Nephrotic syndrome is common kidney disease. Some nephrotic patients have refractory edema resistant to near-maximum doses of diuretics 19, 20. Also, volume correction and the use of diuretics may deteriorate renal function 21,22. Optimal treatment for nephrotic edema without worsening renal function is an important issue. An antagonist to V2 receptor, TLV, blocks water reabsorption via aquaporin 2 in cortical collecting ducts without activating the renin-angiotensin-aldosterone axis and the sympathetic nervous system 6. TLV is expected as a novel drug for nephrotic edema. However, to date, it remains to be clarified who is responsive to TLV though some researchers reported the effect of TLV on nephrotic edema. Then our study challenged to elucidate the association of responsiveness to TLV with pathological evaluation and serological or urinary markers. And the novel findings are as below. First, urine output change at day 1 was correlated with the degree of weight loss at the final. Second, the proportion of AQP2 staining was correlated with the increase of urine output by TLV while urine and blood measurements including uAQP2 and TLV were not correlated. And finally, TLV could be used safely for some nephrotic patients without adverse effects in the short term.
Previous reports showed that responders to TLV in heart failure patients had a significant increase in urine volume soon after administration and improved clinical course with significant weight loss 23. As similar to the previous studies, our study demonstrated that weight loss was also significantly related to the increase of urine volume at day 1 in nephrotic syndrome. This indicated that urine volume soon after TLV administration was enough to evaluate whether it was responsive to TLV and the clinical course was improved in nephrotic syndrome patients.
A transient increase in urine output on day 1 was not reflected in a concomitant weight loss on day 2. This undesirable result is attributed to arbitrary water intake. In general, fluid restriction is needed for volume control irrespective of the use of diuretics. However, at the time when this study was conducted, Pharmaceuticals and Medical Devices Agency in Japan did not recommend fluid restriction to avoid volume depletion. Moreover, we could not predict the urine output increase so that we could not manage volume control appropriately. But the result in this study revealed the effect of TLV and we would manage the proper fluid restriction.
Urine AQP2, urine osmolality change and serum TLV concentration can be predictors for TLV efficacy in heart failure 18, 24, 25. However, these measurements did not correlate with urine output change and weight loss in our study despite detected urine AQP2, the reduction of urine osmolality and elevated TLV concentration. Moreover, serum ADH was not correlated with the effect of TLV. There were no precise explanations, but some reasons could be speculated. First, evidence was not enough about the association with urine AQP2 and pathological AQP2 staining in nephrotic syndrome though AQP2 expression in kidney tissues and net urine AQP2 were increased in a previous report 26. Urine output in nephrotic patients sometimes decreases and urine AQP2 concentration needs to be adjusted when it is interpreted. However, AQP2 is located and excreted in principal cells of collecting ducts. Urine creatinine or other filtration makers were not enough as calibrations because they do not reflect the dynamics of collecting ducts precisely. Thus, urine AQP2 concentration did not correlate with AQP2 staining and urine output change in nephrotic patients. Second, the majority in our study had renal impairment, unlike previous reports. Patients with decreased eGFR disable to dilute or concentrate urine despite elevated vasopressin concentration 27, which indicates collecting ducts in the diseased kidney are reluctant to respond to vasopressin and V2 receptor antagonists. Serum ADH is slightly higher in CKD patients, which indicates that the response to ADH would be sluggish. Although the mechanism of urine dilution and concentration is not clearly understood, it is considered that urine osmolality, serum ADH or TLV concentration were not enough to predict the aquauresis by TLV.
Although the finding in this study indicates that it requires a renal biopsy to predict urine output change by TLV in nephrotic patients, renal biopsy is impractical only for the purpose. Biopsy has several risks such as flank pain, infection and bleeding. A few days are necessary for the result of the biopsy. Thus, the finding in this study may makes little clinical sense and a novel, easier manner will be expected for predicting the responsiveness. However, although it may not give a suggestion to our clinical practice immediately, we believe that this finding in this study is academically important. Our findings are not totally consistent with previous studies because we found that the effect of tolvaptan retained for patients with kidney dysfunction, but was correlated with AQP2 in biopsied kidney, not urine and blood parameters like the previous studies. Thus, we consider this finding should be described in this article to further understand the physiology of diuresis under kidney impairment.
The limitation of this study is a small exploratory study in a single center for the short term. The population in this study was limited to nephrotic patients with diabetic nephropathy and CKD stage 3–4. The pathophysiology of diabetic nephropathy and nephrotic patients may be different as indicated in the previous report28. It is postulated that nephrotic syndrome results from permeability factors affecting podocyte function such as cardiotrophin-like cytokine 1, which is not regarded as a cause of diabetic nephrophaty29, 30. Therefore, this study cannot tell that tolvaptan is effective for idiopathic nephrotic syndrome and further studied are required. Second, the number of enrolled patients could not be reached to the target size (N = 20) during the trial. More detail evaluation for the larger population and other types of nephrotic syndrome is needed. The long term effect of TLV should be evaluated in further study. Third, this study was an exploratory study, not a randomized trial with controls of conventional therapy. Further randomized comparative trials are needed to validate the efficacy of tolvaptan. Fourth, low dose TLV in this study may be a potential limitation. According to the report on the pharmacokinetics of TLV, even higher dose TLV have less effect on urine excretion in advanced kidney disease31. Therefore, higher dose might have increased urine output in some patients without any improvement of symptom in this study.