Memorias Conferencia Científica Anual sobre Síndrome Metabólico 2017 - Programa Científico Nefropatía diabética. Nuevos aspectos Dr. Francisco Gómez Pérez Jefe del Departamento de Endocrinología y Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”

1. US Renal Data System- Incidence of ESRD by Primary Diagnosis.
La diabetes es la principal causa de insuficiencia renal en fase substitutiva

2. Mecanismos implicados en el daño renal y la expansión mesangial en la nefropatía
diabética
• Activación de PKC y MAPK
• Aumento de la formación de productos de Amadori.
• Aumento de formación de productos avanzados de glucación. (AGES)
• Aumento del flujo de glucosa a través de la vía de los polioles.
• Incremento de la vía de aldosa reductasa.
• Aumento del paso de glucosa por la vía de las hexosaminas.
• Aumento de producción de tromboxane y otros eicosanoides.
• Aumento del estrés oxidativo y de carbonilos.
• Aumento de la producción renal de factores de crecimiento proescleróticos TGF-
β, PDGF, IGF-1, HGF, substancias vasoactivas: Ang-II, ET-1 y quimiocinas (IL-8,
MCP-1)
Sperling MA. Type 1 Diabetes, Etiology and Treatment 2003. Humana Press
SINDROME METABOLICO

3. Specific classes of oral hypoglycemic and hypolipidemic agents
are associated with renoprotective effects. RAS blockade
remains the mainstay of treatment. Novel agents that target
different pathophysiologic pathways in diabetic nephropathy
are being investigated.
Algunas medidas orientadas al control de la nefropatía diabética
Dounousi E, et al. Rev Diabet Stud (2015) 12:119-133

4. Esquema preventivo y terapéutico en la nefropatía diabetica
Intervención Meta
Tratamiento renoprotector
ACEi o BRA(Evitar combinar ACEi y BRA) Meta < 130/80 en algunos casos resistentes < 140/90
Antihipertensivo Utilizar en casos con Proteína urinaria de 0.5-1 g/d
TFG que disminuye > 2 ml/min/año
Control glucémico Hba1c  7 %
Restricción de proteínas 0.8 g/Kg/día en TFG < 30 ml/min/1.73m2
Protección cardiorenal adicional
Restricción de sal < 5g/día o mayor
Hipolipemiantes <70-100 mg/dl de LDL-C, < 150 mg/dl Tg
Antiplaquetarios Profilaxis de trombosis
Ejercicio Al menos 30 min/día 5 días/semana
Control de peso Perseguir el peso ideal
Tabaquismo Supresión total del hábito
Modificado de: Satirapoj B, Adler SG Kidney Res Clin Pract 2014;33:121–131
Aspirina

5. HIPERTENSION ARTERIAL SISTOLICA Y DETERIORO DE FUNCION RENAL EN DIABETES

6. NUEVAS OPCIONES DE INTERVENCION EN ESTUDIO EN LA NEFROPATIA DIABETICA
• Antiinflamatorios
- Inhibidores de COX y de xantina oxidasa ??
-Inhibidores de la proteina quimioatrayente de monocitos-1 (MCP-1)
- Inhibidores de TNF-α
-Señalización de NF-β
• Inhibidores de PKC
• Inhibidores de HMG-CoA reductasa
• Papel de receptores de endotelina en la ND
• Señalización Wnt en ND
• Antioxidantes e inhibidores de estrés del retículo
endoplásmico.
• Nuevos enfoques moleculares
-Micro RNAs
- Mecanismos epigenéticos en la ND

7. PAPEL DE COX Y PGE2 EN LA NEFROPATIA DIABETICA
Sharma D et al. Diab Res Clin Pract 2017;1 2 8: 9 1 –1 0 8
PLA2: Phospholipase A2; PGE2: Prostaglandin E2;
COX-1 and COX-2: Cyclooxygenase-1 and 2; EP
receptors: Prostaglandin E2 receptors.
EP Receptors: Receptores de Prostanoides
La inhibición de COX-2 podría tener efectos
benéficos debido a la inhibición de COX-2 en
podocitos y atenuación de la hiperfilttración.
El papel de COX-2 en el daño renal puede
depender de las fuentes de origen de COX, el
mecanismo del daño renal y la expresión y el
subtipo de los receptores de PGE asi como el
momento de la inhibición de COX-2

