Common pathophysiological mechanisms of chronic kidney disease: Therapeutic perspectives

Pharmacology & Therapeutics 128 (2010) 61–81

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Common pathophysiological mechanisms of chronic kidney disease:Therapeutic perspectives

José M. López-Novoa b,d, Carlos Martínez-Salgado a,b,d,Ana B. Rodríguez-Peña c, Francisco J. López Hernández a,b,d,⁎a Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spainb Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spainc National Institutes of Health, Bethesda MD, USAd Instituto Reina Sofía de Investigación Nefrológica, Fundación Íñigo Álvarez de Toledo, Spain

⁎ Corresponding author. Unidad de Investigación, HospPaseo de San Vicente, 58-182, 37007 Salamanca, Spain. Te923 294 669.

E-mail address: [email protected] (F.J.L. Hernández)

0163-7258/$ – see front matter © 2010 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2010.05.006

a b s t r a c t
a r t i c l e i n f o
Keywords:
Chronic renal diseaseAnimal modelsHypertensionDiabetesUreteral obstructionRenal mass reductionTherapy
It is estimated that over 10% of the adult population in developed countries have some degree of chronickidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function thatresults in implementation of renal replacement therapy in the form of dialysis or renal transplant, which mayalso lead to death. CKD poses a growing problem to society as the incidence of the disease increases at anannual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety offactors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of theurinary tract and genetic alterations. The nephropathies associated with some of these conditions have beenmodeled in animals, this being crucial to understanding their pathophysiological mechanism and assessingprospective treatments at the preclinical level. This article reviews and updates the pathophysiologicalknowledge acquired primarily from experimental models and human studies of CKD. It also highlights thecommon mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearanceof a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutichorizon for the treatment of CKD is described. Present therapy primarily based upon renin–angiotensininhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic andhemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and celltherapies, are all elaborated.

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Contents

1. Introduction to chronic renal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612. Hypertensive nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623. Diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624. Renal mass reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625. Obstructive nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636. Common mechanisms of progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637. Current treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648. Therapeutic perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649. Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

64656670707375

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6576

1. Introduction to chronic renal disease

Chronic kidney disease (CKD) is a life-threatening conditioncharacterized by progressive and irreversible loss of renal function.The increasing inability of the kidneys to properly clear the blood of

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62 J.M. López-Novoa et al. / Pharmacology & Therapeutics 128 (2010) 61–81

waste products eventually results in the implementation of dialysis(or kidney transplant) in order to prevent azotemia, systemic organdamage and death. Due to its high prevalence and associatedmortality, CKD is an important human and social burden. It isestimated that over 10% of adults in developed countries suffer somedegree of CKD (De Zeeuw et al., 2005; U.S. Renal Data System, 2005).Direct cost derived from the disease consumes up to ∼2% of healthcare system budgets, themajority of which is consumed by only ∼0.1%of the population receiving dialysis in developed countries (Excerptsfrom the United States Renal Data System, 2000; Xue et al., 2001;Winkelmayer et al., 2002; Szczech & Lazar, 2004; U.S. Renal DataSystem, 2009). CKD can result from a variety of etiologically distinctcauses. Presently, diabetes and hypertension are the two leadingcauses of CKD, although infectious glomerulonephritis, renal vascu-litis, ureteral obstruction, genetic alterations, autoimmune diseasesand others are also common causes of CKD. However, as the diseaseprogresses, a common renal phenotype develops regardless of thecause. In addition to addressing the cause, a greater knowledge of thepathophysiological mechanisms underlying the common progressionof CKD may unravel new targets for pharmacological intervention. Inthis sense, animal models have emerged as important tools forunderstanding the mechanisms implicated in the pathogenic process,and also for the assay of prospective therapies.

2. Hypertensive nephropathy

Hypertension is the second leading cause of end-stage renaldisease (ESRD). As an example, according to the United States RenalData System (U.S. Renal Data System, 2009), about 51–63% of allpatients with CKD are hypertensive. This number grows to 90% inpatients over 65 years. In the corresponding general population theincidence of hypertension is 11–13% and 50%, respectively. Hyper-tension causes a nephrosclerotic glomerulopathy characterized by(i) renal vasculopathy affecting preglomerular arteries and arterioles,resulting mainly from atherosclerosis, endothelial dysfunction, wallthickening and fibrosis; (ii) microvascular disease of the glomerulartuft capillaries; (iii) diffuse glomerulosclerosis and, less often, focaland segmental glomerulosclerosis (FSGS), involving damage to thefiltration barrier constituents (podocytes, mesangial cells and base-ment membranes); and (iv) interstitial fibrosis (Rosario & Wesson,2006). Overall renal blood flow decreases as a consequence ofarteriolar vasculopathy, vascular obstruction and decreased vasculardensity. However, GFR initially stays relatively constant. This is due to(i) increased glomerular capillary pressure resulting from deficient orupwardly reset renal autoregulation; and (ii) damage to the filtrationbarrier resulting in greater permeability. Subsequently, GFR decreasesas a consequence of a progressive loss of surface area, mesangialhypertrophy and increasing glomerular and peritubular fibrosis.Concommitantly, basement membrane alterations produce albumin-uria and protein hyperfiltration.

2.1. The hypertension-renal damage loop

Hypertension is a common outcome of CKD regardless of etiology,which contributes to the progression of renal damage. Approximately40% of patients with stage 2 CKD (glomerular filtration rate, GFR: 60–90 ml/min per 1.73 m2 of body surface), and virtually all in stage 4(GFR: 15–29) or 5 (GFR: b15 ml/min per 1.73 m2 of body surface) arehypertensive (Rosario & Wesson, 2006). Similarly, chronicallyhypertensive animals and humans develop CKD as a consequence ofhigh blood pressure, which mechanically damages renal glomeruliand renal vessels (Wiederkehr et al., 2005). Hypertension-inducedCKD can be also the consequence of non-mechanical damage (e.g.increased angiotensin II (ANG-II) or decreased NO). Epidemiologicalcorrelations between hypertension and renal damage can be inter-preted in both ways. In fact, hypertension may arise from subtle renal

lesions (arteriosclerosis and endothelial dysfunction) resulting fromacquired (genetic) traits and environmental insults (Johnson et al.,2005a,b). Accordingly, nephropathy can also be viewed as a primaryrenal lesion that progresses in parallel to and initiates the rise in bloodpressure. The multidirectional and complex relation among cardio-vascular and renal disease, atherosclerosis, fibrosis and tissuehypoperfusion and ischemia, is reinforced by the fact that (i) allthese conditions share common risk factors, and (ii) the same genepolymorphisms (e.g. of renin–angiotensin aldosterone system—

RAAS-components) seem to be related to many (if not all) of them(Rosario & Wesson, 2006). A vicious circle is closed by renal damage,renal vascular disease and hypertension. Therefore, it is likely thatentering the circle through any of these avenues ultimately generatesand results in an indistinguishable pattern of disease.

A growing body of evidence suggests that hypertension arises fromarenal vasculopathy initially affecting renal arteries, or from renalmicroangiopathy involving preglomerular arterioles that eventuallycauses preglomerular vascular dysfunction or maladaptive remodelingand intrarenal focal ischemic damage (Johnson et al., 2005a,b; López-Hernández & López-Novoa, 2006). Vasculopathies and microangiopa-thies may be (i) caused by genetic determinants; (ii) provoked byenvironmental insults; (iii) secondary to systemic conditions, likeatherosclerosis or the metabolic syndrome; or (iv) derived fromtransient and intermittent fluctuations in blood pressure, whichovertime slowly inflict progressive damage to intrarenal vessels (evenin the presence of a good renal autoregulation; see below in thissection). Such fluctuations may be derived from hyperactive sympa-thetic activity arising from diverse factors that include stress, exacer-bated cold responses, type A personality, etc. (Johnson et al., 2005).

Clinical, epidemiological and experimental correlations betweenhypertension and renal microvascular disease (with or withoutrelevant renal dysfunction) are strong (Goldblatt, 1947; Sommerset al., 1958; Tracy et al., 1986; Rodriguez-Iturbe et al., 2004; Johnsonet al., 2005a). Ultimately, abnormal preglomerular resistance for anygiven level of blood pressure and skewed autoregulation alter theprecise medullary blood flow that signals for the appropriate level ofnatriuresis and blood pressure, leading to hypertension (López-Hernández & López-Novoa, 2006), as Goldblatt envisioned about60 years ago (Goldblatt, 1947). It is easy to postulate how alterationsin a few glomerular vessels would be able to reset the whole renalfunction. Affected nephrons have modified endocrine profiles (e.g.renin secretion) that alter the function of healthy or mildly injurednephrons (Sealey et al., 1988). Then, hypertension-associated renaldamage would paradoxically originate from renal damage itself or,more precisely, from subtle, focal renovascular damage, wherehypertension would be another mere consequence acting as amagnifying amplifier in the vicious circle of malignancy.

2.2. Hypertensive nephropathy

In general terms, both genetic [e.g. spontaneously hypertensiverats (SHR; Camp et al., 2003); stroke-prone SHR (SHR-SP; Nakamuraet al., 1996); fawn hooded hypertensive rats (FHH; Weichert et al.,2001); Lyon hypertensive rats (LHR; Sassard et al., 2003)] andinduced [e.g. uninephrectomy (UNX)+DOCA salt (Kretzler et al.,1994), or L-NAME administration (Van Dokkum et al., 1998)] animalmodels of hypertension replicate most of the essential eventsassociated with human glomerulopathies. Hypertensive animalsusually develop a clear nephropathy with renal dysfunction biomar-kers and histological alterations, starting with glomerulosclerosis andprogressing to nephron degeneration and tubulointerstitial fibrosis,similar to the findings in human hypertensives (Kriz et al., 1998). Anexception is observed with Milan hypertensive rats, whose age-dependent nephrosclerosis is less evident than in the Milannormotensive rat (Brandis et al., 1986; Menini et al., 2004). However,in general, animal models of hypertension and hypertensive renal

63J.M. López-Novoa et al. / Pharmacology & Therapeutics 128 (2010) 61–81

damage recapitulate specific elements of the corresponding humansituation to a yet undetermined degree. For example, it is unknown towhat extent genetic models of hypertension mimic the geneticbackground that determines not only pressure rise, but also pressure-independent neuroendocrine influences that modulate the extent andmechanisms of pressure elevation and end organ damage (Stoll &Jacob, 2001).

