TX Lupus Comentario

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3. van Bommel EJM, Muskiet MHA, van Baar MJB, et al. The renal Finally, we doubt the usefulness of studying sodium-
hemodynamic effects of the SGLT2 inhibitor dapagliflozin are
caused by post-glomerular vasodilatation rather than pre-glomerular
glucose cotransporter 2 inhibitors in isolated perfused kid-
vasoconstriction in metformin-treated patients with type 2 diabetes in neys. Studies have shown that sodium-glucose cotransporter
the randomized, double-blind RED trial. Kidney Int. 2020;97: 2 inhibitor’s effects on renal hemodynamics differ in people
202–212.
4. Wei J, Zhu J, Zhang J, et al. Aging impairs renal autoregulation in mice.
with type 14 and type 2 diabetes (Ott C, Kannenkeril D,
Hypertension. 2020;75:405–412. Jung S, Schnieder R. Combination therapy of empagliflozin
and linagliptin vs. metformin and insulin glargine on intra-
Marı́a José Soler1,2,3,4, Esteban Porrini1,5, and renal hemodynamics in type 2 diabetes [abstract SA-
Beatriz Fernandez-Fernandez1,6,7 and OR083]. Presented at ASN Kidney Week. November 9, 2019;
Alberto Ortiz1,6,7 Washington, D.C.),1 likely due to differences in baseline
1
Spanish Renal Research Network, Madrid, Spain; 2Nephrology Department, renal hemodynamic functions, age, comedication, and
Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, comorbidities of study participants. Thus, ongoing renal
Spain; 3Nephrology Research Group, Vall d’Hebron Research Institute, Bar-
celona, Spain; 4Grupo Español de Estudio de la Nefropatia Diabetica
outcome and mechanistic studies in larger populations of
(GEENDIAB), Barcelona, Spain; 5Instituto de Tecnologías Biomédicas, Hospital people with and without diabetes are more likely to advance
Universitario de Canarias, Universidad de La Laguna, Santa Cruz de Tenerife, the field.
Spain; 6Department of Nephrology and Hypertension, El Instituto de Inves-
tigación Sanitaria de la Fundación Jiménez Diaz Autónoma de Madrid, 1. van Bommel EJM, Muskiet MHA, van Baar MJB, et al. The renal
Madrid, Spain; and 7School of Medicine, Universidad Autónoma de Madrid, hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by
Madrid, Spain post-glomerular vasodilatation rather than pre-glomerular
vasoconstriction in metformin-treated patients with type 2 diabetes in the
Correspondence: Alberto Ortiz, El Instituto de Investigación Sanitaria de la randomized, double-blind RED trial. Kidney Int. 2020;97:202–212.
Fundación Jiménez Diaz, Avenida Reyes Católicos 2, Madrid, Madrid 28040, 2. Soler MJ, Porrini E, Fernandez-Fernandez B, Ortiz A. SGLT2i and
Spain. E-mail: aortiz@fjd.es postglomerular vasodilation. Kidney Int. 2020;97:805–806.
3. Gomez DM. Evaluation of renal resistances, with special reference to
Kidney International (2020) 97, 805–806; https://doi.org/10.1016/j.kint.2020.01.007 changes in essential hypertension. J Clin Invest. 1951;30:1143–1155.
Copyright ª 2020, International Society of Nephrology. Published by 4. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect
Elsevier Inc. All rights reserved. of sodium-glucose cotransporter 2 inhibition in patients with type 1
diabetes mellitus. Circulation. 2014;129:587–597.