8. COX-2–selective NSAIDs can cause acute renal failure and should be
avoided or at least used cautiously for short periods of time (with close
monitoring) in patients with chronic renal insufficiency.
In addition, randomized, prospective studies should be undertaken to
evaluate the renal safety of COX-2 selective agents compared with
nonselective COX inhibitors in a large number of high-risk patients.
American Journal of Kidney Diseases, Vol 35, No 5 (May), 2000:
pp 937-940
COX inhibition, reduces proteinuria in patients with kidney disease.
However, by diminishing renal blood flow and intraglomerular pressure
it may also precipitate acute kidney injury in predisposed individuals.
Whether therapeutically targeting pathway members that lie
downstream of the COX enzymes themselves can alter the natural
history of kidney disease remains uncertain.
Inhibicion de prostaglandinas y nefropatía diabética
ONO-AE3-208 (selective inhibitor of EP4) prevents podocyte dedifferentiation induced by transforming growth factor-ß1 (TGF-ß1). The
difference in the renal effects of ONO-AE3-208 and captopril, despite both being accompanied by an equivalent reduction in albuminuria,
suggested to us that the reno-protective effects of EP4 inhibition are not limited to actions on hemodynamic forces. Likewise, the observation
that the reno-protective effect of ONO-AE3-208 was also apparent in non-diabetic SNx rats suggested to us that this effect was also not
restricted to high glucose mediated events. Scientific Reports | 7: 3442 | DOI:10.1038/s41598-017-03237-3 June 2017

9. • HIPERGLUCEMIA
• OBESIDAD FACTORES DE
CRECIMIENTO
• AUMENTO DE AGNE
• LIGANDOS CELULARES
• HIPERTENSION
• CITOCINAS
TLR: Toll-like receptors
MCP-1: Proteina quimioatrayente de
monocitos-1
IL-6: Interleucina-1
NF-β: Factor nuclear β
INFLUENCIA DE DIVERSOS FACTORES SOBRE NF-β
NF-β is a protein complex that
controls transcription of DNA,
cytokine production and cell survival.
NF-κB is found in almost all animal
cell types and is involved in cellular
responses to stimuli such as stress,
cytokines, free radicals, heavy metals,
ultraviolet irradiation, oxidized LDL,
and bacterial or viral antigen

10. eNOS  ET-1  VEGF  PAI-1  NF-B  NAD (P) H OXIDASAS
 TGF-
 Colágena
 Fibronectina
 fibrinolisis
 ROS
Flujo
sanguíneo
anormal
Permeabilidad
Vascular
Angiogénesis
Oclusión
Capilar
Oclusión
vascular
Expresión de
Genes
proinflamatorios
Efectos
Múltiples
HIPERGLUCEMIA
 DIACILGLICEROL
 DE FORMAS  Y  DE PKC

11. Have been associated with vascular alterations such as
increases in:
• Permeability
• Contractility
• Extracellular matrix synthesis
• Cell growth and apoptosis
• Angiogenesis,
• Leukocyte adhesión
• Cytokine activation and inhibition.
Linked to
• Development of pathologies affecting Large vessels
(atherosclerosis, cardiomyopathy) and
• Small vessels
(retinopathy, nephropathy and neuropathy)
PKC:Diversas isoformas:
PKC-α, PKC-β 1 / 2 Y PKC-

12. EFECTO DE LA RUBOXISTAURIN (INHIBIDOR ESPECIFICO DE PKC EN LA NEFROPATIA
DIABETICA
Tuttle KR, et al. Am J Kidney Dis. 2015;65(4):632-638

