What is diabetic nephropathy?
Diabetic nephropathy can be defined as a microvascular complication of diabetes marked by albuminuria and a deteriorating course from normal renal function to end-stage renal disease (ESRD). Diabetes is a disease which is caused by the inadequate production of insulin by the body or by the body not being able to properly use the insulin that is produced thereby resulting in hyperglycaemia. The high glucose and other abnormalities of diabetes may lead to kidney damage known as diabetic nephropathy. There are two main types of diabetes, type I, which is insulin dependent, and type II, which is non-insulin dependent. Type 2 diabetes is characterised by insulin resistance, i.e., the failure to respond to normal concentrations of insulin1. Type 1 diabetes is when the body no longer makes insulin.
Diabetic nephropathy occurs in 30-40% of all diabetic patients and has become the leading cause of end stage renal disease in the western world2. Persistent albuminuria is the hallmark of diabetic nephropathy, which can be diagnosed in the presence of diabetic retinopathy but in the absence of any clinical or laboratory evidence of other kidney or renal tract diseases 3-6. This definition is valid in-patients with either type 1 or type 2 diabetes. It is highly consistent with clinical studies showing that hypertensives, diabetics (types 1 and 2), and persons with CKD and proteinuria lose kidney function faster than those without proteinuria 7-13
The clinical syndrome termed ‘diabetic nephropathy’ is characterised by persistent albuminuria, early arterial blood pressure elevation, a relentless decline in glomerular filtration rate (GFR), and a high risk of cardiovascular morbidity and mortality4
To understand therapeutic interventions of diabetic nephropathy I feel it is important to briefly provide a review of the salient pathophysiologic mechanisms involved in the genesis of renal disease (nephropathy) in diabetes.
Pathophysiological mechanisms involved in the genesis of renal disease (nephropathy) in diabetes.
The underlying basis of diabetic complications is the result of prevailing levels of hyperglycaemia. A key step linking glucotoxicity to cell dysfunction in diabetic nephropathy is the association of excessive glucose levels and excess accumulation of extracellular matrix (ECM) within the glomerulus and interstitium14, 15, which leads to renal hypertrophy. Renal hypertrophy is an early event; irreversible changes such as glomerulosclerosis and tubulointerstitial fibrosis are preceded by hypertrophy16. Parallel to and to some extent concomitant with renal hypertrophy, hyperfiltration and intrarenal hypertension develop in type 117 as well as in type 2 diabetes18.
Transforming growth factor-? (TGF-?) appears to be crucial in the accumulation of extracellular matrix and development of renal hypertrophy16. TGF-? has received much support as a critical mediator of the glucotoxicty- induced accumulation of mesangial matrix19, as many metabolic and humural factors that are characteristic of diabetic milieu all converge on a downstream pathway to stimulate the expression of TGF-?20, 21. This information qualifies TGF -? as a causative agent of mesangial ECM expansion and renal insufficiency in diabetic nephropathy.
TGF-? also links the metabolic theory with the hemodynamic theory of formation of diabetic nephropathy, as intraglomerular hypertension is a potent stimulus for activating the renal TGF-B system. Epidemiological data have convincingly shown that BP is linked to CKD and proteinuria 22,23, and kidney disease-related mortality 24. There is a compelling physiologic basis for the observations that sustained BP elevations cause CKD, maybe via the TGF -? pathway, leading to disordered regulation of GFR. As hypertension is a complication present in diabetes, it is another major factor in the pathogenesis of diabetic nephropathy. Therefore drugs that antagonise the renin-angiotensin-aldosterone system (RAAS) such as ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) seem the obvious option for therapy, as it is RAAS that controls blood pressure in normal physiology.
Recent evidence suggests that increased superoxide formation after high glucose-induced throughput in the mitochondrial electron-transport chain generate reactive oxygen species, which are involved in the development of some diabetic complications 25. Particularly in the development of diabetic nephropathy, proteins modified by glucose or glucose-derived products such as methylglyoxal, i.e., Amadori products, and advanced glycation end products (AGE) play a pivotal role 17. Increased mitochondrial oxidation of glucose also activated protein kinase C (PKC) 25and subsequently mitogen activated protein kinases (MAPK) 26.
The pivotal involvement of the rennin-angiotensin-aldosterone system (RAAS) as a risk factor and a therapeutic target:
The RAAS system has evolved to play a primary role in preserving hemodynamic stability. It orchestrates this by regulating extracellular fluid volume, sodium balance and cardiovascular function 27. RAAS is poised to respond to threats that compromise blood pressure stability and extracellular fluid volume homeostasis 28,29. These challenges include loss of effective blood volume, deficiency of intravascular sodium and water content, and any situation associated with unstable hemodynamics 28, 29. The RAAS is classically viewed as an enzymatic proteic cascade, which through the generation of intermediate peptidic products finally leads to the production of angiotensin II (AngII), a small octapeptide. 30, 31.