In this sense, the human corresponding idiopathic (also termedprimary or genetic) hypertension is difficult to represent using asingle animal model. First, because animal models usually havehomogeneous genetic backgrounds derived from in-bred selection,which is at odds with the inter-racial and inter-individual heteroge-neity of the human genome. Second, because the term idiopathichypertension probably embraces etiologically different diseases,phenotypically indistinguishable with present-day knowledge, fur-ther variability is introduced. For example, atherosclerosis is presentin a high proportion of cases of human idiopathic hypertension,whereas it is not observed in genetically hypertensive rat strains suchas SHR and SHR-SP, except when specifically induced by a high lipiddiet (Yamori et al., 1984). Similarly, the activity of systemic RAAS isvariable in human idiopathic hypertensives whereas it is homoge-neously lower in SHR (Watanabe et al., 1983; Zhang et al., 1996) andLHR, compared to their respective normotensives, the Wistar rat andthe Sprague–Dawley rat (Sassard et al., 2003), especially as bloodpressure increases.

2.3. Renal autoregulation: a key to hypertensive nephropathy

Hypertension-associated CKD progression is highly dependent on(i) renal blood flow autoregulation and renal hemodynamics,(ii) artificial maneuvers or genetically-determined factors that modifyrenal function or renal tissue homeostasis, independently of theiraction on blood pressure or renal hemodynamics, and (iii) geneticsusceptibility factors. Renal autoregulation endows the kidneys withthe capacity to maintain constant glomerular flow and pressure uponchanges in systemic and renal perfusion pressure. Autoregulation isattained through vasoconstriction and vasodilation of preglomerular(afferent) arteries and arterioles. In addition to the insulation of renalfunction from the influence of fluctuations in systemic blood pressure,one of the most important physiological functions of autoregulation isbelieved to be the protection of renal tissues from mechanicaloverload derived from high blood pressure (Loutzenhiser et al.,2006). Accordingly, animal strains and experimental models that keepautoregulation physiologically functional are significantly less proneto developing hypertensive renal damage than those that have lostautoregulatory capacity. For example, fawn hooded rats are believedto bear a genetic susceptibility to renal damage. Fawn hoodednormotensive (FHN) rats are more susceptible than other normoten-sive strains to aging-induced renal damage or to artificially inducedhypertensive nephropathy, as by L-NAME administration (VanDokkum et al., 1997, 2000).

Similarly, FHH rats are more susceptible to renal damage thanbetter autoregulating strains, such as the SHR. Both FHN and FHH havea defective autoregulatory capacity (Van Rodijnen et al., 2002).Genetic susceptibility to renal damage in FH rats has been ascribed tofive quantitative trait loci (QTL, named Rf-1 thru Rf-5) mapping tochromosome 1 (Van Dijk et al., 2005; Lopez et al., 2006; Van Dijk et al.,2006). Interestingly, the Rf-1 region is related to renal autoregulationimpairment (Van Dijk et al., 2005, 2006). Cross-breeding experimentsbetween FH rats and renal damage resistant August Copenhagen Irish(ACI) rats have shown that heterozygosity provides some (but notcomplete) protection against L-NAME induced hypertensive nephrop-athy (Van Dokkum et al., 2000). Similarly, the transfer of chromosome1 from BrownNorway (BN) rats to FHH reduces L-NAME hypertensiverenal damage in the latter (Mattson et al., 2005). Furthermore,

susceptibility to renal damage appears to be independent fromsusceptibility to hypertension in FH rats (Brown et al., 1996).

Other models with impaired autoregulation and, thus, acceleratedhypertension-related renal damage include rats with extensive renalmass reduction (RMR; Bidani et al., 2003), rats rendered hypertensiveby constant administration of angiotensin II with subcutaneouslyimplanted minipumps over a period of at least 15 days (Inscho et al.,1999; Wang et al., 2000), the unclipped kidney in the two-kidney,one-clip (2K1C) model (Turkstra et al., 2000) and experimentallyinduced hypertension in the BN rat (Wang et al., 2000). Recentexperiments performed on RMR rats further support the importantrole of autoregulation in the preservation of renal integrity. RMR ratstreated with polysulphate pentosan or mycophenolate mofetil did notdevelop proteinuria, glomerular hypertension or hyperfiltration,despite persisting hypertension. The protective effect correlateswith a higher afferent resistance (Sanchez-Lozada et al., 2003). Theangiotensin II modelmimics the situation of the non-clipped kidney inthe 2K1C Golblatt model. The role of renin release from the clippedkidney in 2K1C, is replaced by angiotensin II administration. Thehypertensive and renal damaging actions of angiotensin-II requirelong term action, coinciding with the time frame necessary to detectan augmented intrarenal amount of angiotensin II (Zou et al., 1996).Indeed, angiotensin II-mediated effects on pressure-natriuresis, bloodpressure and GFR need long term blockade by angiotensin receptorblockers (ARA; Kline & Liu, 1994), demonstrating mechanisticallydifferent effects of angiotensin II on the short and long term pressureregulation. Like the FH rat, the Brown Norway (BN) rat bears a geneticregion on chromosome 1 responsible for renal damage susceptibility.When this 22 cM chromosomic region (identified by D1Mit3 and Igf2markers) is transferred to the SHR background, the resulting crossedanimals experiment a greater renal damage than the parental SHRafter accelerated hypertension with DOCA salt (St Lezin et al., 1999).

In contrast, in well autoregulating strains, such as the SHR or MHR,hypertensive renal damage develops significantly later and moreslowly, in parallel with an aging-dependent loss or a slow hyperten-sion-induced upward shift of autoregulatory capacity, towards higherlevels of pressure (Palmer, 2004). In these strains, uninephrectomy(UNX) forces the remaining kidney to vasodilate, which acceleratesrenal damage (Lopez-Hernandez et al., 1998; Reverte et al., 1998;Kinuno et al., 2005). Very interestingly, a genomic region for renaldamage susceptibility has been identified in African Americans (whoare more susceptible than Caucasians) that appears located atchromosome 10 within the orthologous region of Rf-1 in the FH rat(Hunt et al., 2002). Further genetic analysis is necessary to determineif Caucasians who develop such renal damage bear comparablegenetic polymorphisms as African Americans.

2.4. Consequences of glomerular stretch

Even in well autoregulating models, autoregulation is very, but notabsolutely, effective. The absence of complete protection is derivedfrom the fact that (i) autoregulation mechanisms (i.e. myogenicresponse and tubuloglomerular feedback) take time to respond, and(ii) skewed neuroendocrine influences may modulate the extent ofthe response (Persson, 2002) by confounding afferent arterioles toproperly set the precise resistance through wall tone, or byprogressively inducing an arteriopathy which results in maladaptivefunction (Sanchez-Lozada et al., 2003). As a consequence, uponsystemic pressure oscillations, undetermined renal blood flow andglomerular capillary pressure fluctuations occur (Persson, 2002)which, in the long term, have been associated with the developmentof hypertension and target organ (including renal) damage (Persson,2002). This is how systemic hypertension translates into intrarenalhypertension and progressive damage to the glomerular tuft andfiltration barrier (even reaching very proximal tubular areas). Themore slowly the process the better the autoregulatory capacity. Upon


mechanical overload, glomerular cells adopt a secretory phenotypeand produce cytokines and growth factors, which finally are involvedin the aberrant replacement of functional tissue by fibrotic connectivetissue (Ljutic & Kes, 2003). Mechanical stretch derived from anelevated intraglomerular pressure exerts direct physical actions onglomerular structures, as well as cell signaling regulatory influences.

Stretching of glomerular structures directly increases the perme-ability of the filtration barrier. In addition, stretch probably mediatesresponses of the glomerular structures that attempt to compensate forthe increased stress and filtration barrier disruption; however, theseresponses eventually become pathological and malignant. As for allinitial responses to damage or evolving circumstances affecting thekidneys (and probably any organ, tissue and cell in the organism),these initial responses could be considered merely adaptive. Why andwhat turns them pathological are, as commented through themanuscript, key but unfortunately ignored issues. They includerapid (contraction, transcriptional activity, etc.) and medium termresponses (proliferation, remodeling, fibrosis, etc.) that embraceglomerular endothelial cells, mesangial cells, podocytes, basementmembranes and extracellular matrix (ECM). Paradoxically, extracel-lular and cell signaling mediators of these responses also seem to playpathological roles under pathological circumstances. As a conse-quence of stretch (and of variations in shear stress) or as a response toit: (i) endothelial cells proliferate, synthesize extracellular matrix,reorient their cytoskeleton, remodel their shape and change theirsecretory and signaling patterns (Lacolley, 2004; Wang & Thampatty,2006; Chien, 2007); (ii) mesangial cells proliferate (Ingram et al.,1999), and augment the production of factors known to participate inthe inception and progression of the disease. These include vascularpermeability factor (VPF, Gruden et al., 1997), transforming growthfactor beta (TGF-β) and fibronectin (Gruden et al., 2000), a cellularrenin–angiotensin system (RAS, Becker et al., 1998), and ECM (Ingramet al., 1999); (iii) podocytes reduce their proliferation (Petermannet al., 2002) and undergo hypertrophy (Petermann et al., 2005),activate a local RAS (Durvasula et al., 2004) and also modify theirsignaling pattern with undetermined consequences on glomerularfiltration (Morton et al., 2004).

3. Diabetic nephropathy

3.1. Pathophysiology of diabetic renal damage

Diabetic nephropathy is the most common glomerulopathy, andthe 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 hypergly-cemia is a primary initiator of diabetic nephropathy. In the absence ofelevated glycemia, nephropathy does not develop. However, diabeticnephropathy holds a genetic component at two levels: first, theelevation of glycemia; and second, at establishing a genetic back-ground where nephropathy can occur (in the presence of hypergly-cemia). Only 30% of patients with type 1, and 35–40% of patients withtype 2 diabetes develop diabetic nephropathy irrespective of glycemiccontrol (Diabetes Control & Complications, 1995). The clinical historyof a typical patient starts with symptoms of hyperfiltration (elevatedvalues of GFR) and occasional microalbuminuria, which may lastapproximately 5 years. During the next ∼20 years, microalbuminuriaturns into progressively higher proteinuria, whereas GFR declines.Finally, the patient undergoes renal insufficiency with severeproteinuria, which eventually evolves towards ESRD (Schena &Gesualdo, 2005).