13. The single pivotal study provided only marginal evidence of efficacy in the ITT population. This was not confirmed in the population of
completers or per protocol. Thus, the study does not provide robust evidence of efficacy and does not comply with the CHMP “Points to
consider document” on application with 1. Meta-analysis; 2. One Pivotal study (CPMP/EWP/2330/99). Further confirmatory evidence of efficacy
is required.
• There was a concern regarding QT prolongation with ruboxistaurin.
• There is a concern regarding CPK increase with RBX and in particular
possible interactions with statins.
• Further, the interaction with tricyclic anti-depressants, neuroleptics
and other non anti-arrhythmic QT prolonging drugs, in view of possible
additive/synergistic effects on Q-T interval prolongation is a matter of
concern.

14. Role of inflammatory cascade and its inhibition by 3-Hydroxy-3-methylglutaryl coenzyme A
(HMG-COA) reductase
PAI-1, ECM and
eNOS) in kidney which finally leads to kidney
damage.
ECM: Extracellular matrix; PAI-1: Plasminogen
activator inhibitor-1;
eNOS: Endothelial nitric oxide synthase.
The small GTP-binding proteins Ras
and Rac1 are molecular switches
exchanging GDP for GTP and
converting external signals in
response to a variety of stimuli.
Ras and Rac1 play an important
role in cell proliferation, cell
differentiation, and cell migration.
Rac1 is directly involved in the
reorganization and changes in the
cytoskeleton during cell motility.
Nitric oxide (NO) stimulates the
Ras – ERK1/2 MAP kinases

15. EFECTOS DE ANGIOTENSINA II Y ENDOTELINA EN RIÑON
Am J Physiol Regul Integr Comp
Physiol 2016; 310: R877–R884

16. ENDOTHELIN-1

17. Egido J , Rojas-Rivera J, et al. Expert Opinion on Investigational Drugs 2017 doi.org/10.1080/13543784.2017.1325872
EFECTO PROTECTOR DE INHIBIDORES DE ET R EN NEFROPATIA DIABETICA
ATRESANTAN BOSENTAN
Atresantan produce aumento
de peso, retención de lÍquidos
y disminución de hemoglobina
en pacientes con DM y
nefropatía sin embargo sin
evidencia significativa de
edema o insuficiencia cardiaca.
DISMINUCION DE
ALBUMINURIA Y PROTECCIÓN
RENAL

18. Vías epigenéticas afectadas por la hiperglucemia

19. MECANISMOS EPIGENETICOS EN NEFROPATIA DIABETICA
TGF-β:Transforming growth
factorβ; RAAS: Renin
angiotensin aldosterone
system; PKC: Protein kinase
C; AGEs: Advanced
glycation end produc

22. The RAS including the novel ACE2/Ang(1–7) axis
Karnik SS. British Journal of Pharmacology (2017) 174 737–753 737

23. Efectos potenciales de ACE2 y angiotensina 1-7 sobre la regulación de la presión arterial
Nat. Rev. Cardiol. 11, 413–426 (2014)

24. POSIBLES APLICACIONES EN MEDICINA DE LA ANGIOTENSINA 1-7
Passos-Silva DG, verano-Braga T, Santos RAS. Clinical Science 2013;124:443-456

25. Padda RS, et al. J Diabetes Metab. 2015; 6
Angiotensina 1-7 en la nefropatía diabética

26. CONCEPTO ACTUAL DE LOS RECEPTORES A ANGIOTENSINA 1-7
British Journal of Pharmacology (2017) 174 737–753

27. Los riñones de ratones db/db muestran aumento de la acetilación de FOXO1, y disminución de SIRTUINA1
y PPARα que fueron completamente revertidos por tratamiento con angiotensina 1-7

28. LA AMPLIFICACION DEL RECEPTOR DE ANGIOTENSINA 1-7 NO PROTEGE A LOS RATONES DEL
DESARROLLO DE NEFROPATIA DIABETICA
Wyzoki J, et al. Kidney international 2016

29. HIPERGLUCEMIA
ADP
ATP
Fosforilación oxidatiiva
ROS AGEs
Glucoxidación
AGNE
LDLox
RADICALES LIBRES
AUMENTO DE 2dos
MENSAJEROS
PKC
MAPK
NFB
DISFUNCION Y DAÑO CELULAR
GSH
GSSGANTIOXIDANTES
glutatión se convierte en su
forma oxidada disulfuro de
glutatión (GSSG).