Erik J.M. van Bommel1 and Daniël H. van Raalte1


1
Diabetes Center, Department of Internal Medicine, Amsterdam University
The authors reply: We thank Soler and colleagues Medical Centers, Location VU University Medical Center, Amsterdam, the
for their interest in our work.1 However, we Netherlands
respectfully disagree with their comments.2 Our Correspondence: Erik J.M. van Bommel, Amsterdam University Medical Centers,
trial was a mechanistic physiology study detailing Location VU University Medical Center, Boelelaan 1117, Amsterdam, Noord-
the renal hemodynamic actions of dapagliflozin and should Holland 1081 HZ, the Netherlands. E-mail: e.vanbommel@amsterdamumc.nl
be appreciated as such. The use of costly and burdensome Kidney International (2020) 97, 806; https://doi.org/10.1016/j.kint.2020.01.008
state-of-the-art methodologies limits study size and power. Copyright ª 2020, International Society of Nephrology. Published by
We clearly show that dapagliflozin reduces measured Elsevier Inc. All rights reserved.
glomerular filtration rate (mGFR) (highly significant for each
treatment phase within-group), while mGFR is unaffected by
gliclazide. Between-group testing also shows physiologically Discontinuation of therapy
meaningful mGFR reductions with dapagliflozin versus gli- in lupus nephritis
clazide (fasting 5 [ 12 to 1] ml/min; euglycemia 10 [ 21
to 1] ml/min; hyperglycemia 12 [ 20 to 4] ml/min), To the editor: Malvar et al.1 reported that histologic activity
although significance is only reached during the hyperglyce- is critical for deciding whether therapy may be discontinued
mic clamp. In line, treatment-phase was not an interaction in patients with lupus nephritis. They withdrew therapy if the
term. activity index was 0. Of 54 patients who interrupted immu-
Intrarenal hemodynamic responses estimated by the nosuppression, 6 developed flares during a mean follow-up of
Gomez equations3 have several limitations and should be 50 months at a flare rate of 1.44 flares/yr. However, decision
cautiously interpreted. We based our conclusion of based only on renal biopsy may be criticized. A score of 1 may
dapagliflozin-induced efferent arteriolar dilation on mGFR represent an innocent marker of an incomplete recovery,2
reductions in absence of changes in renal vascular resistance. while patients with complete histologic remission on renal
This was confirmed by consistent reductions in estimated biopsy may be clinically active.3 In our experience, we dis-
efferent arteriolar resistances. As gliclazide did not alter continued therapy in 52 patients with stable lupus nephritis
mGFR or effective renal plasma flow, potential changes in on the basis of normal serum creatinine concentration,
estimated intrarenal hemodynamic are physiologically not proteinuria #0.5 g/24 h, inactive urine sediment, and no
relevant. Given the within-group results, stating that dapa- clinical signs of lupus activity for 12 months. After a mean
gliflozin does not alter renal hemodynamics compared with follow-up of 286 months, 20 patients developed flares at a
gliclazide would be a type 2 error. flare rate of 0.8 flares/yr. They had shorter treatment and

