Tratamiento Nefropatia Diabética

4/12/2018 Treatment of diabetic nephropathy - UpToDate
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Tratamiento de la nefropatía diabética.
Autor: George L Bakris, MD

Editores de secciones: Richard J Glassock, MD, MACP, David M. Nathan, MD
Editor Adjunto: John P Forman, MD, MSc
Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso
de revisión por pares .
Revisión de literatura vigente hasta: nov 2018. | Este tema se actualizó por última vez el 31 de octubre
de 2017.
INTRODUCCIÓN - La nefropatía diabética, definida clásicamente por la presencia de proteinuria

(macroalbuminuria o "albuminuria severamente aumentada" en la nueva nomenclatura [ 1 ]), es un problema
común que es más probable que ocurra en pacientes con peor control glucémico, hipertensión,
Hiperfiltración glomerular o una predisposición genética. El riesgo de nefropatía de por vida es
aproximadamente equivalente en la diabetes tipo 1 y tipo 2 [ 2 ]. (Ver "Resumen de la nefropatía diabética" .)
La manifestación clínica más temprana de compromiso renal en la diabetes es un aumento en la excreción

de albúmina (microalbuminuria o "albuminuria moderadamente incrementada" en la nueva nomenclatura [ 1
]), una etapa en la cual la histología renal puede ser relativamente normal o puede revelar
glomerulosclerosis [ 3- 6 ]. Sin embargo, la regresión de albuminuria moderadamente incrementada a
normoalbuminuria ocurre espontáneamente en una proporción sustancial de pacientes con diabetes tipo 1 y
tipo 2. (Consulte "Albuminuria moderadamente aumentada (microalbuminuria) en la diabetes mellitus tipo 1"
y "Albuminuria moderadamente incrementada (microalbuminuria) en la diabetes mellitus tipo 2" .)
La proteinuria en la diabetes mellitus se debe ocasionalmente a una enfermedad glomerular distinta de la

nefropatía diabética. Las principales pistas clínicas que sugieren que la enfermedad glomerular no diabética
son la aparición de proteinuria a menos de cinco años de la aparición documentada de diabetes en la
diabetes tipo 1, la aparición aguda de enfermedad renal, la presencia de un sedimento urinario activo que
contiene glóbulos rojos (particularmente acantocitos) y cilindros celulares, y en la diabetes tipo 1, la ausencia
de retinopatía diabética o neuropatía. (Ver "Descripción de la nefropatía diabética", sección "Enfermedad
renal no diabética" .)
Esta revisión abordará el tratamiento de la nefropatía diabética, en particular la importancia del control
glucémico y de la terapia antihipertensiva rigurosa, con énfasis en el uso de inhibidores de la enzima
convertidora de angiotensina (ECA) o bloqueadores del receptor de la angiotensina II (BRA). Además de los
datos de los ensayos controlados, una prueba adicional del beneficio de estas terapias es la observación de
que la incidencia de enfermedad renal en etapa terminal entre los pacientes con diabetes tipo 1 puede estar
disminuyendo [ 7 ].
CONTROL GLICÉMICO : la eficacia del control glucémico estricto depende en parte de la etapa en que se
inicia y del grado de normalización del metabolismo de la glucosa; La evidencia está mejor establecida en la
diabetes tipo 1. (Consulte "Control glucémico y complicaciones vasculares en la diabetes mellitus tipo 1" y
"Control glucémico y complicaciones vasculares en la diabetes mellitus tipo 2" .)
Revisado brevemente, la terapia intensiva de insulina tiene los siguientes beneficios con respecto al riñón:
https://www.uptodate.com/contents/treatment-of-diabetic-nephropathy/print?search=nefropatia%20diab%C3%A9tica&source=search_result&sel… 1/43
● Puede revertir parcialmente la hipertrofia e hiperfiltración glomerular (tanto en el estado basal como
después de una carga de proteínas) que se consideran factores de riesgo importantes para la lesión
glomerular.
● Puede retrasar el desarrollo de la excreción de albúmina elevada ( figura 1 ) [ 8-10 ]. La terapia intensiva
para la glucemia casi normal reduce la aparición o la progresión de la nefropatía diabética durante años
después de una terapia menos intensiva [ 11 ].
● Puede estabilizar o disminuir la excreción de proteínas en pacientes con mayor excreción de albúmina,
aunque este efecto puede no ser evidente hasta que la normoglucemia relativa se haya mantenido
durante dos años. Además, la restauración de la euglucemia con trasplante de páncreas en pacientes
con diabetes tipo 1 previene la nefropatía recurrente en un aloinjerto renal [ 12 ].
● Puede retardar la progresión de la disminución de la tasa de filtración glomerular (GFR) [ 13 ].
Los estudios sugieren que el control glucémico estricto también puede disminuir la tasa de lesión renal
progresiva incluso después de que se haya desarrollado una proteinuria positiva con varilla [ 14-17 ]. Ocho
pacientes en quienes se realizó con éxito el trasplante de páncreas se sometieron a biopsias renales en
serie a los cero, cinco y diez años posteriores al trasplante. Todos los pacientes tenían injertos funcionales
en todos los puntos temporales; antes del trasplante, tres pacientes tenían una excreción normal de
albúmina, tres tenían albuminuria moderadamente incrementada (anteriormente, microalbuminuria) y dos
tenían proteinuria manifiesta.
El trasplante se estabilizó pero no mejoró la estructura glomerular a los cinco años de seguimiento [ 14 ]. Sin
embargo, los siguientes beneficios se observaron a los diez años ( figura 2 ) [ 15,16 ]:
volumen mesangial y el volumen de la matriz mesangial disminuyeron significativamente en

● El
comparación con las mismas mediciones a cero y cinco años.
● En algunos pacientes, el ancho de las membranas basales glomerular y tubular y los volúmenes
mesangiales se normalizaron y las lesiones glomerulares nodulares desaparecieron.
atrofia tubular parecía mejorada, posiblemente debido a la reabsorción de nefronas enfermas.

● La
INHIBICIÓN DE ANGIOTENSINA PARA LA PREVENCIÓN PRIMARIA - Además de su eficacia en

pacientes diabéticos con albuminuria moderadamente incrementada (anteriormente, microalbuminuria) o
nefropatía diabética manifiesta (albuminuria severamente aumentada, antes macroalbuminuria) como se
describe a continuación, inhibidores de la enzima convertidora de angiotensina (ACE) o angiotensina II. Los
bloqueadores de receptores (BRA) se han evaluado para determinar su eficacia en la prevención primaria de
la nefropatía diabética. Los datos relevantes se discuten por separado. (Ver "Albuminuria moderadamente
aumentada (microalbuminuria) en la diabetes mellitus tipo 1", sección "Prevención primaria" y "Albuminuria
moderadamente aumentada (microalbuminuria) en la diabetes mellitus tipo 2", sección sobre "Prevención
primaria" .)
FUNCIÓN DE OTROS FACTORES : además de la hiperglucemia, otros factores contribuyen a la lesión

glomerular en este contexto. (Consulte "Descripción general de la nefropatía diabética", sección
"Patogénesis" .)
Los estudios extensos en animales diabéticos sugieren que la hipertensión intraglomerular y la hipertrofia
glomerular desempeñan un papel importante, ya que se presentan temprano en la enfermedad (ya que la
diabetes induce vasodilatación renal y con frecuencia un aumento en la tasa de filtración glomerular [GFR]) y
luego se ve exacerbada por la respuesta compensatoria a Pérdida de nefrona. (Ver "Mecanismos de
hiperfiltración glomerular en la diabetes mellitus" .)
Por otro lado, la presión intraglomerular reducida como resultado de la restricción de proteínas en la dieta, el
control de la hipertensión con un inhibidor de la angiotensina (es decir, el inhibidor de la enzima convertidora
de la angiotensina [ACE] o el bloqueador del receptor de la angiotensina [ARB]), o la estenosis concurrente

de la arteria renal pueden minimizar la progresión de o incluso prevenir la enfermedad glomerular en
ausencia de control glucémico ( foto 1 ) [ 18-21 ]. Además, la inhibición de la ECA fue más efectiva que la
terapia triple con hidroclorotiazida , hidralazina y reserpina, tanto para disminuir la presión intraglomerular
como para minimizar la lesión glomerular ( figura 3 ) [ 18 ].
El factor de crecimiento transformante beta (TGF-beta) puede contribuir tanto a la hipertrofia celular como a
la síntesis mejorada de colágeno que se observa en la nefropatía diabética. La inhibición de TGF-beta
parece mejorar la nefropatía diabética en modelos experimentales de diabetes y en estudios preliminares en
humanos [ 22-24 ]. (Consulte "Descripción general de la nefropatía diabética", sección "Citoquinas" .)
Los estudios experimentales sugieren que los bloqueadores de los canales de calcio que no son de la
hidropiridina (como el diltiazem ) pueden disminuir la velocidad de progresión de la mayoría de las
características morfológicas de la enfermedad renal diabética [ 25 ]. Sin embargo, el diltiazem solo se asoció
con un aumento de la fibrosis tubulointersticial y glomeruloesclerosis global (no segmentaria); este efecto se
evitó mediante la terapia combinada con un inhibidor de la ECA.
Agonistas de PPAR-gamma : los receptores activados por el proliferador de peroxisoma (PPAR), que son
factores de transcripción activados por ligando, parecen tener un papel en la regulación de la adipogénesis,
el metabolismo de los lípidos, la sensibilidad a la insulina, la inflamación y la presión arterial. También
pueden tener un papel en el desarrollo de la nefropatía en la diabetes tipo 2 [ 26 ]. (Ver "Patogenia de la
diabetes mellitus tipo 2" .)
Los agonistas de PPAR-gamma, como las tiazolidinedionas (p. Ej., Pioglitazona ), se pueden usar para
disminuir la glucosa en sangre en pacientes con diabetes tipo 2. Sin embargo, el uso de estos agentes está
limitado por múltiples preocupaciones de seguridad.
PRESERVACIÓN DE LA FUNCIÓN RENAL : Ahora hay pruebas claras de que la terapia antihipertensiva
(especialmente con bloqueadores del sistema renina-angiotensina) y quizás la restricción de proteínas
puede reducir la tasa de progresión en pacientes con diabetes y nefropatía manifiesta. Si bien existe
evidencia específica para los inhibidores de la enzima convertidora de angiotensina (ECA) en la diabetes
tipo 1 y los bloqueadores de los receptores de la angiotensina (BRA) para la diabetes tipo 2 para reducir la
progresión, no hay razón para creer que estas clases no sean eficaces en ambas enfermedades [ 27 ].
La eficacia de la presión arterial y la reducción de la proteinuria en pacientes con nefropatía diabética es

