Effect of Tolvaptan in Patients With Chronic Kidney Disease Due to Diabetic Nephropathy With Heart Failure

Satô, Eiichi; Nakamura, Tsukasa; Amaha, Mayuko; Nomura, Motoo; Matsumura, Daiju; Yamagishi, Hidetsugu; Ono, Yuko; Ueda, Yoshihiko

doi:10.1536/ihj.14-190

Cited by 23 publications

(26 citation statements)

References 22 publications

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“…Sato, et al demonstrated in a recent study that some responders with diabetes mellitus nephropathy received a clinical benefit from TLV treatment even though their renal dysfunction was approximately equivalent to stage G4 CKD (22.1 ± 18.1 mL/minute/1.73m 2 of estimated glomerular filtration ratio). 4) Among the 8 patients from whom renal specimens were obtained, 7 were responders and simultaneously had explicit expression of aquaporin-2 (AQP2) in the collecting ducts. The remaining patient was a non-responder showing no expression of AQP2 with histological evidence of tubulointerstitial damage.…”

Section: Article P533mentioning

confidence: 99%

“…However, how can we measure the expression of AQP2 in the human kidney? Sato, et al obtained renal biopsy specimens and demonstrated the expression of AQP2 immunohistologically, 4) but such an invasive procedure is rarely feasible, especially in patients with coagulopathy due to hepatic congestion or those treated with anticoagulants. We recently proposed urine AQP2 (U-AQP2) as a novel noninvasive marker to predict responses to TLV.…”

Section: Article P533mentioning

confidence: 99%

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Aquaporin-2-Guided Tolvaptan Therapy in Patients With Congestive Heart Failure Accompanied by Chronic Kidney Disease

Imamura

2014

Int. Heart J.

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R ecently, there has been increasing evidence supporting the efficacy and safety of the arginine vasopressin (AVP) type 2 (V 2 ) antagonist tolvaptan (TLV) in the improvement of hyponatremia or amelioration of congestion sparing renal function in acute/chronic heart failure (HF) patients refractory to considerable amounts of loop diuretics. 1)However, such a clinical benefit of TLV-incorporated diuretic therapy is not necessarily observed in all HF patients. In other words, we sometimes experience non-responders to TLV, whose clinical course worsens regardless of the initiation of TLV. 2)Although the precise mechanism of resistance to TLV is unknown, we previously speculated that aging and chronic kidney disease (CKD) were major risk factors of non-responders.3) In fact, concentrating and diluting ability in the collecting ducts is essential for the efficacy of TLV, but is often impaired in elderly or those with advanced CKD. However, according to our clinical experience, there were several responders to TLV even though they were complicated with stage G4 CKD. Article p.533The efficacy of TLV treatment in patients with CKD is controversial. Sato, et al demonstrated in a recent study that some responders with diabetes mellitus nephropathy received a clinical benefit from TLV treatment even though their renal dysfunction was approximately equivalent to stage G4 CKD (22.1 ± 18.1 mL/minute/1.73m 2 of estimated glomerular filtration ratio). 4) Among the 8 patients from whom renal specimens were obtained, 7 were responders and simultaneously had explicit expression of aquaporin-2 (AQP2) in the collecting ducts. The remaining patient was a non-responder showing no expression of AQP2 with histological evidence of tubulointerstitial damage. Although the sample number was very small, they speculated that some, albeit not all, patients with advanced CKD did respond to TLV, and that the responses to TLV might be dependent on residual expression of AQP2 in the collecting ducts.AQP2 is the recently characterized AVP-regulated water channel expressed in the collecting ducts in the kidney.5,6) Secreted AVP from the pituitary gland binds to V 2 receptors located in the basolateral membrane of principal cells in the collecting ducts, and then the activated V 2 receptors trigger the transport of AQP2 from intracellular storage vesicles into the apical membrane. The amount of AQP2 activated determines the water permeability in the apical membrane and then dominates urinary concentrating ability. 7) Expression of AQP2 in the apical membrane is considered as an index of the V2-receptor dependent activity of the collecting ducts, which may be essential for the response to TLV because TLV cannot block water-reabsorption there without baseline expression or activation of AQP2 protein.Considering the above mechanism, AQP2 can be a good marker for predicting responses to TLV especially in patients with CKD. However, how can we measure the expression of AQP2 in the human kidney? Sato, et al obtained renal biopsy specimens and demonstrated ...

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Section: Article P533mentioning

confidence: 99%

Section: Article P533mentioning

confidence: 99%

Aquaporin-2-Guided Tolvaptan Therapy in Patients With Congestive Heart Failure Accompanied by Chronic Kidney Disease

Imamura

2014

Int. Heart J.

