1. Epigenetic modifications; micro-RNAs dysregulation
Poor HLA matching
DGF
Infection (CMV, …)
Allospecific response
Black race
Preservation/harvesting/
reperfusion, cold & warm ischemia
Risk factors for DGF
Donor/recipient-related age
Weight, Cause of death
Urine output & Creatinine
Time on dialysis
Type of dialysis
Comorbidities
Duration of surgery
Ca, P
Diet
Folate depletion
Smoking
Epigenetic modifications;
micro-RNAs dysregulation
I/R
Acute rejection
Up regulation of GFs, Cytokines,
Adhesion molecules
EMT, Myofibroblast activation
senescence
Renal quality
Deceased donor
Cause of death (brain death)
Donor age, race
Acute tubular necrosis
Glomerular/vascular diseases Hypertension
Tubular damage, nephron loss &
CAD/IFTA
CNI Nephrotoxicity
Inflammatory infiltration
Overweight
Klotho
Infection
Obstruction
Microbiome
Hormones
RAS
Aldostron
FGF23
PTH
Recipients alloimmunity
HLA mismatch,
Panel reactive antibodies
Regraft
young recipient age
Suboptimal immunosupression
Biocomplexity of chronic allograft dysfunction
Diseases
Hypertension
Hyperglicemia
Hyperlipidemia
Hyperuricemia
Hypomagnesemia
Older kidney age
Salt depletion
Nonsteroidal anti-inflammatory drugs
Genetics & Pharmacogenetics
Figure 1

2. Myofibroblast activation &
Klotho
Wnt/β-catenin
Senescence
apoptosis
Accumulation
of ECM
EMT
Fibroblast activation,
Myofibroblast activation &
proliferation
TGF-
Renal Tubule cells
Renal fibrosis β
Figure 2

3. Renal Fibrosis TGF-β TNF-α miR-433 Smad7 (+) EMT TGF-β2 miR-200s
TIMP1,
Col 1A1
Col 1A2
α-SMA
Fibronectin
MMP9
Lipid oxidation
ROS production
Oxidative stress
Col1A1
Col1A2
EMT
TGF-β2
miR-200s
(miR-200a-c, miR-141 & miR-429)
miR-192
miR-377
Col1 1, 2
miR-216
miR-217
Col 1,2,3,4, 5,7,8 A1
Col 5A2, 5A3
Fibrillin
TPM1
miR-29s
(miR-29a/b1, b2/c)
Podocytes apoptosis
Mesangial matrix
accumulation
miR-30s
(miR-30a-e)
miR-324-3p
miR-382
miR-214
miR-433
(+)
Renal Fibrosis
miR-93
Figure 3
mir-382
miR-216/217
miR-30

4. Epigenetic alteration
Epigenetics
Recipient
Donor
I/R
Reperfusion….
free radicals
Viral infection
CNI therapy
Smoking
Diet
Folic depletion
Habits
Weight
Epigenome
Pharmacogenetics
Graft outcome
Epigenetic alteration
Altered DNA
Methylation
Gene expression
Histone modifications
Aberrant miRNA
expression
Donor genome
Recipient genome
Genetics