing earlier and perhaps repeated biopsies in patients with diabetes so that we can better define the pathogenic processes that occur.
Kidney biopsies may not only be useful for diagnostic purposes, confirming changes of diabetic nephropathy, but they may also tell us if certain pathways are active in particular patients and could form a rational basis for treatment. In addition, better markers that define who is at greatest risk of developing diabetic nephropathy and progressing to end-stage renal disease would allow for more tailored approaches to treating these patients.
It is now clear that there are indeed other potential means of interfering with the development and progression of diabetic nephropathy beyond angiotensin inhibition and tight diabetic and blood pressure control. Defining which patients would benefit the most, what pathway we should target, and when we should target them are the key questions we need to answer before we can put a brake on what, at the moment, appears to be a runaway train.
1. D'Agati V, Schmidt AM. RAGE and the pathogenesis of chronic kidney disease. Nat Rev Nephrol 2010;6:352–360.
2. Sourris KC, Morley AL, Koitka A, et al. Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor. Diabetologia 2010;53:2442–2451.
3. Flyvbjerg A, Denner L, Schrijvers BF, et al. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes 2004;53:166–172.
4. Nguyen D, Ping F, Mu W, Hill P, Atkins RC, Chadban SJ. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology 2006;11:226–231.
5. Eardley KS, Kubal C, Zehnder D, et al. The role of capillary density, macrophage infiltration, and interstitial scarring in the pathogenesis of human chronic kidney disease. Kidney Int 2008;74:495–504.
6. Han KH, Han SY, Kim HS, Kang YS, Cha DR. Prolonged administration enhances the renoprotective effect of pentoxifylline via anti-inflammatory activity in streptozotocin-induced diabetic nephropathy. Inflammation 2010;33:137–143.
7. Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators Inflamm 2012;2012:146154.
© 2012 Lippincott Williams & Wilkins, Inc.