Very early, hyperglycemia increases endothelial NO synthase(eNOS) expression in afferent arteries and glomerular capillaries,which leads to vasodilation and increased GFR (Sugimoto et al., 1998).Progressively, glomerular distension causes endothelial dysfunctionand hemodynamic alterations, loss of the glomerular basement

membrane (GBM) electric charge and GBM thickening, decreasednumber of podocytes, foot process effacement and mesangialexpansion have been shown to underlie the initial glomerular injury(Lehmann & Schleicher, 2000; Wolf & Ziyadeh, 2007; Munusamy &MacMillan-Crow, 2009), which eventually leads to glomerulosclero-sis. Damage to podocytes is emerging as a critical event inglomerulosclerosis (Kretzler, 2005; Reddy et al., 2008), which haslead to propose diabetic nephropathy as a disease of podocyte loss.Besides direct effects of hyperglycemia on tubular cells (Munusamy &MacMillan-Crow, 2009), glomerular damage causes tubular injuryresulting in tubular cell death, epithelial to mesenchymal transition(EMT), cell infiltration, tubule degeneration and interstitial fibrosis, bydifferent mechanisms (Kriz et al., 1998; Remuzzi et al., 2006; Wolf &Ziyadeh, 2007; Ziyadeh & Wolf, 2008): (i) the proteinuria derivedfrom GBM alterations activates tubular cells to produce mediators(TGF-β, angiotensin-II, etc.) and proinflammatory cytokines;(ii) growth factors derived from glomerular cells (TGF-β, insulin-like growth factor—IGF-1, angiotensin II, etc.) stimulates the uptake ofproteins, which amplifies the effect of proteinuria, and activates celldeath and the profibrotic program in tubule cells; (iii) microangio-pathy results in reduced postglomerular blood flow to peritubularcapillaries. Renal structures become gradually impaired throughchanges that start diffusely and spread through the glomerulus, orfocally localized as FSGS (Kimmelsteil–Wilson disease). Initiallylocalized sites of focal sclerosis may extend and coalesce throughthe glomeruli, giving rise to a greater diffuse sclerosis. Alternatively,initial focal sclerosis may progress more rapidly towards tubuledegeneration as opposed to glomerular collapse (as described below).Alternatively, diffuse and focal glomerulosclerosis can be contem-plated as etiologically or mechanistically different events. Typically,an early histological finding is the adhesion of a glomerular capillaryto Bowman's capsule at a podocyte deprived basement membranepoint. These adhesions create gaps in the parietal epithelium thatallow ectopic filtration out of Bowman's capsule into the paraglo-merular, interstitial space.

Two primary pathological pathways have been identified in totalnephron degeneration. Through pathway I, glomerular collapse occursbefore or parallels tubular degeneration, whereas through pathway II,tubular atrophy precedes glomerular degeneration (Kriz et al., 1998).Pathway I involves the propagation of glomerular adhesions at thevascular pole, and the formation of a progressively larger paraglomer-ular space (PGS) which contains ectopic filtrate and the remains ofcapillary tufts, which eventually reaches the urinary pole and thetubular structure. The PGS is formed initially within the GBM, whichprogressively disappears as the paraglomerular space enlarges andbecomes surrounded by a sheath of fibroblasts (at the interstitial side).When the PGS reaches the urinary pole, it penetrates within the tubularbasement membrane and separates it from the tubular epithelium,which correlates with tubule degeneration. Focal adhesions becomeareas of increasing sclerosis, capillary and perfusion collapse, all ofwhich eventually embraces the whole glomerulus. In pathway II, thePGS initiated by the original focal adhesion reaches the urinary polebefore further damage occurs at the vascular pole. As such, tubularfibrosis and degeneration preceeds extensive glomerular damage. Astubule flow decreases, pressurewithin Bowman's capsule increases andit dilates. Finally, total tubule collapse occurs and the urinary orifice inBowman's capsule disappears, giving rise to the physical separation ofthe glomerulus and the tubule, and the formation of a glomerular cystwith substantial remnant perfusion. ThePGS content is proposed toplaya significant role in the initiation of damage and in the connection ofglomerular and tubular disease. PGS contains renal filtrate (or exudate),cell debris from podocytes, ECM and basement membrane material,which may prospectively trigger proinflammatory, profibrotic and celldeath-inducing responses. Interestingly, these histopathological pat-terns have been observed both in diabetic rats and humans (Kriz et al.,1998).


Traditionally, diabetic nephropathy has been considered a glo-merular disease, in which tubular damage is a consequence of primaryglomerular events. However, some results challenge this concept(Lapsley et al., 1993; Hong et al., 2003; Thomas et al., 2005; Thomsonet al., 2006; Singh et al., 2008). Signs of impaired renal function havebeen detected before the evidence of glomerular malfunction inanimals and humans, including increased excretion of small proteins(Lapsley et al., 1993; Hong et al., 2003). Accordingly, diabeticnephropathy is now presented in a holistic view as a disease affectingthe whole nephron simultaneously. More investigation is necessary tounravel the mechanisms through which hyperglycemia injures thetubules in an early and glomerulus-independent manner.

3.2. Cellular effects of hyperglycemia

An unsolved question is through whichmechanisms hyperglycemiatriggers the observed histopathological alterations. Hyperglycemia actson renal endothelial and mesangial cells, podocytes and also tubularcells. The cellular consequences derived from hyperglycemia resultingfrom types 1 and 2 diabetes are largely similar (Kanwar et al., 2005).Also, the cellular consequences of exposure tohigh glucose are similar inall renal cells (Orasanu & Plutzky, 2009). Hyperglycemia initiates cellsignaling pathways in renal cells (Orasanu & Plutzky, 2009), includinghyperactivation of protein kinase C (Ishii et al., 1996; Koya et al., 1997),oxidative stress through an excessive production of reactive oxygenspecies (ROS) (Palm et al., 2003; Tesch & Nikolic-Paterson, 2006) andothers. This activation results in overexpressionof (i) growth factors likeTGF-β (Di Paolo et al., 1996; Heilig et al., 1997; Weigert et al., 2000),PDGF (Di Paolo et al., 1996) and connective tissue growth factor (CTGF;Connolly et al., 2003), (ii) inflammatory cytokines (Connolly et al., 2003;Lorz et al., 2009), ECM elements (fibronectin, collagens I and IV)(Connolly et al., 2003) and matrix deposition (Bolick et al., 2003),cytoskeleton reorganization (Dai et al., 2006), cell cycle arrest (Massonet al., 2006), and hypertrophy (Fan &Weiss, 2004; Masson et al., 2006).ROS attenuation in vivo (Brezniceanu et al., 2008) and in vitro(Munusamy & MacMillan-Crow, 2009) significantly reduces hypergly-cemic cell damage.

Besides glucose, other mediators of hyperglycemia-associateddamage include the advanced glycosylation end-products (AGEs),which result from the non-enzymatic glycation of proteins and lipids.Accumulation of AGEs in the kidney is associated with thedevelopment of nephropathy (Singh et al., 2001; Tesch & Nikolic-Paterson, 2006), both in type 1 (Cohen et al., 2000) and type 2 diabeticmice (Lassila et al., 2004). Interaction of AGEs with their membranereceptor (RAGE) is necessary for their action (Flyvbjerg et al., 2004;Wendt et al., 2004). On the other hand, hyperglycemia also increasesthe ubiquitous glucose transporter GLUT-1 mRNA and protein, andglucose transport in mesangial cells (Schena & Gesualdo, 2005). Thishas been proposed as a positive feedback mechanism in theappearance of glucose-induced damage.

Hyperglycemia induces hyaluronan (an anionic, non-sulfatedglycosaminoglycan) overproduction in the mesangial matrix. Hyalur-onans are potential binding sites for monocytes and macrophages invitro and in vivo (Wang & Hascall, 2004). Hyperglycemia also inducesROS-mediated apoptosis in podocytes (Susztak et al., 2006), tubulecells (Verzola et al., 2004) and endothelial cells (Tawfik et al., 2005).In the vasculature, hyperglycemia induces an oxidative stress(Giardino et al., 1996; Bellin et al., 2006) that results in endothelialdysfunction (Price et al., 2001; Yu & Lyons, 2005; Zurova-Nedelcevovaet al., 2006) and impaired relaxations (Sercombe et al., 2004). Highblood glucose is also involved in the development of dyslipidemia(Veiraiah, 2005) and atherosclerosis (Price et al., 2001). In all renalcells, high glucose and AGEs induce the production of angiotensin IIand growth factors (TGF-β, CTGF, vascular endothelial growth factor—VEGF, etc.) that act in an auto or paracrinemanner to activate a fibrotic

and inflammatory pathway in glomeruli and tubules (Lehmann &Schleicher, 2000; Wolf & Ziyadeh, 2007).

It is expected that, at least initially, all endothelial cells in theglomerular capillaries are subject to a similar glycemic stress, whereasonly a few initially undergo a damage that likely translates toneighboring areas. It thus can be speculated that (i) for undeterminedreasons every cell processes stimuli differently; or (ii) cell–cell andcell–matrix interactions, in conjunction with neuroendocrine influ-ences modulate (and even null) the effect of hyperglycemia on mostcells. It is only when these and certain other localized conditions (e.g.hypoxia, rupture or disorganization of basement membranes or ECM)merge in a particular manner and localization that hyperglycemia-associated damage begins. On the contrary, a homogeneous glycemicstress on all mesangial cells, inducing a similar effect in all or mostcells would better correlate with the appearance of a diffuseglomerular sclerosis. The question is why a particular glomerulusshows diffused sclerosis, whereas a neighboring one exhibits focaladhesions.

4. Renal mass reduction

Regardless of etiology, the number of nephrons decreases duringthe progression of CKD. The space formerly occupied by glomeruli andtubuli becomes replaced with an extracellular matrix through afibrotic process largely resembling scarring (Garber et al., 2003; Prietoet al., 2005). The remaining nephrons increase their filtration rate inorder to maintain the excretory need of the organism. Renaldysfunction appears when the remaining nephrons cannot copewith the sustained extra load. However, over time the adaptivemechanisms contribute to the deterioration of the remnant nephrons.This situation has beenmodeled in experimental animals by surgicallydissecting a large part of the renal mass in order to accelerate theprogression of nephron loss towards the verge of renal dysfunction.

4.1. Relevance

Experimentally, renal mass reduction (RMR) is almost exclusivelypracticed in rats. It is achieved by either surgical ablation, ligation ofthe renal artery branches, or a combination of both procedures, so that1/2 to 5/6 of the total renal mass becomes functionally nulled. Theextent of RMR depends on the desired degree of damage to beinflicted, the evolution time course and the concomitant presence ofother renal insults such as pre-existent hypertension. Mainly, twoRMR models have been used for the study of renal disease:(i) unilateral nephrectomy plus polectomy of the remnant kidneyresulting in approximately 5/6 RMR (Rodriguez-Peña et al., 2001);and (ii) unilateral nephrectomy plus complete ligation of 2 branchesof the contralateral renal artery, resulting in infarction of approx-imately 2/3 of the remnant kidney, which produces an overall 5/6renal mass nullification (Flores et al., 1998). Uninephrectomy (UNX)models are not true models of RMR, because one kidney is capable ofassuming the whole renal function without evident signs of damage,under otherwise normal conditions. UNX in SHR is a model ofaccelerated hypertensive nephropathy (as commented in Section 2).RMR is a very goodmodel for the study of themechanisms involved incompensatory adaptations to nephron loss (Kim et al., 2003). As aconsequence of RMR, the number of functional nephrons is drasticallyand suddenly reduced. Remnant nephrons set on functional andstructural compensations, and renal damage eventually appears in amanner and time course dependent on the experimental maneuver,extent of RMR, genetic background, sex and other determinants. Alimitation posed by this model is the fact that this abrupt andextensive loss of renal mass occurs very rarely in human diseases,where a more gradual loss of nephrons is observed.