The steps or the make up of the RAAS cascade is as follows. Renin is a proteolytic enzyme stored in the granular cells of the renal juxtaglomerular apparatus. Once released, renin cleaves a plasma ?2 – globulin, angiotensinogen, liberating the decapeptide angiotensin I. Plasma angiotensin I is then acted on by angiotensin converting enzyme (ACE) on the surface of endothelial cells, giving rise to the octapeptide angiotensin II, a major effect of Ang II is vasoconstriction amongst others. This is the target of ACE inhibitors and Angiotensin receptor blockers. The next stage in the cascade is the action of angiotensin II promoting release of the steroid hormone aldosterone from the zona glomerulosa cells of the adrenal cortex. Aldosterone increases Na+ retention and enhances Na+ reabsorption 32. See figure 1:
Figure 1: Renin-angiotensin-aldosterone system
There have be links found between glucotoxicity and increases in certain factors (e.g. TGF -?) and pathways, which have been shown to lead to damage of the kidney. There must be other factors and bodily systems which a play an intermediate role between metabolic and humural factors that are characteristic of diabetic milieu and the stimulation and expression the damaging entities causing diabetic nephropathy. RAAS and in particular Angiotensin II (see section of RAS) is one of the probably many missing parts to this puzzle.
RAAS is critical in maintaining normal hemodynamics and electrolyte balance, excessive or maladaptive activation of this hormonal cascade can engender pathologic changes in the kidney. High glucose stimulates the synthesis of angiotensinogen and angiotensin II (AngII) 33. This may lead to unregulated and excessive production of AII and is associated with renal injury. Kidney disease results from any pathologic process that leads to nephron injury and loss. With a fall in the number of functioning nephrons, those that remain experience glomerular capillary hypertension and increased single nephron GFR with resulting hyper filtration. These changes are initially adaptive to maintain GFR, over the long term, however, they have a deleterious effect on renal function because of pressure-related glomerular injury 34. In addition to hyperfiltration-associated glomerular injury, transmission of systemic pressures through dilated afferent arterioles to the glomerular capillaries promotes cell death. The damage caused by glomerular hyperfiltration and its associated adverse effects is also important in the pathophysiology of diabetic nephropathy. With excessive glomerular capillary pressure and hyperfiltration, the RAAS is also significantly up-regulated, which further contributes to progressive kidney damage from any cause. Local stimulation of RAAS from pressure related glomerular damage further increases glomerular capillary pressure through AII driven efferent arteriolar vasoconstriction, contributing significantly to renal injury that develops in diabetic nephropathy 35.
In general the angiotensin polypeptide exerts hemodynamic as well as trophic, inflammatory, and profibrogenic effects on renal cells36. More specifically angiotensin has a role as a potent vasoconstrictor. It also possesses significant mitogenic properties; it activates AT1 receptors and MAP (mitogen-activated protein) kinase pathway, inducing cell proliferation and tissue remodelling 37, 38. By acting through multiple pathways, AII stimulates the production of a group of cytokines and growth factors.
AII-induced stimulation of transforming growth factor [beta] (TGF-[beta]), platelet-derived growth factor, and nuclear factor-[kappa]B leads to inflammation, fibroblast formation, and collagen deposition 37,38. AII also promotes collagen deposition by inhibiting the action of proteases that are normally required to degrade abnormal tissue proteins 27. The sum of all of these effects in the kidney is the increased development of glomerulosclerosis and tubulointerstitial fibrosis, ultimately enhancing renal injury 37,38. On the other hand, shear stress and mechanical strain, resulting from altered glomerular hemodynamics and glomerular hypertension, induce the autocrine and/or paracrine release of cytokines and growth factors 33, which in turn plays a role in genesis of glomerulosclerosis and interstitial fibrosis.
Therefore it can be said that the overactivity of the Renin-angiotensin-aldosterone system (RAAS) plays an essential role in the pathophysiology of diabetes-related complications 39, 40. From this is it can be appreciated why the Renin-angiotensin-aldosterone system and in particular angiotensin II is the therapeutic target for therapies to reduce damage to the kidneys that has been initiated by high glucose levels thereby taking the name of diabetic nephropathy or diabetic kidney disease. As it can be seen hemodynamic, metabolic and the subsequent structural changes are important and are all interrelated in causing diabetic nephropathy (and many renal diseases).
Angiotensin converting enzyme inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs):
As the pathophysiology of kidney disease has been established above I feel it is now appropriate to discuss the therapies that I used to prevent diabetic nephropathy occurring or progressing. In this section I shall discuss the mechanisms by which angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) act, their relative merits, disadvantages and differences. Also discussing the differences in therapy if any between type 1 diabetics with nephropathy and type 2. Finally I shall discuss the action of these drugs when used in combination.
