Before the Pressure Rises

Hypertension is among the earliest and most consequential manifestations of autosomal dominant polycystic kidney disease (ADPKD). It frequently develops before measurable kidney function decline, accelerates cyst expansion, and contributes to cardiovascular morbidity and premature mortality.1,2 The 2025 Kidney Disease Improving Global Outcomes guidelines emphasize early BP monitoring and timely intervention.3 Although multiple mechanisms have been implicated—including renin-angiotensin-aldosterone system (RAAS) activation, renal ischemia due to cyst compression, sympathetic overactivity, systemic inflammation, and endothelial dysfunction—the temporal sequence remains unclear.2,4,5 Whether autonomic dysregulation initiates or follows sustained hypertension is particularly debated. In this issue of Kidney360, Rocha and colleagues offer mechanistic insight by characterizing autonomic function and intrarenal RAAS activity in normotensive young adults with ADPKD and preserved kidney function.6 By focusing on the earliest stage—before clinical hypertension or decline in eGFR—they test whether systemic abnormalities precede renal changes or whether disease begins within the kidney itself. The study enrolled 18 individuals with ADPKD and 19 age-matched and sex-matched healthy controls.6 All participants had eGFR ≥60 ml/min per 1.73 m2, body mass index <30, and normal office BP. The cohort was carefully selected to isolate early disease signals, free from comorbid confounding. Participants underwent a battery of physiologic and biochemical tests to assess autonomic function, systemic inflammation, endothelial health, and neurohormonal activity. Autonomic evaluation included heart rate and BP variability, baroreflex sensitivity at rest and Valsalva maneuver, and responses to sympathetic stressors including cold pressor testing, isometric handgrip, and cognitive challenge. Circulating biomarkers of systemic inflammation (IL-6, TNF-α), endothelial dysfunction (asymmetric dimethylarginine), and neurohormonal activity (neuropeptide Y and circulating angiotensinogen [uAGT]) were also measured, alongside urinary levels of albumin, monocyte chemoattractant protein-1, and angiotensinogen (uAGT). Most striking were the negative systemic findings. Across all autonomic parameters—heart rate variability, baroreflex sensitivity, and sympathetic responsiveness—no differences emerged between ADPKD and controls. Subgroup analysis by Mayo Imaging Classification, performed to distinguish potential rapid from slow progressors, revealed no significant abnormalities. Similarly, systemic biomarkers of inflammation, endothelial injury, and neurohormonal activation were comparable. These negative findings are mechanistically informative. They suggest that, in early-stage ADPKD, there is no sympathetic activation, systemic inflammation, or vascular injury. This challenges the hypothesis that autonomic dysfunction indicates hypertension in ADPKD. By contrast, abnormalities were detected in urine. Compared with controls, ADPKD participants had elevated urinary angiotensinogen and low-grade albuminuria—early markers of glomerular and tubular stress. Angiotensinogen is too large to be freely filtered; its urinary presence reflects local intrarenal RAAS activation. Albuminuria, even at minimal levels, indicates glomerular barrier disruption. Together, these findings localize the first detectable abnormalities of ADPKD within the kidney (Figure 1).Figure 1: Proposed temporal sequence of pathogenic mechanisms in ADPKD, illustrating the emergence of early intrarenal RAAS activation before the onset of systemic abnormalities. This schematic highlights stages in the evolution of ADPKD: normotensive ADPKD, hypertensive ADPKD, and CKD progression. In healthy kidneys, BP is normal, and there is no evidence of RAAS activation or albuminuria. In the earliest detectable phase of ADPKD—before clinical hypertension—patients exhibit elevated urinary angiotensinogen and low-grade albuminuria, indicating intrarenal RAAS activation and glomerular stress despite normal systemic BP and absence of sympathetic or endothelial dysfunction. As the disease progresses, hypertension emerges, accompanied by systemic pathophysiologic changes including autonomic dysregulation, endothelial dysfunction, and inflammation marked by elevated IL-6 and TNF-α levels. These changes are further associated with increased neurohormonal activity and plasma RAAS activation. Ultimately, persistent hypertension and progressive cyst growth lead to cardiac remodeling (e.g., left ventricular hypertrophy) and deterioration in kidney function consistent with CKD. This figure underscores that the earliest measurable abnormalities in ADPKD occur within the kidney and can be detected through noninvasive urinary biomarkers—well before clinical hypertension or systemic derangements arise. ADPKD, autosomal dominant polycystic kidney disease; LVH, left ventricular hypertrophy; RAAS, renin-angiotensin-aldosterone system.These results align with earlier studies suggesting that RAAS activation within the kidney precedes systemic hypertension. Cyst expansion triggers ischemia and mechanical stress, which upregulates renin and angiotensinogen in tubular and cystic epithelial cells.2,4,7 These cells may secrete RAAS components, creating