El documento habla sobre el tratamiento y manejo de la enfermedad renal crónica (ERC). Describe las estrategias para retrasar la progresión de la ERC, incluyendo el tratamiento de la hipertensión, diabetes, dislipidemia, anemia y desórdenes de calcio y hueso. También discute el uso de inhibidores de la enzima de conversión de angiotensin (IECA), bloqueadores de receptores de angiotensin (BRA), antagonistas de aldosterona y otros fármacos para reducir la proteinuria y proteger
6. REDUCCIÓN DE LA PROTEINURIA CON ALTAS
DOSIS DE CONDESARTÁN.
Burgess, E. Supramaximal Dose of Candesartan in Proteinuric Renal Disease J Am Soc Nephrol 20: 893–900, 2009
7. Los niveles séricos de
creatinina aumentaron en
7,85, 8,82 y 6,74% en los
grupos de 16 -, 64 -, y 128
mg.
No hubo variación
significativa de la TFG.
No hubo diferencia
significativa en los niveles
de potasio sérico.
REDUCCIÓN DE LA PROTEINURIA CON ALTAS
DOSIS DE CONDESARTÁN.
Burgess, E. Supramaximal Dose of Candesartan in Proteinuric Renal Disease J Am Soc Nephrol 20: 893–900, 2009
8. IRBESARTAN EN EL TRATAMIENTO DE LA
NEFROPATÍA DIABETICA.
Parving H. The effect of irbesartan on the development of diabetic Nephropathy in patients with type 2 diabetes. N engl J med 2001;345:870-8.
9. Parving H. The effect of irbesartan on the development of diabetic Nephropathy in patients with type 2 diabetes. N engl J med 2001;345:870-8.
IRBESARTAN EN EL TRATAMIENTO DE LA
NEFROPATÍA DIABETICA.
10. TRANDOPRIL Y VERAPAMIL EN ND
Ruggenenti P. Preventing Microalbuminuria in Type 2 Diabetes. n engl j med 351;19
11. PENTOXIFILINA EN EL TRATAMIENTO DE LA
ALBUMINURIA EN NEFROPATÍA DIABÉTICA.
Navarro J. Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin
II Receptor Blockade: A Short-Term, Randomized, J Am Soc Nephrol 16: 2119–2126, 2005 Controlled Trial
Con función renal normal.
Los pacientes tenían 1 año con
las dosis recomendadas de BRA
+ PTF 1,200 mg/d.
Hubo una reducción significativa
de la proteinuria.
Hubo una reducción de 900
mg/24 h (466 a 1542 mg / d) a
791 mg/24 h (309 a 1400
mg / d, p <0,001), mientras que
no se observaron cambios
significativos en el grupo control:
920 mg/24 h (450 a 1489 mg /
d), y 900 mg/24 h (428 a 1800
mg / d) al final de 4 meses.
12. ANTAGONISTAS DE LA ENDOTELINA A EN ND.
Rene´ R. WenzelAvosentan Reduces Albumin Excretion in Diabetics with MacroalbuminuriaJ Am Soc Nephrol 20: 655–664, 2009.
•Estudio placebo controlado doble ciego.
•Involucraron 286 pacientes con nefropatía diabética
•Se les administro avosentan durante 12 semanas.
13. ALISKIREN EN EL TRATAMIENTO DE LA
PROTEINURIA.
Persson, F. Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy. N Engl J Med 2008;358:2433-46.
•Se involucro a 599 pacientes tratados con losartan 100 mg.
•Se les administro aliskiren 150 mg durante 3 meses y luego 300 mg vs placebo
14. IECA Ó BRA?
Gozewijn d. Inhibition versus angiotensin receptor blockade: which Is better for renal and
cardiovascular protection? J am soc nephrol 15: S64–S70, 2004
15. BRA VS IECA EN NEFROPATÍA DIABÉTICA.
Barnett A. Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy.
N Engl J Med 2004;351:1952-61.
Se involucro 250 pts.