4.2. Structural and functional adaptations

Early in the aftermath of RMR, the remaining renal mass under-goes an adaptive and compensatory response in order to maintainrenal function. This response comprises (i) hypertrophy of remnantnephrons mediated by cellular hyperplasia and hypertrophy; and(ii) hemodynamic alterations including an increase in blood flow dueto efferent and, especially, afferent vasodilation, as a mechanism toincrease glomerular filtration (Neuringer & Brenner, 1993; Griffinet al., 2000). Consequently, intraglomerular pressure increases(Hostetter et al., 1981; Brenner, 1985) which causes distension ofglomerular structures. Initially, pressure and stretch induce a numberof adaptative responses, which eventually corrupt and becomemalignant (as commented throughout this manuscript). Theseresponses include (i) mesangial cell proliferation and fibrogenesis(Mertens et al., 1998; Riser et al., 1998; Cortes et al., 1999); (ii)mesangial increased expression of TGF-β receptors (Riser et al., 1999)and activation of the Raf/mitogen-activated protein kinases (MAPKs)pathway (Krepinsky et al., 2005); (iii) local activation of RAS(Ichikawi & Harris, 1991) with potent effects on glomerulosclerosispartially mediated by TGF-β (Kagami et al., 1994) and CTGF (Guptaet al., 2000); (iv) podocyte alterations, such as cytoskeletonreorganization (Endlich et al., 2001), RAS activation (Durvasulaet al., 2004), increased expression of fibrosis-related molecules likeosteopontin (Endlich et al., 2002), and TGF-β-mediated podocyteproliferation and apoptosis (Schiffer et al., 2001; Petermann et al.,2002). All these events eventually progress to a generalized fibrosisand loss of glomerular and tubular cells (Makino et al., 1996), finallyleading to glomerulosclerosis and tubular atrophy (Fig. 3).

4.3. Pathophysiology of RMR-induced renal damage

Initially, the RMR-induced increment of glomerular volumereflects the compensatory response of the remnant renal mass. RMRdevelops different degrees of systemic and glomerular hypertensionand proteinuria, initially focal in nature but developing to globalglomerulosclerosis accompanied by a gradual reduction of GFR andprogressive tubulointerstitial damage. This culminates in renal failureand death (Griffin et al., 2000; Kim et al., 2003). Ultrastructuralchanges in the GBM after 5/6 RMR, which resembles the characteristicphenotype of focal glomerulosclerosis, includes alterations in thefiltration membrane which contributes to glomerular dysfunction,proteinuria and renal disease progression (Aunapuu et al., 2003). Inaddition, podocytes show hypertrophy, proliferation and foot processeffacement. It has been proposed that proteinuria occurs specificallyas a proliferative defect of epithelial cells after glomerular andfiltration surface expansion, and TGF-β1-induced podocyte apoptosis(Schiffer et al., 2001), favoring the separation of the podocyte layer,and thus creating a more permeable barrier (Noel, 1999; Petermannet al., 2002). Numerous studies have revealed a correlation betweenproteinuria and interstitial and tubular damage (Kim et al., 2003).Immunohistochemical studies reveal an expansion of the glomerulartuft compartment and focal sclerosis twoweeks after 5/6 RMR (Floegeet al., 1992a). Macrophage infiltration and a progressive deposition ofcollagens I and IV, fibronectin, laminin, heparans and entactin aredetected in the next weeks, correlating with the degree of glomerulo-sclerosis that develops (Floege et al., 1992a). Infiltrated lymphocytes,monocytes and platelets in the interstitium also contribute to renalscar progression (El Nahas, 1992).

From early phases of glomerular damage, mesangial cell prolifer-ation and ECM overproduction occur (Cortes et al., 1996). In vitroexperiments have detected and proposed as potential mitogens formesangial cells: angiotensin II (Ichikawi & Harris, 1991), PDGF, basicfibroblast growth factor (bFGF), TGF-β (Floege et al., 1992b,c) andendothelin-1 (Bruzzi et al., 1997). These factors also cause vasocon-striction, reduction of renal blood flow (RBF) and, consequently, a

decrease of GFR. Reduced RBF, and a progressive reduction in renalinducible NO synthase (iNOS) and NO production all have importantroles in mesangial and vascular contraction (Aiello et al., 1998).Angiotensin II seems to be important for fibroblast and macrophageproliferation in the remnant renal mass, as demonstrated by RAAS-inhibition with angiotensin converting enzyme inhibitors (ACEIs) andARA (Wu et al., 1997). Indeed, the observed tubular expression ofRAAS components might contribute to tubulointerstitial damage inthis model (Gilbert et al., 1999). Simultaneously, along withproliferation, apoptosis takes place as well in glomeruli and tubulesof 5/6 RMR rats, and both processes contribute to the damage, inwhich TGF-β appears to be involved (Thomas et al., 1998). In supportof this hypothesis, simultaneous glomerular and tubular cell prolif-eration and apoptosis has been already described in the uninephrec-tomized spontaneously hypertensive rat (SHR) (Rodriguez-Lopezet al., 1998, 2002). Tubular EMT is detected 3 weeks after 5/6 RMR,and tubular cells acquire de novo expression of alpha smooth muscleactin (α-SMA), lose apical-basal polarity, transform into myofibro-blasts, and migrate to the interstitiumwhere they undertake a pivotaltask in fibrogenesis (Ng et al., 1998).

In RMR animals, hypertension develops very soon after renal massablation (Benchetrit et al., 1999; Pires et al., 2007). In these models,hypertension contributes to glomerular damage, especially because ofthe compensatory afferent vasodilation occurring after RMR (Figs. 1and 3).

5. Obstructive nephropathy

Obstruction of the urinary pathway (chiefly resulting fromblockade of one or, exceptionally, both ureters) causes progressivedeterioration of renal structures leading to chronic dysfunction.Ureteral obstruction gives rise to the hydronephrotic syndrome,characterized by kidney enlargement due to urine collection in therenal pelvis or calyces (Mendelsohn, 2004). It appears clinically asdecreased renal function due to anatomical or functional abnormal-ities compromising urine flow through the urethra, bladder, ureters orrenal pelvis (Klahr, 1998). Congenital obstructive nephropathyconstitutes the principal cause of renal failure in children of theUnited States, accounting for 16% of pediatric kidney transplants, incontrast to the 0.3% in adults (Benfield et al., 2003). Though incidenceof obstructive nephropathy decreases after childhood, it has beendetected an increase after the age of 60–65, especially in men as aconsequence of prostate hyperplasia and cancer (Klahr, 1998).Unilateral ureteral obstruction (UUO) in animals is also used as anexperimental model for the investigation of the pathological mechan-isms implicated in tubulointerstitial fibrotic diseases (Chevalier et al.,2009).

5.1. Relevance

A clear etiological parallelism exists between experimental UUOand human obstructive nephropathies. Experimental UUO is amaneuver that causes a complete obstruction of the manipulatedureter. This is an extreme situation that is rarely observed in humans,which however accurately reproduces the fibrotic sequence of eventsseen in patients, through an accelerated time course (Klahr &Morrissey, 2002). Extensive work has demonstrated the usefulnessof this model for the study of histopathological, cellular andmolecularalterations, for the identification of extracellular and intracellularmediators, and also for its predictive capacity for drug discoveryprocesses (Chevalier, 1998; Klahr & Morrissey, 1998, 2002; Bascands& Schanstra, 2005). Contralateral kidneys undergo compensatoryphysiological alterations such as increased blood flow and hypertro-phy. They also suffer structural damage posed by glomerular edema,congested blood vessels, dilated tubuli, epithelial necrosis andapoptosis (Ekinci et al., 2003).

Fig. 1. Schematic representation of the key pathophysiological events underlying the origin and evolution of hypertensive nephropathy. GFR: glomerular filtration rate; Kf:ultrafiltration coefficient; PAF: platelet activating factor; RAS: renin angiotensin system; RBF: renal blood flow.


5.2. Pathogenesis of the obstructed kidney

Following complete UUO, there is a progressive fall in renal bloodflow and GFR, and an increased intratubular pressure ensues whichstretches the tubule walls. As a result, the plasma and renal RAASbecomes activated, which determines subsequent pathological altera-tions through the activation of TGF-β, immune cell infiltration, fibrosisand renal hypoperfusion (Klahr &Morrissey, 2002). Immediately aftertotal UUO, the increase in ureteral pressure translates into anincremental increase in tubular pressure, which decreases thehydraulic pressure gradient across the glomerular filtration barrier.This increase in intratubular pressure is thought to be the result (atleast partially) of cyclic refractory peristaltic-like contractions of theureter from the point of occlusion upward. However, as early as fivehours after UUO, intratubular pressure declines. Notwithstanding,glomerular filtration rate continues to fall because of the reduction inrenal blood flow (secondary to renal vasoconstriction) and in the

ultrafiltration coefficient (Kf). It has also been postulated that uponUUO cortical interstitial pressure also increases. The transienthydrodynamic perturbations that develop shortly after UUO in theobstructed kidney produce a mechanical disturbance to the proximaltubular epithelium (e.g. membrane stretch), which causes theincreased production of components of the renin–angiotensin II axiswithin the proximal tubular epithelium, and consequent auto andparacrine chemokine generation (Diamond et al., 1998).

The pathology of obstructed kidneys faithfully recreates thecommon alterations observed in most tubulointerstitial diseases,including tubular atrophy, proliferation and apoptosis of epithelialtubular cells, EMT, interstitial cell infiltration, ECM deposition, andaccumulation of fibroblasts and myofibroblasts (Klahr & Morrissey,2002). According to Young et al. (Young et al., 1998) and Klahr (Klahr,1998), within the first few hours following a complete UUO,intratubular pressure, increased tubular volume, and appearance ofglomerular pressure and renal blood flow alterations have been

Fig. 2. Schematic representation of the key pathophysiological events underlying the origin and evolution of diabetic nephropathy. AGEs: advanced glycosilation end-products; EMT:epithelial-to-mesenchymal transition; eNOS: endothelial NO synthase; GFB: glomerular filtration barrier; GFR: glomerular filtration rate; Kf: ultrafiltration coefficient; PAF: plateletactivating factor; PKC: protein kinase C; RAS: renin angiotensin system; RBF: renal blood flow; ROS: reactive oxygen species.


described. During the first phase (0–90 min), renal blood flow andglomerular pressure augment because of rapid, prostaglandin-mediated vasodilation of the afferent arterioles (Klahr, 1998). In thesecond phase (90 min–5 h), renal blood flow decreases but glomer-ular pressure rises due to vasoconstriction of efferent arterioles, as aconsequence of intrarenal release of vasoconstrictors such asangiotensin II (Frokiaer et al., 1996), thromboxane A2 (TXA2)(Klahr, 1998) and endothelin-1 (Kahn et al., 1997). From 5 to 18 hpost obstruction, afferent arterioles also contract, and glomerularpressure and blood flow decrease (Young et al., 1998).