similar a la observada en pacientes con insuficiencia renal proteinúrica no diabética. (Consulte "Terapia
antihipertensiva y progresión de la enfermedad renal crónica no diabética en adultos" .)
Diabetes tipo 1
Inhibidores de la ECA : el beneficio de la terapia antihipertensiva con un inhibidor de la ECA en la

diabetes tipo 1 se puede demostrar de manera temprana en el curso de la enfermedad cuando la
albuminuria moderadamente aumentada (anteriormente denominada microalbuminuria) es la única
manifestación clínica. En un estudio, por ejemplo, la administración de un inhibidor de la ECA a los
diabéticos tipo 1 normotensos con albuminuria moderadamente incrementada disminuyó la excreción de
albúmina y, a los dos años, la progresión a nefropatía diabética manifiesta en comparación con los pacientes
tratados con placebo ( figura 4 ) [ 28 , 29 ]. (Consulte "Albuminuria moderadamente incrementada
(microalbuminuria) en la diabetes mellitus tipo 1" .)
Se demostró un beneficio más pronunciado en el mayor ensayo hasta la fecha en pacientes con diabetes
tipo 1 que ya tenían nefropatía manifiesta [ 30,31 ]. Cuatrocientos nueve pacientes con proteinuria manifiesta
y una concentración plasmática de creatinina ≤2.5 mg / dL (220 micromol / L) fueron asignados al azar al
tratamiento con captopril o placebo. Luego se agregaron otros fármacos antihipertensivos según fue
necesario, aunque se excluyeron los bloqueadores de los canales de calcio y otros inhibidores de la ECA.
Aproximadamente a los cuatro años de control de la presión arterial casi equivalente, los pacientes tratados
con captopril tuvieron una tasa más lenta de aumento de la concentración plasmática de creatinina y una
menor probabilidad de progresar a enfermedad renal terminal o muerte ( figura 5 ). Este beneficio se limitó a
los pacientes con una concentración plasmática inicial de creatinina ≥1.5 mg / dL (132 micromol / L) en
quienes esa tasa de aumento en la concentración plasmática de creatinina se redujo en más del 50 por
ciento desde 1.4 mg / dL por año (123 micromol / L) en el grupo placebo a 0,6 mg / dL por año (53
micromol / L)Con captopril. En comparación, no se pudo demostrar una mejoría en los pacientes con una
concentración plasmática de creatinina basal más baja, porque la tasa de progresión fue muy lenta en este
grupo, con un aumento de la concentración de creatinina en plasma de solo 0,1 a 0,2 mg / dl por año (9 a 18
micromol / L) .
La respuesta beneficiosa al captopril , que se observó en sujetos hipertensos y normotensos, es consistente

con estudios más pequeños que sugirieron que el tratamiento antihipertensivo, en particular con un inhibidor
de la ECA, disminuyó la tasa de progresión en la nefropatía diabética [ 32,33 ]. La reducción de la presión
arterial sola, especialmente a menos de 120/75 mmHg, puede ser suficiente para disminuir la tasa de
progresión de la nefropatía, independientemente del agente utilizado [ 33 ].
Remisión o regresión : algunos pacientes con diabetes tipo 1 tienen un marcado efecto antiproteinúrico
con remisión sostenida a largo plazo o regresión de la nefropatía y / o el síndrome nefrótico; Tales pacientes
parecen tener un buen resultado renal:
● En el gran ensayo aleatorizado, 108 de 409 pacientes tenían proteinuria de rango nefrótico, 40 de los
cuales fueron asignados aleatoriamente a terapia activa con captopril . A los 7,7 años, seis de estos
pacientes permanecieron en remisión clínica con proteinuria sustancialmente menor (media de 1 g / 24
horas) y una concentración plasmática estable de creatinina (1,6 mg / dL [140 micromol / L]) [ 34 ].
● Un segundo estudio prospectivo de 301 pacientes (de los cuales 271 fueron tratados con medicamentos
antihipertensivos y 30 normotensos) evaluó la incidencia de remisión (definida como una disminución de
la albuminuria a menos de 200 mcg / min [288 mg / día] al menos una año y una disminución en la
proteinuria de más del 30 por ciento) y regresión (definida como una tasa de disminución en la tasa de
filtración glomerular [GFR] de ≤1 ml / min por año) de acuerdo con el grado de control de la presión
arterial durante un seguimiento medio de siete años [ 35]. Los inhibidores de la ECA fueron los
principales agentes antihipertensivos en 179 pacientes. El control de la presión arterial agresiva se
correlacionó directamente con la remisión y la regresión, con los quintiles más altos (presión arterial
media de 113 mmHg) y la presión arterial más baja (93 mmHg) asociados con tasas de remisión y
regresión del 17 y 7 por ciento y 58 y 42 por ciento, respectivamente .
● Entre 126 pacientes con diabetes tipo 1 y proteinuria de rango nefrótico, 28 se sometieron a remisión
sostenida (definida como albuminuria <600 mg / 24 horas durante al menos un año) después del
tratamiento con inhibidores de la ECA (21 pacientes) y medicamentos no inhibidores de la ECA ( 7
pacientes) [ 36 ]. El seguimiento promedio desde el inicio de la proteinuria en rango nefrótico fue de casi
nueve años. En comparación con aquellos que no experimentaron remisión, la tasa de disminución de la
TFG fue notablemente más lenta en aquellos que sufrieron remisión (3,8 frente a 7,5 ml / min por año) [
36 ]. En un estudio de seguimiento posterior (período de remisión promedio de 5,5 años [1 a 22 años]),
el grupo de remisión tuvo un riesgo significativamente menor de diálisis, trasplante o muerte (RR 0,28)
[37 ].
Por lo tanto, entre los pacientes con nefropatía diabética debida a diabetes mellitus tipo 1, incluidos algunos
con enfermedad avanzada, puede ocurrir una remisión o regresión con un control agresivo de la presión
arterial sistémica, particularmente con inhibidores de la ECA [ 38 ].
En comparación con la monoterapia con un inhibidor de la ECA o un ARB solo, la terapia combinada con un
inhibidor de la ECA y un ARB administrados juntos puede producir una mayor reducción en la excreción de
proteínas (consulte "Reducción de la excreción de proteínas" a continuación). En dos estudios a corto plazo
(ocho semanas) en pacientes con diabetes tipo 1, la terapia de combinación produjo una reducción superior
de la albuminuria y la presión arterial en comparación con la observada con la monoterapia sola [ 39,40 ].
Sin embargo, el beneficio de la proteinuria puede deberse a una mejor respuesta de la presión arterial con la
terapia combinada.
Diabetes tipo 2 : ha habido mucha menos información sobre el efecto de la terapia antihipertensiva con
inhibidores de la ECA en pacientes con nefropatía por diabetes tipo 2, aunque parece haber un beneficio
similar. Hay más datos disponibles sobre la eficacia de los BRA.
Control de la presión de la sangre - control de la presión arterial estricta es importante para prevenir la
progresión de la nefropatía diabética y otras complicaciones en pacientes con diabetes tipo 2, pero el límite
inferior óptima para la presión arterial sistólica no está claro. En el Estudio prospectivo de diabetes del Reino
Unido (UKPDS), cada reducción de 10 mmHg en la presión sistólica se asoció con una reducción del 12 por
ciento en el riesgo de complicaciones diabéticas (P <0,001); el riesgo más bajo ocurrió a una presión
sistólica por debajo de 120 mmHg ( figura 6 ) [ 41 ]. Análisis observacional post-hoc del IrbesartanEl ensayo
de nefropatía diabética (IDNT, por sus siglas en inglés) también concluyó que una menor presión arterial
alcanzada (hasta presiones sistólicas de 120 mmHg) se asoció con un menor riesgo de eventos
cardiovasculares y renales [ 42,43 ]. Por el contrario, la presión arterial alcanzada por debajo de este nivel se
asoció con un mayor riesgo. Sin embargo, estas observaciones epidemiológicas no prueban causalidad.
Una posible explicación para estos hallazgos de mayor riesgo con presión arterial baja es que una
proporción significativamente mayor de pacientes en el grupo que lograron una presión arterial sistólica por
debajo de 120 mmHg tenían antecedentes de enfermedad cardíaca o insuficiencia cardíaca, pero el número
de pacientes era demasiado elevado. pequeño para determinar si el efecto de la presión arterial baja fue
independiente de la historia previa de enfermedad cardiovascular. Dadas estas limitaciones, estos hallazgos
son insuficientes para justificar el cambio de nuestras recomendaciones con respecto a la presión arterial
objetivo. (Consulte "Tratamiento de la hipertensión en pacientes con diabetes mellitus", en la sección
"Presión arterial objetivo" .)
Protección renal con BRA : dos ensayos principales han demostrado un claro beneficio en términos de
renoprotección con BRA en pacientes con nefropatía manifiesta debida a la diabetes tipo 2. Estos ensayos
compararon ARB con placebo u otros fármacos, pero no con inhibidores de la ECA [ 44 ].
● En el IDNT, 1715 pacientes hipertensos con nefropatía (media de creatinina sérica 1,7 mg / dL [150
micromol / L]) debido a diabetes tipo 2 fueron asignados al azar a irbesartan (300 mg / día), amlodipino
(10 mg / día), o placebo [ 45,46 ]. A los 2,6 años, irbesartan se asoció con un riesgo de punto final
combinado (duplicación de la creatinina plasmática, desarrollo de enfermedad renal en etapa terminal o
muerte por cualquier causa) que fue 23 y 20 por ciento menor que con amlodipina y placebo,
respectivamente ( figura 7); the values were 37 and 30 percent lower for doubling of the plasma
creatinine. These benefits were independent of the differences in the magnitude of blood pressure
reduction among the groups [42,43], and the renal outcomes were best at systolic pressures below 134
mmHg [43].
● In the RENAAL trial, 1513 patients with type 2 diabetes and nephropathy (mean serum creatinine 1.9
mg/dL [168 micromol/L]) were randomly assigned to losartan (50 titrating up to 100 mg once daily) or
placebo, both in addition to conventional antihypertensive therapy (but not ACE inhibitors) [47].
Compared to placebo, losartan reduced the incidence of a doubling of the plasma creatinine by 25
percent and end-stage renal disease by 28 percent; the mean follow-up was 3.4 years. These benefits
were again not associated with differences in blood pressure levels between the groups.
Subsequent analysis of the RENAAL trial found that the most significant risk factor for progressive
kidney disease was the degree of proteinuria, both initially and after six months of therapy [48-50].
Additional post-hoc evaluations of RENAAL revealed the following [51-54]:
• Every 10 mmHg increase in the baseline systolic blood pressure was associated with an enhanced
risk of end-stage renal disease or death of 6.7 percent [51].
• Lowering albuminuria within the first six months correlated with a decreased subsequent
cardiovascular risk [52]. There was an 18 percent decrease in risk of a cardiovascular event for
every 50 percent decrease in the rate of albumin excretion.
• Within all categories of attained blood pressure, a larger reduction in albuminuria correlated with a
progressively lower risk of end-stage renal disease [54].
• The presence of baseline retinopathy was associated with a poor renal outcome (increased
proteinuria, decreased GFR, and development of end-stage renal disease) and a higher risk of
death [53].
Although both studies showed that the ARB groups had significant reductions in the development of and
subsequent hospitalization for heart failure [55], neither study initially found significant cardiovascular
mortality reduction or, in the IDNT, a decrease in the composite cardiovascular event rate [56]. These ARB
trials were underpowered and of too short duration to detect a possible cardiovascular effect, but post-hoc
analyses yielded further information. (See "Treatment of hypertension in patients with diabetes mellitus".)
Renal protection with ACE inhibitors — ACE inhibitors have been compared with placebo and with
ARBs in two trials (ADVANCE and DETAIL) of patients with type 2 diabetes.
The ADVANCE trial compared the use of a fixed combination of perindopril-indapamide to placebo in over
11,000 patients with type 2 diabetes [57]. The mean baseline serum creatinine was 1 mg/dL (87 micromol/L),
and moderately increased albuminuria was present in 26 percent. The details and results of this trial, which
included macrovascular outcomes, are discussed separately. What follows is a summary of the renal
benefits. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'ADVANCE trial'.)
After a mean of 4.3 years, the patients treated with active therapy had the following differences in renal
parameters compared to those treated with placebo:
● A significant decrease in mean blood pressure (5.6/2.2 mmHg)
● A significant reduction in the rate of new onset of moderately increased albuminuria (19.6 versus 23.6
percent) and in the combined endpoint of new onset of moderately increased albuminuria, worsening of
moderately increased albuminuria, or new onset or worsening of severely increased albuminuria
(formerly, macroalbuminuria) [58]
The renal benefits of active treatment were consistent across all subgroups, including those that started with
the lowest baseline blood pressure (mean systolic pressure <120 mmHg [median 113 mmHg]) [58]. There
was no significant difference between the groups in doubling of the serum creatinine or progression to end-
stage renal disease.
It is not possible to determine the degree to which the renal benefits in ADVANCE were due to the ACE
inhibitor or to the lower blood pressure [59,60].
DETAIL was a randomized controlled trial that compared enalapril to the ARB telmisartan in 250 patients with
early nephropathy as defined by albuminuria (82 percent moderately increased albuminuria and 18 percent
severely increased albuminuria to a maximum of 1.4 g/day) and a baseline GFR (measured isotopically) of
approximately 93 mL/min per 1.73 m2 [27]. A greater fall in GFR of at least 10 mL/min per 1.73 m2 at five
years was predefined as suggesting a clinically significant difference between the groups.
At five years, there was a smaller decline in GFR in the enalapril that was not significant (14.9 versus 17.9
mL/min per 1.73 m2 with telmisartan). Both groups had similar rates or findings for the secondary endpoints,
which included annual changes in the GFR, blood pressure, serum creatinine, urinary albumin excretion,
end-stage kidney disease, cardiovascular events, and mortality.
Two limitations of the trial were that only 168 of the original 250 patients completed the trial and that only 20
percent had severely increased albuminuria. Nevertheless, the results are consistent with the conclusion that
ACE inhibitors are at least as effective as ARBs in diabetic patients with moderately increased albuminuria.
Given the available evidence, ACE inhibitors or ARBs appear to provide preferential renoprotection in
patients with diabetic nephropathy. However, patients with type 2 diabetes and advanced kidney disease are
likely to progress relentlessly to end-stage renal disease despite treatment with ACE inhibitors or ARBs,
although more slowly.
Sodium-glucose cotransporter 2 inhibitors — The use of sodium-glucose cotransporter 2 (SGLT-2)

