Target blood pressure

By conducting a systematic review and meta-analysis, systematic review group of JSH2025 guidelines found that blood pressure (BP) control targeting <130/80 mmHg may reduce the risk of all-cause mortality and cardiovascular (CV) events in patients with chronic kidney disease (CKD), without increasing the risk of serious renal events [1]. Based on these findings, JSH2025 guidelines suggest that adult with high BP and CKD should be treated with a target BP of <130/80 mmHg, if tolerated, using standard office BP measurement [2]. However, in patients without proteinuria, especially elderly patients, individualized management based on renal function and age may be necessary. Thus, in these patients cautious proceed to reduce BP to below 130/80 mmHg, with an intermediate target of below 140/90 mmHg, is sometimes required. Anyway, careful monitoring for signs of hypotension or dizziness associated with intensive lowering BP is recommended in all cases.

This target BP is consistent with that of recent international guidelines [3,4,5] except for KDIGO (Kidney Disease: Improving Global Outcomes) guidelines [6] (Table 1). The 2024 KDIGO guideline suggested that adults with elevated BP and CKD should be treated to target systolic blood pressure (sBP) of <120 mmHg, if tolerated, using standardized office BP measurement [6]. This suggestion was based, in part, on the SPRINT (Systolic Blood Pressure Intervention Trial) [7], which randomized 9361 hypertensive patients at increased CV risk to intensive (sBP <120 mmHg) or standard treatment (sBP <140 mmHg) and found that the primary composite outcome (CV events as well as CV and total mortality) but not kidney outcome was significantly lower in the intensive-treatment group. However, the SPRINT was not designed or powered to study kidney outcomes. About 28% had CKD with eGFR 20-60/ml/min/1.73m2, but very few patients had proteinuria because individuals with proteinuria >1 g/day or 1 g/g creatinine (Cr) were excluded. Diabetes mellitus, i.e. the most common cause of end-stage kidney disease (ESKD), or prior stroke were also exclusion criteria. A sub-analysis of the SPRINT CKD sub-population [8] showed no difference between groups for the primary outcome nor the prespecified kidney outcomes. In addition, the SPRINT used a trial specific automated BP measurement, in which sBP is likely to be lower compared to the standard office BP measurement, and the 2024 KDIGO guideline states that By aiming for an sBP <120 mmHg, more adults with CKD will achieve an sBP <130 mmHg, even if they do not meet the <120 mmHg target [6]. Thus, by mutually evaluating these, we believe that targeting sBP <130 mmHg, if tolerated, is appropriate recommendation in adult patients with CKD.

Table 1 Summary of recent guideline recommendation for the management of hypertension in CKD patients (Graphical Opinion Image)
Full size table

Pharmacological anti-hypertensive therapy

In CKD with moderate or severe proteinuria (≥0.15 g/gCr, or albuminuria ≥30 mg/gCr in diabetes), there is a high likelihood of the presence of glomerular hypertension requiring treatment. Thus, as the first-line treatments for this JSH2025 [2] recommends renin-angiotensin system (RAS) inhibitors that dilate efferent arterioles and reduce glomerular BP. This recommendation is consistent with all major international guidelines [3,4,5,6] (Table 1), though ESH/ISH (European Society of Hypertension/International Society of Hypertension) guideline recommends starting from combination therapy; RAS inhibitors + calcium channel blockers (CCBs) or diuretics [3]. The latter is also consistent with JSH2025 since it states as appropriate to initiate treatment from combination therapy (STEP 2) in patients at high risk such as proteinuria-positive CKD [2]. Indeed, in most CKD cases achieving BP targets is often difficult with RAS inhibitors alone, so CCBs or thiazide diuretics should be added to achieve adequate BP control. JSH2025 recommends CCBs addition in cases of stage III hypertension or high CV disease risk since it have a reliable antihypertensive effect and are expected to increase organ blood flow. In contrast, in cases where fluid volume remains excessive despite salt restriction, thiazide diuretics are recommended in combination; however, in cases of impaired renal function (CKD stage G4–G5: eGFR <30 mL/min/1.73m2), switch to or add loop diuretics. This treatment strategy is also consistent with other international guidelines [3,4,5,6].

In patients with impaired renal function, particularly in elderly patients aged 75 years or older, RAS inhibitors are often withheld or discontinued. This is due to concerns about the risk of hyperkalemia or the need for earlier initiation of renal replacement therapy, even if proteinuria is positive. However, as with other international guidelines [3,4,5,6], JSH2025 encourages continuing RAS inhibitors even in patients with severe renal impairment based on recent studies reporting that discontinuing RAS inhibitors in CKD patients significantly increases the risk of all-cause mortality and CV events [9] without improving the long-term eGFR decline [10]. Thus, JSH2025 recommends as follows; in patients with CKD stage G4, G5, or aged 75 years or older, RAS inhibitors should be initiated at a low dose, and rapid dose reduction or discontinuation should be considered if renal function worsens or hyperkalemia occurs [2]. In addition, considering that there is a higher likelihood of underlying renal ischemia in elderly patients aged 75 years or older with CKD stage G4 or G5, JSH2025 also mention that “in the case of elderly CKD patients, even if proteinuria is present, it is safer to start with CCBs and confirm that there is no worsening of renal function due to the lowering of BP before switching to RAS inhibitors” and that “if renal function deteriorates despite CCBs, referral to a nephrologist is recommended” [2]. In addition to that, JSH2025 creates a table summarizing precautions for administering RAS inhibitors to patients with renal dysfunction, and measures to take in case of elevated serum potassium levels (Table 2). We believe that JSH2025 is superior to other international guidelines in providing such detailed cautionary statements.

Table 2 Precautions for administering RAS inhibitors to patients with renal dysfunction, and measures to take in case of elevated serum potassium levels [2]
Full size table

If target BP is not achieved, even with the combination of RAS inhibitors, CCBs, or diuretics, mineralocorticoid receptor antagonists (MRAs) are often effective for BP and proteinuria reduction. Although other four guidelines recommend spironolactone in these cases [3,4,5,6], JSH2025 recommends esaxerenone, a nonsteroidal anti-hypertensive MRA available only in Japan, for patients with diabetes accompanied by albuminuria/proteinuria or moderate renal dysfunction (eGFR ≥30/ml/min/1.73m2) [2]. When adding an MRA to RAS inhibitors, careful monitoring of serum potassium levels and renal function is essential. Compared with other international guidelines, more detailed precautions to be adhered are also outlined in JSH2025 (Table 2).

Only JSH2025 [2] and the 2024 KDIGO guideline [6] recommend the first-line treatment for CKD patients without proteinuria. That is, it should be selected from among RAS inhibitors, CCBs, and thiazide diuretics (instead loop diuretics in case eGFR < 30 ml/min/1.73m2) based on the individual patient’s condition (including complications). In older adults aged 75 years or older with suspected nephrosclerosis (severe atherosclerosis and negative proteinuria), JSH2025 especially recommends CCB as the first-line [2].