Maximum doses of renin-angiotensin axis blockers in diabetic nephropathy?

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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "20" "paginaFinal" => "21" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Nicolás Roberto Robles Pérez-Monteoliva, José Carlos Arévalo Lorido" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Nicolás Roberto" "apellidos" => "Robles Pérez-Monteoliva" "email" => array:1 [ 0 => "nrrobles@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "José Carlos" "apellidos" => "Arévalo Lorido" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Hipertensión Arterial, Servicio de Nefrología, Hospital Universitario de Badajoz, Universidad de Extremadura, Badajoz, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medicina Interna, Hospital de Zafra, Zafra, Badajoz, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Dosis máximas de bloqueantes del eje renina-angiotensina en nefropatía diabética?" ] ] "textoCompleto" => "Kidney disease is an especially common pathological process among patients with diabetes mellitus. The classical form of diabetic nephropathy remains the leading cause of renal replacement therapy worldwide and the atypical or non-proteinuric diabetic nephropathy is probably the leading cause of mild-moderate renal failure in the world.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>In diabetic kidney disease, albuminuria is a poor prognostic sign, especially when it reaches the macroalbuminuria range (>300 mg/day or mg/g). However, mild elevations in urinary albumin excretion (between 30 and 300 mg/day or mg/g) already indicate a risk of progression to chronic renal failure in the long term.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> For the treatment of proteinuria, drugs that block the renin-angiotensin-aldosterone system have been indicated for years, such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and, with much less use, direct renin inhibitors. It is therefore not surprising that the recently published KDIGO Guidelines (Kidney Disease: Improving Global Outcomes) on the management of diabetes in chronic kidney disease<a class="elsevierStyleCrossRef" href="#bib0015">3</a> recommend the use of this class of drugs in the treatment of patients with diabetes, hypertension, and increased albuminuria. So far, this recommendation seems more than reasonable. The problem appears when the full recommendation is read: “We recommend that treatment with an ACEI or an ARB be initiated in patients with diabetes, hypertension and albuminuria, and that these medications should be titrated to the highest approved dose that is well tolerated”.Here is the first question: What is the maximum applicable dose of these drugs? In general, ACEIs and ARBs have few side effects -the most specific is cough with ACEIs, which is bothersome but not dangerous- and therefore they have a wide range of doses. In fact, the guidelines include a dosage table whose maximums are rarely used in Spain (e.g., 80 mg/day of fosinopril, 450 mg/day of captopril or 20 mg/day of ramipril). From a clinical point of view, such doses might be indicated in patients with proteinuria in the nephrotic range in the absence of aetiological treatment, but their use in other types of patients, particularly those with microalbuminuria or mild proteinuria, seems excessive from the outset.Firstly, the higher the dose of these drugs, which are essentially antihypertensives, the greater the reduction in blood pressure in the patient receiving them. Although the J-curve has never ceased to be controversial,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> numerous studies point to its presence particularly in patients with kidney disease. In fact, the latest edition of the European Guidelines for the management of arterial hypertension sets a higher goal for the reduction of blood pressure in patients with chronic kidney disease (it should not be reduced below 130/70 mmHg).<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The reasons for this decision are clearly documented.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> Moreover, probably reflecting the current dissent in clinical guidelines on hypertension on both sides of the Atlantic, the KDIGO guidelines for the management of diabetes in chronic kidney disease do not indicate what the treatment thresholds and targets should be in these patients.On the other hand, these patients, based on these KDIGO guidelines and other similar ones, will be treated with drugs that can be associated with the onset -generally with a primary triggering cause, such as gastroenteritis or heart failure among others- of acute renal failure, such as metformin.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> On the other hand, it has been pointed out that Na-glucose transporter inhibitors produce a reduction in glomerular filtration similar to that which occurs when treatment with ACEIs or ARBs is initiated.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Consequently, a very high dose of drugs blocking the renin-angiotensin-aldosterone system, associated with the above-mentioned medications, may be the pathway to acute renal failure which may even be unrecoverable or have an incomplete recovery. Multiple observational studies have demonstrated the relationship between acute renal failure and the development of chronic renal failure and cardiovascular morbidity and mortality, even in patients who recovered from renal failure, even more so when partial or complete recovery did not occur.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Not to mention that hypotension is, “per se”, a common cause of mild impairment of renal function.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>This would also be related to another important problem, namely, falls in elderly patients. These are often associated with low blood pressure and result in both increased mortality and extremely high economic costs (falls are the fifth leading cause of health care expenditure in the United States, second only to ischaemic heart disease).<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a>On the other hand, as in the same KDIGO Guidelines on the treatment of diabetes in chronic kidney disease, the therapeutic targets are limited with regard to the reduction of blood glucose in elderly patients; the same can be said of the reduction goals for albuminuria. According to classical studies in type 1 diabetics, microalbuminuria takes about ten years to transform into proteinuria and/or kidney failure<a class="elsevierStyleCrossRef" href="#bib0070">14</a>: Is it worth treating a patient over 80 years of age and with a limited life expectancy with maximum doses of ACEIs or ARBs to prevent the onset of kidney disease?An important point to consider is the risk of causing an atypical diabetic nephropathy. According to some studies, treatment with renin-angiotensin aldosterone system blockers reverses hyperfiltration-induced glomerular hypertrophy that occurs in patients with diabetes, however, the juxtaglomerular interstitial hypertrophy is not reduced despite treatment and it is thought that ischaemia in this area may be the cause of renal failure without proteinuria that can be found in a higher percentage of diabetics compared to typical diabetic nephropathy. Assuming this hypothesis is true, treatment with high doses of ACEIs or ARBs would not be beneficial in the long term for patients with diabetes.<a class="elsevierStyleCrossRefs" href="#bib0005">1,15</a>On the other hand, the evidence rating system used in the KDIGO Guidelines for the management of diabetes in chronic kidney disease should not be disregarded. As in previous guidelines, the “GRADE” system has been used but with plenty of “suggestions” (called in the document Practice Points) when the accumulated evidence on the subject is small. The problem with these is that the recommendation is based on the fact that clinicians agree that “most patients should receive the recommended treatment” and that “the true effect is likely to be close to the estimate but there is a possibility that it is substantially different”.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Unfortunately, in the more classical US Agency for Health Care Policy and Research Guidelines, this would be level IV evidence: “evidence obtained from expert committee reports or opinions or clinical experience of respected authorities”.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> It is true that it is generally difficult to find evidence in kidney patients who are often excluded in many cases from clinical trials due to their own condition, but this is not applicable to albuminuria where there is extensive and robust evidence of the use of renin-angiotensin-aldosterone system blockers in patients with diabetes and hypertensive patients with increased albumin excretion.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Treatment with renin-angiotensin-aldosterone system blockers has been shown to reduce and even reverse albuminuria in patients with hypertensive diabetes and is therefore an essential tool in the prevention and treatment of this disorder. However, doses should be adjusted according to the intensity of albuminuria, the patient’s blood pressure, age, and tolerance to previous treatment.Conflict of interestsThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Robles Pérez-Monteoliva NR, Arévalo Lorido JC. ¿Dosis máximas de bloqueantes del eje renina-angiotensina en nefropatía diabética? Med Clin (Barc). 2021;157:20–21." ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Non-proteinuric diabetic nephropathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N.R. Robles" 1 => "J. Villa" 2 => "R.H. 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