a self-reinforcing paracrine loop.2,4,7 Elevated urinary angiotensinogen has been observed in ADPKD, despite normal plasma RAAS components, and correlates with more rapid eGFR decline.7,8 In Pkd1-deficient mice, intrarenal RAAS activity is detectable before hypertension or GFR loss and is linked to cyst burden.9 Rocha and colleagues extend these findings to early human ADPKD, showing that uAGT is elevated even in normotensive individuals with preserved function.6 This supports a model in which renal parenchymal stress and RAAS activation initiate disease, with systemic hypertension arising downstream. Preclinical work further implicates renal sympathetic nervous system in amplifying local RAAS signaling.10 In polycystic kidney models, renal denervation lowers BP, suggesting a kidney-nerve-RAAS feedback loop.10 Historically, increased sympathetic tone in ADPKD was inferred from studies in more advanced disease, where muscle sympathetic nerve activity and baroreflex impairment were evident.5 However, such cohorts typically included hypertensive or proteinuric individuals, blurring causality. The strength of this study lies in its focus on the earliest, subclinical phase.6 By showing preserved systemic physiology alongside abnormal urinary biomarkers, Rocha et al.6 compellingly reposition intrarenal signaling—not systemic autonomic dysfunction—as the incipient driver of disease. From a clinical perspective, several takeaways emerge. First, autonomic dysfunction is not a feature of early ADPKD, and routine autonomic testing is unlikely to add clinical value in normotensive patients. Second, urinary angiotensinogen and albuminuria represent accessible, noninvasive biomarkers of early intrarenal stress. Both are well-suited for integration into clinical trials and longitudinal cohorts. In individuals with elevated urinary markers despite normotension, clinicians should consider screening for masked hypertension, which is prevalent in ADPKD and may accelerate disease progression if unrecognized. Ambulatory blood pressure monitoring or serial home measurements are appropriate tools for this purpose. These findings also prompt reconsideration of the therapeutic window for RAAS blockade. Currently, Kidney Disease Improving Global Outcomes guidelines endorse RAAS inhibition only after hypertension is established,3 and the HALT Progression of Polycystic Kidney Disease trial demonstrated that intensive BP control slows cyst growth and reduces left ventricular hypertrophy.11 However, the data by Rocha et al.6 suggest that intrarenal RAAS activation may precede clinical hypertension by years. This raises the provocative question: could initiating RAAS blockade earlier—based on urinary biomarkers rather than BP readings—delay the onset of hypertension or mitigate cyst expansion? Although unproven, this hypothesis is biologically plausible and ripe for testing. A biomarker-enriched trial design could stratify normotensive ADPKD patients by urinary angiotensinogen or albumin levels and randomize them to early versus delayed initiation of RAAS blockade. Such a design would help determine whether early suppression of intrarenal signaling can meaningfully alter the natural history of disease. Until such data emerge, elevated urinary biomarkers may still inform clinical monitoring strategies. In high-risk patients—those with rapid cyst growth or elevated urinary angiotensinogen—clinicians may consider intensifying BP surveillance, even in the absence of abnormal office readings. Several limitations of the study merit mention. As a cross-sectional analysis, causality cannot be inferred nor can the prognostic value of elevated uAGT be determined. The sample size, while acceptable for physiologic studies, may have limited statistical power to detect subtle abnormalities. Normotension was defined based on office BP, but ambulatory blood pressure monitoring would have provided a more definitive exclusion of masked hypertension. Autonomic testing, while comprehensive, relied on indirect measures and did not include direct sympathetic nerve recordings. Finally, although urinary angiotensinogen and albumin are widely accepted proxies for intrarenal RAAS activation and glomerular stress, they remain indirect markers that may be influenced by factors not captured in this analysis. Nonetheless, the internal consistency of the findings—preserved systemic parameters alongside abnormal urinary biomarkers—supports their validity and relevance. In summary, Rocha and colleagues make a timely and impactful contribution to our understanding of the earliest stages of ADPKD pathogenesis. By examining a carefully selected normotensive cohort with preserved kidney function, they show that intrarenal RAAS activation and albuminuria are the first detectable abnormalities—arising before any systemic autonomic, inflammatory, or endothelial changes. These findings reposition the kidney, not the vasculature or nervous system, as the initial site of disease activity. Clinically, they offer a compelling rationale for integrating urinary biomarkers into early risk stratification protocols, potentially guiding more proactive monitoring or treatment strategies. For clinicians and researchers alike, the message is clear: in ADPKD, the earliest trouble starts before the pressure rises, and it starts inside the kidney.