5.3. Involvement of cell infiltration

In normal kidneys, macrophages are scarce and restricted to therenal cortex (Schreiner & Unanue, 1984). As a response to themechanical stress, ligated kidneys synthesize chemoattractants thatevoke interstitial monocyte and T lymphocyte infiltration during thefirst 4 h (Schreiner et al., 1988). The infiltrating cells contribute todevelopment of the lesion by synthesizing profibrogenic TGF-β1(Diamond, 1995) and by reducing renal blood flow and GFR (Klahr,1998) through the release of vasoactive compounds such asinterleukin 1 (IL-1), thromboxane A2 and leukotriene D4 (Schreiner

& Kohan, 1990). T lymphocytes and macrophages also contribute tothe progression of renal disease by inducing dysfunction of tubulartransport, tubular atrophy and interstitial fibrosis. In the obstructedkidney, increased and sustained expression of the adhesionmoleculesICAM-1 and VCAM-1 in the tubuli and interstitium, and theirdecreased glomerular expression suggest an important role forthese molecules in the infiltration of inflammatory cells into thetubulointerstitium during chronic hydronephrosis (Shappell et al.,2000). Interestingly, the pattern of tubular ICAM-1 expression(increased between days 6 and 25, and normalized afterward),coincides with tubular apoptosis and proliferation, suggesting a rolefor activated inflammatory cells in these processes (see below in thissection for further details). Experiments carried out by inducing UUOin KO mice have demonstrated that other cell-to-cell and ECM-to-cellinteraction-related molecules, such as selectins (Lange-Sperandioet al., 2002), osteopontin and its receptor, CD44 (Ophascharoensuk etal., 1999; Rouschop et al., 2004), intervene to a significant degree incell infiltration, tubular atrophy, apoptosis and interstitial fibrosis. Inaddition, a gradual increased expression of the chemoattractant andprofibrotic cytokineMCP-1 is observed in tubular cells after 12, 48 and96 h of ligation (Diamond et al., 1994). Three days post-occlusion,expansion of the cortical interstitial volume, deposition of collagens I,

image of Fig.�2

Fig. 3. Schematic representation of the key pathophysiological events underlying the chronic nephropathy caused by extensive renal mass reduction (RMR). ECM: extracellularmatrix; ET-1: endothelin 1; GFR: glomerular filtration rate; iNOS: inducible NO synthase; Kf: ultrafiltration coefficient; RBF: renal blood flow; RAS: renin angiotensin system; RMR:renal mass reduction; TGFβ: transforming growth factor beta; VD: vasodilation.


III and IV in the cortical interstitium, and collagen IV overexpression intubular basement membranes, are detected (Kaneto et al., 1994).Maintenance of ligation originates a generalized interstitial fibrosis,proliferation of activated fibroblasts and myofibroblasts during thefirst week, and parenchymal scars afterwards (Gonzalez-Avila et al.,1988; Klahr, 1998). Fifteen days after obstruction, a pronouncedinterstitial fibrosis is observed with accumulation of fibronectin,laminin and collagens I and IV (Rodriguez-Peña et al., 2002). Anincreased expression of TGF-β1 and the TGF-β type III receptorendoglinmRNA levels are also observed (Rodriguez-Peña et al., 2002).

5.4. Participation and fate of renal cells

Ureteral obstruction induces complex changes in renal cellsincluding phenotypic alterations and loss of renal mass that reflectsa skewed balance between cell death and proliferation. From the firstweek after ligation, loss of tissue mass is detected (most rapidlyoccurring between 2 and 4 weeks) which correlates with the extent of

tubular cell apoptosis and tubular atrophy observed (Gobe & Axelsen,1987). These data suggest that tubular apoptosis may play animportant role in tubular atrophy and renal mass loss. It has alsobeen demonstrated that tubular cells undergo proliferation just beforedetecting an increase in apoptosis rates, which then return to thoselevels associated with healthy kidneys (Truong et al., 1996). Incontrast, proliferation and apoptosis of interstitial cells progressivelyincrease in the obstructed kidney from day 1, and both proliferationand apoptosis seem also to participate in the renal damage (Truonget al., 1996; Rodríguez-Peña et al., 2008; Grande & López-Novoa,2009). Ex vivo studies demonstrate that cortical interstitial fibroblastsobtained from ligated kidneys show a higher proliferation rate thanthose obtained from contralateral and healthy kidneys (Davis et al.,1983). Proliferation and apoptosis do not become altered inglomerular cells from UUO kidneys (Truong et al., 1996).

Studies carried out in cyclin kinase inhibitor p21WAF/CIF or p27KIP1

KO mice subject to UUO reveal that p21 and p27 are, respectively,important controllers of myofibroblast (Hughes et al., 1999) and

image of Fig.�3


tubular cell proliferation (Ophascharoensuk et al., 1998), with noeffect detectable on interstitial fibrosis. Moreover, increased p53expression has been detected in kidneys after UUO (Morrissey et al.,1996), and a role in obstructive pathogenesis has been demonstratedfor this proapoptotic transcription factor since UUO p53 KO micepresent 50–70% lower tubular and interstitial apoptosis, lesser tubularatrophy, and reduced interstitial volume, compared with UUO wildtype mice (Choi et al., 2001).

Tubular EMT is also a characteristic hallmark of obstructedkidneys. Tubular cells dedifferentiate to fibroblasts and migrate tothe interstitium. Cells undergoing EMT acquire mesenchymal markerssuch as α-SMA and vimentin, lose epithelial markers like E-cadherin,while they maintain tubular markers (e.g. lectin) and synthesize ECMproducts such as fibronectin and collagen I (Yang & Liu, 2001; Iwanoet al., 2002; Yang & Liu, 2002). The biphasic expression time course ofthe myofibroblast marker α-SMA suggests that during days 1–3 afterobstruction myofibroblasts originate by activation of resident fibro-blasts, whereas the second peak (at the 7th day) respond tomyofibroblasts derived from tubular EMT (Yang et al., 2002a; Liu,2004). Tissue plasminogen activator (tPA) is a central mediator ofEMT as demonstrated some studies performed with tPA null mice,which show reduced tubulointerstitial fibrosis after UUO (Yang et al.,2002b). This inhibition, which seems specific for the EMT process,appears to be based on a marked decrease in MMP-9 (Yang et al.,2002b).

Activation of the small GTPase Ras plays a major role in UUO-induced EMT. It has been demonstrated that both Ras and itsdownstream pathways ERK1/2 and PI3K/Akt are activated in theobstructed kidney (Rodríguez-Peña et al., 2008). In addition, EMT andrenal fibrosis are markedly reduced in H-Ras KO mice 15 days afterUUO (Grande et al., 2009). Interestingly, 3 days after UUO, a time atwich EMT does not seem to play a role in UUO-induced renal fibrosis,no differences in renal fibrosis between H-Ras KO and WT mice areobserved (Grande et al., 2010).

5.5. Role of the renin–angiotensin aldosterone system

IECA-mediated RAAS inhibition (Kaneto et al., 1994; Ishidoya et al.,1995; Klahr & Morrissey, 1997) and mice KO of RAAS-elements (Maet al., 1998; Satoh et al., 2001) have provided demonstration for animportant role of angiotensin II in UUO renal damage. After UUO,there is a considerable increase in all the components of renal RAAS.Renal parenchymal cells synthesize angiotensin II, which decisivelyparticipates in renal damage through direct hemodynamic andprofibrogenic actions (Kellner et al., 2006), and the induction ofprofibrotic mediators like nuclear factor kappa B (NFκB) and TGF-β1(Pimentel et al., 1995; Klahr & Morrissey, 1998). In addition,angiotensin II synergizes with TGF-β1 to induce tubular EMT inUUO (Yang et al., 2002a). TGF-β1 is a pivotal executor of fibrogenesisin UUO (Klahr, 1998). Ligation induces an increment in TGF-β1expression in epithelial tubular cells (Kaneto et al., 1993) andperitubular interstitial cells (Diamond et al., 1994). TGF-β1 over-expression induces (i) macrophage infiltration, and synthesis andinterstitial accumulation of fibronectin and collagens I, III and IV in theobstructed kidney (Diamond et al., 1994); (ii) ECM degradationinhibition through the stimulation of TIMPs expression and inhibitionof MMPs (Klahr, 1998); (iii) induction of adhesion molecules,chemotaxis of fibroblast and immune cells, fibroblast proliferation;and (iv) tubular EMT (Klahr & Morrissey, 1998; Yang et al., 2002a).

6. Common mechanisms of progression

Animal models have provided valuable insights into the patho-genesis of chronic kidney diseases. They have proved to be extremelyuseful for studying and understanding the pathogenetic mechanismsinvolved in their onset and progression, and for testing new

treatments. Knowledge gathered from animal models increases ourunderstanding of human pathology, which in turn helps us to developnew and more specific animal models in which to evaluate noveltherapeutic interventions at the preclinical level. In this intertwingledrelation, animal models play a pivotal role between pathologicalinformation and clinical development.

Whereas the pathophysiological events underlying the inceptionof every nephropathy are different, those involved in the progressionof the disease are, to a certain extent, common tomany nephropathies(see Figs. 1–4). This may explain why, as different diseases progress,an increasingly common renal phenotype of tissue destruction,inflammation and scarring ensues, regardless of etiology. Persistentinsults to renal cells by chemical or physical action eventually activateinflammatory and fibrotic responses that not only interfere with therepair processes, but also redirect the renal tissue status throughsimilar mechanisms of irreversible degeneration. Regardless ofwhether the disease starts mostly as a glomerular (i.e. hypertensivenephropathy) or tubular (RMR and UUO) insult, the initial cellulardamage eventually activates responses that finally damage othernephron structures. This leads to a vicious circle of malignancy wherenephrons progressively disappear and are substituted by scar tissue.As depicted in Figs. 1–4, cell damage and activation leads in all cases toinflammation and cytokine imbalance, which activates other celltypes and contributes to unleashing fibrosis, mesangial and vascularcontraction contributing to the reduced GFR, tubule degeneration andscarring (Fig. 5). These are logical targets for pharmacologicalintervention aimed at slowing down disease progression (Remuzziet al., 2006). Yet, a challenge for the future is to unravel the keymolecular events that specifically drive each disease beyond the noreturn point, and to identify early and etiologically specific markers,that allow us to detect the inception of malignant damage andintervene appropriately.

7. Current treatments

7.1. Renin–angiotensin aldosterone system inhibition

RAAS inhibition has proved to be the most effective therapy atreducing proteinuria and slowing CKD progression in animals andhumans (Perico et al., 2008). Furthermore, RAAS inhibition has provedto cause regression and repair of certain apects of CKD, such asglomerular fibrosis, in experimental models (Fogo, 2006a,b; Remuzziet al., 2006).

