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  • Review Article
  • Published:

Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection

Nature Reviews Drug Discovery volume 7, pages 936–953 (2008)Cite this article

Key Points

  • Chronic kidney disease (CKD) is a worldwide threat to public health, but the scale of the problem is probably not fully appreciated. At present, there are no specific cures for most of the acquired CKDs and renal transplantation is limited by organ shortage. So, efforts are underway to discover new drugs to prevent the progression of renal diseases.

  • More common nephropathies progress slowly, but evolve to end-stage renal disease (ESRD) at different rates. Research in animals and humans have established that progressive deterioration of renal function is the result of compensatory glomerular haemodynamic changes in response to nephron loss due to various original insults. Intraglomerular haemodynamic changes and proteinuria play a key role in this process.

  • Angiotensin converting enzyme (ACE) inhibitors and, increasingly, angiotensin II receptor antagonists are now widely prescribed for the treatment of proteinuric renal diseases, including diabetic nephropathy. Animal and human studies have consistently found that ACE inhibitors and angiotensin II receptor antagonists in combination reduce proteinuria more effectively than the two agents alone. Renin inhibitors and aldosterone antagonists are novel classes of drugs that have been recently proposed as additional tools for renoprotection in clinical trials.

  • In addition to components of the renin–angiotensin–aldosterone system, a large variety of inflammatory cells are recruited in the kidney tissue and are activated to produce mediators that trigger progression of renal disease towards ESRD. Inflammatory cells, apart from being involved in the development of glomerular injury, are key players of tubulointerstitial damage, which eventually leads to interstitial fibrosis. Novel drugs and biological agents that target inflammatory and profibrotic processes are still in the preclinical development, although some are now reaching the clinical arena.

  • Besides statins, the focus is mainly on cytokine/chemokine receptor antagonists, chemokine inhibitors, transforming growth factor-β (TGF-β)-specific antibodies and new TGF-β receptor kinase inhibitors, and thiazolidinediones. Preclinical studies have demonstrated that these show promise as renoprotection agents. However, there is need to assess the safety profile of these molecules in the clinic.

  • Novel drugs and biological agents that target immunological processes of glomerular injury have also been developed. Of note are cyclin-dependent kinase/glycogen synthase kinase-3 inhibitors that have been tested in preclinical animal models of CKD.

  • Based on its property of selectively depleting CD20+ B cells, rituximab has recently been proposed as a therapeutic option for antibody-mediated glomerulonephrities, namely membranous nephropathy, cryoglobulinaemic glomerulonephrities and systemic lupus erythematosus.

  • Overall, as existing drugs for the treatment of chronic nephropathies have a favourable risk/benefit ratio, new therapies to implement renoprotection will require a similar or better safety profile if they are to be widely used and accepted.

Abstract

At present, there are no specific cures for most of the acquired chronic kidney diseases, and renal transplantation is limited by organ shortage, therefore present efforts are concentrated on the prevention of progression of renal diseases. There is robust experimental and clinical evidence that progression of chronic nephropathies is multifactorial; however, intraglomerular haemodynamic changes and proteinuria play a key role in this process. With a focus on renoprotection, we first examine more established therapies — such as those that modulate the renin–angiotensin–aldosterone system — that can be used for the treatment of proteinuric renal diseases. We then discuss examples of novel drugs and biologics that might be used to target the inflammatory and profibrotic process, and glomerular injury, highlighting results from recent clinical trials.

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Figure 1: Mechanisms of progressive glomerular injury.
Figure 2: Mechanisms of aldosterone-induced kidney damage.
Figure 3: Mechanisms of renal interstitial fibrosis.
Figure 4: Structures of TGF-β receptor inhibitors and their inhibitory actions.
Figure 5: Structures and agonistic effects of thiazolidinediones.
Figure 6: Structure and function of γ-secretase inhibitors on podocytes.

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Acknowledgements

We are deeply grateful to P. Ruggenenti, M. Abbate and B. Bikbov for their suggestions and criticisms. We also thank F. Gaspari for technical assistance in preparing the manuscript.

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Authors and Affiliations

  1. Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo - Mario Negri Institute for Pharmacological Research, Via Gavazzeni, Bergamo, 11-24125, Italy

    Norberto Perico, Ariela Benigni & Giuseppe Remuzzi

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  1. Norberto Perico
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  2. Ariela Benigni
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  3. Giuseppe Remuzzi
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Correspondence to Giuseppe Remuzzi.