30. REPRESENTACION ESQUEMATICA DEL ESTADO DE MARCADORES DE ESTRÉS OXIDATIVO EN
PRESENCIA DE DIABETES
MDA: malondialdehyde, AOPP: Advanced oxidation protein
products, PCO: protein carbonyls, GSH: reduced glutathione,
and SOD: superoxide dismutase.
Existe un aumento de oxidación y
una disminución del sistema
antioxidante
Journal of Biomarkers 2013http://dx.doi.org/10.1155/2013/378790

31. ESTRÉS OXIDATIVO Y RESPUESTAS CELULARES
Japan Medical Association Journal 2002; 45: 271

32. Deen WM. J. Clin. Invest. 114:1412–1414
Glomerular capillary wall, consisting principally of a fenestrated endothelium, a basement membrane, and epithelial foot
processes. The foot processes form filtration slits spanned by slit diaphragms. Also shown is the endothelial cell coat, or
glycocalyx. Some approximate dimensions are (8, 10): minimum diameter of fenestra, 30 nm; GBM thickness, 200–400 nm
(depending on species); width of filtration slit, 40 nm. The glycocalyx thickness is uncertain

33. P = Podocitos. Las flechas indican la localización de la nefrina
GBM = Membrana basal glomerular
LOCALIZACION GLOMERULAR DE LA NEFRINA (MICROSCOPIA ELECTRÓNICA) EN LAS HENDIDURAS DIAFRAGMATICAS.
DE LOS PODOCITOS
Ruotsalainen V, Jungberg L, Wartiovaara P, et al Proc Nat Acad Sci USA 1999; 96: 7962

34. Toyoda M, Suzuki D, Umezono T, et al, Nephrol Dial Transplant 2004; 19: 380–385
EXPRESIÓN DEL RNAm DE LA NEFRINA HUMANA EN LA NEFROPATIA DIABÉTICA

35. Conadesuca.gob.mx
Utilización del jarabe de maíz de alta fructosa en la industria en
México desde 1970 y mortalidad por diabetes

36. Consumo de jarabe de maíz de alta fructosa (HFCS), fructosa libre y consumo total de fructosa,
y prevalencia de obesidad

37. Promoción del desarrollo de diabetes ?
Daño renal

39. Señales de insulina, inflamación y señales de estrés
En presencia de resistencia a la insulina, mediadores inflamatorios y lípidos activan una cascada de señales que dispara cinasas
inflamatorias como JNK e IKK asi como PKC,S6K,mTOR y ERK. La activación de JNK e IKK resulta en la inhibición de la acción
de insulina en parte a través de la fosforilación en la serina de los substratos del receptor de insulina (IRS) 1 y 2. La energía del
exceso de nutrientes puede inducir estrés del retículo endoplásmico que esta directamente ligado a la activación de vías
inflamatorias que a su vez bloquean la acción de la insulina y regulan transcripcionalmente la producción de citocinas
inflamatorias. Los ROS que se producen durante el estrés de organelos y disfunción mitocondrial contribuyen a estos efectos. La
consecuencias finales son estrés del RE, aumento de la inflamación, inhibición de la acción de insulina y posiblemente de la
acción de Leptina que culminan en disfunción metabólica.

40. Cell 2010;140: 900–917
Hotamisligil GKS
Factores que pueden afectar el funcionamiento del retículo endoplásmico
Failure of the ER’s adaptive capacity results in activation of the unfolded protein response (UPR), which
intersects with many different inflammatory and stress signaling pathways. These pathways are also critical
in chronic metabolic diseases such as obesity, insulin resistance, and type 2 diabetes. The ER and related
signaling networks are emerging as a potential site for the intersection of inflammation and metabolic
disease.
Falla de la capacidad adaptativa del reticuloendoplásmico (ER) resulta en activación de la respuesta de proteínas no
plegadas (UPR) que es afectada por diferentes vías y señales de señalamiento de estrés. Estas vías también son críticas en
enfermedades metabólicas crónicas tales como obesidad, resistencia a la insulina y DMT2. El RE y las redes de
señalamiento están emergiendo como un posible sitio de importancia en enfermedades metabólicas e inflamatorias.