inhibitors, such as canagliflozin and empagliflozin, in patients with type 2 diabetes reduced the risk of kidney
disease progression and of renal endpoints in some trials [61,62]. This issue is discussed elsewhere in detail.
(See "Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus", section on
'Microvascular outcomes'.)
Glucagon-like peptide-1 receptor agonists — The glucagon-like peptide-1 (GLP-1) receptor agonist
liraglutide reduced the incidence of a composite renal endpoint (consisting of new onset of albuminuria >300
mg/day, doubling of serum creatinine, end-stage renal disease, or renal death) in a large trial of patients with
type 2 diabetes [63]. The effect was predominantly due to a reduction in new-onset albuminuria. This issue is
presented in detail elsewhere. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2
diabetes mellitus", section on 'Microvascular outcomes'.)
Therapies associated with harm, no benefit, or uncertain benefit — Several therapeutic approaches
that have been rigorously tested in patients with type 2 diabetes and nephropathy are associated with harm,
no benefit, or uncertain benefit. Such therapies should not be used unless future studies indicate a beneficial
role for these agents. These include:
● Combination therapy with an ACE inhibitor and ARB (see 'Combination ACE inhibitor and ARB therapy'
below)
● Combination therapy with a direct renin inhibitor (aliskiren) and either an ACE inhibitor or ARB (see
'Aliskiren plus angiotensin inhibition' below)
● Bardoxolone methyl therapy (see 'Bardoxolone methyl' below)
● Pentoxifylline (see 'Pentoxifylline therapy' below)
Combination ACE inhibitor and ARB therapy — Combination therapy with an ACE inhibitor and an
ARB compared with either therapy alone decreases proteinuria in patients with type 1 and type 2 diabetes
[39,64,65]. However, combination therapy does not prevent renal disease progression or death, and it
increases the rate of serious adverse events. Thus, combination therapy with an ACE inhibitor plus an ARB
should not be used in patients with diabetic nephropathy.
The best data come from the Veterans Affairs Nephropathy in Diabetes study (VA NEPHRON-D), a
randomized placebo-controlled double-blind trial performed in 1448 mostly male patients with diabetic
nephropathy (mean estimated GFR [eGFR], 54 mL/min/1.73 m2; mean albumin-to-creatinine ratio, 852 mg/g)
[66]. All patients received 100 mg/day of losartan and were then randomly assigned to placebo or lisinopril
(10 to 40 mg/day as tolerated); the primary endpoint was a composite of a 50 percent eGFR decline (or more
than 30 mL/min/1.73 m2), end-stage renal disease, or death. The trial was discontinued early after a median
of 2.2 years because of safety concerns. The combination therapy and monotherapy groups had a similar
rate of primary events (18.2 versus 21 percent). However, acute kidney injury requiring hospitalization or
occurring during hospitalization was significantly more common with combination therapy (18 versus 11
percent), as was severe hyperkalemia (9.9 versus 4.4 percent).
Additional data come from the diabetes subgroup of the ONTARGET trial. The ONTARGET trial compared
combination ramipril and telmisartan therapy with ramipril alone in 25,620 patients with vascular disease or
diabetes [67,68]. Results from the ONTARGET trial are presented in detail elsewhere. (See "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Combination of ACE
inhibitors and ARBs' and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)
In the subset of 3163 patients from ONTARGET with diabetic kidney disease, combination therapy was
associated with a nonsignificantly higher incidence of chronic dialysis or doubling of serum creatinine (5.3
versus 4.8 percent), and a similar death rate (2.3 versus 2.2 percent), as compared with monotherapy [69]. In
addition, patients with diabetic kidney disease who received combination therapy had higher rates of acute
kidney injury requiring dialysis (1.4 versus 0.8 percent), hyperkalemia (11.3 versus 7.8 percent), and
hypotension (2.8 versus 1.9 percent).
Aliskiren plus angiotensin inhibition — The use of aliskiren, a direct renin inhibitor, in combination
with either an ACE inhibitor or ARB does not appear to preserve renal function and increases the risk of
adverse events. This was shown in the multinational Aliskiren Trial in Type 2 Diabetes Using Cardiorenal
Endpoints (ALTITUDE trial), which randomly assigned 8561 diabetic patients with either preexisting renal or
cardiovascular disease to 300 mg/day aliskiren or placebo [70]. At baseline, the majority of patients had
nephropathy (59 percent had an albumin-to-creatinine ratio of 200 mg/g or greater, and 26 percent had an
albumin-to-creatinine ratio between 20 and 199 mg/g; the mean eGFR was 57 mL/min per 1.73 m2); all
patients were receiving an ACE inhibitor or ARB at baseline. After a median follow-up of 32.9 months, more
patients in the aliskiren group reached the composite primary endpoint of end-stage renal disease, doubling
of serum creatinine, renal death, cardiovascular death, cardiac arrest, heart failure, nonfatal myocardial
infarction, or nonfatal stroke (18.3 versus 17.1 percent). The incidence of renal events (end-stage renal
disease, renal death, or doubling of serum creatinine) was similar with aliskiren and placebo (6 versus 5.9
percent). Adverse events requiring cessation of randomized therapy (usually hyperkalemia) were significantly
more frequent with aliskiren (13.2 versus 10.2 percent). Due to the lack of apparent benefit and higher risk of
side effects, the trial was stopped early for futility.
Bardoxolone methyl — Bardoxolone methyl is an antioxidant inflammatory modulator that may also
have prostaglandin-like effects. It has been beneficial in animal models of drug-induced or ischemic acute
kidney injury (see "Inflammation in renal insufficiency", section on 'Management issues'). However, this drug
should not be used in patients with diabetic kidney disease.
In the Bardoxolone Methyl Treatment: Renal Function in Chronic Kidney Disease/Type 2 Diabetes (BEAM)
trial, 227 patients with type 2 diabetes and an eGFR between 20 and 45 mL/min per 1.73 m2 were randomly
assigned to either placebo or one of three doses of bardoxolone methyl (25, 75, or 150 mg/day) [71].
Bardoxolone methyl therapy at all three doses significantly increased eGFR at 52 weeks of follow-up by 6 to
10 mL/min per 1.73 m2, while placebo therapy had no effect.
In a subsequent trial (Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2
Diabetes Mellitus, BEACON), 2185 patients with diabetes and eGFR between 15 and 30 mL/min per 1.73 m2
were randomly assigned to bardoxolone methyl (20 mg/day) or placebo; all patients were receiving therapy
with an ACE inhibitor or ARB [72]. The trial was stopped early for safety concerns after a median follow-up of
nine months. The following findings were noted:
● The incidence of the primary endpoint (a composite of end-stage renal disease and cardiovascular
death) was identical (six percent) in both groups.
● However, bardoxolone methyl significantly increased the rate of cardiovascular events, which was a
composite of cardiovascular death, hospitalization for heart failure, nonfatal stroke, and nonfatal
myocardial infarction (12.8 versus 7.8 percent).
● Bardoxolone methyl significantly increased eGFR, but also significantly increased blood pressure and
albuminuria, possibly via sodium and water retention [73].
Pentoxifylline therapy — Pentoxifylline is a nonspecific phosphodiesterase inhibitor and putative anti-

