La Pentoxifilina, un fármaco comúnmente empleado en el tratamiento de la enfermedad vascular periférica, puede retrasar el deterioro de la función renal en pacientes con diabetes tipo 2 como renoprotectivo.
El estudio PREDIAN (Pentoxifilina para la renoprotección en la nefropatía diabética), cuyo investigador principal es el Dr. Juan Navarro González, Jefe de Servicio de la Unidad de Investigación, es un estudio realizado en el Servicio de Nefrología del Hospital Universitario Nuestra Señora de Candelaria de Santa Cruz de Tenerife que se ha publicado en la revista Journal of the American Society of Nephrology, la revista oficial de la Sociedad Americana de Nefrología y la de más prestigio en el ámbito de las enfermedades renales.
El estudio PREDIAN incluyó 169 pacientes con diabetes tipo 2 e insuficiencia renal (filtrado glomerular estimado inferior a 60 ml/min) que fueron seguidos durante dos años. Aproximadamente la mitad de los pacientes (82) recibieron, además del tratamiento habitual, pentoxifilina, y su evolución fue comparada con la del resto de pacientes (87) que recibieron solamente el tratamiento habitual (grupo control). Al final del estudio, la pérdida media de filtrado glomerular estimado en los pacientes que recibieron pentoxifilina fue de 2.1 ml/min, frente a una reducción de 6.5 ml/min en los pacientes que no recibieron este tratamiento. Además, se observó que la excreción urinaria de albúmina (un marcador de daño renal) experimentó un aumento de un 5.7% en el grupo control, mientras que en los pacientes que recibieron pentoxifilina se observó un descenso de casi un 15%. Estas diferencias observadas entre ambos grupos fueron estadísticamente significativas.
En conclusión, el estudio PREDIAN demuestra que pacientes con diabetes tipo 2 e insuficiencia renal que reciben pentoxifilina además de su tratamiento habitual presentan una menor pérdida de filtrado glomerular estimado y una mayor reducción de la excreción urinaria de albúmina, lo cual es consistente con un potencial efecto renoprotector de la pentoxifilina.
Felicidades a los jóvenes investigadores Canarios del grupo de Nefrología del Hospital Ntra. Sra. de la Candelaria y la Unidad de Investigación. Ya se puede considerar la Pentoxifilina como un fármaco de obligado uso en diabéticos orientado a la nefroprotección.
Comentarios publicados en MEDSCAPE a propósito de la publicación de la pentoxifilina.
Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients With Diabetic Kidney Disease: The PREDIAN Trial
- Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial.
- AU
- Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, Chahin J, Méndez ML, Gallego E, Macía M, del Castillo N, Rivero A, Getino MA, García P, Jarque A, García J
- SO
- J Am Soc Nephrol. 2015;26(1):220. Epub 2014 Jun 26.
- Diabetic kidney disease (DKD) is the leading cause of ESRD. We conducted an open-label, prospective, randomized trial to determine whether pentoxifylline (PTF), which reduces albuminuria, in addition to renin-angiotensin system (RAS) blockade, can slow progression of renal disease in patients with type 2 diabetes and stages 3-4 CKD. Participants were assigned to receive PTF (1200 mg/d) (n=82) or to a control group (n=87) for 2 years. All patients received similar doses of RAS inhibitors. At study end, eGFR had decreased by a mean±SEM of 2.1±0.4 ml/min per 1.73 m(2) in the PTF group compared with 6.5±0.4 ml/min per 1.73 m(2) in the control group, with a between-group difference of 4.3 ml/min per 1.73 m(2) (95% confidence interval [95% CI], 3.1 to 5.5 ml/min per 1.73 m(2); P<0.001) in favor of PTF. The proportion of patients with a rate of eGFR decline greater than the median rate of decline (0.16 ml/min per 1.73 m(2) per month) was lower in the PTF group than in the control group (33.3% versus 68.2%; P<0.001). Percentage change in urinary albumin excretion was 5.7% (95% CI, -0.3% to 11.1%) in the control group and -14.9% (95% CI, -20.4% to -9.4%) in the PTF group (P=0.001). Urine TNF-αdecreased from a median 16 ng/g (interquartile range, 11-20.1 ng/g) to 14.3 ng/g (interquartile range, 9.2-18.4 ng/g) in the PTF group (P<0.01), with no changes in the control group. In this population, addition of PTF to RAS inhibitors resulted in a smaller decrease in eGFR and a greater reduction of residual albuminuria.