41. Endoplasmic reticulum (ER) stress response
The UPR has three aims: initially to
restore normal function of the cell by
halting protein translation, degrading
misfolded proteins, and activating the
signaling pathways that lead to
increasing the production of
molecular chaperones involved
in protein folding. If these objectives
are not achieved within a certain time
span or the disruption is prolonged,
the UPR aims towards apoptosis.
UPR = Unfolded protein response
PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby
PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription
factor as a novel PERK substrate
IRE1: ER stress sensor and cell fate executor
ATF6 is an endoplasmic reticulum (ER) membrane-anchored transcription factor

42. Al unirse oxLDL al receptor escavenger CD36 dispara la activación de la transcripción del factor PPARγ lo que induce a una
presentación aumentada del receptor en la superficie del macrófago. NFB también es estimulado por oxLDL induciendo la
síntesis de diversas citocinas. Además oxLDL desencadena la activación de cinasas relacionadas con CD36 tales como Lyn,MEKK2,
JNK1 y JNK2
Efecto de oxLDL sobre macrófagos via el receptor scavenger CD36,
NF-kB (factor nuclear potenciador de las cadenas ligeras kappa de las células B activadas) es un complejo proteico que controla la transcripción del ADN. NF-kB se
encuentra en la mayoría de tipos de células animales y está implicado en la respuesta celular frente a estímulos como el estrés, las citoquinas, radiación
ultravioleta, LDL oxidadas y antígenos bacterianos o virales

43. Consequences of VEGF-A increase in diabetic nephropathy
VEGF-induced thickening and distortion of podocyte foot processes in
diabetic mice, observed by scanning electron microscopy. A) Control
diabetic glomerulus; B) Vegf164 overexpressing glomerulus showing
wider foot processes. Scale bars=2 μm.
Tufro A, Veron D,
Semin Nephrol. 2012 July ; 32(4): 385–393.
VEGF-A increases TGFβ, CTGF and established a positive feedback loop, leading to extracellular matrix (ECM) accumulation and GBM
thickening (orange); VEGF-A induces nephrin downregulation and foot process effacement (FPE) (green); VEGF-A stimulates eNOS,
which in the setting of high ROS leads to peroxinitrite (ONOO−) and further ROS generation, a positive feedback loop (blue), the
dashed line represents the normal negative feedback regulation of VEGF-A by NO, not operative in DN. Low NO and high ROS
damage endothelial cells and induce HTN.

44. Vitamin D binding to VDR inhibits targets responsible for declining renal function. The combined inhibition of heparanase
and the RAA axis has proved capable of controlling the onset of proteinuria. In addition, the combined inhibition of
heparanase and the TGFβ pathway may prevent the progression of fibrosis mediated by tubular epithelial–mesenchymal
transi
EFECTO DE VITAMINA D EN LA NEFROPATIA DIABETICA
Masola V et al. J Pathol 2016;238: 7-9

45. Mechanism by which uric acid contributes to the development of
renal and non-renal diseases. RAS, renin–angiotensin system.
Johnson RJ , Nakagawa T, Jalal D , Sánchez-Lozada LG et al.
Nephrol Dial Transplant 2013; 28: 2221–2228