Angiotensinogen is cleaved by the enzyme renin into thedecapeptide angiotensin I, which in turn is cleaved by the zincmetallopeptidase angiotensin converting enzyme (ACE) and othercarboxypeptidases into the highly active octapeptide angiotensin II,with potent functional and structural effects on the vascular wall,heart, renal tissues, nervous system and many others (Mire et al.,2005). Two pharmacologically distinct, G-protein coupled, seven-transmembrane spanning, cell surface receptors for angiotensin IIhave been identified (i.e. AT-1, AT-2). AT-1 and AT-2 have been clonedand characterized. Two additional high affinity binding sites forangiotensin II have been proposed, designated AT-3 and AT-4. Thesehave not been molecularly characterized to date (Bernstein et al.,2001; Berry et al., 2001). Most pivotal effects of angiotensin-II inrelation with CKD and hypertension are mediated by activation of theAT-1 receptor. Activation of the AT-2 receptor exerts actions ratherantagonistic to those mediated by AT-1 (Ardaillou et al., 1999; Kim &Iwao, 2000; Touyz & Schiffrin, 2000), although its physiological andpathological roles are not clearly ascertained. AT-3 and AT-4 receptorsare functionally still poorly characterized (Touyz & Schiffrin, 2000).

RAAS inhibition can be achieved with two families of compoundsangiotensin–converting enzyme inhibitors [i.e. ACEIs (Sica, 2005)]and angiotensin receptor antagonists [ARA (Sica, 2006)]. Both drugtypes are clinically approved and commonly used for the treatment of

Fig. 4. Schematic representation of the key pathophysiological events underlying the nephropathy caused by ureteral obstruction. GFR: glomerular filtration rate; Kf: ultrafiltrationcoefficient; RAS: renin angiotensin system; RBF: renal blood flow; TGF: tubuloglomerular feedback; UUO: unilateral ureteral obstruction; VC: vasoconstriction; VD: vasodilation.


hypertension as well as other cardiovascular disorders (Fig. 6). As aclass, both families of compounds have good pharmacological profileswith high efficacy and low toxicity. ACEIs (e.g. enalapril, trandolapril,ramipril, lisinopril, benazepril and fosinopril) prevent angiotensin IIfrom being produced by ACE, whereas ARA (e.g. losartan, valsartan,

Fig. 5. Schematic representation of mechanisms that may be responsible forprogression of most chronic kidney diseases, regardless of etiology. GFR: glomerularfiltration rate; RBF: renal blood flow.

irbesartan, candesartan, eprosartan, olmesartan and telmisartan)prevent angiotensin II from binding and activating its cell receptors.ARA are selective for the AT-1 receptor. Other RAAS blockers includerenin inhibitors (e.g. aliskiren) (Azizi et al., 2006), whichmight have apotential usage for the therapeutic management of CKD (Perico et al.,2008) although to date this has not been investigated. Recently,aliskiren has been approved by the Food and Drug Administration(FDA) of the United States of America for use in the treatment ofhypertension. Aliskiren (Tekturna) has also recently been approved incombination with valsartan (Valturna) for hypertension.

The accumulated clinical experience during the last severaldecades and knowledge acquired from landmark clinical trials withRAAS blockers, plus information derived from clinical meta-analyses(MacKinnon et al., 2006) have demonstrated that RAAS inhibitionusing ACEIs and ARA is the most effective single therapy to attenuateprogression of CKD, despite being almost equally effective to otherantihypertensive drugs at reducing blood pressure (Epstein, 2002a,b).RAAS inhibitors are considered as first line therapy for patients withdiabetic and non-diabetic kidney disease (Brewster & Perazella, 2004).Their distinctive effect is more evident the more advanced and moreproteinuric the kidney disease (Nigbor & Lewis, 2003; Rahn, 2005).Clinical studies involving RAAS inhibitors include the Irbesartan Type 2Diabetic Nephropathy Trial (IDNT) (Pohl et al., 2005), the Reductionof Endpoints in NIDDM with Angiotensin II Antagonist Losartan(RENAAL) (Shahinfar et al., 2006), the Valsartan AntihypertensiveLong-term Use Evaluation (VALUE) trial (Julius et al., 2006), theInternational Verapamil–Trandolapril Study (INVEST) (Pepine et al.,2003), the combination treatmentof anARAand anACEI in non-diabeticrenal disease (COOPERATE) study (Nakao et al., 2003) study, and others.

RAS inhibitors are superior to other antihypertensive agents atreducing progression of CKD, proteinuria and mortality end-points

image of Fig.�5

image of Fig.�4

Fig. 6. A schematic representation of the direct and indirect components of the renin–angiotensin aldosterone system (RAAS) and their effects on the progression of CKD.ACE: angiotensin converting enzyme; ACEI: angiotensin converting enzyme inhibitor;Aliskiren is a renin inhibitor; APP: aminopeptidase P; ARA: angiotensin receptorantagonists; AT-1: angiotensin II type 1 receptor; AT-2: angiotensin II type 2 receptor;B2: Bradykinin type 2 receptor; CKD: chronic kidney disease; CTGF: connective tissuegrowth factor; ECM: extracellular matrix; EMT: epithelial-to-mesenchymal transition;GFR: glomerular filtration rate; NEP: neutral endopeptidase; PD123391 is an AT-2receptor selective antagonist; RBF: renal blood flow; TGFβ: transforming growth factor beta.


(reviewed in Rahn, 2005). Indeed, in addition to the benefits derivedfrom blood pressure control, RAAS inhibitors hold pressure-indepen-dent, beneficial actions on diseased kidneys (Jafar et al., 2001; Lewis,2002; Pugsley, 2005). This, in turn, highlights the important role ofRAAS (and its main effector, angiotensin II) in the pathology of CKD.For these reasons, RAAS inhibition, along with control of comorbidconditions (e.g. diabetes, hypertension, and hypercholesterolemia), isan independent goal in CKD therapeutic management (Rahn, 2005).Apparently, ACEIs and ARA. are similarly effective at slowing chronicrenal damage progression (Mangrum & Bakris, 2004). Yet, there arenon-trivial pharmacological differences between the two drugfamilies (Fig. 6), these include:

(i) ARA do not interfere with angiotensin II-mediated signalingthrough the type II receptor, whose activation leads, in generalterms, to effects that oppose that of the type I receptor (Touyz &Schiffrin, 2000). Thus, ARA unmask the vasodilating andnatriuretic–diuretic actions of angiotensin II, otherwise out-weighed by type I receptor-mediated effects whereas ACEIsimpede both type I and II signaling (Wolf & Ritz, 2005). Theeffects of AT-2 activation remain controversial, though. In fact,deleterious effects on kidney structure and function derivedfrom AT-2 stimulation have also been reported, which includeactivation of NF-κB-mediated inflammatory pathways (Ruiz-Ortega et al., 2000, 2001a, 2001b; Wolf et al., 2002).Interestingly, AT-2 inhibitors exhibit anti-inflammatory andrenoprotective effects in animal models of renal damage (Caoet al., 2002). Moreover, AT-4 (in addition to AT-1) stimulationhas been implicated in the induction of expression of thefibrogenic and thrombotic factor, plasminogen activator inhib-itor (PAI)-1 (Fogo, 1999). This is an action theoretically affecteddifferentially by ARA and IECAs. Indeed, both an ACEI and an

ARA decrease PAI-1 levels, but the effect is more lasting withthe ACEI (Brown et al., 2002). Taken as a whole, these studieshighlight a potentially important difference between ACEIs andARA in renal disease whose clinical consequences need to beevaluated.

(ii) Bradykinin, a vasodilatory peptide that also provides cardio-protection in hypertensive rats (Tanaka et al., 2004), isinactivated by ACE (Yang et al., 1970). Accordingly, in contrastto ARA, ACEIs increase bradykinin levels. Bradykinin affordsconsiderable renoprotection in diabetic nephropathy (Doggrell,2005). Indeed, a part of the renoprotective effect of IECAs ismediated by bradykinin because bradykinin antagonists par-tially block IECA-induced benefits. This has been shown inseveral experimental models including diabetic (Tschope et al.,2003) and hypertensive nephropathy (Yokota et al., 2003;Seccia et al., 2006). These results are, however, disputed byothers who found no effect of bradykinin antagonists on IECA-induced protection in rats rendered hypertensive by subtotal(5/6) nephrectomy (Nabokov et al., 1998), and in 5/6nephrectomized SHR (Kohzuki et al., 1995). Other peptidasessuch as neutral endopeptidase, basic carboxypeptidase andaminopeptidase P also degrade bradykinin, although theirrelative contribution to overall bradykinin degradation (ascompared with ACE) appears to be negligible (Bagate et al.,2000).

(iii) Peptidases other than ACE (chiefly the chymotrypsin-like serinprotease, chymase) have been shown to be responsible for an80% of angiotensin II generation in the heart, and a 60% in bloodvessels (Richard et al., 2001; Miyazaki & Takai, 2006).Furthermore, angiotensin II levels are not significantly alteredin ACE−/− mice, which have been attributed to the compen-satory enhanced chymase activity observed in these mice (Weiet al., 2002). Interestingly, ACEIs do not inhibit chymase(Richard et al., 2001). Chymase levels are low in normalkidneys and seem to contribute little to RAAS-dependent renalfunction (Urata et al., 1994; Hollenberg et al., 1998; Hollenberg,2000). However, chymase is overexpressed in the diseasedkidneys of different experimental models of CKD and patientswith different chronic nephropathies, not only in resident mastcells but also in renal glomerular, tubular and interstitial cells(Huang et al., 2003; Ritz, 2003; McPherson et al., 2004; Miyake-Ogawa et al., 2005; Morikawa et al., 2005; Sadjadi et al., 2005).Unfortunately, the effect of chymase inhibitors on experimen-tal models of nephropathy and in patients has not beencharacterized, such studies are needed.

(iv) Pleiotropic actions of ACE beyond angiotensin II generationmay also respond to differences in the action of ACEIs and ARA.For instance, ACE is involved in signaling cascades independentof angiotensin II production and bradykinin degradation. Infact, ACE mediates the activation of cyclooxygenase-2 (COX-2)and prostacyclin expression, in cultured endothelial cells, in thepresence of ACEIs (Kohlstedt et al., 2005). Moreover, (i) ACEIsincrease casein kinase (CK)2-mediated serine1270 phosphor-ylation of ACE; and (ii) mitogen-activated protein kinase(MAPK) kinase (MAPKK) 7 and JNK coprecipitates with ACE,and ACEIs increase ACE-associated JNK activity (Kohlstedt et al.,2004).