The main common action of ACEIs and ARBs is the reduction of the stimulation of the Angiotensin II type 1 receptors (AT1) by its ligand angiotensin II 41, however, this is achieved by different mechanisms by each drug
ACEI inhibitors achieve this effect by blocking angiotensin converting enzyme (ACE) 41, which retards the conversion of angiotensin I to angiotensin II 42, thus limiting the amount of angiotensin II (AngII) available for binding to the AT1 receptor 41. However, it is now recognised that this inhibition is far from complete, as measurable plasma concentrations of ACE are known to exist during chronic therapy 43. It is now postulated that alternative pathways for the formation of angiotensin II, either directly from angiotensinogen or from angiotensin I, can circumvent the intended action of ACE inhibitors 44, possibly by alternative non-ACEI-sensitive enzymes such as chymase and other serine proteases 45, which may lead to a less effective RAAS block (see figure 2).
Such incomplete blockade may explain the observation that plasma angiotensin II levels return to normal after chronic ACEI treatment, the so-called ‘ACE-Escape’ phenomenon. 46,47. In addition, ACE is responsible for the catabolism of bradykinin 40, therefore ACEI appear capable of inhibiting the breakdown of Bradykinin, which results in the increased availability of bradykinin 38. Kinins (bradykinin) contribute significantly to the blood pressure lowering effects of ACEI 48 through the exhibition of vasodilatory and growth inhibitory properties. (See figure 3). Whereas elevated bradykinin levels have been shown to mediate at least part of the therapeutic benefit of ACEI in the settings of hypertension 48 and cardiac failure 49, the role of bradykinin in the renoprotective effects of ACEI is uncertain 50,51. In type 1 diabetes ACE-I are the first choice drug.
Blockade of angiotensin subtype 1 (AT1) receptor inhibits RAAS by an entirely distinct mechanism, and also produces antihypertensive and renoprotective effects. Their mechanism of action is based on antagonism (blocking) of the (AT1) receptor and, potentially, allowing AII stimulation of the AT2 receptor. Therefore ARBs work selectively at the AT1 receptor, leaving the AT2 unaffected; this leads to exaggerated stimulation of the AT2 receptor. Unlike ACE inhibitors they do not directly affect the formation of bradykinin 52. However, animal models suggest that by allowing AII to bind the AT2, ARBs facilitate the formation of bradykinin, other antimitogenic 53 and growth inhibitory substances associated with this receptor pathway. Furthermore most studies indicate that AT2 counteracts the vasoconstrictor 54 and proliferative action 55 of AT1 e.g. by promoting apoptosis 56,57.
However, it should be noted new data from animal studies indicate that some deleterious effects of angiotensin II on glomerular cell migration, tubular cell proliferation, and development of urinary protein excretion may be mediated through the angiotensin II type 2 receptor 58,59,60. As explained above it is the unopposed activation of the AngII type 2 receptor (AT2) by which AT1 antagonists can also increase bradykinin levels e.g. in the vessels 61 or in the kidney 54. However, the magnitude of bradykinin increases after AT1 antagonists are presumably much less than after ACE Inhibitors. The role of unopposed stimulation of AT2 for the effects of AT1 antagonists will have a major bearing on the question of whether combined therapy with AT1 antagonists and ACE inhibitors will exert additive benefit.
As ARBs antagonise the actions of angiotensin II at the receptor level, their effects would not be overcome by non- ACE dependent angiotensin II production. On the other hand, ARB therapy results in elevated angiotensin II levels (through loss of feedback inhibition of renin by the juxtaglomerular apparatus) that would tend to antagonise its therapeutic effects if non-competitive blockade of all AT1 receptors was not achieved. The lack of suppression of the degradation of bradykinin and possibly the incomplete inhibition of aldosterone seem to be the main drawbacks of ARBs.
There have been some dose escalation studies specific ARBs, 62 evaluated the optimal dose of losartan for renoprotection and blood pressure reduction. Fifty consecutive type 1 diabetic patients with diabetic nephropathy received increasing doses of losartan 50,100 and 150mg a day in three periods each lasting 2 months. The study measured albuminuria, 24hr BP and GFR. All doses reduced levels of all three measures. The results showed that the optimum dose of Losartan is 100mg. In type 2 diabetes, ARBs are considered as the first choice drug.
There is evidence in published studies to show that ARBs reduce microalbuminuria/ proteinuria and prevent progression of diabetic and non-diabetic chronic kidney disease. In the RENAAL study, losartan was compared with conventional therapy in 1513 persons with type 2 diabetes with hypertension and nephropathy 63. Fewer patients in the losartan group (16% risk reduction) reached the primary composite end points of time to doubling of serum creatinine, progression to ESRD, or death over a mean follow-up of 3.4 years 63.