46. Patel1 SR, Malhotra A, White DP, Gottlieb DJ. Et al. Am J Epidemiol. 2006;
164: 947–954.
Mean age-adjusted weight of the Nurses’ Health Study cohort from 1986 to 2002 as a function of
habitual sleep duration
Patel et al.
In analyses adjusted for age and body mass
index, women sleeping 5 hours or less gained 1.14
kg (95% (CI): 0.49, 1.79) more than did those sleeping 7
hours over 16 years, and women sleeping 6 hours
gained 0.71 kg (95% CI: 0.41, 1.00) more.
The relative risks of a 15-kg weight gain were 1.32
(95% CI: 1.19,1.47) and 1.12 (95% CI: 1.06, 1.19) for those
sleeping 5 and 6 hours, respectively. The relative
risks for incident obesity (body mass index: >30
kg/m2) were 1.15 (95% CI: 1.04, 1.26) and 1.06 (95% CI:
1.01, 1.11).
These associations remained significant after
inclusion of important covariates and were not
affected by adjustment for physical activity or
dietary consumption

47. Hydration and Chronic Kidney Disease Progression: A Critical Review of the Evidence
Am J Nephrol 2016;43:281–292
Clark WF, Sontrop JM, Huang SH

48. A number of experimental studies in rats and a few observations in humans suggest
that vasopressin increases GFR and albuminuria, thus inducing a vicious circle as suggested
by Brenner for a high protein diet. Adapted from Brenner.
Am J Nephrol 2016;43:281–292

49. Prevalencia de patrón A o B de acuerdo con la proporción de hidratos de carbono en la dieta
Ronald M Krauss
Annu. Rev. Nutr. 2001. 21:283–95
Men with a predominance of small, dense LDL (pattern B) on the high-fat diet (n D 18) exhibited a twofold greater reduction
in LDL cholesterol than did pattern A men. This was associated with significantly greater reductions in mass of midsized
(LDL2) and small (LDL3) LDL subfractions measured by analytic ultracentrifugation. Only pattern B subjects showed
significant reductions in plasma apoB, and in LDL relative to HDL cholesterol levels
Patron A No aterogénico sin hiperlipidemia
postprandial.
Patron B Aterogénico con hiperlipidemia
postprandial

50. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats
Laura G. Sanchez-Lozada,1 Edilia Tapia,1 Adriana Jiménez,1 Pablo Bautista,1 Magdalena Cristobal,1 Tomas Nepomuceno,1 Virgilia Soto,2 Carmen Avila-Casado,2 Takahiko
Nakagawa,3 Richard J. Johnson,3 Jaime Herrera-Acosta,1† and Martha Franco1
In the present study, plasma UA levels correlated with fructose ingestion even in
individual animals as demonstrated by the positive correlation between %
fructose caloric intake and UA at week 8. Previously, we demonstrated that rats
made hyperuricemic by inhibiting uricase with oxonic acid had increased blood
pressure, afferent arteriole thickening,glomerular hypertension, and cortical
vasoconstriction (29). In the present study, we found positive linear relationships
between plasma uric acid and SBP (r 0.54, P 0.01) and arteriolar area (r 0.64, P
0.001) and a negative correlation with ultrafiltration coefficient, a marker of
glomerular vasoconstriction(r 0.41, P 0.05). Therefore, higher UA levels induced
by 60% fructose diet may be partially responsible for the glomerular
hemodynamic alteration
Am J Physiol Renal Physiol 292: F423–F429, 2007.
Departments of 1Nephrology and 2Pathology, Instituto Nacional de Cardiología Ignacio Chávez,
Mexico City, Mexico; and 3Nephrology, Hypertension and Transplantation, University of Florida,
Gainesville, Florida

51. Hazard ratios greater than 1 demonstrate an increased risk for composite outcome with sulfonylurea compared with
metformin.
ACEi=angiotensinconverting enzyme inhibitor;
ARB=angiotensin receptor blocker.
N Engl J Med 2008; 359: 1577–15
METFORMIN SULFONYLUREA
Adjusted hazard ratios for the composite outcome of glomerular filtration rate event or end-stage renal
disease among age, race, HbA1c, and renin–angiotensin– aldosterone system blockade subgroups
Kidney International 2012; 81: 698–706

