The renin-angiotensin-aldosterone system (RAAS) is an enzymatic cascade functioning in a paracrine and autocrine fashion. In animals and humans, RAAS intrinsic to tissues modulates food intake, metabolic rate, adiposity, insulin sensitivity, and insulin secretion. A large array of observations shows that dysregulation of RAAS in the metabolic syndrome favors type 2 diabetes. Remarkably, angiotensin-converting enzyme inhibitors, suppressing the synthesis of angiotensin II (ANG II), and angiotensin receptor blockers, targeting the ANG II type 1 receptor, prevent diabetes in patients with hypertensive or ischemic cardiopathy. These drugs interrupt the negative feedback loop of ANG II on the RAAS cascade, which results in increased production of angiotensins. In addition, they change the tissue expression of RAAS components. Therefore, the concept of a dual axis of RAAS regarding glucose homeostasis has emerged. The RAAS deleterious axis increases the production of inflammatory cytokines and raises oxidative stress, exacerbating the insulin resistance and decreasing insulin secretion. The beneficial axis promotes adipogenesis, blocks the production of inflammatory cytokines, and lowers oxidative stress, thereby improving insulin sensitivity and secretion. Currently, drugs targeting RAAS are not given for the purpose of preventing diabetes in humans. However, we anticipate that in the near future the discovery of novel means to modulate the RAAS beneficial axis will result in a decisive therapeutic breakthrough.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics may exert synergistic antiproteinuric effects. Eighteen patients with a proteinuria >1 g/24 h after 6 mo of treatment with ramipril at 5 mg/d were assigned to receive in random order ramipril at 10 mg/d, valsartan at 160 mg/d, or combined ramipril at 5 mg/d and valsartan at 80 mg/d in addition to their antihypertensive treatment. The treatment periods lasted 4 wk and were separated by a 4-wk washout with ramipril at 5 mg/d. At the end of this crossover sequence, patients received combined ramipril at 5 mg/d, valsartan at 80 mg/d, and an increased furosemide dosage for an additional 4-wk period. The primary end point was the urinary protein/creatinine ratio for two 24-h urine collections at the end of each treatment period. No significant differences were noted between the study end points of the ramipril 10, valsartan 160, and combined ramipril 5 and valsartan 80 treatment groups. However, the urinary protein/creatinine ratio was lower with combined ramipril 5 and valsartan 80–increased furosemide dosage than with valsartan 160 and combined ramipril 5 and valsartan 80, with a similar tendency compared with ramipril 10. Combined ramipril 5 and valsartan 80–increased furosemide dosage decreased systolic home BP and increased serum creatinine but did not significantly increase the number of symptomatic hypotension cases compared with the other three treatments. Thus, in patients with severe proteinuria and hypertension, a cautious increase in diuretic dosage in addition to combined angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decreases proteinuria and BP but may expose the patient to prerenal failure.

The predictive value of anti-M-type phospholipase A2 receptor (PLA2R1) autoantibodies for membranous nephropathy (MN) recurrence after renal transplantation remains controversial. Our aim was to monitor anti-PLA2R1 IgG4 activity using a sensitive enzyme-linked immunosorbent assay in 15 kidney transplant recipients with MN, and to test the correlation between antibody titres and MN recurrence. Five patients never exhibited anti-PLA2R1 antibodies, and one of them relapsed. Ten patients (67%) had IgG4 anti-PLA2R1 antibodies at the time of transplantation and during follow-up. The presence of IgG4 anti-PLA2R1 antibodies at the time of kidney transplantation does not imply MN recurrence (P = 0.600, n = 15). However, a positive IgG4 anti-PLA2R1 activity during follow-up (>Month 6) was a significant risk factor for MN relapse (P = 0.0048, n = 10). Indeed, four patients had persistent IgG4 anti-PLA2R1 activity after transplantation and relapsed. Among them, one was successfully treated with rituximab. Another had persistently high IgG4 anti-PLA2R1 activity and exhibited a histological relapse but no proteinuria while on treatment with renin-angiotensin system inhibitors. In contrast, the six other patients who did not relapse exhibited a decrease of their IgG4 anti-PLA2R1 activity following transplant immunosuppression, including two with proteinuria due to biopsy-proven differential diagnoses. A weak transplant immunosuppressive regimen was also a risk factor of MN recurrence (P = 0.0048, n = 10). Indeed, the six patients who received both an induction therapy and a combined treatment with calcineurin inhibitors/mycophenolate exhibited a decrease of IgG4 anti-PLA2R1 activity and did not relapse, while the four patients who did not receive this strong immunosuppressive treatment association had persistently high IgG4 anti-PLA2R1 activity and relapsed. The monitoring of IgG4 anti-PLA2R1 titres during follow-up helps to predict MN recurrence, and a strong immunosuppressive treatment of anti-PLA2R1 positive patients may prevent recurrence.

The COVID-19 pandemic is the major health crisis of our time. It bears the potential to create devastating social, economic, and political consequences in all the countries it touches. At the same time, it represents a great challenge for the entire scientific community. Indeed, the latter is currently making extraordinary efforts to increase knowledge on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), and so helps in containing the pandemic and hopefully in eradicating it. The renin-angiotensin-aldosterone system (RAAS) has recently been put on the forefront as the angiotensin-converting enzyme (ACE) 2 is targeted by SARS-CoV 2. In parallel, obesity appears as the main risk factor for severe forms of COVID-19. The RAAS and obesity are closely related, leading to the aggravation of the disease. Here, we focus on the endogenous imbalance of RAAS in obesity.