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“…In general, expression of AQP-2 decreases in patients with CKD (8). We have reported that AQP-2 immunostaining is absent in renal tissues of tolvaptan non-responders with diabetic nephropathy but expressed strongly in responders (11). In the present cases, AQP-2 was expressed strongly in the renal tissue of the tolvaptan responder (Case 1) but only weakly in the non-responder (Case 2).…”

Section: Discussionmentioning

confidence: 95%

“…AQP-2 immunohistochemistry was performed via the following method (polymer technique): The kidney tissues were fixed in 20% neutral buffered formalin and embedded in paraffin, and sections 2-3 μm in thickness were prepared. The details of the method have been reported previously (11). Briefly, the simple statin MAX-PO (MULTI) (NICHIREI BIOSCIENCES INC., Tokyo, Japan) Polymer reagent instillation was performed as follows: incubation at room temperature for 30 minutes, and then washing with TBS for 5 minutes, 3 times.…”

Section: Case Reportmentioning

confidence: 99%

Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome

et al. 2017

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This case report discusses the clinical indication for immunosuppressants in patients with idiopathic membranous nephropathy (IMN). Because this disease occasionally shows spontaneous remission, it is necessary to determine the predictive values for a therapeutic effect in order to provide appropriate treatment. Two distinct cases described herein illustrate the different effects of tolvaptan in responders and non-responders, according to the pre-treatment levels of AQP-2 immunostaining in the samples from renal biopsy and urinary levels of AQP-2 and osmolality, suggesting that these values may be useful predictors of response to tolvaptan in patients with nephrotic IMN.

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“…Finally, the effects of tolvaptan treatment in patients with moderate to severe renal dysfunction warrant further evaluation. 22) Conclusions: Tolvaptan therapy provided body weight reduction mainly via high-volume diuresis in most patients, and about 80% of the patients were identified as clinical responders. However, this therapy was insufficient for symptom relief and hemodynamic improvement in a minority of the patients.…”

Section: Figure 2 Amentioning

confidence: 98%

Combination of Urinary Sodium/Creatinine Ratio and Plasma Brain Natriuretic Peptide Level Predicts Successful Tolvaptan Therapy in Patients With Heart Failure and Volume Overload

et al. 2016

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SummaryTo evaluate the short-term clinical and hemodynamic effects of tolvaptan therapy and to identify predictors of the therapeutic outcomes, we retrospectively recruited 60 consecutive hospitalized heart failure (HF) patients (70 ± 11 years) with volume overload. The subjects were divided into two groups on the basis of the changes in HF symptom scores and hemodynamic status assessed by right heart catheterization after tolvaptan therapy (median: 7 days). The majority of patients were successfully treated (group 1). However, 22% of patients (group 2) were unsuccessfully treated, in whom 1) the HF symptom score worsened or 2) there was a stationary HF symptom score ≥ 6 points, and mean PCWP > 18 mmHg and mean RAP > 10 mmHg, after tolvaptan therapy. HF symptom scores, hemodynamic parameters, and plasma brain natriuretic peptide (BNP) level improved in group 1, but all of these parameters remained unchanged in group 2. Lower urine sodium/creatinine ratio (UNa/UCr) and higher BNP level at baseline were independently associated with unsuccessful tolvaptan therapy, and UNa/UCr best predicts unsuccessful tolvaptan therapy with a cut-off value of 46.5 mEq/g·Cr (AUC 0.847, 95% CI: 0.718-0.976, sensitivity 77%, specificity 81%, P < 0.01). Double-positive results of UNa/UCr < 46.5 mEq/g·Cr and plasma BNP level > 778 pg/mL predicted unsuccessful tolvaptan therapy with high diagnostic accuracy (sensitivity 54%, specificity 100%, positive predictive value 100%, negative predictive value 89%, and accuracy 90%). In summary, short-term tolvaptan therapy ameliorated HF symptoms and provided hemodynamic improvement in the majority of patients, and UNa/UCr and BNP level strongly predicted the therapeutic outcomes. (Int Heart J 2016; 57: 211-219)

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Effect of Tolvaptan in Patients With Chronic Kidney Disease Due to Diabetic Nephropathy With Heart Failure

Cited by 23 publications

References 22 publications

Aquaporin-2-Guided Tolvaptan Therapy in Patients With Congestive Heart Failure Accompanied by Chronic Kidney Disease

Aquaporin-2-Guided Tolvaptan Therapy in Patients With Congestive Heart Failure Accompanied by Chronic Kidney Disease

Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome

Combination of Urinary Sodium/Creatinine Ratio and Plasma Brain Natriuretic Peptide Level Predicts Successful Tolvaptan Therapy in Patients With Heart Failure and Volume Overload

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