Recent years have seen the emergence of sodium-glucose co-transporter type 2 (SGLT2)
inhibitors, also known as gliflozins, which represent a real therapeutic innovation in
the management of type 2 diabetes, heart failure and chronic kidney disease.
The prevalence of chronic kidney disease is rising steadily and represents a major public
health challenge. Hypertension and proteinuria are two factors strongly associated with
the progression of chronic kidney disease (CKD) and the high risk of cardiovascular
complications. Achieving blood pressure control and reducing proteinuria is therefore a
major objective in the management of chronic renal failure. Until recently, inhibitors of
the renin-angiotensin-aldosterone system were the only therapeutic class known to have
both anti-proteinuric and anti-hypertensive action, reducing the risk of progression to
end-stage renal disease.
Several large international studies, initially investigating the efficacy of SGLT2
inhibitors as anti-diabetic therapy, reported that this new therapeutic class reduced the
risk of cardiovascular complications and end-stage renal disease. This nephroprotective
and cardioprotective effect was independent of the anti-diabetic effect of the drug. The
nephroprotective effect is explained in particular by a decrease in proteinuria via a
reduction in glomerular hyperfiltration, and a reduction in intraglomerular pressure via
vasoconstriction of the afferent artery in response to the blockade of glucose and sodium
reabsorption in the proximal convoluted tubule.
An international study (Dapagliflozin and Prevention of Adverse Outcomes in Chronic
Kidney Disease study) was specifically designed to investigate the nephroprotective
effect of dapagliflozin in both diabetic and non-diabetic proteinuric CKD patients. This
study, which included 4,300 patients with glomerular filtration rate (GFR) between 25 and
75ml/min/1.73m2 and an albuminuria/creatinuria ratio between 200 and 5,000mg/g, confirmed
a significant reduction in proteinuria, a lower risk of progression to end-stage CKD and
a lower mortality rate in patients treated with dapagliflozin compared with those who
received placebo. Following this study, Dapagliflozin was granted marketing authorization
in France in October 2021 for any patient with chronic kidney disease, in patients with a
GFR between 25 and 75ml/min/1.73m2 and an albuminuria/creatinuria ratio between 200 and
5000mg/g despite treatment with converting enzyme inhibitor/Angiotensin II receptor
antagonists for at least 4 weeks. Renal transplantation is not a contraindication to the
use of dapagliflozin, so renal transplant patients meeting these same criteria may
receive dapagliflozin as nephroprotective therapy. However, few data are currently
available on the evolution of proteinuria and GFR in this population.
After renal transplantation, proteinuria is also a major factor associated with impaired
graft function and cardiovascular risk. However, transplant patients have specific
characteristics compared with non-transplant CKD patients: by definition, they have a
single functional kidney and receive immunosuppressive treatments that modify renal
hemodynamics, including calcineurin inhibitors, drugs that also have a vasoconstrictive
effect. In addition, a moderate increase in the risk of urinary tract infection and
genital mycotic infection has been reported with the use of gliflozins, necessitating
careful monitoring of the incidence of these side effects in this population.
The investigators have been progressively introducing the use of dapagliflozin as a
nephroprotective treatment in transplant patients meeting marketing authorisation
criteria (chronic renal failure with GFR between 25-75ml/min/1.73m2,
albuminuria/creatinuria ratio 200-5000mg/g despite treatment with converting enzyme
inhibitors and Angiotensin II receptor antagonists for at least 4 weeks) within the
nephrology department of Montpellier University Hospital for several months. To date,
more than 30 transplant patients have been treated with dapagliflozin (of whom 12 treated
patients have usable data and may be included retrospectively in this study). In this
recent experience, a very good safety profile was observed and no drug interactions were
identified. Although a reduction in early proteinuria was observed, the follow-up of
these patients is not yet long enough to carry out a preliminary analysis.
The investigators intend to conduct an observational study with the primary objective of
studying the evolution of proteinuria in kidney transplant patients treated with
dapagliflozin according to marketing authorization criteria. The secondary objectives of
the study are to investigate other expected benefits, including effects on renal function
and metabolic effects, as well as potential side-effects of this treatment in this
population.