2012 update on diabetic kidney disease: the expanding spectrum, novel pathogenic insights and recent clinical trials.
Diabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease in western countries. This implies that current methods based of renin angiotensin aldosterone system (RAAS) targeting for preventing, slowing or promoting regression of DKD are insufficient. Podocyte injury and albuminuria are thought to be key events in DKD. Indeed several DKD stages are recognized based on the magnitude of albuminuria. However, the spectrum of DKD has recently expanded, as lack of significant albuminuria is present in 30% of diabetics with kidney function impairment. This may result from the widespread use of drugs targeting the RAAS. However, it may also indicate that additional pathogenic factors contribute to renal function deterioration despite control of albuminuria. In this regard, double blockade of the RAAS is more effective in reducing albuminuria that blockade of a single component. However, clinical trials assessing double blockade for renal function preservation have been disappointing and raised safety issues. Non-biased -omics approaches have uncovered alternative therapeutic targets, including the cytokine TRAIL, the MIF receptor CD74 and the proapoptotic intracellular protein BASP1. In addition, urinary proteomics has uncovered a peptidomic fingerprint for DKD progression that precedes the onset of microalbuminuria. Studies are underway to validate this fingerprint for early treatment of high risk patients. Recent clinical trials suggest a potential role of bardoxolone methyl to improve renal function in advanced DKD, while trials of avosentan, pirfenidone, sulodexide and pyridoxamine have been disappointing and further data are needed for paricalcitol and vitamin D, newer generation endothelin receptor antagonists and pentoxifylline.
Nephrology, IIS-Fundación Jiménez Díaz, Madrid, Spain.
B
B
Fernández Fernández
U
U
Elewa
M D
MD
Sánchez-Niño
J E
JE
Rojas-Rivera
C
C
Martin-Cleary
J
J
Egido
A
A
Ortiz
D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000944:Antigens, Differentiation, B-Lymphocyte; D015415:Biomarkers / Q000032:analysis; D002986:Clinical Trials as Topic; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy*; D018450:Disease Progression; D004359:Drug Therapy, Combination / Q000379:methods; D000949:Histocompatibility Antigens Class II; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy / Q000379:methods*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D050199:Podocytes / Q000502:physiology; D040901:Proteomics / Q000379:methods; D012076:Renal Agents / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000944:Antigens, Differentiation, B-Lymphocyte; C104089:BASP1 protein, human; D015415:Biomarkers; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012076:Renal Agents; D012097:Repressor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C045084:invariant chain