Supplementary information

Supplementary information S1 (box)

Renin-angiotensin-aldosterone cascade and site of action of specific inhibitors (PDF 510 kb)

Supplementary information S2 (box)

Effects of statins on cholesterol and beyond (PDF 242 kb)

Supplementary information S3 (table)

Effectiveness of therapeutic interventions in animal models of PKD (PDF 166 kb)

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FURTHER INFORMATION

ClinicalTrials.gov

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National Monitoring Centre for Clinical Trials

NKF, FDA Host Conference to Assess Proteinuria as a Surrogate Outcome in Chronic Kidney Disease

Glossary

Mesangial cell

A key cell of the glomerulus with enlarged cytoplasmic processes that extend around the capillary lumen and insinuate themselves between the glomerular basement membrane and the overlying endothelium.

Podocytes

The visceral epithelial cells of the glomerulus with large cytoplasmic processes that extend from the main body.

Glomerulosclerosis

Mesangial accumulation of hyaline material that progressively encroaches on capillary lumina, which obliterates the Bowman's space and results in global sclerosis of the glomerulus.

Slit diaphragm

A thin membrane that bridges the gap between adjacent foot processes of the podocytes near the glomerular basement membrane.

Albumnin/creatinine ratio

Ratio between the concentrations of albumin and creatinine measured in urine. It is used to detect early chronic nephropathy, particularly diabetic nephropathy.

Dahl salt-sensitive rat

An experimental model of hypertension and renal injury (glomerulosclerosis and tubulointerstitial damage) induced in rats sensitive to a high-salt diet.

Idiopathic membranous nephropathy

The most common cause for nephrotic syndrome in adults, which occurs as idiopathic (primary) disease of the kidney.

Nephrotic proteinuria

Urinary protein excretion of more than 3 g per day in the setting of glomerular disease.

Heymann nephritis

An experimental model of glomerular disease that mimics membranous nephropathy in humans.

Crescentic glomerulonephritis

An aggressive form of glomerulonephritis that is characterized by intensive glomerular inflammation, which induces epithelial cell proliferation and macrophage maturation (cellular crescents).

ANCA-associated vasculitis

An inflammatory disease involving blood vessels, also of the kidney, characterized by the concomitant presence of antineutrophil cytoplasmic antibodies (ANCA).

Db/db mouse

The db/db mouse is a hyperinsulinaemic model of genetic diabetes that develops abnormalities in renal morphology and function that mimic those in human diabetic nephropathy.

Puromycin-induced nephrotic syndrome

An experimental model of nephrotic syndrome that is characterized by heavy proteinuria and progressive glomerular and tubulointerstitial injury induced by single or repeated injections of the puromycin aminonucleoside.

Focal segmental glomerulosclerosis

A diagnostic term for a clinical pathological syndrome that has multiple aetiologies and pathogenic mechanisms characterized by proteinuria and focal segmental glomerular consolidation or scarring.

Collapsing glomerulopathy

Collapsing glomerulopathy is a morphological variant of focal segmental glomerulosclerosis that is characterized by segmental and global collapse of the glomerular capillaries, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease.

Intestinal crypts

Mucosal epithelium that is extensively invaginated.

Glomerular basement membrane

This is one of the components of filtration barrier between the blood and urinary space, which is composed of a central dense layer, the lamina densa, and two thinner, more electron-lucent layers, the lamina rara externa and the lamina rara interna.

Type II mixed essential cryoglobulinaemia

Cryoglobulinaemia refers to a pathogenic condition caused by the production of circulating immunoglobulins that precipitate upon cooling. Type II cryoglobulinaemia is defined as mixed cryoglobulins containing at least two immunoglobulins, and has no clear aetiology.

Systemic vasculitis

Systemic vasculitis comprises a large group of inflammatory diseases with a suggestive or proven immunopathogenesis involving blood vessels of various sizes and affecting various organs including the kidney.

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Perico, N., Benigni, A. & Remuzzi, G. Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection. Nat Rev Drug Discov 7, 936–953 (2008). https://doi.org/10.1038/nrd2685

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