- AD
- Nephrology Service, Research Unit, GEENDIAB (Spanish Group for the Study of Diabetic Nephropathy), University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain jnavgon@gobiernodecanarias.org.
- PMID
- 24970885
Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, et al
J Am Soc Nephrol. 2015;26:220-229
Time for New Approaches to DKD
Diabetic kidney disease (DKD) is one of the leading causes of kidney failure in the United States. The Centers for Disease Control and Prevention (CDC) estimate that close to half of all cases of end-stage renal disease (ESRD) are related to diabetes.[1]
For decades, the two mainstays of treatment have been strict diabetic control or the addition of renin-angiotensin-aldosterone blocking agents, primarily angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Both strategies have significantly delayed the progression of DKD to ESRD, but both also have limitations.
In recent years, ACE inhibitors and ARBs appear to have reached a “ceiling” in their beneficial effects on DKD. The VA NEPHRON-D trial[2] put a big damper on the idea that dual ACE inhibitor/ARB therapy could provide a synergistic benefit to these patients. A similar therapeutic ceiling has been reached with tight glycemic control (whether through medications or insulin), as seen in both the ADVANCE[3] and ADVANCE-ON[4]trials. Thus, the need for newer pharmaceuticals has never been greater.
This study looked at the potential role of pentoxifylline (PTF), which is not exactly a new agent. It has been around for three decades and is most commonly used to treat claudication in peripheral arterial disease. But researchers in Spain wanted to know whether the anti-inflammatory properties of PTF could be used to slow the damage seen in DKD.
These investigators randomly assigned 169 patients with DKD to receive PTF at 600 mg twice daily vs placebo. All patients had diabetes for at least 8 years and had been treated with a maximum dose of either an ACE inhibitor or ARB for at least 6 months. The primary outcome was the progression of DKD, as measured by the estimated glomerular filtration rate (eGFR) over a 2-year follow-up period.
Patients who received the drug did experience a decline in eGFR over the 2-year period. However, those receiving the medication experienced a significantly slower rate of decline than those receiving placebo. In fact, the therapeutic benefit of PTF was seen within 12 months, when the rate of decline in eGFR was -1.2 mL/min/1.73 m2 vs -3.4 mL/min/1.73 m2 in the placebo group.
There was also a concomitant and significant drop (13 mg/d) in the urinary albumin excretion ratio in the PTF-treated group compared with a rise of 4.9 mg/d in the placebo group. Finally, the dose of 600 mg twice daily did not predispose the patients to any more adverse events than placebo did.
Analysis and Commentary
The PREDIAN trial is a well-executed investigation. It was an investigator-initiated randomized trial—a rarity in today’s world of clinical trials. The 2-year follow-up period is refreshing, as so many trials in recent years have followed patients for only 6 months to a year, which is too short for clinicians to know whether the positive results observed during the study period are sustainable over the long term. Moreover, the investigators chose a “hard endpoint”—eGFR— as their primary outcome rather than the softer urinary albumin excretion.
The biggest surprise in the PREDIAN trial is that the agent being studied is not new. While new therapeutic targets are being elucidated, such as modifiers of the Tie2 or JAK2/STAT pathways or endothelin-1 receptor antagonists (the RADAR and SONAR trials), it is a bit surprising that a 20th-century drug is being repurposed for therapy against DKD. In conjunction with an ACE inhibitor or ARB, PTF offers additional protection against DKD for at least 2 years— and perhaps even longer, given the protective trend over time (a drop in eGFR of 2.1 mL/min/1.73 m2 in the PTF arm vs 6.5 mL/min/1.73 m2in the placebo arm at 24 months).
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