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Chronic kidney disease: a new look at pathogenetic mechanisms and treatment options

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A Publisher's Erratum to this article was published on 23 May 2014

Abstract

The concept of renoprotection has evolved significantly, driven by improved understanding of the pathophysiology of chronic kidney disease (CKD) and the advent of novel treatment options. Glomerular hyperfiltration, hypertension and proteinuria represent key mediators of CKD progression. It is increasingly recognized that proteinuria may actually be pathological and etiological in CKD progression and not just symptomatic. It initiates a sequence of events involving activation of proinflammatory and profibrotic signaling pathways in proximal tubular epithelial cells with transmission of the disease to the tubulointerstitium and progression to end-stage kidney disease (ESKD). Although the etiology and epidemiology of pediatric CKD differs to that in adults, studies in the various animal models of kidney disease, from obstructive uropathy to glomerulonephritis, have revealed that many common proinflammatory and profibrotic pathways are induced in progressive proteinuric CKD, irrespective of the primary disease. This pathomechanistic overlap therefore translates into the potential for common treatment targets for a wide spectrum of kidney diseases. In this review we therefore discuss the experimental and clinical evidence for an array of prospective future drug treatments of CKD progression. While conceptually promising, clear definitive evidence beyond preclinical data does not exist for many of these treatments, and others are limited by serious adverse effects. More studies are needed before general recommendations can be given.

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Abbreviations

ACE:

Angiotensin converting enzyme

ANP:

Atrial natriuretic peptide

ARB:

Angiotensin receptor I blocker

BMI:

Body mass index

CAKUT:

Congenital anomalies of the kidney and urinary tract

CCL 2:

Chemokine (C-C motif) ligand 2 (MCP 1)

CCL 5/RANTES:

Chemokine (C-C motif) ligand 5

CCR:

β chemokine receptor

CKD:

Chronic kidney disease

CKiD:

Chronic Kidney Disease in Children cohort

CTGF:

Connective tissue growth factor

DN:

Diabetic nephropathy

ECM:

Extracellular matrix

ESKD:

End-stage kidney disease

ET:

Endothelin

FSGS:

Focal segmental sclerosis

GBM:

Glomerular basement membrane

GFR:

Glomerular filtration rate

HMG CoA:

3-Hydroxy-3-Methylglutaryl CoA

IF:

Interstitial fibrosis

KDOQI:

Kidney Disease Outcomes Quality Initiative

MCP 1:

Monocyte chemotactic protein 1 (CCL 2)

MMP:

Matrix metalloproteinase

MSC:

Mesenchymal stromal cell

NADPH:

Nicotinamide adenine dinucleotide phosphate

NEP:

Neutral endopeptidase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PAN:

Puromycin aminonucleoside

PPAR γ:

Peroxisome-proliferator-activated-receptor γ

PTEC:

Peritubular epithelial cell

RAAS:

Renin angiotensin aldosterone system

RANTES:

Regulated upon activation normal T-cell expressed, and secreted (CCL 5)

ROS:

Reactive oxygen species

TGF β:

Transforming growth factor β

TNF α:

Tumor necrosis factor α

VDR:

Vitamin D receptor

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Division of Nephrology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, ON, Canada

    Damien Noone & Christoph Licht

  2. Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Damien Noone & Christoph Licht

  3. Department of Paediatrics, University of Toronto, Toronto, ON, Canada

    Christoph Licht

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Noone, D., Licht, C. Chronic kidney disease: a new look at pathogenetic mechanisms and treatment options. Pediatr Nephrol 29, 779–792 (2014). https://doi.org/10.1007/s00467-013-2436-5

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