inflammatory agent that is occasionally used in patients with claudication or alcoholic hepatitis. Several small
studies including patients with diabetic nephropathy found that pentoxifylline either improved or stabilized
eGFR [74-76]. The largest of these was a single-center, open-label trial in which 169 diabetic patients with
urine albumin excretion >30 mg/day and eGFR 15 to 59 mL/min/1.73 m2 while receiving an ACE inhibitor or
ARB were randomly assigned to pentoxifylline (600 mg twice daily) or no therapy [74]. At two years,
pentoxifylline significantly reduced the rate of decline in eGFR (ie, eGFR decreased by 2 mL/min/1.73 m2
with pentoxifylline and by 6 mL/min/1.73 m2 with control). The proportion of patients who lost more than 25
percent of their renal function was also significantly lower with pentoxifylline (4 versus 27 percent). However,
the open-label design and envelope (rather than computer-generated) randomization system could have
biased the results of the study. Additional data are needed before pentoxifylline can be recommended as
treatment for diabetic nephropathy.
The effects of pentoxifylline on protein excretion are discussed below. (See 'Pentoxifylline' below.)
Protein restriction — It remains uncertain whether dietary protein restriction slows the long-term decline in
GFR in diabetic nephropathy. Two small controlled trials (35 and 19 patients with type 1 diabetes,
respectively) demonstrated that protein (and phosphate) restriction (0.6 g/kg per day) slowed the rate of
decline in GFR by 60 to 75 percent from, for example, approximately 12 mL/min per year to 3 mL/min per
year (figure 8) [77,78].
Different results were noted in a prospective randomized trial of 82 patients with type 1 diabetic nephropathy:
the rate of decline in the GFR was similar with a low-protein (0.6 g/kg per day) or usual-protein diet (3.8 and
3.9 mL/min per year, respectively) [79]. However, although the number of events was low, the incidence of
death or the onset of end-stage renal disease was significantly reduced with protein restriction. The
mechanism underlying this apparent benefit is unclear.
There are at least two explanations for the relative lack of benefit of a low-protein diet on GFR in the last
study compared to the two previous trials. First, the different in protein intake between the two groups was
probably substantially less in the last trial (0.89 versus 1.02 g/kg per day). Second, blood pressure,
albuminuria, and glycemia were aggressively and similarly controlled in both groups. Given that these factors
are independent and significant risk factors for deterioration in GFR, the ability to detect subtle differences in
the rate of decline due to protein restriction alone may have been masked.
There are several potential problems associated with a low-protein diet. In addition to difficulty with
compliance due to concurrent fat and simple carbohydrate restriction, diabetics are at increased risk for
protein malnutrition because the reduction in intake may be associated with enhanced protein breakdown
induced by insulin deficiency [80].
REDUCTION OF PROTEIN EXCRETION — The degree of proteinuria in glomerular disease tends to vary
directly with the intraglomerular pressure. It was therefore proposed that a treatment-induced reduction in
protein excretion (in the absence of a large fall in glomerular filtration rate [GFR]) reflected a desirable decline
in intraglomerular pressure, and would result in improved renal outcomes.
There is now consensus that a decrease in protein excretion has predictive importance for improved renal
outcomes. There is evidence in nondiabetic patients, for example, that those with more than a 50 percent
reduction in protein excretion following antihypertensive therapy have a better long-term outcome than those
with little or no reduction in protein excretion. (See "Antihypertensive therapy and progression of nondiabetic
chronic kidney disease in adults", section on 'The proteinuric response as a predictor of outcome'.)
The Captopril-Diabetes study that was previously described suggested that these findings also apply to
diabetic patients [31]. Patients with nephrotic-range proteinuria at baseline were evaluated according to
whether they underwent remission after therapy (defined as mean protein excretion less than 1.5 g/day) or
did not remit. The remission group had a relatively stable GFR (70 mL/min at baseline and 59 mL/min at final
evaluation) while the nonremitters tended to progress (GFR 66 mL/min at baseline and 38 mL/min at final
evaluation). The remission group also had better control of hypertension – blood pressure at final evaluation
119/76 versus 143/85 in nonremitters – a finding that could also have contributed to the better outcome.
Subsequently, post-hoc analyses of multiple large studies in types 1 and 2 diabetes, such as the Irbesartan
Diabetic Nephropathy Trial (IDNT) and the RENAAL trials as well as meta-analyses, have shown that
lowering proteinuria is associated with improved outcomes in patients with overt diabetic nephropathy and a
decreased risk of end-stage renal disease [30,33,45-49,81-83]. There appears to be a dose-response
relationship, with a greater reduction in proteinuria associated with greater reduction in risk of renal failure
[46].
ACE inhibitor or ARB — Angiotensin-converting enzyme (ACE) inhibition or ARB therapy and dietary
protein restriction lower protein excretion in diabetic patients with moderately increased albuminuria (formerly
called microalbuminuria) (figure 4) [28,29,84-86] and in those with overt (dipstick-positive proteinuria) renal
disease [45-49,87-93].
The addition of an ACE inhibitor will also lower protein excretion in patients already being treated with agents
such as a beta blocker and a thiazide diuretic [94]. The trials that have evaluated the prognostic value of
lowering protein excretion are described in detail above. (See 'Type 1 diabetes' above and 'Type 2 diabetes'
above.)
The association between antihypertensive therapy, decrease in protein excretion, and improved renal
outcomes in diabetic nephropathy was illustrated in analyses of the Irbesartan and RENAAL trials [46,49]:
● A post-hoc analysis of the IDNT reported that the risk for renal failure doubled with each doubling of
baseline protein excretion [46]. With therapy, significantly lower levels of proteinuria at one year were
obtained with irbesartan (41 percent average decrease) than with amlodipine (11 percent) or control (16
percent). Although the reduction in proteinuria was significantly associated with decreased blood
pressure, proteinuria reduction was more with the ARB for each decrement in blood pressure observed.
With respect to renal outcomes at one year, a decrease in proteinuria by one-half with therapy lowered
the overall risk of developing renal failure by one-half. In addition, for the same proportional reduction in
protein excretion, the risk reduction for renal failure was significantly greater for irbesartan compared
with amlodipine. With multivariate analysis, it was estimated that approximately one-third of the
renoprotective effect associated with irbesartan was due to proteinuria reduction in the first 12 months of
therapy.
● In the first six months of the RENAAL trial, losartan reduced albuminuria by 28 percent, while placebo
was associated with a 4 percent increase in albuminuria [49]. With post-hoc analysis, albuminuria
reduction by one-half in the first six months was associated with a 36 percent decreased risk for the
renal endpoint and 45 percent lower risk for the development of end-stage renal disease at follow-up.
After accounting for lower blood pressures with antihypertensive therapy, decreased albuminuria with
losartan accounted nearly all of the benefits with respect to the renal endpoint and approximately one-
half of the decreased incidence of end-stage renal disease.
ACE inhibitor plus ARB — Combination therapy with an ACE inhibitor and an ARB may be associated with
worse renal and other outcomes as compared with monotherapy. In addition, combination therapy is
associated with a higher incidence of adverse effects. These issues are discussed in detail above and
elsewhere. (See 'Combination ACE inhibitor and ARB therapy' above and "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults", section on 'Combination of ACE inhibitors and
ARBs' and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers", section on 'Combination of ACE inhibitors and ARBs'.)
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ARB plus aliskiren — The first effective oral direct renin inhibitor, aliskiren, was approved by the United
States Food and Drug Administration in March 2007. Aliskiren lowers blood pressure to a degree comparable
to most other agents. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)
In the AVOID trial, aliskiren plus losartan was associated with a significant 20 percent greater reduction in
proteinuria compared to losartan alone, in the absence of a significantly greater effect on blood pressure [95].
The role of aliskiren in preventing progression of chronic kidney disease is discussed above. (See 'Aliskiren
plus angiotensin inhibition' above.)
Mineralocorticoid receptor antagonism — Diuretics have generally not been considered to have an
antiproteinuric effect despite reductions in blood pressure [89,90]. However, mineralocorticoid receptor
antagonists appear to reduce proteinuria when used alone [96] and to have an additive effect on proteinuria
when used in combination with an ACE inhibitor or an ARB in both type 1 and type 2 diabetes [97-103].
Further blood pressure reduction does not completely explain the beneficial effect. This was demonstrated in
a placebo-controlled trial that included 81 patients with diabetes, hypertension, and albuminuria who were
treated with a high dose of lisinopril (80 mg/day) [103]. In addition to lisinopril, patients were randomly
assigned spironolactone (25 mg/day), losartan (100 mg/day), or placebo. At 48 weeks, patients treated with
spironolactone had a 34 percent decrease in urine albumin-to-creatinine ratio compared to placebo. Patients
who received losartan had only a 17 percent decrease in the albumin-to-creatinine ratio, which was not
significantly different from placebo. Clinic and ambulatory blood pressure, creatinine clearance, and glycemic
control were not different among groups. Serum potassium was significantly higher in patients who received
either spironolactone or losartan compared to placebo.
The efficacy and safety of other mineralocorticoid receptor antagonists (MRAs), including eplerenone (like
spironolactone, a steroidal MRA) and finerenone (a nonsteroidal MRA), have also been examined in diabetic
patients already treated with an ACE inhibitor or ARB [97,104]:
● Eplerenone was evaluated in a randomized trial of 268 patients with type 2 diabetes treated with an ACE
inhibitor [104]. Compared with placebo, eplerenone therapy at a dose of 50 or 100 mg/day was
associated with a significant reduction in urinary albumin excretion (40 to 50 versus <10 percent).
However, severe hyperkalemia (serum potassium >6 mEq/L) occurred in 9 and 23 percent of patients
receiving 50 and 100 mg/day of eplerenone, respectively (compared with 12 percent of patients in the
placebo group). The authors concluded that 50 mg/day of eplerenone in combination with an ACE
inhibitor provides an additive antiproteinuric effect, with the rate of hyperkalemia being similar to placebo.
It should be noted that the estimated GFR (eGFR) of the patients in this study was 74 mL/min per 1.73
m2. In clinical practice, the use of this combination of agents in patients with reduced GFR should only
be undertaken with careful instructions for dietary potassium restriction and avoidance of NSAIDs and
COX-2 inhibitors, and probably with concomitant kaliuretic diuretic therapy. The risk of hyperkalemia may
possibly be lower with an ARB [105].
● Finerenone was evaluated in a phase 2 dose-finding trial of 823 patients with type 2 diabetes treated
with an ACE inhibitor or ARB [97]. The effect of seven different doses of finerenone (ranging from 1.25
mg/day to 20 mg/day) was compared with placebo on the change in albuminuria at 90 days. A dose-
dependent effect was observed, with albuminuria reductions ranging from 21 to 38 percent with doses
ranging from 7.5 mg/day to 20 mg/day. The incidence of hyperkalemia with finerenone treatment was
low (1.5 percent); acute reductions in eGFR were mild and were reversible after cessation of the study
drug. As with the study of eplerenone mentioned above, most patients in the trial had an eGFR >60
mL/min/1.73 m2, and therefore, the low incidence of hyperkalemia may not reflect the rate that would be
observed in patients with more severe kidney disease.
There are no long-term data regarding benefit of combining an ACE inhibitor or ARB with an MRA in terms of
slowing the rate of loss of GFR or preventing end-stage renal disease or death. In addition, the risk of
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inducing or aggravating hyperkalemia in patients with long-standing diabetic nephropathy and reduced GFR
may limit the use of these agents.
Other antihypertensive drugs and combinations — Among the other antihypertensive drugs, only
diltiazem and verapamil appear to be as consistently effective as an ACE inhibitor or ARB in lowering protein
excretion in diabetic patients [88-90,106]. Furthermore, the antiproteinuric effects of verapamil and an ACE
inhibitor may be additive. This was illustrated in a study of 30 patients with type 2 diabetes in which lisinopril
or verapamil alone lowered protein excretion from 5.8 to 2.7 g/day [89]. By comparison, using roughly one-
half the dose of both drugs (mean of 16 mg of lisinopril and 187 mg of sustained-release verapamil) had a
much greater antiproteinuric effect – 6.8 down to 1.7 g/day (figure 9). The low-dose combination regimen was
also associated with fewer drug-induced side effects (such as constipation with verapamil and dizziness with
lisinopril). A similar antiproteinuric advantage has been demonstrated with combination therapy with
verapamil and trandolapril (figure 10) [107].
In addition to a possible reduction in intraglomerular pressure, nondihydropyridine calcium channel blockers