Telmisartan 80mg/d.
17.9ml/min en 5 años.
Enalapril 20 mg/d.
14.9 ml/min en 5 años
Ambos mostraron
renoproteccion, pero
ninguno fue superior.
16. INHIBICIÓN DE LA ALDOSTERONA.
Akira Nishiyama. Molecular Mechanisms and Therapeutic Strategies of Chronic Renal Injury: Renoprotective Effects of
Aldosterone Blockade. Journal of Pharmacological Sciences. 2006.
La aldosterona juega
un papel importante en
la producción de
especies de oxígeno
reactivo (ROS) y la
generación de las
proteínas quinasas
activadas por
mitógenos (MAPKs),
siendo estas causantes
de daño renal.
La administración de
eplerenone demostró
en ratas inhibición de
la producción de estas
sustancias
disminuyendo así el
daño renal.
17. Bomback S: Change in Proteinuria After Adding Aldosterone Blockers to ACE Inhibitors or Angiotensin Receptor Blockers in CKD: A
Systematic Review. American Journal of Kidney Diseases, Vol 51, No 2 (February), 2008: pp 199-211
18. BLOQUEADORES DE LOS CANALES DE CALCIO
Las dihidropiridinas no muestran un efecto
antiproteinurico. En contraste las no dihidropiridinas
muestran este efecto al menos en la nefropatía
diabética (diltiazem y verapamil).
Henry T.,Progression of Chronic Renal Failure. Arch Intern Med. 2003;163:1417-1429
19. OBJETIVO DE TX DE DISLIPIDEMIA EN IRC
Colesterol- LDL < 100 mg/ dl.
Colesterol- HDL > 40 mg/ dl.
Colesterol Total < 175 mg/dl.
Trigliceridos < 200 mg/ dl.
Colesterol no HDL < 130 mg/ dl.
Alcazar J, Aranda P, Et al. Guias Sociedad Española de Nefrologia. Nefrologia vol.24,
2004
20. ESTRATEGIAS A SEGUIR.
TREATING DYSLIPIDEMIAS, American journal of kidney diseases, vol 41, no 4, suppl 3 (april), 2003: pp S39-S58
21. ESTATINAS.
Las estatinas aparte funcionar en el tratamiento de la
dislipidemia han probado a través de sus efectos
pleitrópicos (antioxidante, antiinflamatorio,
immunomodulador, y antitrombotico) que dan
protección vascular y nefroproteccion a través de
diversos mecanismos.
Giuseppe D’Amico. Statins and Renal Diseases: From Primary Prevention to Renal Replacement Therapy. J Am Soc Nephrol 17:
S148–S152, 2006.
24. Objetivo: 11-12 Gr/dl
Corrección parcial (Hb 10 – 12g/dl)
Calidad de vida
Reducción del gasto cardiaco
Reducción en hipertrofia de
ventrículo izquierdo
Capacidad máxima de ejercicio
Función cognoscitiva
Reducción en angina (si está
presente)
Mejora la función sexual
Reanudación de la menstruación
Inmunocompetencia
Corrección de la función plaquetaria
Corrección completa
(Hb 12 -14g/dl)
Calidad de vida
Reducción del gasto
cardiaco
Reducción en hipertrofia
ventricular izquierda
Capacidad máxima de
ejercicio
Función cognoscitiva
Patrones de sueño
Nutrición
Signos y síntomas en IRC que mejoran con la corrección de la anemia
Alcazar J, Aranda P, Et al. Guias Sociedad Española de Nefrologia. Nefrologia vol.24,
2004
TRATAMIENTO DE LA ANEMIA
25. CORRECCIÓN DE ANEMIA
Eritropoyetina: 50 a 150 U/kg/semana IV o SC dos o tres veces
por semana.
Darbepoyetina alfa: 0.75 ug/kg/dos semana IV o SC
Harrison Principios de Medicina Interna 17 Edicion vol. 2
26. CAUSAS DE RESPUESTA INADECUADA A LA
TERAPIA CON ERITROPOYETINA
Baja sensibilidad.
