Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Renal thrombotic microangiopathy revisited: When a lesion is not a clinical finding

Despite advances in the field of thrombotic microangiopathy (TMA) and associated syndromes such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), they still leave several issues unresolved. For instance, actual diagnostic criteria on which therapeutic decisions rely are relatively narrow and focused on TTP-HUS, with the consequence that non-idiopathic and atypically-presenting TMA are overlooked. In addition, nosologic classifi-cations of TMA disorders have varied substantially over the years, but are still devised from historical rather than mechanistic data. As such, it is perhaps not surprising that even today TMA is erroneously used as an interchangeable term with TTP-HUS, and missed or inappropriately diagnosed on various occasions. Yet, recognizing TMA is of crucial importance given that this lesion often manifests with potentially reversible renal failure. In this editorial, which is presented from a Nephrologist′s perspective, we propose that TMA disorders need to be reclassified to include most types of presentations and confirmed or excluded through more elaborate diagnostic approaches

Effectiveness of Haemodiafiltration with Heat Sterilized High-Flux Polyphenylene HF Dialyzer in Reducing Free Light Chains in Patients with Myeloma Cast Nephropathy

<div><p>Introduction</p><p>In cases of myeloma cast nephropathy in need of haemodialysis (HD), reduction of free light chains using HD with High-Cut-Off filters (HCO-HD), in combination with chemotherapy, may be associated with better renal recovery. The aim of the present study is to evaluate the effectiveness of haemodiafiltration (HDF) in reducing free light chain levels using a less expensive heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF).</p><p>Methods</p><p>In a single-centre prospective cohort study, 327 dialysis sessions were performed using a 2.2 m² heat sterilized high-flux polyphenylene HF dialyzer (Phylther HF22SD), a small (1.1m²) or large (2.1 m²) high-cut-off (HCO) dialyzer (HCO_S and HCO_L) in a cohort of 16 patients presenting with dialysis-dependent acute cast nephropathy and elevated free light chains (10 kappa, 6 lambda). The outcomes of the study were the mean reduction ratio (RR) of kappa and lambda, the proportion of treatments with an RR of at least 0.65, albumin loss and the description of patient outcomes. Statistical analysis was performed using linear and logistic regression through generalized estimating equation analysis so as to take into account repeated observation within subjects and adjust for session duration.</p><p>Results</p><p>There were no significant differences in the estimated marginal mean of kappa RR, which were respectively 0.67, 0.69 and 0.70 with HCO_L-HD, HCO_S-HDF and HF-HDF (P = 0.950). The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCO_L-HD, HCO_S-HDF and HF-HDF, respectively (P = 0.913). The estimated marginal mean of lambda RR were higher with HCO_L-HDF (0.78), compared to HCO_L-HD and HF-HDF (0.62, and 0.61 respectively). The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCO_L-HDF (81%), compared to 57% in HF-HDF (P = 0.042). The median albumin loss were 7, 21 and 63 g/session with HF-HDF, HCO_L-HD and HCO_L-HDF respectively (P = 0.044). Among survivors, 9 out of 10 episodes of acute kidney injuries became dialysis-independent following a median time of renal replacement therapy of 40 days (range 7–181).</p><p>Conclusion</p><p>Therefore, in patients with acute dialysis-dependent myeloma cast nephropathy, in addition to chemotherapy, HDF with a heat sterilized high-flux polyphenylene HF dialyzer could offer an alternative to HCO dialysis for extracorporeal kappa reduction with lower albumin loss.</p></div

Impact of haemodiafiltration method of free light chain reduction ratio.

<p>The impact of haemodiafiltration (HDF) in predilution (Pre), low-efficiency post-dilution (<15L post), and high-efficiency post-dilution (>15L post) are performed using large (2.1 m²) high cut-off filters (HCO_L), small (1.1 m²) high cut-off filters (HCO_S), and the 2.2 m² heat sterilized high-flux polyphenylene HF (HF). The estimated marginal means of kappa (A) and lambda (B) light chain reduction ratio taking into account repeated measures and duration of each treatment session. P-values reported are adjusted for multiple comparisons using the Bonferroni correction method.* indicates that values are statistically different from other groups (P<0.01), ** indicates that values are statistically not different compared to other groups.</p

Clinical and biochemical characteristics.

<p>CN: Myeloma Cast Nephropathy;LCDD: Light Chain Deposition Disease; MM: Multiple Myeloma; AKI: acute kidney injury. Values are mean ±SD or median (range)</p><p>* 1 subject had two distinct episodes of AKI</p><p>One patient received bortezomid- and Revlimid-based regimen. Another patient with two episodes of AKI received Bortezomib and Revlimid respectively for the first and second episode.</p><p>Clinical and biochemical characteristics.</p

Reduction ratio of molecules of increasing molecular weights.

<p>The figure shows the reduction ratio (RR) of creatinine (113 Da), β-2 microglobulin (β2M, 11.8kDa), kappa (22.5 kDa) and lambda (45 kDa) free light chains, using haemodiafiltration with heat sterilized high-flux polyphenylene HF (HF-HDF), compared to haemodialysis or haemodiafiltration with a large (2.1 m²) high-cut-off dialyzer (HCO_L). Estimates are obtained by generalized estimating equation taking into account repeated measures and session duration. * indicates a P-value of <0.05.</p

Dialyzers characteristics and performance.

<p>*Heat sterilized</p><p>PAES: polyarylethersulfone; PVP: polyvinylpyrrolidone.</p><p>Dialyzers characteristics and performance.</p

Kappa free light chain reduction ratio per patient and treatment protocol.

<p>Values are mean±SD</p><p>RRT: Renal replacement therapy;HF-HDF: Haemodiafiltration with heat sterilized Polyphenylene HF of 2.2 m²; HCOs-HDF: Haemodiafiltration with high cut-off small surface area membrane (1.1 m²); HCO_L-HD: Hemodialysis with high cut-off large surface area membrane (2.1 m²).</p><p>Kappa free light chain reduction ratio per patient and treatment protocol.</p

Lambda free light chain reduction ratio per patient and treatment protocol.

<p>Values are mean±SD</p><p>RRT: Renal replacement therapy;HF-HDF: Haemodiafiltration with heat sterilized Polyphenylene HF of 2.2 m²; HCO_L-HDF: Haemodiafiltration with high cut-off large surface area membrane (2.1 m²); HCO_L-HD: Hemodialysis with high cut-off large surface area membrane (2.1 m²).</p><p>Lambda free light chain reduction ratio per patient and treatment protocol.</p