may have other protective actions. Some, but not all [108], studies in animals suggest that such calcium
channel blockers may minimize progressive glomerular injury independent of a reduction in the
intraglomerular pressure, perhaps by reducing the associated glomerular hypertrophy (figure 11) [107]. In
humans, antiproteinuric effects with diltiazem may also be due to improved glomerular size permselectivity
[109].
These observations on the potential benefit of calcium channel blockers are of uncertain clinical relevance.
These drugs were excluded in the captopril-diabetes trial noted above; as a result, their efficacy in the
preservation of renal function in relation to ACE inhibitors has not yet been evaluated in humans [30].
In contrast to the efficacy of diltiazem and verapamil in reducing protein excretion, the dihydropyridine
calcium channel blockers (such as amlodipine, nifedipine, nitrendipine) have a variable effect ranging from
increased protein excretion to no effect to a fall in protein excretion in different studies [45,46,89-91,110-113].
Beta blockers have shown a variable response: the fall in protein excretion is generally [87,90,106,114], but
not always [92] substantially less than that induced by an ACE inhibitor or ARB.
Salt intake and proteinuria — A high salt intake has been shown to blunt the antiproteinuric effects of
angiotensin inhibitors in patients with nondiabetic kidney disease. Salt restriction and/or diuretics enhance the
effect of renin-angiotensin blockade on proteinuria in these patients. (See "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults".)
Fewer studies have also demonstrated this in patients with diabetic kidney disease [115-117]. Thus, patients
on ACE inhibitors or ARBs who do not have sufficient reduction in proteinuria despite appropriate blood
pressure goals should be instructed to take a low-sodium diet [118,119]. An assessment of baseline sodium
intake can be undertaken by obtaining a 24-hour urine for sodium and creatinine. This can be repeated after
several months on the low-sodium diet to determine the actual sodium intake if there is insufficient reduction
in proteinuria.
Salt restriction to ≤70 mEq/day has been found to enhance the antiproteinuric effects of ARB in patients with
type 2 diabetes [116]. However, this degree of restriction may be difficult to achieve and maintain, and we
advocate restricting sodium intake to approximately ≤100 mEq/day. The effects of salt intake and restriction
on hypertension are discussed separately. (See "Salt intake, salt restriction, and primary (essential)
hypertension".)
If a low-sodium diet is not possible, administration of a diuretic partially corrects the loss of antiproteinuric
effect due to a high sodium intake [117].
Therapies of uncertain efficacy
Pentoxifylline — Pentoxifylline is a nonspecific phosphodiesterase inhibitor and putative anti-

inflammatory agent that is occasionally used in patients with claudication or alcoholic hepatitis. The effects of
pentoxifylline on proteinuria in patients with type 2 diabetes was evaluated in a single-center, open-label trial
in which 169 patients with urine albumin excretion >30 mg/day and eGFR 15 to 59 mL/min/1.73 m2 while
receiving an ACE inhibitor or ARB were randomly assigned to pentoxifylline (600 mg twice daily) or no
therapy [74]. At two years, pentoxifylline significantly reduced protein excretion by 15 percent as compared
with a 6 percent increase in the control group. However, the open-label design and envelope (rather than
computer-generated) randomization system could have biased the results of the study. Additional data are
needed before pentoxifylline can be recommended as treatment for diabetic nephropathy.
These findings support those of a previously published meta-analysis involving small studies that suggested
pentoxifylline lowers proteinuria and may have antiproteinuric effects similar to ACE inhibitors [120].
The effect of pentoxifylline on renal function is discussed above. (See 'Pentoxifylline therapy' above.)
Other agents — A variety of other agents have been tried with the goal of reduction of proteinuria in
diabetes and other proteinuric nephropathies. However, the quality of studies is poor. As an example,
silymarin (an herbal drug with antioxidant properties used in patients with hepatic disease) was shown to
reduce proteinuria in patients with diabetic nephropathy, although this trial was small, of short duration, and
will need confirmation [121].
Other agents, some experimental and others in clinical use for other indications, have also been studied,
including endothelin receptor antagonists, protein kinase C inhibitors, fenofibrate (a peroxisome proliferator-
activated receptor [PPAR]-alpha specific ligand), sulodexide, and fish oil [122-132]. (See 'Hyperlipidemia'
below.)
There are insufficient data on any of these agents to advocate their use for the treatment or prevention of
diabetic nephropathy.
Summary — In the aggregate, the above studies suggest that ACE inhibitors, ARBs, diltiazem, and
verapamil have relatively unique beneficial effects on proteinuria [90]. The reduction in protein excretion may
reflect both a fall in intraglomerular pressure and, at least with the ACE inhibitors, an apparent direct
improvement in the size-selective properties of the glomerular capillary wall (via an uncertain mechanism)
[133]. The observation that protein excretion progressively declines over time is consistent with an effect on
permselectivity since the hemodynamic effects of ACE inhibition occur very rapidly and are then stable [29].
Two final points deserve repeat emphasis. First, although accepted, it has yet to be clearly and directly
proven that a fall in protein excretion in overt nephropathy is an indicator of a better long-term outcome in
diabetic nephropathy. There is, however, a very strong association, as shown in observational, post-hoc
analyses, and meta-analyses, between decreased proteinuria and slowing of progressive nephropathy and
decreased risk of end-stage renal disease [30,33,45,47,49,81,82]. (See "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults", section on 'The proteinuric response as a
predictor of outcome'.)
Second, proteinuria tends to increase over time in untreated patients [29,84,85]. Thus, those antihypertensive
drugs that produce no or a lesser fall in protein excretion may still be having a beneficial effect when
compared to the progressive course in untreated patients.
WEIGHT REDUCTION — Marked decreases in proteinuria may be observed in obese diabetics who lose
weight [134]. This was illustrated in a randomized trial of 30 overweight patients (body mass index >27
kg/m2) with proteinuric nephropathy, 14 of whom had type 2 diabetes; proteinuria significantly decreased at
five months among dieters versus the nondieters control group (31 percent decrease versus a slight
increase) [134]. A mean weight loss of four percent was observed in the diet group. Although no significant
differences in renal function were reported in either group, the length of follow-up was probably too short to
have observed such an effect.
HYPERLIPIDEMIA — Hyperlipidemia is common in diabetic patients, a tendency that is increased by the