52. Número de eventos, personas/año, tasas e índices de riesgo ajustados por cada resultado final en relación
con medicamentos antidiabéticos
469 688 participantes con DM tipo 2 edades 25-84 entre abril 2007 a enero de 2015
Hippisley-Cox J, Coupland C. BMJ 2016;352
Hazard ratios adjusted for: sex; age; calendar year; duration since diagnosis of diabetes (five levels); ethnicity (nine levels); Townsend deprivation score; smoking status (five levels); use of
anticoagulants, thiazides, ACE inhibitors, angiotensin 2 blockers; calcium channel blockers; statins; aspirin; existing complications (blindness, hyperglycaemia, hypoglycaemia, amputation, severe
kidney failure); hypertension; cardiovascular disease; atrial fibrillation; chronic renal disease; rheumatoid arthritis; valvular heart disease; peripheral vascular disease; body mass index; systolic
blood pressure; HbA1c; serum creatinine; cholesterol:high density lipoprotein ratio. Hazard ratios also mutually adjusted for use of each of the other diabetes drug classes.
BLINDNESS
RENAL FAILURE

53. Número de eventos, personas/año, tasas e índices de riesgo ajustados por cada resultado final en relación
con medicamentos antidiabéticos
469 688 participantes con DM tipo 2 edades 25-84 entre abril 2007 a enero de 2015
Hippisley-Cox J, Coupland C. BMJ 2016;352
Hazard ratios adjusted for: sex; age; calendar year; duration since diagnosis of diabetes (five levels); ethnicity (nine levels); Townsend deprivation score; smoking status (five levels); use of
anticoagulants, thiazides, ACE inhibitors, angiotensin 2 blockers; calcium channel blockers; statins; aspirin; existing complications (blindness, hyperglycaemia, hypoglycaemia, amputation, severe
kidney failure); hypertension; cardiovascular disease; atrial fibrillation; chronic renal disease; rheumatoid arthritis; valvular heart disease; peripheral vascular disease; body mass index; systolic
blood pressure; HbA1c; serum creatinine; cholesterol:high density lipoprotein ratio. Hazard ratios also mutually adjusted for use of each of the other diabetes drug classes.
BLINDNESS
RENAL FAILURE

54. Annuzzi G, Bozzetto L, Costabile G et al.
Polyphenols improve fasting and postprandial dyslipidemia and reduce oxidative stress: a randomized controlled
trial1–3
Am J Clin Nutr 2014;99:463–7100

55. Sachiko Hattori
Sitagliptin reduces albuminuria in patients with type 2 diabetes
Endocrine Journal 2011, 58 (1), 69-73

56. Comparación de linagliptina y placebo en varios puntos finales relacionados con nefropatía
Am J Kidney Dis. 2015;66:441-449
Cooper ME, Perkovic V, McGill, JB, et al

59. Lang F. Kidney Blood Press
Res 2017;42:483-494
LA INGESTION SUBOPTIMA DE LIQUIDOS PUEDE AUMENTAR LOS NIVELES DE
VASOPRESINA Y GLUCOCORTICOIDES AUMENTANDO LA EXPRESION DE SGK1
FAVORECIENDO LAS PATOLOGIAS QUE SE SEÑALAN
SGK1: Serine/threonine-protein kinase is also known
as serum and glucocorticoid-regulated kinase 1
NFAT5, is a human gene that encodes a transcription factor that
regulates the expression of genes involved in the osmotic stress

60. HIDRATACION Y ENFERMEDAD RENAL CRONICA

62. Am J Nephrol 2016; 43:281-92

63. Sirtuins target many proteins that are not histones they havebeen demonstrated
to bind and deacetylate p53 in vitro and in vivo [32,33,41]. p53 is transcriptional
activator, and its activation results in cell cycle arrest, senescence or the
initiation of programmed cell death. Over expression of sirtuins has been shown
to inhibit p53-dependent apoptosis in response to DNA damage and oxidative
stress [33]. Recently, it has been reported that increased expression of p53 gene
under diabetic
condition is associated with renal apoptosis [42]. We found increasedexpression
of p53 protein in the kidneys of diabetic animals as compared to their respective
controls. However, the expression of p53 is reduced significantly in the kidneys
of diabetic rats on IF regimen. The expression as well as activationof p53 is
thought to be mediated by Sir2 dependent deacetylation. They both share an
inverse relationship as is evident from our results wherein the Sir2 expression is
decreased and at the same time p53 is upregulated.
Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and
changes the expression of Sir2 and p53
FEBS Letters 581 (2007) 1071–1078

