Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial

Gansevoort, Ron T.; Meijer, Esther; Chapman, Arlene B.; Czerwiec, Frank S.; Devuyst, Olivier; Grantham, Jared J.; Higashihara, Eiji; Krasa, Holly B.; Ouyang, John; Perrone, Ronald D.; Torres, Vicente E.

doi:10.1093/ndt/gfv422

Cited by 50 publications

(30 citation statements)

References 32 publications

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“…Given the wide variance of GFR within and between individuals, measurement of GFR is an insensitive way to monitor the early, irreversible renal changes that occur in all slowly progressive renal disorders. Alternative biomarkers of disease progression, such as urinary albumin excretion for glomerular diseases, have been suggested, but as yet have not won widespread support from regulatory agencies 48 . In ADPKD, a reduction in renal blood flow seems to precede the decline in GFR, but the use of MRI to measure changes in renal blood flow requires further validation 49 .…”

Section: Tkv As a Measure Of Adpkd Progressionmentioning

confidence: 99%

The importance of total kidney volume in evaluating progression of polycystic kidney disease

2016

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The rate at which autosomal dominant polycystic kidney disease (ADPKD) progresses to end-stage renal disease varies widely and is determined by genetic and non-genetic factors. The ability to determine the prognosis of children and young adults with ADPKD is important for the effective life-long management of the disease and to enable the efficacy of emerging therapies to be determined. Total kidney volume (TKV) reflects the sum volume of hundreds of individual cysts with potentially devastating effects on renal function. The sequential measurement of TKV has been advanced as a dynamic biomarker of disease progression, yet doubt remains among nephrologists and regulatory agencies as to its usefulness. Here, we review the mechanisms that lead to an increase in TKV in ADPKD, and examine the evidence supporting the conclusion that TKV provides a metric of disease progression that can be used to assess the efficacy of potential therapeutic regimens in children and adults with ADPKD. Moreover, we propose that TKV can be used to monitor treatment efficacy in patients with normal levels of renal function, before the pathologic processes of ADPKD cause extensive fibrosis and irreversible loss of functioning renal tissue.

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Section: Tkv As a Measure Of Adpkd Progressionmentioning

confidence: 99%

The importance of total kidney volume in evaluating progression of polycystic kidney disease

2016

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“…Patients were eligible if they had an estimated creatinine clearance of ≥ 60 mL/min. Recent post hoc analyses found similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3 [13] , showed that tolvaptan use lowered albuminuria [14] and monocyte chemotactic protein-1 excretion [15] , whereas it increased copeptin concentration [16] , and significantly lowered the incidence of kidney pain events from 16.8 to 10.1% with a risk reduction of 36% [17] . A higher albuminuria and a higher copeptin concentration at baseline both predicted renal function decline in placebo-as well as tolvaptan-treated patients, and were both associated with a stronger tolvaptan treatment effect [14,16] .…”

Section: Tolvaptan As Treatment For Pkdmentioning

confidence: 99%

Polycystic Kidney Disease and the Vasopressin Pathway

Gastel

Torres

2017

Ann Nutr Metab

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Vasopressin, also known as arginine vasopressin or antidiuretic hormone, plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease progression in polycystic kidney disease (PKD), and in experimental studies vasopressin has been shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2-receptor and lower circulating vasopressin concentration are potential treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2-receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD, lowering total kidney volume growth from 5.5 to 2.8%, and the slope of the reciprocal of the serum creatinine level from -3.81 to -2.61 mg per mL^-1/year. Alternatively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake. Other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. In this study, we also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, especially by fluid intake.

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“…Moreover, in a more recent study, tolvaptan slowed the decline in kidney function in patients with later-stage ADPKD [73]. Gansevoort et al [74] showed that tolvaptan decreased albuminuria without affecting blood pressure in patients with ADPKD. This beneficial effect remained after withdrawal of the drug.…”

Section: Autosomal Dominant Polycystic Kidney Diseasementioning

confidence: 99%

Impact of Recent Clinical Trials on Nephrology Practice: Are We in a Stagnant Era?

et al. 2018

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Background: Although renal replacement therapy prevents death from uremia, survival among patients with acute and chronic kidney diseases (CKD) remains an imperative concern. The expected life span of US dialysis patients 60–64 years of age is approximately 4.5 years; this is similar to that of patients with lung cancer. Despite substantial progress in many medical specialties over the past decades (e.g., notable reductions in myocardial infarction, stroke, and mortality rates in the general population), survival among dialysis patients has not improved significantly over the same period. A few decades ago, HIV infection and AIDS were pretty much a death sentence. Because of progress in HIV treatment, now it can be controlled with a daily pill, and ongoing research is pushing treatment even further and controls the virus with longer-acting treatment. A cure is no longer impossible for HIV and other viral infections such as hepatitis B and C and many malignancies, but so far there is no cure for CKD. Summary: Billions of dollars have been spent on kidney disease research in the past decades, with no tangible progress in clinical practice. The challenges of improving the quantity and quality of trials in nephrology are enormous. The number of randomized controlled trials (RCTs) published in nephrology is lower than that in other medical subspecialties, and most of the big RCTs in nephrology yield negative results. Nephrology studies evaluating hard clinical endpoints or surrogate endpoints are scarce. Key Message: Herein we discuss the slow progress in nephrology research that has impacted clinical practice over the last couple of decades and highlight the major obstacles, challenges, and potential solutions.

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Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial

Abstract: In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.

Cited by 50 publications

References 32 publications

The importance of total kidney volume in evaluating progression of polycystic kidney disease

The importance of total kidney volume in evaluating progression of polycystic kidney disease

Polycystic Kidney Disease and the Vasopressin Pathway

Impact of Recent Clinical Trials on Nephrology Practice: Are We in a Stagnant Era?

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