letter to the editor

subjects, GLP-1 has no effect on GFR, suggesting a mechanism that may be dependent on the baseline filtration rate.4 To conclude, incretin-based therapies may reduce renal risk by targeting glomerular hypertension/hyperfiltration in patients with diabetes and increased baseline GFR. Longterm trials are, however, needed to further explore whether these and other potential ‘off-target’ effects of incretin-based therapies result in meaningful renoprotection.

progression. Indeed, incretin-based drugs ameliorated AKI via anti-apoptotic, anti-inflammatory, and anti-oxidative effects. Therefore, we consider that incretin-based therapy might have the potential to ameliorate DKD via additional mechanisms beyond glomerular hemodynamics. Further studies are needed to understand the underlying mechanisms of incretin-based therapy against DKD in humans. 1.

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Tanaka T, Higashijima Y, Wada T et al. The potential for renoprotection with incretin-based drugs. Kidney Int 2014; 86: 701–711. Muskiet MH, Smits MM, Morsink LM et al. The gut-renal axis: do incretinbased agents confer renoprotection in diabetes? Nat Rev Nephrol 2014; 10: 88–103. Gutzwiller JP, Tschopp S, Bock A et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004; 89: 3055–3061. Skov J, Dejgaard A, Frkiær J et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J Clin Endocrinol Metab 2013; 98: E664–E671.

Lennart Tonneijck1, Mark M. Smits1, Danie¨l H van Raalte1 and Marcel H.A. Muskiet1 1 Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands Correspondence: Lennart Tonneijck, Diabetes Center, Department of Internal Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail: [email protected]

Kidney International (2015) 87, 660–661; doi:10.1038/ki.2014.398

The Authors Reply: We thank Tonneijck et al.1 for their interest in our recent paper2 and agree to their view that renoprotection by incretin-based therapy may be associated with a reduction in glomerular hypertension/hyperfiltration. Glomerular hyperfiltration is an early manifestation in diabetic kidney disease (DKD). Given that the clinical improvement in albuminuria appears, in selected patients, several weeks after the first administration of incretin-based drugs, it is expected that the plastic, not structural, changes, such as hemodynamic factors, might be involved. Indeed, a double-blind, placebo-controlled, crossover study demonstrated that glucagon-like peptide-1 (GLP-1) reduced glomerular hyperfiltration in obese subjects.3 Alterations in glomerular hemodynamics may be mediated by multiple factors. Incretin-based therapy facilitates natriuresis in the salt-sensitive population, which increases the amount of luminal fluid that reaches macula densa, thus leading to afferent arteriolar constriction. Incretins may also mediate vasodilation and improve endothelial dysfunction via its direct action on vascular endothelium. Importantly, a recent in situ hybridization study demonstrated predominant expression of GLP-1 receptor in vascular endothelium in the mouse kidney.4 Incretin-based therapy also exhibits reno-protective effects against rodent acute kidney injury (AKI) models, such as cisplatin-induced nephrotoxicity and ischemia–reperfusion injury.5–6 In these models, glomerular hypertension/ hyperfiltration is not a major determinant of disease Kidney International (2015) 87, 660–664

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Tonneijck L, Smits M, van Raalte D et al. Incretion-based drugs and renoprotection—is hyperfiltration key. Kidney Int 2015; 87: 660–661. Tanaka T, Higashijima Y, Wada T et al. The potential for renoprotection with incretin-based drugs. Kidney Int 2014; 86: 701–711. Gutzwiller JP, Tschopp S, Bock A et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004; 89: 3055–3061. Fujita H, Morii T, Fujishima H et al. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int 2014; 85: 579–589. Glorie LL, Verhulst A, Matheeussen V et al. DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2012; 303: F681–F688. Katagiri D, Hamasaki Y, Doi K et al. Protection of glucagon-like peptide-1 in cisplatin-induced renal injury elucidates gut-kidney connection. J Am Soc Nephrol 2013; 24: 2034–2043.

Yoshiki Higashijima1, Tetsuhiro Tanaka1 and Masaomi Nangaku1 1 Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan Correspondence: Masaomi Nangaku, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113 8655, Japan. E-mail: [email protected]

Kidney International (2015) 87, 661; doi:10.1038/ki.2014.410

Validation of the Oxford classification of IgA nephropathy: valid or invalid? To the Editor: Coppo et al.1 assess the validity of the Oxford classification of IgA nephropathy by evaluating what they call the predictive value of renal pathology variables on the rate of renal function decline and renal survival. What they appear to be doing, however, is reporting the ability of the said variables to ‘explain’ the observed outcomes in the samples generating the model. When the authors state that they validated the multivariate models from the original Oxford classification study, does that mean that the identified models were used on patients not generating the models? The variability in a predictive model is likely to be greater than in an explanatory model and the form different,2 was that the case? Trying to understand what has then in fact been ‘explained’ is not easy. In Table 4 is presented the results of ‘prediction’ of rapid progression versus observed rapid progression. For those not on immunosuppression therapy and using both clinical and pathological variables, a positive predictive value (PPV) of 0.77 and a negative predictive value (NPV) of 0.65 can be calculated compared with 0.63 for both PPV and NPV for those on immunosuppression. This is 661

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