806 Kidney International (2020) 97, 805–807


letters to the editor

duration of remission before therapy discontinuation than patients (29%) had at least 1 LN flare. We found a similar
did 32 patients without flares. At the last visit, in patients with incidence (31%) of LN flare when immunosuppression was
flares the mean serum creatinine concentration was 0.9 mg/dl discontinued on clinical grounds alone4; however, if kidney
and mean proteinuria was 0.13 g/d. Two patients doubled histology showing no residual immunologic activity was
their serum creatinine, and 2 patients died. Compared with incorporated into the withdrawal decision, the incidence of
109 patients who continued immunosuppression, patients LN flare fell to 9%.2 The key issue is whether it is important
who flared had a significantly lower risk of chronic renal to avoid LN flares. There is abundant evidence in ethnically
insufficiency, end-stage renal disease, hypertension, and diverse populations with LN that LN flares predispose to
cardiovascular events.4 chronic and end-stage kidney disease.5 Counterintuitively,
In lupus nephritis, therapy can be discontinued on the patients in the Ponticelli and Moroni study who flared did
basis of clinical data. In spite of flares, patients who discon- well over a follow-up of 25 years and did not develop more
tinue immunosuppression have better outcome than do chronic kidney disease than the 32 patients who never flared
patients who continue therapy. Long treatment and duration after immunosuppression was discontinued. We are con-
of remission can reduce the risk of flares. cerned that this remarkable long-term renal survival may
not be generalizable. It is premature to suggest that patients
1. Malvar A, Alberton V, Lococo B, et al. Kidney biopsy–based management who have LN flares but spend some time off immunosup-
of maintenance immunosuppression is safe and may ameliorate flare rate
in lupus nephritis. Kidney Int. 2020;97:156–162. pression will do as well as patients who never had a flare.
2. Nachman PH. Repeat kidney biopsy for lupus nephritis: an important step Until we have robust noninvasive biomarkers of renal his-
forward. Kidney Int. 2018;94:659–661. tologic activity, a repeat kidney biopsy critically informs a
3. Malvar A, Pirruccio P, Alberton V, et al. Histologic versus clinical remission
in proliferative lupus nephritis. Nephrol Dial Transplant. 2015;32:1338– decision to withdraw immunosuppression.
1344.
4. Moroni G, Longhi S, Giglio E, et al. What happens after complete
withdrawal of therapy in patients with lupus nephritis. Clin Exp Rheumatol. 1. Ponticelli C, Moroni G. Discontinuation of therapy in lupus nephritis.
2013;31(suppl 78):S75–S81. Kidney Int. 2020;97:806–807.
2. Malvar A, Alberton V, Lococo B, et al. Kidney biopsy–based management
Claudio Ponticelli1 and Gabriella Moroni1,2 of maintenance immunosuppression is safe and may ameliorate flare rate
1 in lupus nephritis. Kidney Int. 2020;97:156–162.
Division of Nephrology, IRCCS Ospedale Maggiore Milano (retired), Milan,
Lombardia, Italy; and 2Nephrology and Dialysis Unit, Nefrologia e Dialisi, 3. Moroni G, Longhi S, Giglio E, et al. What happens after complete
withdrawal of therapy in patients with lupus nephritis. Clin Exp Rheumatol.
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
2013;31(4, suppl 78):S75–S81.
Correspondence: Claudio Ponticelli, via Ampere 126, Milano 20131, Italy. 4. De Rosa M, Azzato F, Toblli JE, et al. A prospective observational cohort
E-mail: ponticelli.claudio@gmail.com study highlights kidney biopsy findings of lupus nephritis patients in
remission who flare following withdrawal of maintenance therapy. Kidney
Kidney International (2020) 97, 806–807; https://doi.org/10.1016/j.kint.2020.01.009 Int. 2018;94:788–794.
Copyright ª 2020, Published by Elsevier, Inc., on behalf of the International 5. Parikh SV, Nagaraja HN, Hebert L, et al. Renal flare as a predictor of
Society of Nephrology. incident and progressive CKD in patients with lupus nephritis. Clin J Am
Soc Nephrol. 2014;9:279–284.

The authors reply: We thank Drs. Ponticelli and Ana Malvar1 and Brad H. Rovin1
Moroni for providing a contrasting perspective1 to 1
Department of Internal Medicine-Nephrology, The Ohio State University,
our recent demonstration that a repeat kidney Columbus, Ohio, USA
biopsy done during lupus nephritis (LN) remis- Correspondence: Brad H. Rovin, Department of Internal Medicine-
sion may help inform the decision to withdraw immuno- Nephrology, The Ohio State University, 395 W. 12th Avenue Ground Floor,
suppression.2 They contend that a repeat biopsy is Columbus, Ohio 43210, USA. E-mail: Brad.Rovin@osumc.edu
unnecessary in complete responders, citing evidence from Kidney International (2020) 97, 807; https://doi.org/10.1016/j.kint.2020.01.010
their cohort of 52 Caucasian patients with LN in whom Copyright ª 2020, International Society of Nephrology. Published by
immunosuppression was discontinued.3 After withdrawal, 15 Elsevier Inc. All rights reserved.

Kidney International (2020) 97, 805–807 807

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