Because of the distinct differences that exist between themechanisms of action of ACEIs and ARA it could be anticipated thatdifferences in their clinical effects exist; however such effects are notreadily observed. ACEIs and ARA utilized at the highest possible dose(considering their particular therapeutic and toxic ranges) appearequally effective in the management of CKD. Head to head clinicalcomparisons are scarce, although a few can be found in combinationstudies, where single therapy groups are included as controls.

image of Fig.�6


Interestingly, combination of ACEIs with ARA exerts additivenephroprotection (reviewed in Song et al., 2006 and Tsouli et al.,2006). As depicted in Fig. 6, both drug families interfere with directactions of angiotensin-II, and with the production of other key factorssuch as transforming growth factor beta. RAAS blockade not onlyreduces hemodynamic and pro fibrotic effects (Brewster & Perazella,2004), but also cardiovascular events derived from uremia (Kim &Iwao, 2000), and controls comorbid factors such as hypertension(López-Hernández & López-Novoa, 2006) and renal atherosclerosis(Suganuma et al., 2006).

7.2. Calcium channel antagonists

Calcium channel antagonists (CAs) are a family of compounds thatinhibit L and T voltage dependent calcium channels. These moleculesare either dihydropyridine (nifedipine, nisoldipine, amlodipine,nicardipine, nitrendipine) or non-dihydropyridine (verapamil, diltia-zem) chemical structures which vary in their mode of action dueprimarily to differences in lipophilicity. Non-dihydropyridines haveboth vascular and cardiac effects (vasodilation and negative inotropy,respectively), whereas dihydropyridines are quite selective for thevasculature (Abernethy & Schwartz, 1999). CAs are reasonably welltolerated drugs widely used for the treatment of cardiovasculardiseases, including hypertension (Nathan et al., 2005), whose mainside effect is oedema of the lower extremities (Weir et al., 2001). Bothdihydropiridines and non-dihydropyridines reduce elevated bloodpressure similarly and cardiovascular risk and all-cause mortality tothe same extent as other antihypertensive agents. This has beenshown in several clinical trials including the Antihypertensive andLipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),VALUE, and INVEST studies, and the Controlled Onset VerapamilInvestigation of Cardiovascular Endpoints (CONVINCE) trial andNORdic DILtiazem (NORDIL) study (reviewed in Nathan et al.,2005). CAs and all other antihypertensive agents are similarlyeffective at attenuating hypertension-related renal damage progres-sion, when administered during incipient, non-proteinuric stages ofdisease (Nathan et al., 2005), suggesting that blood pressure loweringis a decisive component of the effect. In these cases, bothdihydropyridines and non-dihydropyridines substantially reduceprogression rate and proteinuria. However, non-dihydropyridinesare substantially more effective than dihydropyridines at reducingproteinuria, and they are thus preferred in overtly proteinuric renaldisease and renal dysfunction (Nathan et al., 2005), especially ininsulin independent diabetic nephropathy (Nielsen & Flyvbjerg,2000). In general terms, both subclasses of CAs exert beneficial effectson renal damage and renal dysfunction progression in overt disease,either alone or in combination with ACEIs or ARA (Segura et al., 2005),provided that a tight control of blood pressure is achieved and, in thecase of diabetic nephropathy, strict control of glycemia. Thesebeneficial effects are derived partially from their capacity to attenuatethe decline in GFR (Nielsen & Flyvbjerg, 2000).

Presently, CAs are utilized as part of multiple drug or combinationtherapies addressed at normalizing blood pressure, in patients whoneed more than one drug to achieve normotension (Epstein, 2002a,b;Segura et al., 2005). In addition, studies with CAs suggest that thesemolecules provide an additive renal protective effect in multidrugtherapies (along with RAS inhibitors), an effect independent fromblood pressure reduction. Specifically, but not limited, this might bethe case of diabetic nephropathy (Ma et al., 2004) and cases ofimpaired renal hemodynamics, such as post-renal transplant patients(Nigbor & Lewis, 2003) or radiocontrast-induced nephropathy(Epstein, 1993). This is because, acting on the renal vasculature, CAsproduce vasodilation preferentially at the afferent level, which resultsin an increased GFR (Epstein, 1993). This effect may be a double-edged sword if blood pressure is not strictly controlled.

8. Therapeutic perspectives

The horizon for the clinical handling of CKD may be analyzed fromdifferent perspectives. First, diagnosis must be improved for an earlierdetection of progression and for identification of prognostic markersthat anticipate which patients will progress more rapidly than others.Second, new forms of therapy are needed to improve our capacity toslow and even halt progression, and to reverse the damage andregenerate renal tissues.

8.1. Pharmacological inhibition of common mechanisms of progression

According to the discussion in Section 6, the key, commonpathological mechanisms of CKD progression pose attractive targetsfor pharmacological intervention. Inhibition of inflammation, fibrosis,specific mechanisms involved in progressive tubular degenerationand nephron loss (García-Sánchez et al., 2010), cell activation andaberrant production of cytokines and their effects leading to a reducedRBF, mesangial contraction and increasingly lower GFR, are specificdrugable candidates. Indeed, several drugs are under different degreesof experimental and clinical development (reviewed in Perico et al.,2008; also see Grande & López-Novoa, 2008 and Gonçalves et al.,2010). Prominent, prospective antifibrotic and anti-inflammatorydrugs and strategies under different levels of development areoutlined in Table 1. Besides these inhibitory drugs, other strategiesexist that are based on the exogenous administration of endogenousmolecules known to counteract the action of profibrotic mediators.Chiefly, it is the case of bone morphogenetic protein 7 (BMP-7) andhepatocyte growth factor (HGF), which outweigh the profibroticeffect of TGF-β (Chatziantoniou & Dussaule, 2005) and are known toreduce and even reverse fibrosis, inflammation and renal damage inexperimental CKD (García-Sánchez et al., 2010).

As indicated in Fig. 5, an imbalance in cytokines and inflammatorymediators can reduce RBF and GFR independently from progressivenephron loss, which then limits filtration in remnant nephrons andfurther contributes to developing renal injury. Thus, inhibition of theeffects of these molecules may contribute to decelerating diseaseprogression by improving the outcome of functional nephrons,increasing their lifespan. In the pathological scenario, the equilibriumbetween molecules that cause vascular and mesangial contraction(ANG-II, endothelin-1—ET-1, platelet activating factor—PAF, TXA2, etc.)and those causing relaxation (NO, PGE2, etc.) is displaced towards theformer. The effects of ANG-II can be blockedwith renin inhibitors, ACEIsand ARA (reviwed in Perico et al., 2008). The potential efficacy of ET-1antagonists (such as avosentan and tezosentan) is also underdevelopment for the treatment of CKD (reviewed in Longaretti &Benigni, 2009).

A potential candidate to which little attention has been addressedis PAF. PAF is an acetylated alkyl phosphoglyceride synthesized bymany cell types, including different renal cells (López-Novoa, 1999).PAF contracts mesangial cells and blood vessels and exerts a pro-inflammatory action by contributing to leukocyte infiltration (Doi etal., 2006). Increased production of PAF has a key role in maintaining areduced GFR in different models of acute renal injury (AKI; López-Novoa, 1999), and has pro-fibrotic effects as a result of stimulating thesynthesis of ECM components on mesangial and tubular cells (Torraset al., 1999). Inhibition of PAF effects with PAF receptor antagonistsreduces AKI in vivo (López-Farré et al., 1990; Dos Santos et al., 1991;Rodriguez-Barbero et al., 1992; Bagnis et al., 1996; Rodriguez-Barberoet al., 1997), and direct cellular effect in vitro, such as mesangial cellcontraction (Martínez-Salgado et al., 2008). Interestingly, inhibitionof PAF with the PAF receptor (PAF-R) antagonist UR-12670, not onlyretards but also significantly reduces the intensity of the progressiveand chronic renal damage induced by ischemia in uninephrectomizedrats during 52 weeks of treatment (Torras et al., 1999). PAF-Rantagonists are classified into five groups (Chen et al., 2008): nitrogen

Table 1Drugs under development for the treatment of progressive chronic kidney disease (CKD).

↑RH AF AI ↓TI Drugs Refs.

StatinsX Fluvastatin, atorvastatin Perico et al., 2008

Inhibitors of cytokines and growth factorsAnti TGF-β antibodies X X X mAbs Perico et al., 2008; García-Sánchez et al., 2010TGF-β production inhibitors X X X Pirfenidone Perico et al., 2008Tyrosine kinase inhibitors X X X Imatinib, AG490 Gonçalves et al., 2010; Perico et al., 2008● ALK inhibitors X X X IN-1130, SB431542, GW788388 Moon et al., 2006CTGF inhibitors X X anti-CTGF Perico et al., 2008PDGF, EGF, FGF, VEGF inhibitors X Motesanib, aflibercept, cediranib Grande & López-Novoa, 2008; Perico et al., 2008MCP1 production X Bindarit Perico et al., 2008CCRs antagonists X BX471 Perico et al., 2008Complement C5 inhibitors X X Eculizumab, pexelizumab Perico et al., 2008

Activators of PPARsThiazolidinediones (PPAR-γ) X Pioglitazone, rosiglitazone Perico et al., 2008PPAR-α activators X Fibrate, WY14643 López-Hernández & López Novoa, 2009

Inhibitors of signaling pathwaysRas inhibitors X Statins; FTIs Martínez-Salgado et al., 2008Erk 1/2 inhibitors X X PD98059, U0126, GW5074 Grande & López-Novoa, 2008Akt inhibitors X Triciribine, perifosine, INCB-18424 Grande & López-Novoa, 2008p38 inhibitors X X X X SB203580, FR165673, NPC31145 Grande & López-Novoa, 2008Jun kinase inhibitors X X SP600125, AS602801, CEP1347 Grande & López-Novoa, 2008CDK inhibitors X Roscovitine, flavopiridol Perico et al., 2008

Vitamin D analogs X X Paricalcitol Perico et al., 2008

Endothelin antagonistsET-1A receptor antagonists X X X Ambrisentan, avosentan Longaretti & Benigni, 2009ET-1A+B receptor antagonists X X X Bosentan, tezosentan Longaretti & Benigni, 2009

PAF antagonistsX UR-12670, WEB2086, Ginkolide Torras et al., 1999; López-Novoa, 1999

Endogenous antifibrotic and antiinflammatory mediatorsBMP-7 X X X BMP-7 García-Sánchez et al., 2010HGF X X X HGF García-Sánchez et al., 2010

AF: antifibrotic; AI: antiinflammatory; ALK: Activin receptor-like kinase; BMP-7: bone morphogenetic protein-7; CCRs: CC chemokine receptors; CDK: cyclin-dependent kinase;CTGF: conective tissue growth factor; EGF: epidermal growth factor; ET: endothelin; FGF: fibroblast growth factor; FTIs: farnesyltransferase inhibitors; HGF: hepatocyte growthfactor; mAbs: monoclonal antibodies; MCP1: monocyte chemotactic protein-1; PAF: platelet activating factor; PDGF: platelet derived growth factor; PPAR: peroxisome proliferator-activated receptor; RH: renal hemodynamics; TGF-β: transforming growth factor-beta; TI: tubular injury; VEGF: vascular endothelial growth factor.


heterocyclic compounds (such as WEB2086 and WEB2170), PAFanalogues (e.g. CV3988 and SDZ63072), dihydropyridines (e.g.PCV4233 and PVA4248), plant extracts (e.g. BN52021—Ginkolide B-and kadsurenone), and others (e.g. 52 770 RP and TCV309). PAFantagonists should be further developed in CKD therapeutics.