development of renal insufficiency. Aggressive lipid lowering is an important part of the medical management
of all diabetic patients since diabetes is considered a coronary heart disease equivalent. (See "Prevalence of
and risk factors for coronary heart disease in diabetes mellitus".)
In addition to promoting systemic atherosclerosis, an elevation in lipid levels also may contribute to the
development of glomerulosclerosis in chronic kidney disease. (See "Secondary factors and progression of
chronic kidney disease", section on 'Hyperlipidemia'.)
The applicability of these findings to diabetic nephropathy is uncertain. A prospective study in patients with
type 1 diabetes mellitus found that a plasma cholesterol concentration above 220 mg/dL (5.7 mmol/L) was an
important risk factor for progressive renal disease, particularly if the diastolic pressure were also above 85
mmHg [135]. In addition, lipid lowering (at least with statins) may slow the rate of progression of chronic
kidney disease, including diabetic nephropathy [136]. (See "Statins and chronic kidney disease".)
There is a paucity of data concerning the effects of lipid lowering alone in terms of preventing diabetic
nephropathy. Among 314 participants in the Diabetes Atherosclerosis Intervention Study, all but three
patients with type 2 diabetes had either normal albuminuria (214 patients) or moderately increased
albuminuria (formerly called microalbuminuria) (97) prior to being randomly assigned to fenofibrate or
placebo [122]. In a post-hoc analysis, worsening of proteinuria was significantly less with active therapy. Most
prominently, the rate of progression from normal albumin excretion to moderately increased albuminuria at
three years was significantly lower with fenofibrate (3 of 101 versus 20 of 113 for placebo).
Possible mechanisms of benefit with fenofibrate include suppression of inflammation and decreased
production of type 1 collagen in mesangial cells. These effects may be related to increased activity of PPAR
(peroxisome proliferator-activated receptor)-alpha [137,138]. (See "Low density lipoprotein cholesterol
lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates'.)
Intensive combined therapy, including lipid lowering, is likely to be the optimal therapeutic approach to
patients with diabetic nephropathy (including those moderately increased albuminuria). This was perhaps
best shown in the Steno-2 studies of patients with type 2 diabetes. (See 'Combined therapy' below.)
COMBINED THERAPY — The optimal therapeutic approach to the treatment of diabetic nephropathy may
be intensive combined therapy, thereby targeting the many factors underlying the disease, including
hyperglycemia, hypertension, and dyslipidemia.
Type 1 — The potential efficacy of early, intensive, combined therapy was evaluated in an uncontrolled study
of 13 patients with type 1 diabetes mellitus, who, at baseline, had a mean glomerular filtration rate (GFR) of
58 mL/min and mean albumin excretion of approximately 300 mg/day [139]. Treatment consisted of an
intensive insulin regimen (which lowered the hemoglobin A1c concentration from 8.7 to 6.5 percent), dietary
protein restriction, and antihypertensive therapy with an angiotensin-converting enzyme (ACE) inhibitor
(which lowered the blood pressure to 120/75). At the end of three years, the GFR had increased to 84
mL/min and albumin excretion had fallen to 92 mg/day.
Type 2 — The potential efficacy of intensive combined therapy in patients with type 2 diabetes and
moderately increased albuminuria (formerly called microalbuminuria) was examined in the Steno type 2 trial
[140-142]. In this controlled clinical trial, 160 patients were randomly assigned to standard care or
multifactorial intensive therapy. The intensive regimen consisted of behavioral therapy (including advice
concerning diet, exercise, and smoking cessation) and pharmacologic intervention (consisting of the
administration of an ACE inhibitor and multiple other agents to attain several aggressive therapeutic goals)
(table 1). The primary endpoint was progression to overt nephropathy at four years [140] and a composite
cardiovascular endpoint at eight years [141].
At a mean follow-up of 7.8 years, intensive therapy reduced both microvascular and macrovascular disease
[141]. With respect to diabetic nephropathy, there were significant improvements in albumin excretion (-20
versus +30 mg/day) and in progression to overt nephropathy, defined as urine albumin excretion greater than
300 mg/day (20 versus 39 percent, relative risk 0.39). By contrast, the GFR fell to the same degree in both
groups (-30 versus -32 mL/min per 1.73 m2).
At the end of the trial, all patients were offered intensive combined therapy [142]. After an additional 20 years
of follow-up, those who were assigned to intensive therapy during the first 7.8 years of the trial had a
significantly lower annual decline in GFR (3.1 versus 4.0 mL/min/year) and a higher likelihood of survival
without end-stage renal disease (approximately 50 versus 30 percent).
The details of the protocol and overall results of the Steno type 2 trial are discussed elsewhere. (See
"Overview of medical care in adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)
Thus, an aggressive combined approach may offer optimal protection against disease progression for
patients with either type 1 and type 2 disease [143,144].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Glomerular
disease in adults" and "Society guideline links: Chronic kidney disease in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Beyond the Basics topic (see "Patient education: Diabetic kidney disease (Beyond the Basics)")
RECOMMENDATIONS — The optimal therapy of diabetic nephropathy continues to evolve. It now seems
clear in type 1 diabetes that angiotensin-converting enzyme (ACE) inhibitors, as part of a therapeutic regimen
to achieve blood pressure goals, both lower protein excretion and slow the rate of disease progression in
patients with moderately increased albuminuria (the new nomenclature for what was formerly called
microalbuminuria) and in those with severely increased albuminuria (the new nomenclature for what was
formerly called macroalbuminuria or overt nephropathy) [29,30,32,35,36]; a similar effect is seen in type 2
diabetes with ARBs or ACE inhibitors [27,45,47,145-147]. The blood pressure and proteinuria goals are
similar to those in patients with proteinuric nondiabetic chronic kidney disease. (See "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Proteinuria goal' and
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Blood
pressure goal'.)
It is important to appreciate, however, that these agents slow the rate of progression, but do not stop
progression (figure 5 and figure 7) [30]. Thus, other modalities are also required [143]. Probably most
important is maintenance of strict blood pressure and glycemic control early in the course of the disease. In
addition, dietary protein restriction may be beneficial in patients with established nephropathy and aggressive
lipid lowering is likely to improve cardiovascular outcomes. (See "Prevalence of and risk factors for coronary
heart disease in diabetes mellitus".)
Measurement of protein excretion — We generally monitor protein excretion in patients with chronic renal
failure by repeated measurement of the urine protein- or albumin- to-creatinine ratio every few months, using
a first-morning void whenever feasible. (See "Assessment of urinary protein excretion and evaluation of
isolated non-nephrotic proteinuria in adults".)
The normal rate of albumin excretion is less than 10 mg/day (7 mcg/min); persistent albumin excretion
between 10 and 29 mg/day (7 to 19 mcg/min) is called high-normal albuminuria; persistent albumin excretion
between 30 and 300 mg/day (20 to 200 mcg/min) is called moderately increased albuminuria and, in patients
with diabetes (particularly type 1 diabetes), is usually indicative of diabetic nephropathy (unless there is some
coexistent renal disease) [148]. Values above 300 mg/day (200 mcg/min) are considered to represent
severely increased albuminuria [149]. Although these cutoffs defining normal albuminuria, high-normal
albuminuria, moderately increased albuminuria, and severely increased albuminuria facilitate determining risk
for progression of nephropathy, the risk of developing overt diabetic nephropathy is probably related to higher
albumin excretion rates at all levels without arbitrary thresholds.
Type 1 diabetes — Patients with type 1 diabetes should probably be screened yearly (after the first five
years) for the presence of moderately increased albuminuria [150]. Use of the albumin-to-creatinine ratio in
an untimed urinary sample is recommended as the preferred screening strategy for all diabetic patients [151].
Measurement of the serum creatinine concentration and estimation of the glomerular filtration rate (GFR)
should also be performed. An elevated albumin-to-creatinine ratio should be confirmed with at least two
additional tests performed over the subsequent 3 to 6 months, with confirmation of the diagnosis requiring at
least 2 of 3 positive samples. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes
mellitus", section on 'Screening'.)
We recommend that patients with type 1 diabetes and persistent moderately increased albuminuria be
treated with strict glycemic and lipid control. An ACE inhibitor should be given to patients with blood
pressures greater than 130/80 mmHg. Among patients with lower pressures who are not given an ACE
inhibitor, the albumin-to-creatinine ratio should be monitored at six to twelve month intervals and an ACE
inhibitor begun if there is reproducible evidence of a clear increase in albumin excretion and/or blood
pressure [6,152]. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Goal blood
pressure'.)
Recommendations concerning treatment of normotensive patients with type 1 diabetes with and without
persistent moderately increased albuminuria are discussed in detail separately. (See "Moderately increased
albuminuria (microalbuminuria) in type 1 diabetes mellitus".)
Type 2 diabetes — Screening for moderately increased albuminuria is not as useful in type 2 diabetes,
because it is not as predictive of progression to severely increased albuminuria as in type 1 diabetes. In
many cases, moderately increased albuminuria is present at the time of diagnosis of diabetes. This most
likely reflects delayed diagnosis of diabetes, but obesity and atherosclerosis may also account for moderately
increased albuminuria. Nevertheless, the presence of moderately increased albuminuria is associated with
an increased risk of developing cardiovascular disease, and most patients with moderately increased
albuminuria have other reasons for therapy with an ACE inhibitor or ARB [153]. (See "Moderately increased
albuminuria (microalbuminuria) in type 2 diabetes mellitus", section on 'Screening' and "Moderately increased
albuminuria (microalbuminuria) and cardiovascular disease", section on 'Screening'.)
Once severely increased albuminuria occurs, the rate of loss of GFR and the deleterious effect of
hypertension are equivalent to that seen in type 1 diabetes, suggesting similar pathogenetic mechanisms
[154,155]. In the absence of aggressive intervention, the time to progression from severely increased
albuminuria to end-stage renal disease in either form of diabetes averages six to seven years [154,155].
Overall, a faster rate of decline in GFR is associated with higher levels of albuminuria, HgA1c, and systolic
blood pressure [156].
The optimal initial therapy of nephropathy in patients with type 2 diabetes is angiotensin inhibition. Although
there are more data on the renoprotective effect of ARBs, ACE inhibitors can be also be used
[27,45,47,146,147]. However, almost all patients with diabetic nephropathy will require additional agents
[152]. Diltiazem or verapamil can produce a further reduction in protein excretion, which may correlate with
further protection against progression of the renal disease, while a loop diuretic is typically required in
patients with edema or renal insufficiency. Despite the demonstrated beneficial effect on proteinuria, we
recommend not using combined therapy with ACE inhibitors plus ARBs, since no reliable study has
demonstrated a long-term beneficial effect on renal function with combined therapy, and there is an increase
in adverse side effects, particularly mortality [68,157]. (See 'ACE inhibitor plus ARB' above.)
Therapeutic goals — The general aim with an ACE inhibitor or ARB in patients with diabetic nephropathy
and proteinuria (at least 500 to 1000 mg/day) is to reduce the blood pressure [152,158,159]. Almost all
patients require more than one drug to achieve the target blood pressure; in the UKPDS, for example,
approximately 30 percent of patients were taking three or more drugs (figure 12) [160]. Goal blood pressure
in patients with diabetes mellitus is discussed elsewhere. (See "Treatment of hypertension in patients with
diabetes mellitus".)
In patients with underlying cardiovascular disease (prior MI, angina), diastolic blood pressures should not be
lowered too much given concerns that lower blood pressures may be associated with a higher risk of
coronary events [42,51,161]. This issue is discussed separately. (See "Goal blood pressure in adults with
hypertension".)
Patients with the desired fall in intraglomerular pressure should also have a significant reduction in protein
excretion and the degree of antiproteinuric response correlates with protection against disease progression
[45-49] (see 'Preservation of renal function' above). To achieve maximal antiproteinuric effects with ACE
inhibitors, sodium intake must be restricted to less than 90 mEq/day [162].
It is not clear whether the pressure at which the maximum antiproteinuric response occurs represents the
optimal pressure for protection against glomerular injury. Patients who underwent remission of proteinuria in
the captopril-diabetes trial had a lower diastolic pressure (and less disease progression) than those who did
not remit (76 versus 85 mmHg) [163]. Similar observations have been made in nondiabetics with protein
excretion above 1 g/day in whom lowering the blood pressure to approximately 120/75 was associated with a
slower rate of disease progression (figure 13) [164].
Further impetus for aggressive blood pressure lowering comes from the observation in UKPDS that each 10
mmHg reduction in systolic pressure was associated with a 12 percent risk reduction in total diabetic
complications (p<0.001); the lowest risk occurred at a systolic pressure below 120 mmHg (figure 6) [41]. (See
"Treatment of hypertension in patients with diabetes mellitus", section on 'Goal blood pressure'.)
As mentioned above, the data for renal protection clearly support administration of an ACE inhibitor in
patients with type 1 diabetes; an ARB can be given if the ACE inhibitor is limited by side effects (usually
cough). Although there are more data on the renoprotective effect of ARBs in patients with nephropathy due
to type 2 diabetes, in particular among patients with overt proteinuria, it is probable that ACE inhibitors are a
reasonable alternative [27,45,47,51].
Compared to monotherapy with an ACE inhibitor or ARB alone, combined therapy produced a greater
reduction in protein excretion in most studies [39,40]. On the other hand, combination therapy with an ACE
inhibitor and ARB is associated with a higher incidence of adverse effects [67,68]. In the ONTARGET trial,
which comprised 25,620 patients with vascular disease or diabetes, there was an increase in adverse side
effects. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers".)
Recommendations — The following recommendations for therapeutic goals are consistent with the
K/DOQI Clinical Practice Guidelines for diabetes and chronic kidney disease and the Guidelines on
hypertension and antihypertensive agents in chronic kidney disease [6,151,152]. Aggressive goals are
recommended for both proteinuria and blood pressure. Antihypertensive therapy is given for both renal
protection and cardiovascular protection since chronic kidney disease and diabetes are independently
associated with a marked increase in cardiovascular risk. (See "Chronic kidney disease and coronary heart
disease".)
● A reduction in protein excretion to less than 500 to 1000 mg/day – Recognizing the difficulty of achieving
such a goal in many patients, we recommend a minimum reduction of at least 60 percent of baseline
values. Our renal goals related to moderately increased albuminuria are discussed elsewhere. (See
"Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus".)
● A reduction in blood pressure to less than 130/80 mmHg in patients with proteinuria – Data from patients
with nondiabetic proteinuric chronic kidney disease suggest that an even lower systolic pressure may be
more effective in slowing progressive renal disease in patients with a spot urine total protein-to-creatinine
ratio ≥1000 mg/g (which usually represents protein excretion of greater than 1000 mg/day) [152]. This
observation probably extends to those with diabetic nephropathy. (See "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults" and "Assessment of urinary protein
excretion and evaluation of isolated non-nephrotic proteinuria in adults".)
Caution: The diastolic blood pressure should not be lowered below 75 mmHg in patients with active
coronary disease, and the systolic blood pressure should not be lowered to below 110 mmHg in any
patient.
These aggressive goals will, in most patients, require therapy with multiple drugs [165]:
● It seems likely that ACE inhibitors and ARBs are equally effective in the treatment of diabetic
nephropathy in patients with type 1 or 2 diabetic nephropathy. Nevertheless, we prefer initiating therapy
with an ACE inhibitor in type 1 diabetic nephropathy and either an ACE inhibitor or an ARB in type 2
diabetic nephropathy [27,152]. We recommend not using combination therapy with ACE inhibitors and
ARBs. (See 'Therapeutic goals' above.)
● Almost all patients will require a diuretic to attain goal blood pressure. Because subclinical fluid overload
can maintain hypertension in patients with chronic kidney disease, the goal of diuretic therapy is to attain
dry weight which, in the presence of persistent hypertension, is defined as the weight at which further
fluid loss leads to symptoms (fatigue, orthostatic hypotension) or to decreased tissue perfusion as
evidenced by an elevation in the blood urea nitrogen and/or serum creatinine concentration. (See
"Overview of hypertension in acute and chronic kidney disease", section on 'Choice of antihypertensive
therapy'.)
● If appropriate diuretic therapy plus either an ACE inhibitor or ARB does not achieve goal blood pressure,
we suggest a nondihydropyridine calcium channel blocker (diltiazem or verapamil). However, these
drugs should not be given in combination with a beta blocker. Thus, in patients already being treated
with a beta blocker for another indication, we suggest adding a long-acting dihydropyridine calcium
channel blocker.
● If the proteinuria goal is not reached after the blood pressure goal has been attained, we add a
nondihydropyridine calcium channel blocker (diltiazem or verapamil) if not already being used and if the
patient is not being treated with a beta blocker.
Adverse effects — Two potential complications of ACE inhibitor or ARB therapy in patients with chronic
kidney disease are an initial fall in GFR and the development of hyperkalemia:
● An initial fall in GFR resulting in an elevation in serum creatinine is due to the associated reduction in
glomerular capillary pressure. The rise in serum creatinine typically occurs early during dose titration.
Late acute increases in serum creatinine (as opposed to gradual increases due to disease progression)
can occur if diuretics are started or the dose is increased or if some other renal insult is superimposed,
such as a nonsteroidal anti-inflammatory drug [157].
An elevation in serum creatinine of as much as 30 to 35 percent above baseline that stabilizes within the
first two to four months of therapy is considered acceptable and not a reason to discontinue therapy with
these drugs [157,166]. A review of 12 randomized trials of chronic kidney disease progression found that
patients with a limited early acute increase in serum creatinine after initiation of ACE inhibitors were
more likely to have long-term preservation of kidney function [157]:
● Hyperkalemia due to removal of the angiotensin II-mediated stimulus to the release of aldosterone is
most likely to occur in patients in whom the plasma potassium concentration is elevated or in the high-
normal range prior to therapy. This is discussed in detail separately. (See "Treatment and prevention of
hyperkalemia in adults".)
Because of the decline in renal function and a rise in plasma potassium that typically occur soon after
the onset of therapy, a plasma creatinine and potassium should be measured within three to five days.
Protein restriction — The role of dietary protein restriction is uncertain in diabetics, particularly in view of
problems with compliance in patients already being treated with fat and simple carbohydrate restriction.
Furthermore, it is uncertain whether a low-protein diet is significantly additive to other measures aimed at
preserving renal function, such as ACE inhibition and aggressive control of blood pressure and blood glucose
[79]. It is reasonable, however, to avoid a high-protein diet by limiting protein intake to a level at which
compliance is not difficult for the patient (approximately 1 g/kg per day).
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and deaths in IDDM patients with nephropathy. Kidney Int Suppl 1994; 45:S125.
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and expression of slit diaphragm proteins in type II diabetes. Kidney Int 2006; 70:177.
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db/db mice. Kidney Int 2006; 69:1511.
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diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353:617.
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148. Mogensen CE. Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to
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156. Rossing K, Christensen PK, Hovind P, et al. Progression of nephropathy in type 2 diabetic patients.
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160. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in
type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998; 317:713.
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progression in diabetic nephropathy. Kidney Int Suppl 1994; 45:S145.
164. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control
on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl
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Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA
2003; 289:2560.
Topic 3052 Version 41.0
GRAPHICS
Strict glycemic control prevents moderately increased