Most important to the nephrology community, losartan reduced progression to ESRD (28% risk reduction) and doubling of serum creatinine (25% risk reduction) in these patients 63. These positive findings were associated with an average reduction in the level of proteinuria of 35%, despite similar blood pressure control between the groups. Similar findings were noted in the IDNT study, which employed irbesartan (300 mg/day) in persons with type 2 diabetes mellitus and nephropathy 64. During a mean follow-up of 2.6 years, irbesartan therapy was associated with a 20% risk reduction in composite end points compared with placebo. These data suggest that modulation of the RAAS with ARBs in persons with type 2 diabetes is a useful and logical strategy.
ACEIs and ARBs like many other drug therapies are not without there side effects. Increased Bradykinin levels may account for important differences in tolerability between ACE inhibitors and angiotensin II receptor blockers. Dry cough occurs in 5% to 15% of patients taking ACE inhibitors, but the relatively common problem of cough observed with ACE inhibitors does not occur with the ARBs 65. Not infrequently, ‘ACE inhibitor cough’ is a manifestation of pulmonary congestion and improves with diuresis.
Angioedema, a potentially life threatening complication of ACEIs in 0.1% to 0.5% of patients, has been reported only rarely with ARBs, and a direct causal link is unproven. First- dose hypotension with ACE inhibitors typically occurs in patients who are volume depleted due to diuretics and/ or sodium restriction. Hyperkalaemia can occur with both ACEI and ARBs, especially in diabetic patient and also those with chronic renal insufficiency, taking potassium sparing diuretics or potassium supplements. Both ACEIs and ARBs are contraindicated during pregnancy. The majority of studies have shown that there is no significant difference in protection and remission of patients with diabetic nephropathy in terms of reduction in proteinuria between ACEIs and ARBs.
The rationale for a combination therapy with AT1 antagonists and ACE inhibitors is based on the assumption that certain non-classical or alternative pathways of the RAAS produce substantial amounts of Ang II. Also ACEIs and ARBs antagonise the RAAS at different sites, therefore the dual RAAS blockade with both ACEI and ARBs may lead to a synergistic blockade of RAAS not obtainable by either drug alone. AT1 antagonists would counteract the AT1- mediated effects of residual Ang II formation by non-ACE enzymes like chymase (see figure 2), whereas ACE inhibitors would additionally increase kinins see (figure 3.) Therefore using the combination therapy cancels out some of the drawbacks of the individual therapies.
As with many drug therapies there is always a concern with the safety of the intervention. However, the potential concern that combining AT1 antagonists and ACE inhibitors may lead to more side effects, e.g., hyperkalemia, has been alleviated by three recent randomised double-blind parallel and cross-over studies 66,67,68 in type 2 diabetic patients with microalbuminuria 67 or overt nephropathy 68.
The combination of candesartan and lisinopril turned out to be safe in 68 patients with type 2 diabetes and albuminuria 67, and the combination of valsartan and benazepril in 86 patients with renal insufficiency of various etiologies 66. The side effects were said to be similar to those, which occur when using ACE inhibitors alone, it was concluded from these studies that the combination was well tolerated and know severe side effects were observed. However, one must add cautionary note that these studies had insufficient power to address the frequency of rare serious adverse events e.g. angioneurotic oedema.
The CALM study 69 was designed to compare the efficacy of AT1 antagonists and ACE inhibitors for lowering microalbuminuria in-patients with type 2 diabetes. Combination therapy decreased albumin excretion (by 50%) significantly more than candesartan alone (24%) but not significantly more than lisinopril alone (39%).
In light with the information in this section I feel there is a key role for the double blockade in the therapy of diabetic nephropathy. It seems reasonable to recommend combination ACEI and ARB therapy in any CRD patient in whom blood pressure (<130/80) and antiproteinuria (<1g/day) goals are not achieved with monotherapy.
In conclusion, it can be said that multiple factors and complications in diabetes lead to the development of diabetic nephropathy. The functioning or overactivity of the renin-angiotensin-aldosterone system plays a central role in the pathogenesis. Its protein cascade being effected by the high glucose levels typical of diabetes causing increases in angiotensin II and other peptides which set off other sets of reactions which result in damage to the kidneys, through certain factor, TGF- ? being a prominent one. The main target ACEI and ARBs is the RAAS and both have been shown to be effective individually and in combination. I do not feel that either one ACEI or ARBs outplays the other in effectiveness of renoprotection. Therefore, the choice of drug or drug combination will depend on the individual patient, his or her response to certain drugs in terms of adverse side effects, the type of diabetes present and the stage at which their nephropathy is residing.
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