64. TRATAMIENTO POTENCIAL DE LA NEFROPATIA DIABETICA CON ANGIOTENSINA 1-7
Padda RS, et al. J Diabetes Metab. 2015; 6

68. POSIBLES EFECTOS DEL
METILGLIOXAL EN
DIVERSAS PATOLOGIAS
DEL PACIENTE CON
DIABETES

71. ENDOTHELIN-1
INHIBIDORES DE ENDOTELINA EN NEFROPATIA
Expert Opinion on Investigational Drugs 2017

72. Compared with other types of tea, green tea is
unfermented and contains the highest concentration of
catechins, in which EGCG accounts for as much as 50%
of its total polyphenols and has been reported to
possess antioxidative, antiinflammatory, and
anticarcinogenic effects[EGCG is estimated to be 25
times more potent than vitamin E and 100 times more
potent than vitamin C.
Bao H, Peng A. J Translat Int Med
2016;4: 99-103
EFECTOS DEL TE VERDE COMO
ANTIOXIDANTE EN LA ALBUMINURIA
SEVERAL
MECHANISMS

73. Growth hormone (GH)–GH receptor (GHR)–IGF-1 axis in type 1 diabetes
(1) reduced portal insulin levels results in decreased expression of hepatic GHR, impaired IGF-1 production and elevated
IGFBP-1 levels (2). Low bioavailability of IGF-1 leads to compensatory GH hypersecretion via negative feedback loop
mechanism (3). Except in liver, GHR expression in other tissues including kidney is not compromised. Elevated GH levels
in poorly controlled type 1 diabetes associated with elevated GHR and IGF-1 in the kidney (4). Elevated GH levels are
implicated in the renal hyperfiltration, glomerulosclerosis, nephromegaly, and proteinuria (5).
Frontiers in Medicine 2017: (July )

74. MODELO PROPUESTO DE LA ACCION DE LA HORMONA DE CRECIMIENTO SOBRE LOS
PODOCITOS
Los efectos de GH incluyen: desdiferenciacion de podocitos, engrosamiento y/o formación de puentes cruzados de la membrana basa,l deterioro de
los podocitos y puede producir apoptosis e hipertrofia. Todos estos efectos resultan en disminución del número de podocitos y alteración de la función
glomerular. Este efecto puede verse tanto en la acromegalia como en la diabetes tipo 1.

76. Conclusiones
• Existen múltiples líneas de investigación dirigidas a la fisiopatología, prevención y tratamiento de los pacientes
con nefropatía diabética.
• Varias de estas líneas han establecido conocimientos sólidos, muchos de ellos en animales de experimentación
pero aun con pocos estudios clínicos y aun en etapas tempranas de evaluación.
• Las recomendaciones vigentes siguen siendo las que tienen más bases en estudios controlados.
• El control de la glucemia, de la hipertensión arterial, de los lípidos, el evitar medicamentos nefrotóxicos y
controlar adecuadamente cada elemento del síndrome metabólico siguen siendo los mejores lineamientos en la
prevención y tratamiento de los pacientes con diversos grados de compromiso renal.
• La monitorización del control y las posibles complicaciones a intervalos adecuados es de vital importancia.
• El obtener consejo de los especialistas en nefrología es muy importante para los médicos que tratan pacientes
diabéticos sobre todo cuando ya existe evidencia de compromiso renal.
• Es muy importante que el paciente reciba una educación adecuada en relación con los factores de riesgo de esta
y otras complicaciones de la diabetes, y la necesidad de mantener un control estricto y con los exámenes
pertinentes que permitan valorar sud condiciones de salud, para poder detectar tempranamente esta alteración.