Many of these drugs and therapeutic approaches exert effects atdifferent levels. The case of PAF is not the only one. For example, ET-1and RAS besides modulating renal vascular resistance, also participatein fibroblast and infiltrated cell stimulation and secretion ofprofibrotic mediators. Their inhibition improves RBF and reducesfibrosis (Perico et al., 2008). EGF has been shown to be involved infibrosis, EMT and vascular homeostasis. However, its inhibition notonly has antifibrotic effects but also improves renal hemodynamics(Helle et al., 2009). Because many mediators and signaling pathwaysseem to be redundant at inducing specific pathological effects, veryprobably, an effective prevention of progression must count on theidentification of crucial targets and should contain a cocktail ofdifferent molecules targeting all these key pathophysiologicalmechanisms at different levels (Perico et al., 2008). Moreover, specificactions require strict control of other comorbid factors. For example,increasing GFR through elevating RBFmust be accompanied by a strictcontrol of blood pressure and of tubular damage, in order to preventglomerular hypertensive injury (especially if hypertension is present),and excessive water and electrolytic loss, respectively. RAS inhibitorsare probably effective (to a certain extent) because they combine

multiple effects improving at the same time RBF and GFR, but alsolimiting tubulointerstitial damage.

8.2. Gene therapy

Gene therapy is another therapeutic strategy under preclinicaldevelopment. The renal delivery of gene-carrying vectors can beattempted through the renal artery, the renal vein, the ureter and bydirect injection into the renal parenchyma (Imai & Isaka, 2004). Tissuebarriers posed by capillary endothelium, basal membranes and renalepithelia limit the access of vector and cells to target sites from thecirculation (Imai & Isaka, 2004). Alternatively, gene therapy may beaddressed to the skeletal muscle so it continuously produces thetransgenic protein product and releases it to the circulation for asustained bioavailability (Imai & Isaka, 1999). Gene therapies are stillin a developmental state, but they hold promising potential for thetreatment of CKD.

For gene therapy, an appropriate vector containing a gene of interestor genetic materials (antisense oligonucleotides, decoy DNA orinterference RNAs), either alone or as a part of a genetic construct(plasmid, etc.) is introduced into the target (andother) cells. Vectors areviral and non-viral. Exceptionally, small genetic materials (oligonucleo-tides) can be directly endocytosed by cells without the help of a vector.Viral vectors have the intrinsic capacity for infection since the geneticmaterial is incorporated into engineered retro, lenti or adenoviruses.


Non-viral vectors must be forced into the cells though differenttechniques, including in vivo transfections with liposome-basedcomplexes, electroporation, and ultrasound-microbubbles (Imai &Isaka, 2004; Lien & Lai, 2004). Gene therapy has been first attemptedtowards monogenetic diseases, like Alports syndrome and polycystickidney disease (reviewed by Imai & Isaka, 2004). Monogenetic diseaseswith identified mutated genes are clear candidates for genetic therapy.Skeletal muscle erythropoietin-based gene therapy has also beenattempted to treat CKD-associated anemia (Oh et al., 2006). In the lastdecade, intense research has been conducted at the preclinical leveltowards the application of gene therapy to the treatment of CKD. Anumber of strategies have been attempted with variable results onspecific pathological events and disease progression in differentexperimental models and human nephropathies. These strategies areaimed at (i) introducing functional genes substituting for mutated ones[type-IV collagen α5 chain—COL4A5 (Heikkila et al., 2001; Imai et al.,2004), carbonic anhydrase II—CAII (Lai et al., 1998)]; (ii) overexpressionof transgenes involved in the regulation of renal function and structure[like lipoxygenase (Munger et al., 1999)]; (iii) interrupting signalingcascades involved in the development of pathological events [e.g. c-myc(Ricker et al., 2002), egr-1 (Carl et al., 2003)]; (iv) inhibiting theexpression of pro disease mediators [e.g. TGFβ (Akagi et al., 1996)]; (v)producing factors that prevent or soften disease [HGF (Herrero-Fresneda et al., 2006)]; (vi) producing molecules addressed toimprovement of CKD-derived systemic effects [e.g. anemia, witherythropoietin (Lippin et al., 2005)]. Future perspectives contemplateDNA repair (through homologous recombination of small DNAfragments for mutation reversal) as a more definitive therapeuticstrategy, envisioned initially formonogenic diseases (Goncz et al., 2002;Yoonet al., 2002).Gene therapy canbe combinedwithdrugs (e.g. ACEIs)in the search for synergistic effects (Yang et al., 2002a,b,c); it can also beapplied on cell therapy (see below) by priming and geneticallyengineering stem cells with specific and effective tissue regeneratingproperties, which opens new frontiers in therapeutics (Hanss &Bruggeman, 2003).

8.3. Cell therapy

Cell-based regeneration of degenerated tissues by redirectingrenal or extrarenal cells to proliferate or differentiate, or both, intospecific renal cell linages is also an area of active preclinicaldevelopment. Cellular therapy is currently also under development,both for the regeneration of damaged tissues and for the design ofbioartificial kidneys (Humes, 2005; Schachinger & Zeiher, 2005). Therapidly evolving field of cell biology has changed many old conceptsregarding cell differentiation and plasticity. Mature, terminallydifferentiated cells have now been demonstrated to hold the capacityto de-differentiate and cis- or trans-re-differentiate into distinctphenotypes, with different degrees of pluripotency (Odelberg, 2002;Bonventre, 2003). Moreover, the discovery of pluripotent and multi-potent stem cells has revolutionized the field of tissue engineeringand tissue repair through cell therapy (Bianco & Gehron Robey, 2000;Korbling & Estrov, 2003; Passier & Mummery, 2003). An advantage ofcell-based therapy is to supercede the difficulty of correcting theskewed homeostasis of diseased cells, where a myriad ofinterconnected and altered pathways seems to be difficult to reversethrough the pharmacological or genetic manipulation of a single or afew molecular targets (Humes & Szczypka, 2004). The kidneypossesses an extraordinary capacity for spontaneous regenerationand self repair (Anglani et al., 2004). Restitution of cells lost to damageor pathological events seems to be closing up through a variety ofpossibilities. Epithelial (e.g. tubular) cells destroyed during renaldamage (especially during acute injury) have been shown to bereplaced and the epithelium reconstituted. Sources for renal (tubule)epithelial cells are hypothesized to include (Humphreys et al., 2006):(i) surviving renal epithelial (or even interstitial) cells, which might

directly proliferate or de-differentiate into a mesenchymal pheno-type, proliferate to restore the integrity of the basement membraneand then redifferentiate into a normal epithelium (Rookmaaker et al.,2004); (ii) surviving renal stem cells or resident tubule progenitorswhich selectively proliferate after the damage. Recent evidencestrongly suggests that adult renal stem cells exist, although rigorouscorroboration and precise intrarenal location (i.e. the papilla) wait tobe established (Oliver et al., 2004); (iii) extrarenal, bone marrow-derived or circulating cells. Several cell types derived from the bonemarrow (also found in the circulation) bear transdifferentiatingcapability, includingmesenchymal stem cells and hematopoietic stemcells. Circulating monocytoid cells (derived from the neural crest) andfibrocytes are postulated as candidates (Anglani et al., 2004).

Consequently, cell therapy can theoretically be approached (i) byappropriately driving resident renal cells (stem, progenitor or differen-tiated) to restore the damaged tissues, or alternatively (ii) by injectingrenal cells or bone marrow-derived cells with transdifferentiating andrepair capabilities. So far, only the second option has been experimen-tally tested, with variable outcomes. Primarily, bone marrow-derivedmesenchymal cells (with distinct phenotypes) have been used(reviewed in Brodie & Humes, 2005) for their ability to transdiffer-entiate into renal epithelial tubular (Kale et al., 2003; Herrera et al.,2004) andmesangial (Masuya et al., 2003) cells, andendothelial cells forre- and neo-vascularization (Takahashi et al., 1999; Patschan et al.,2006). Bonemarrow-derivedmesenchymal cells have been reported tocontribute to the repair of drug- or ischemia/reperfusion-injuredkidneys (Herrera et al., 2004), although the efficacy of these cells hasalso been challenged (reviewed in Brodie & Humes, 2005).

Adult tubule epithelial cells have been used to construct abioartificial kidney. This biodialysis device consists of a synthetichemofilter coupled in series with a bioartificial tubule which containsapproximately one billion tubule cells (Humes et al., 2004). Abioartificial kidney has been used to treat a CKD patient with multi-organ failure in the intensive care unit, resulting in some improve-ment of cardiovascular and renal parameters (Humes et al., 2004).Other cell based therapies conducted at the experimental levelinclude encapsulated cell implants to remove uremic toxins anddeliver therapeutic agents (see Brodie & Humes, 2005), and foetalkidney transplantation (Hammerman, 2003).

9. Final remarks

A greater specific knowledge regarding the pathophysiologicalmechanisms underlying the inception, transformation and progres-sion of pathologies that lead to the development of chronic kidneydisease is expected to enable, in the near future, the development ofbetter and earlier diagnostics. This, in turn, should provide a betterclinical management of disease progression in order to prevent theneed for renal replacement therapy (RRT) or secondary healthcomplications during the patient's lifespan. This improvement willprovide an enormous human benefit based on a better quality of life,andwill reduce the disproportionate socioeconomic cost associated toCKD. Therapeutic improvement will be based (i) on the discovery ofbetter molecular targets on which to act with existing and new drugs;and (ii) on therapy optimization through drug combinations, throughthe development of novel molecules bearing different biologicalactivities, and through drug targeting to specific action sites.

However, a greater level of understanding of CKD must beachieved in order to facilitate effective control of this disease. Onthe one hand, it is not well known why and how renal repairmechanisms, which function reasonably well under such circum-stances as acute renal injury, eventually become non-functional andprecipitate disease (García-Sánchez et al., 2010). Understanding thecomponents involved in this transformation is of grave importance inorder to prevent rather than only slow the progression of CKD. Thesecond aspect for further future consideration, which is dependent


upon the previous goal, is the capability of tissue regeneration andrestoration of renal function.

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Common pathophysiological mechanisms of chronic kidney disease: Therapeutic perspectives

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