Sacubitril/Valsartan treatment has differential effects in modulating diabetic kidney disease in db/db mice and KKAy mice when compared to valsartan treatment

Although renin-angiotensin blockade has shown the beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug sacubitril/valsartan (Sac/Val), a combination of angiotensin II receptor blocker valsartan and neprilysin inhibitor prodrug sacubitril, has been shown more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study we tested the effects of Sac/Val in the diabetic kidney disease. We administered Sac/Val or valsartan to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3-month treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Valsartan shared the similar improvement but to a lesser degree in some parameters compared to Sac/Val. Sac/Val but not valsartan decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on anti-oxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self DNA activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by Sac/Val or valsartan treatment. Present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease and its effectiveness could be better than valsartan alone.

A Nephrologist Perspective on Obesity: From Kidney Injury to Clinical Management

Obesity is one of the epidemics of our era. Its prevalence is higher than 30% in the U.S. and it is estimated to increase by 50% in 2030. Obesity is associated with a higher risk of all-cause mortality and it is known to be a cause of chronic kidney disease (CKD). Typically, obesity-related glomerulopathy (ORG) is ascribed to renal hemodynamic changes that lead to hyperfiltration, albuminuria and, finally, impairment in glomerular filtration rate due to glomerulosclerosis. Though not only hemodynamics are responsible for ORG: adipokines could cause local effects on mesangial and tubular cells and podocytes promoting maladaptive responses to hyperfiltration. Furthermore, hypertension and type 2 diabetes mellitus, two conditions generally associated with obesity, are both amplifiers of obesity injury in the renal parenchyma, as well as complications of overweight. As in the native kidney, obesity is also related to worse outcomes in kidney transplantation. Despite its impact in CKD and cardiovascular morbility and mortality, therapeutic strategies to fight against obesity-related CKD were limited for decades to renin-angiotensin blockade and bariatric surgery for patients who accomplished very restrictive criteria. Last years, different drugs have been approved or are under study for the treatment of obesity. Glucagon-like peptide-1 receptor agonists are promising in obesity-related CKD since they have shown benefits in terms of losing weight in obese patients, as well as preventing the onset of macroalbuminuria and slowing the decline of eGFR in type 2 diabetes. These new families of glucose-lowering drugs are a new frontier to be crossed by nephrologists to stop obesity-related CKD progression.

Continuous hypergammaglobulinemia and proteinuria after the recovery of the visceral Leishmaniasis: a case report

Background Kidney involvement of visceral Leishmaniasis is previously reported, but knowledge is limited. Hypergammaglobulinemia is common in visceral leishmaniasis patients. Whether hypergammaglobulinemia after leishmaniasis depletion can cause kidney injury is not well reported yet. Case presentation We reported a patient who recovered from visceral Leishmaniasis but showed persistent hypergammaglobulinemia and elevated urinary protein. Kidney biopsy showed glomerular hypertrophy with mild segmental mesangial proliferation without tubulointerstitial involvement in light microscopy. No immune complex deposit was found in the mesangial area by neither immunofluorescent staining nor electronic microscope. Increased lysosomes were observed in proximal tubules by electronic microscope. Valsartan was administered to decrease urinary protein, and no immune-suppressive therapy was added. The urinary protein and serum IgG level gradually dropped, and serum creatinine level remained stable during three- month follow up. Conclusions Hypergammaglobulinemia is unlikely to cause renal structural or functional damage in the short term. Angiotensin blockade significantly reduced urine protein, with a minor effect on IgG elimination.