albuminuria (formerly called microalbuminuria) in
patients with type 1 diabetes mellitus
Cumulative incidence of moderately increased albuminuria (formerly called

microalbuminuria) in patients with type 1 diabetes treated with either
conventional or intensive insulin therapy for up to nine years. There was an
increasing benefit of intensive therapy over time (p<0.04).
Data from: The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus. The
Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;
329:977.
Graphic 73143 Version 7.0
Reversal of diabetic nephropathy after pancreas

transplantation
The thickness of the glomerular (A) and tubular (B) basement membranes, mesangial
fractional volume (C), and mesangial-matrix fractional volume (D) at baseline, 5, and
10 years after pancreas transplantation. All four parameters fell toward or reached
the normal range (shaded areas) at 10 years. The mesangial fractional volume is the
proportion of the glomerulus occupied by the mesangium; the mesangial-matrix
fractional volume is that fraction of the glomerulus consisting of the mesangial
matrix.
Data from Fioretto P, Steffes MW, Sutherland DER, et al. Reversal of lesions of diabetic
nephropathy after pancreas transplantation. N Engl J Med 1998; 339:69.
Unilateral diabetic glomerulosclerosis
Light micrographs from a postmortem examination of a diabetic patient with

unilateral renal artery stenosis on the right side. Classic Kimmelstiel-Wilson
nodules are seen in the glomeruli in the left kidney (left panel); in contrast, the
glomeruli are normal in the "protected" right kidney (right panel).
Courtesy of Helmut Rennke, MD.
ACE inhibitor is more effective than triple therapy in

protecting against experimental diabetic nephropathy
Efficacy of antihypertensive therapy in diabetic rats in reducing the number of

sclerotic glomeruli at 70 weeks. Triple therapy with hydrochlorothiazide,
hydralazine, and reserpine was partially protective, but captopril was completely
protective, with the degree of glomerulosclerosis being less than that in control
(normal) rats (left column). Captopril also normalized the intraglomerular pressure
(46 mmHg) versus 64 mmHg in untreated diabetic animals and 56 mmHg with
triple therapy.
Data from Anderson S, Rennke HG, Garcia DL, et al. Kidney Int 1989; 36:526.
Captopril delays progression of moderately increased

albuminuria (formerly called microalbuminuria) in
diabetes
Effect of captopril or placebo in 225 patients with type 1 diabetes mellitus,

normal blood pressure, and moderately increased albuminuria (formerly called
microalbuminuria). At two years, captopril slowed the rate of progression to
overt, dipstick-positive proteinuria and lowered the AER compared with placebo.
AER: albumin excretion rate.
Data from: Captopril reduces the risk of nephropathy in IDDM patients with
microalbuminuria. The Microalbuminuria Captopril Study Group. Diabetologia 1996;
39:587.
ACE inhibitor slows progression of diabetic nephropathy
The effect of the administration of placebo or captopril to patients with type 1

diabetes with overt proteinuria and a Pcr equal to or greater than 1.5 mg/dL
(132 µmol/L). The likelihood of a doubling of the Pcr was reduced by more than
50 percent in the captopril group.
ACE: angiotensin-converting enzyme; Pcr: plasma creatinine concentration.
Data from: Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-
converting enzyme inhibition on diabetic nephropathy. The Collaborative Study
Group. N Engl J Med 1993; 329:1456.
Lower systolic blood pressure (BP) is associated with

fewer complications in patients with type 2 diabetes
Among 3642 patients with type 2 diabetes mellitus in the United Kingdom
Prospective Diabetes Study (UKPDS), there was an inverse correlation between
the updated mean systolic blood pressure and the aggregate end point for any
complication related to diabetes (myocardial infarction, sudden death, angina,
stroke, renal failure, lower extremity amputation or death from peripheral
vascular disease, death from hyperglycemia or hypoglycemia, heart failure,
vitreous hemorrhage, retinal photocoagulation, and cataract extraction). The
lowest risk occurred at a systolic pressure below 120 mmHg. The values,
adjusted for age, sex, and ethnic group, are expressed for white men aged 50 to
54 years at diagnosis with a mean duration of diabetes of ten years.
Data from Adler AI, Stratton IM, Neil HA, et al. BMJ 2000; 321:412.
Irbesartan slows progression of nephropathy in type 2