Deficiencia de hierro.
Sobrecarga de aluminio.
Infecciones y enfermedades inflamatorias cronicas.
Malignidad.
Deficiencias vitamínicas.
Diálisis inadecuada.
Fibrosis de medula ósea.
Harrison Principios de Medicina Interna 17 Edicion vol. 2
29. ANORMALIDADES DEL CALCIO
Las guías recomiendan
3 cosas en estadios 3-5:
Disminución del fosfato
de la dieta.
Quelantes de fosfato.
Incrementar la frecuencia
o duración de la diálisis.
30. KDIGO, Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral
and bone disorder. Vol 76, suplement 113, august 2009.
31. OSTEOPOROSIS
Gordon p, Management of Osteoporosis in CKD Stages 3 to 5. American Journal of Kidney Diseases, Vol 55, No 5 (May), 2010: pp 941-956
32. EN RESUMEN
Proteinuria de 1 Gr IECA
Si no se logra TA 120/80mmhg + proteinuria >0.3
Gr/24 hr BRA
Si no se logra TA 120/80mmhg + proteinuria
>0.3 Gr/24 hr. Ca antagonista.
LDL de >100 mg / dl Estatina
HBA1C < 7.5%.
Figure 2. Incidence of Progression to Diabetic Nephropathy during Treatment with 150 mg of Irbesartan
Daily, 300 mg of Irbesartan Daily, or Placebo in Hypertensive Patients with Type 2 Diabetes and Persistent
Microalbuminuria.
The difference between the placebo group and the 150-mg group was not significant (P=0.08 by the
log-rank test), but the difference between the placebo group and the 300-mg group was significant
(P<0.001 by the log-rank test).
The base-line characteristics in the three
groups were similar. Ten of the 194 patients in the
300-mg group (5.2 percent) and 19 of the 195 patients
in the 150-mg group (9.7 percent) reached the primary
end point, as compared with 30 of the 201 patients
in the placebo group (14.9 percent) (hazard ratios, 0.30
[95 percent confidence interval, 0.14 to 0.61; P<
0.001] and 0.61 [95 percent confidence interval, 0.34
to 1.08; P=0.08] for the two irbesartan groups, respectively).
The average blood pressure during the course
of the study was 144/83 mm Hg in the placebo
group, 143/83 mm Hg in the 150-mg group, and 141/
83 mm Hg in the 300-mg group (P=0.004 for the comparison
of systolic blood pressure between the placebo
group and the combined irbesartan groups). Serious
adverse events were less frequent among the
patients treated with irbesartan (P=0.02).
Conclusions
Irbesartan is renoprotective independently
of its blood-pressure–lowering effect in
patients with type 2 diabetes and microalbuminuria.
(N Engl J Med 2001;345:870-8.)
Figure 3. Geometric Mean Rate of Urinary Albumin Excretion (Panel A), Estimated Mean Creatinine
Clearance (Panel B), and Trough Mean Arterial Blood Pressure (Panel C) in Hypertensive Patients with
Type 2 Diabetes and Persistent Microalbuminuria, According to Treatment Group.
The average urinary albumin excretion rate (geometric mean) was significantly reduced in both irbesartan
groups (P<0.001). There were no significant differences among the three groups in the initial
or the sustained (3-to-24-month) rate of decline in creatinine clearance. The average trough mean arterial
blood pressure during the study was 103 mm Hg in the placebo group, 103 mm Hg in the 150-mg
group, and 102 mm Hg in the 300-mg group (P=0.005 for the comparison between the 300-mg group
and the placebo group).
