Retardation of Kidney Failure

By 2010 there are more than 2 million patients worldwide on maintenance dialysis, a 400% increase in 20 years. This increase in prevalence, occurring predominantly in developing nations, is being driven especially by an increase in the incidence of diabetes. This is an impossible burden for developing nations to meet standard medical care for patient with end stage renal disease. The number of patients with end-stage renal disease (ESRD) is but the tip of the iceberg of the total number of patients with progressive chronic kidney disease (CKD). There are several therapeutic strategies for slowing or even preventing the progression of CKD. These therapies may be effective in patients with even advanced disease. Universal application of these therapies has the potential to greatly reduce the burden of renal failure worldwide.

Factors Causing Progression

Without treatment, renal function declines gradually in the majority of patients with CKD (Stages 2 to 4), eventually leading to kidney failure (Stage 5). The rate of progression shows considerable interindividual variability, and is dependent on multiple factors. The latter can be divided into at least 3 groups (Table 1): (i) susceptibility factors that increase vulnerability to develop chronic renal injury; (ii) initiation factors that directly cause renal damage; and (iii) progression factors that accelerate the deterioration in renal function following injury to the kidney. Susceptibility factors cannot be specifically modified by current therapy, and are therefore defined as “non- modifiable”. Males have a two-fold higher rate of decline of chronic renal disease. The natural loss of glomerular filtration rate (GFR) of 1 mL/min/year from age 25, suggests that the age at the time of CKD onset influences the amount of remaining viable kidney tissue (renal reserve). Recent studies suggest that nephron development at birth may have an important role in determining the rate of progression. Undetermined genetics factors may also mediate progression. Polymorphism of the angiotensin-converting enzyme is the most well studied and many other candidate genes are under investigation. The most important initiation factor, the cause of the underlying nephropathy, is an important determinant of rate of progression. Untreated diabetic nephropathy is considered to have the fastest rate of progression, with a typical rate of loss of GFR being 10 mL/min/year. Sustained elevation in the systemic blood pressure (greater than 140/90 mm Hg) and nephrotic-range proteinuria are the most important progression factors that strongly predict renal function decline, regardless of the underlying cause of CKD. In addition, it is well established that the severity of tubular atrophy and interstitial fibrosis on the renal biopsy predicts a poor renal outcome. Studies suggest that factors such as hyperglycaemia, hyperlipidaemia, smoking and pregnancy (in the presence of impaired GFR) also predict a more rapid progression. Other factors for which there is some evidence include obesity, hyperuricaemia, increased sympathetic nervous system activity, hyperphosphataemia, acidosis, and endogenous cortisol synthesis.

Slowing or Reversing Progression

Proven Strategies Strategies which have been proven in randomised controlled trials to slow the progression of diabetic and non-diabetic CKD are summarised in Table 2. The single most important means of slowing disease progression is adequate control of systemic blood pressure. The need for a low-normal blood pressure applies particularly to proteinuric patients and those with diabetes. The evidence has been gleaned from trials involving angiotensin- converting enzyme (ACE) inhibitors but probably applies to other antihypertensive therapies as well. As a result of this evidence, the current guidelines are for a blood pressure <130/805 and a systolic as low as 110 in proteinuric patients, if tolerated. It should be remembered that the goals of anti-hypertensive treatment in CKD are not only to lower blood pressure and slow disease progression, but also to reduce the risk of cardiovascular disease.

ACE inhibitors- ACE inhibitors have been shown to slow the progression of diabetic and non-diabetic renal disease in comparison to placebo, and also in comparison to a non dihydropyridine channel blocker. Higher doses have a greater anti-proteinuric effect (even in the absence of a greater reduction in blood pressure), the maximum tolerated dose should be used. The protective effect of ACE inhibitors is seen even in patients with low-grade proteinuria, or advanced renal disease. The anti-hypertensive effect of ACE inhibitors can be significantly improved by the addition of a diuretic or salt restriction. The cardio-protective effect of ACE inhibitors appears to be greater for high-risk patients, such as diabetics with renal insufficiency.

Angiotensin receptor antagonists- Angiotensin receptor antagonists (ARBs) have been shown to slow progression in patients with type 2 diabetes. The relative risk of ESRD was reduced by 20% to 30% in these studies. In type 2 diabetic patients with microalbuminuria, the ARB irbesartan was shown to reduce the progression to clinical diabetic nephropathy. ARBs are the first-line therapy for ACE inhibitor-intolerant patients, but probably not in others until they have shown to be as cardio-protective as ACE inhibitors.

Combined ACE inhibitor and ARB- A combination of an ACE inhibitor and ARB has been shown in several trials to have a greater anti-proteinuric effect than either treatment alone, and recently has been shown to have a greater effect on slowing the progression of renal disease. However, it remains uncertain whether combination therapy in non-maximal doses is really more efficacious than either drug in maximal doses

Dietary protein restriction- Restriction of dietary intake is anti-proteinuric and may reduce disease progression in diabetic and non-diabetic renal disease, but the clinical effect is probably small and therefore recommendations are to avoid malnutrition by following a normal protein diet of 0.5 to 1.0 g/kg/day.