diabetes
Effect of irbesartan, amlodipine, and placebo on the course of hypertensive patients

with nephropathy due to type 2 diabetes; the target blood pressure was similar in the
three groups. Treatment with irbesartan was associated with a risk of the primary end
point (doubling of the baseline serum creatinine, development of end-stage renal
disease, or death from any cause) that was 20 percent lower than placebo and 23
percent lower than amlodipine.
Adapted from data published in: Lewis EJ, Hunsicker LG, Clarke WR, et al. N Engl J Med
2001; 345:851.
Graph showing effect of dietary protein restriction on

progression of diabetic nephropathy
Dietary protein restriction - to about 0.6 g/kg per day or 30 to 40 percent lower
than the control group - in two trials (left and right panels) of patients with type
1 diabetes and diabetic nephropathy led to a 75 percent reduction in the rate of
loss of glomerular filtration rate (GFR) at 18 to 36 months.
Data from: Walker JD, Bending JJ, Dodds RA, et al, Lancet 1989; 2:1411.
Zeller K, Whittaker E, Sullivan L, et al. N Engl J Med 1991; 324:78.
Antihypertensive drugs and urinary protein excretion in

diabetic nephropathy
Protein excretion at baseline (black columns) and after one year of

antihypertensive therapy (hatched columns) in patients with type 2 diabetes
treated with lisinopril (mean dose 29 mg/day), verapamil (mean dose 360
mg/day), half-dose lisinopril plus verapamil, or hydrochlorothiazide plus
guanfacine (which has a mechanism of action similar to methyldopa). The last
regimen had little or no antiproteinuric effect while the fall in protein excretion
with the lisinopril-verapamil combination (75 percent) was additive to the action
of either drug alone (roughly 50 percent).
Data from: Bakris GL, Barnhill BW, Sadler R. Kidney Int 1992; 41:912.
Superior antiproteinuric effect with combination

antihypertensive therapy
Changes in protein excretion over a one-year period in patients with type 2 diabetes
mellitus randomly assigned to verapamil SR, trandolapril, or combination. Protein
excretion was significantly less at nine and 12 months in the combination therapy group,
as compared with either of the single-drug groups.
Data from: Bakris GL, Weir MR, DeQuattro V, et al. Kidney Int 1998; 54:1283.
ACE inhibitor and calcium blocker therapy protect

against progressive glomerulosclerosis in rats by
different mechanisms
Beneficial effect of antihypertensive therapy with the calcium channel blocker

nifedipine and the angiotensin-converting enzyme inhibitor enalapril in rats with
subtotal nephrectomy. At eight weeks, both drugs lowered the blood pressure to
an equivalent degree and were associated with better maintenance of the
glomerular filtration rate (GFR) and a lesser degree of glomerulosclerosis than
untreated rats. However, the mechanism of protection appeared to be different:
enalapril lowered the glomerular capillary pressure (PGC), while nifedipine
minimized glomerular hypertrophy as manifested by a reduction in glomerular
volume.
Data from: Dworkin LD, Burstein JA, Parker M, et al. Kidney Int 1993; 43:808.
Treatment goals in the Steno type 2 diabetes study
Standard Intensive
Systolic blood pressure (mmHg) <160 <140
Diastolic blood pressure (mmHg) <95 <85
HbA1c (percent) <7.5 <6.5
Serum triglycerides (mg/dL) <194 <150
Serum total cholesterol (mg/dL) <250 <193
Serum HDL cholesterol (mg/dL) >35 >42
ACE inhibitor therapy independent of blood pressure No Yes
Aspirin therapy in patients with known ischemia Yes Yes
Aspirin therapy in patients with peripheral vascular disease No Yes
To convert serum triglyceride values to mmol/L multiply by 0.011, and to convert serum cholesterol values to
mmol/L multiply by 0.026.
Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus
and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353:617.
Average number of antihypertensive agents needed per

patient to achieve target systolic BP goals
Updated from: Bakris GL. Preserving renal function in adults with hypertension and
diabetes: A consensus approach. Am J Kidney Dis 2000; 36:646.
Aggressive BP control preserves renal function in

proteinuric patients
Mean fall in glomerular filtration rate (GFR) according to the degree of

proteinuria in patients treated with usual BP control (mean BP about 130/80
mmHg) or with more aggressive antihypertensive therapy in which the mean BP
was 4.7 mmHg lower over a three-year period. The rate of fall in GFR varied
directly with protein excretion, and the benefit of aggressive BP control was
absent in the 420 patients excreting less than 1 g/day, modest in the 104
patients excreting between 1 and 3 g/day, and substantial (3.5 mL/min/year
slower) and statistically significant in the 54 patients excreting at least 3 g/day.
BP: blood pressure.
Data from: Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction
and blood-pressure control on the progression of chronic renal disease. Modification
of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:877.
Contributor Disclosures
George L Bakris, MD Grant/Research/Clinical Trial Support: Bayer; Relypsa; Vascular Dynamics, Janssen
[Diabetic neuropathy, diabetes, hypertension (Empagliflozin, patiromer)]. Consultant/Advisory Boards:
AstraZeneca; Bayer; Relypsa; Vascular Dynamics; Merck [Nephropathy, diabetes, hypertension
(Empagliflozin, patiromer). Richard J Glassock, MD, MACP Speaker's Bureau: Genentech [Vasculitis
(Rituximab)]. Consultant/Advisory Boards: Bristol-Myers Squibb [Lupus Nephritis, Focal Segmental
Glomerulosclerosis (Abatacept)]; ChemoCentryx [Vasculitis, C3 Glomerulopathy, Focal Segmental
Glomerulosclerosis (CCX-168, CCX-140)]; Retrophin [Focal Segmental Glomerulosclerosis (Sparsentan)];
Omeros [IgA Nephropathy]; Ionis [C3 Glomerulopathy]; Apellis [Complement Inhibition on Glomerular
Disease]. Employment: American Society of Nephrology [Nephrology Self-Assessment Program]; Karger
Publishers [American Journal of Nephrology]. Equity Ownership/Stock Options: Reata [Alport Syndrome,
Pulmonary Hypertension, Diabetic Nephropathy (Bardoxolone)]. David M Nathan, MD Research Support:
Abbott [Diabetes (point-of-care A1C assay)]. John P Forman, MD, MSc Nothing to disclose
Las revelaciones del colaborador son revisadas por conflictos de interés por el grupo editorial. Cuando se
encuentran, estos se abordan examinando un proceso de revisión multinivel y los requisitos para que se
proporcionen referencias que respalden el contenido. El contenido apropiadamente referenciado es
requerido por todos los autores y debe cumplir con los estándares de evidencia UpToDate.
Política de conflicto de intereses.

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4/12/2018 Treatment of diabetic nephropathy - UpToDate

Reimpresión oficial de UpToDate ®

Tratamiento de la nefropatía diabética.

Autor: George L Bakris, MD

INTRODUCCIÓN - La nefropatía diabética, definida clásicamente por la presencia de proteinuria

La manifestación clínica más temprana de compromiso renal en la diabetes es un aumento en la excreción

La proteinuria en la diabetes mellitus se debe ocasionalmente a una enfermedad glomerular distinta de la

● Puede retardar la progresión de la disminución de la tasa de filtración glomerular (GFR) [ 13 ].

volumen mesangial y el volumen de la matriz mesangial disminuyeron significativamente en

atrofia tubular parecía mejorada, posiblemente debido a la reabsorción de nefronas enfermas.

INHIBICIÓN DE ANGIOTENSINA PARA LA PREVENCIÓN PRIMARIA - Además de su eficacia en

FUNCIÓN DE OTROS FACTORES : además de la hiperglucemia, otros factores contribuyen a la lesión

de la angiotensina [ACE] o el bloqueador del receptor de la angiotensina [ARB]), o la estenosis concurrente

La eficacia de la presión arterial y la reducción de la proteinuria en pacientes con nefropatía diabética es

Inhibidores de la ECA : el beneficio de la terapia antihipertensiva con un inhibidor de la ECA en la

La respuesta beneficiosa al captopril , que se observó en sujetos hipertensos y normotensos, es consistente

● A significant decrease in mean blood pressure (5.6/2.2 mmHg)

Sodium-glucose cotransporter 2 inhibitors — The use of sodium-glucose cotransporter 2 (SGLT-2)

● Bardoxolone methyl therapy (see 'Bardoxolone methyl' below)

● Pentoxifylline (see 'Pentoxifylline therapy' below)

Pentoxifylline therapy — Pentoxifylline is a nonspecific phosphodiesterase inhibitor and putative anti-

In addition to a possible reduction in intraglomerular pressure, nondihydropyridine calcium channel blockers

Therapies of uncertain efficacy

Pentoxifylline — Pentoxifylline is a nonspecific phosphodiesterase inhibitor and putative anti-

HYPERLIPIDEMIA — Hyperlipidemia is common in diabetic patients, a tendency that is increased by the

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Topic 3052 Version 41.0

Strict glycemic control prevents moderately increased

Cumulative incidence of moderately increased albuminuria (formerly called

Graphic 73143 Version 7.0

Reversal of diabetic nephropathy after pancreas

Graphic 67651 Version 3.0

Unilateral diabetic glomerulosclerosis

Light micrographs from a postmortem examination of a diabetic patient with

Courtesy of Helmut Rennke, MD.

Graphic 64632 Version 1.0

ACE inhibitor is more effective than triple therapy in

Efficacy of antihypertensive therapy in diabetic rats in reducing the number of

Graphic 53771 Version 2.0

Captopril delays progression of moderately increased

Effect of captopril or placebo in 225 patients with type 1 diabetes mellitus,

AER: albumin excretion rate.

Graphic 80409 Version 6.0

ACE inhibitor slows progression of diabetic nephropathy

The effect of the administration of placebo or captopril to patients with type 1

ACE: angiotensin-converting enzyme; Pcr: plasma creatinine concentration.

Graphic 60878 Version 4.0

Lower systolic blood pressure (BP) is associated with

Graphic 77963 Version 4.0

Irbesartan slows progression of nephropathy in type 2

Effect of irbesartan, amlodipine, and placebo on the course of hypertensive patients

Graphic 80116 Version 2.0

Graph showing effect of dietary protein restriction on

Graphic 50017 Version 3.0

Antihypertensive drugs and urinary protein excretion in

Protein excretion at baseline (black columns) and after one year of

Graphic 57267 Version 2.0

Superior antiproteinuric effect with combination

Graphic 69411 Version 2.0

ACE inhibitor and calcium blocker therapy protect

Beneficial effect of antihypertensive therapy with the calcium channel blocker

Graphic 72717 Version 2.0

Treatment goals in the Steno type 2 diabetes study

Systolic blood pressure (mmHg) <160 <140