A pesar de los efectos beneficiosos del bloqueo del sistema renina-angiotensina en la nefropatía diabética (ND), albuminuria y la progresión de la enfermedad renal no está completamente detenido por estos agentes. Por lo tanto, es necesario explorar el potencial efectos antiproteinúrico y renoprotector de innovadores enfoques terapéuticos. El estudio probó la hipótesis de que la combinación de pentoxifilina (PTF) con los bloqueadores del receptor de angiotensina II en pacientes normotensos con diabetes tipo 2 produce un efecto aditivo antiproteinúrico. Sesenta y un pacientes con DN y albuminuria residual, a pesar del tratamiento con el las dosis recomendadas de ARB por más de 1 año fueron asignados aleatoriamente para recibir la adición de 1200 mg de PTF al día (n? 30) o un grupo control (n? 31). Las características basales fueron similares entre los grupos, y mostró un análisis de correlación significativa asociación entre la excreción urinaria de albúmina (EUA) y urinarios de TNF-? (R? 0,53, P <0,001). Después de 4 meses, albuminuria mostró una disminución significativa en los pacientes que recibieron PTF, de 900 mg/24 h (466 a 1542 mg / d) a 791 mg/24 h (309 a 1400 mg / d, p <0,001), mientras que no se observaron cambios significativos en el grupo control: 920 mg/24 h (450 a 1489 mg / d) en línea de base, y 900 mg/24 h (428 a 1800 mg / d) al final del estudio. La variación porcentual media de los Emiratos Árabes Unidos en el tratamiento y el grupo control fue? 16,7 y 5,5%, respectivamente (entre los grupos de comparación, P <0,001). Este aditivo antiproteinúrico efecto no fue dependiente de los cambios de la presión arterial o el control metabólico. No obstante, ambos niveles séricos y urinarios de TNF-? también disminuida en los pacientes que recibieron PTF, de 6,4 pg / ml (2,1 a 9,7) y 16 pg / mg (8 a 29) al inicio del estudio a 4,6 pg / ml (0,4 a 9) y 14,2 pg / mg (3 a 26) al final del estudio, respectivamente (P <0,01), sin variaciones significativas en el grupo control. Por otra parte, análisis de regresión al final del estudio mostraron una correlación entre el cambio en los Emiratos Árabes Unidos y el cambio en urinaria TNF-? en pacientes que fueron tratados con PTF (R? 0,49, P <0,001). En conclusión, la administración de PTF a los pacientes que tienen el tipo 2 diabetes y está bajo tratamiento a largo plazo con un ARA produce un significativo efecto aditivo antiproteinúrico asociados
Patients
A previous sample size calculation to detect a 25% relative difference
in the change in UAE rate with an value of 0.05 and a value of 0.80
showed a need for a minimum of 26 patients. The criteria for the
selection of patients were diabetic nephropathy, defined by persistent
albuminuria 300 mg/24 h in two consecutive determinations, no
other kidney or renal tract disease, and presence of diabetic retinopathy
(20,21) and normal BP (140/90 mmHg); treatment with the recommended
doses of ARB for 1 yr; normal renal function, defined as a
GFR 90 ml/min (calculated using the Modification of Diet in Renal
Disease study equation) (22); and insufficient response to conventional
therapy, defined as albuminuria 400 mg/24 h in three consecutive
measurements in the 3 mo before inclusion in the study.
All of
the patients received treatment with ARB at the recommended
dosage (irbesartan 300 mg, 31 patients; losartan 100 mg, 26
patients; and candesartan 16 mg, 18 patients). The baseline
demographic, clinical, and laboratory characteristics of the two
groups were similar (Table 1). There were no significant differences
in BP, renal function, or metabolic control. All patients
showed residual albuminuria despite treatment with ARB at
the maximal dosage for 1 yr. UAE was similar in both groups:
900 mg/d (range 466 to 1542 mg/d) in the treatment group and
910 mg/d (range 450 to 1489 mg/d) in the control group.
Likewise, the serum and urinary levels of TNF- were similar
between groups.
Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor
blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic
nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory,
antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized,
placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A
antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic
nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER
0.2 to 5.6 mg/min), and BP 180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo,
in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean
relative UAER (16.3 to 29.9%) compared with placebo (35.5%). Median relative UAER decreased with
all avosentan dosages (28.7 to 44.8%) compared with placebo (12.1%). Creatinine clearance and BP
were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (25
mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%)
patients experienced adverse events that led to withdrawal from study medication. In summary, the
endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER
in patients with diabetic nephropathy and macroalbuminuria.
Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor
blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic
nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory,
antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized,
placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A
antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic
nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER
0.2 to 5.6 mg/min), and BP 180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo,
in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean
relative UAER (16.3 to 29.9%) compared with placebo (35.5%). Median relative UAER decreased with
all avosentan dosages (28.7 to 44.8%) compared with placebo (12.1%). Creatinine clearance and BP
were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (25
mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%)
patients experienced adverse events that led to withdrawal from study medication. In summary, the
endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER
in patients with diabetic nephropathy and macroalbuminuria.
Background
Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries.
We evaluated the renoprotective effects of dual blockade of the renin−angiotensin−
aldosterone system by adding treatment with aliskiren, an oral direct renin
inhibitor, to treatment with the maximal recommended dose of losartan (100
mg daily) and optimal antihypertensive therapy in patients who had hypertension
and type 2 diabetes with nephropathy.
Methods
We enrolled 599 patients in this multinational, randomized, double-blind study. After
a 3-month, open-label, run-in period during which patients received 100 mg of losartan
daily, patients were randomly assigned to receive 6 months of treatment with
aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg
daily for another 3 months) or placebo, in addition to losartan. The primary outcome
was a reduction in the ratio of albumin to creatinine, as measured in an earlymorning
urine sample, at 6 months.
Results
The baseline characteristics of the two groups were similar. Treatment with 300 mg
of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-tocreatinine
ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction
of 50% or more in 24.7% of the patients who received aliskiren as compared with
12.5% of those who received placebo (P<0.001). A small difference in blood pressure
was seen between the treatment groups by the end of the study period (systolic,
2 mm Hg lower [P = 0.07] and diastolic, 1 mm Hg lower [P = 0.08] in the aliskiren
group). The total numbers of adverse and serious adverse events were similar in the
groups.
Conclusions
Aliskiren may have renoprotective effects that are independent of its bloodpressure−
lowering effect in patients with hypertension, type 2 diabetes, and nephropathy
who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov
number, NCT00097955.)
Few studies have directly compared the renoprotective effects of angiotensin II–receptor
blockers and angiotensin-converting–enzyme (ACE) inhibitors in persons with
type 2 diabetes.
methods
In this prospective, multicenter, double-blind, five-year study, we randomly assigned
250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin
II–receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor
enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the
glomerular filtration rate (determined by measuring the plasma clearance of iohexol)
between the baseline value and the last available value during the five-year treatment
period. Secondary end points included the annual changes in the glomerular filtration
rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of
end-stage renal disease and cardiovascular events; and the rate of death from all causes.
results
After five years, the change in the glomerular filtration rate was ¡17.9 ml per minute
per 1.73 m
2
of body-surface area, where the minus sign denotes a decrement, with
telmisartan (in 103 subjects), as compared with ¡14.9 ml per minute per 1.73 m
2
with
enalapril (in 113 subjects), for a treatment difference of ¡3.0 ml per minute per 1.73 m
2
(95 percent confidence interval, ¡7.6 to 1.6 ml per minute per 1.73 m
2
). The lower
boundary of the confidence interval, in favor of enalapril, was greater than the predefined
margin of ¡10.0 ml per minute per 1.73 m
2
, indicating that telmisartan was
not inferior to enalapril. The effects of the two agents on the secondary end points were
not significantly different after five years.
conclusions
Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons
with type 2 diabetes. These findings do not necessarily apply to persons with
more advanced nephropathy, but they support the clinical equivalence of angiotensin
II–receptor blockers and ACE inhibitors in persons with conditions that place them at
high risk for cardiovascular events.