Blood sugar control- In type 1 diabetes, intensive glucose control has been shown to reduce the development and progression of albuminuria, a surrogate for disease progression. In type 2 diabetics, intensive glycaemic control produced better microvascular outcome with slowed progression.

Unproven TherapiesThere are many other therapies that have been proposed to slow the progression of CKD. With some, evidence is based on surrogate markers such as proteinuria, or comes from small trials. As proteinuria is a hallmark of, and pathogenetic factor for, disease progression, it is likely that anti-proteinuric therapies may also slow progression to ESRD. Other anti-proteinuric therapies with this potential are summarised in Table 3

Calcium entry blockers- Dihydropyridine calcium entry blockers (CEBs) do not reduce proteinuria despite lowering blood pressure, and may hasten disease progression in comparison with ACE inhibitors and beta blockers. In contrast, non-dihydropyridine CEBs are anti-proteinuric, and therefore have the potential to retard progression. Dihydropyridine CEBs may be used in patients with renal disease when combined with anti-proteinuric drugs such as ACE inhibitors and ARBs.

Beta blockers- Beta blockers may have as great an anti- proteinuric effect as ACE inhibitors. Some of their probable ability to slow disease progression may involve a sympatholytic action. In fact, ACE inhibitors and ARBs are also have sympatholytic effect.

Aldosterone antagonists- Patients on ACE inhibitors who develop “aldosterone escape” may also escape from their anti-proteinuric effect and the addition of spirono-lactone (25 mg/day) to type 2 diabetics with aldosterone escape has recently been shown to reduce urinary albumin excretion.

Lipid control- The potential of anti-lipidemic therapy, in particular HMG CoA reductase inhibitors, to retard disease progression remains unproven. The added benefit of anti-lipidemic therapy, of course, is its beneficial effect on vascular disease, which is so prevalent in patients with CKD.

Smoking- Epidemiological studies show that cigarette smoking is associated with proteinuria and disease progression. Given the marked effects of smoking on cardiovascular risk, there is no doubt that renal patients should be strongly advised to cease. There are a number of other treatments, including control of uric acid, phosphate restriction, exercise and erythropoietin for which there is circumstantial, anecdotal or inconsistent evidence favouring their efficacy. Whether or not they should be applied universally or in particular patient sub-groups to slow disease progression, will need to wait the outcome of adequately designed studies.

Experimental PossibilitiesRecent studies suggest that the early institution of existing therapies, such as angiotensin blockade, has the potential to reverse established scarring in experimental models of CKD. In addition, as a result of intense basic science research activity, the next decade may see the clinical application of some of newer therapeutic approaches, synergistically with existing therapy. Recently, rapid progress has been made in understanding the molecular structure of the glomerular filtration barrier, and it is expected that this will lead to new and more specific therapies to reduce proteinuria. Other potential experimental approaches to reduce proteinuria include pharmacological agents that modify glomerular basement membrane turnover (such as pentosane polysulphate or heparanase) and block inflammatory mediators which increase glomerular permeability (such as complement C5b-9). Methods to prevent protein-mediated tubulointerstitial injury might include agents that block receptors (megalin and cubulin) which mediate protein uptake into proximal tubular cells or drugs that neutralise the cytotoxic effects of filtered plasma proteins (e.g., complement C5b-9) on tubular cells. Experimental approaches to reactivate signal transduction pathways that were induced at the time of embryonic kidney development may help regenerate a chronically injured kidney. Bone morphogenetic protein (BMP)-7, a member of the TGF-β superfamily, is highly conserved and has an important role in the formation of the developing kidney. Interestingly, the administration of recombinant BMP-7 prevented tubular atrophy, interstitial inflammation and fibrosis in rats with unilateral ureteric obstruction. Similarly, chronic BMP-7 administration reduced tubulointerstitial fibrosis and glomerulosclerosis in the MRL lpr/lpr mouse model of lupus nephritis, and reduced renal hypertrophy and proteinuria in rats with streptozotocin-induced diabetes. Other molecular targets for intervention include growth factors [transforming growth factor-β1, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), connective tissue growth factor, fibroblast growth factor], cytokines (interleukins and TNF), chemokines (MCP-1 and others), cell cycle regulatory proteins, inflammatory mediators (such as complement), endothelin, aldosterone, anti-fibrotic molecules (relaxin), components of intracellular signalling pathways (such as ruboxistaurin, a protein kinase C inhibitor; or mitogen-activated protein kinase system) and antioxidants. The results of these studies in humans are awaited with interest. Uncertainty remains about which of these molecular mediator/s should be targeted, and at what point in the disease process, and how their renal expression should be modified in vivo in a cell-specific manner. The cost-effectiveness of these new agents will require proof and may limit their clinical application. Despite these problems, there is no doubt that the next few decades will yield important advances in the treatment of CKD progression.