Associate editor: M.K. Pugsley
Common pathophysiological mechanisms of chronic kidney disease: Therapeutic perspectives

https://doi.org/10.1016/j.pharmthera.2010.05.006Get rights and content

Abstract

It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety of factors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of the urinary tract and genetic alterations. The nephropathies associated with some of these conditions have been modeled in animals, this being crucial to understanding their pathophysiological mechanism and assessing prospective treatments at the preclinical level. This article reviews and updates the pathophysiological knowledge acquired primarily from experimental models and human studies of CKD. It also highlights the common mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearance of a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutic horizon for the treatment of CKD is described. Present therapy primarily based upon renin–angiotensin inhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic and hemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and cell therapies, are all elaborated.

Section snippets

Introduction to chronic renal disease

Chronic kidney disease (CKD) is a life-threatening condition characterized by progressive and irreversible loss of renal function. The increasing inability of the kidneys to properly clear the blood of waste products eventually results in the implementation of dialysis (or kidney transplant) in order to prevent azotemia, systemic organ damage and death. Due to its high prevalence and associated mortality, CKD is an important human and social burden. It is estimated that over 10% of adults in

Hypertensive nephropathy

Hypertension is the second leading cause of end-stage renal disease (ESRD). As an example, according to the United States Renal Data System (U.S. Renal Data System, 2009), about 51–63% of all patients with CKD are hypertensive. This number grows to 90% in patients over 65 years. In the corresponding general population the incidence of hypertension is 11–13% and 50%, respectively. Hypertension causes a nephrosclerotic glomerulopathy characterized by (i) renal vasculopathy affecting preglomerular

Pathophysiology of diabetic renal damage

Diabetic nephropathy is the most common glomerulopathy, and the leading cause of ESRD in the USA and Europe (Molitch et al., 2004). In fact, about 50% of ESRD patients (in the USA) are diabetic (U.S. Renal Data System, 2009). It is important to consider that hyperglycemia is a primary initiator of diabetic nephropathy. In the absence of elevated glycemia, nephropathy does not develop. However, diabetic nephropathy holds a genetic component at two levels: first, the elevation of glycemia; and

Renal mass reduction

Regardless of etiology, the number of nephrons decreases during the progression of CKD. The space formerly occupied by glomeruli and tubuli becomes replaced with an extracellular matrix through a fibrotic process largely resembling scarring (Garber et al., 2003, Prieto et al., 2005). The remaining nephrons increase their filtration rate in order to maintain the excretory need of the organism. Renal dysfunction appears when the remaining nephrons cannot cope with the sustained extra load.

Obstructive nephropathy

Obstruction of the urinary pathway (chiefly resulting from blockade of one or, exceptionally, both ureters) causes progressive deterioration of renal structures leading to chronic dysfunction. Ureteral obstruction gives rise to the hydronephrotic syndrome, characterized by kidney enlargement due to urine collection in the renal pelvis or calyces (Mendelsohn, 2004). It appears clinically as decreased renal function due to anatomical or functional abnormalities compromising urine flow through the

Common mechanisms of progression

Animal models have provided valuable insights into the pathogenesis of chronic kidney diseases. They have proved to be extremely useful for studying and understanding the pathogenetic mechanisms involved in their onset and progression, and for testing new treatments. Knowledge gathered from animal models increases our understanding of human pathology, which in turn helps us to develop new and more specific animal models in which to evaluate novel therapeutic interventions at the preclinical

Renin–angiotensin aldosterone system inhibition

RAAS inhibition has proved to be the most effective therapy at reducing proteinuria and slowing CKD progression in animals and humans (Perico et al., 2008). Furthermore, RAAS inhibition has proved to cause regression and repair of certain apects of CKD, such as glomerular fibrosis, in experimental models (Fogo, 2006a, Fogo, 2006b, Remuzzi et al., 2006).

Angiotensinogen is cleaved by the enzyme renin into the decapeptide angiotensin I, which in turn is cleaved by the zinc metallopeptidase

Therapeutic perspectives

The horizon for the clinical handling of CKD may be analyzed from different perspectives. First, diagnosis must be improved for an earlier detection of progression and for identification of prognostic markers that anticipate which patients will progress more rapidly than others. Second, new forms of therapy are needed to improve our capacity to slow and even halt progression, and to reverse the damage and regenerate renal tissues.

Final remarks

A greater specific knowledge regarding the pathophysiological mechanisms underlying the inception, transformation and progression of pathologies that lead to the development of chronic kidney disease is expected to enable, in the near future, the development of better and earlier diagnostics. This, in turn, should provide a better clinical management of disease progression in order to prevent the need for renal replacement therapy (RRT) or secondary health complications during the patient's

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