Polycystic Kidney Disease: Ebb and Flozins

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is estimated to affect up to 12 million individuals and is the 4th most common cause of renal replacement therapy worldwide. The diagnosis of this common hereditary disorder can be made by kidney imaging (ultrasound, CT or MRI) or genetic studies. In most affected families, ADPKD is caused by a heterozygous PKD1 or PKD2 pathogenic variant and inherited in an autosomal dominant manner. More rarely, ADPKD is caused by a heterozygous pathogenic variant in ALG5, ALG9, DNAJB11, GANAB, or IFT140 genes identified by molecular genetic testing. ADPKD is commonly associated with ESKD in the 5th to 7th decade of life. Rates of eGFR decline in ADPKD patients are most closely correlated with height-adjusted total kidney volume (htTKV).

The patient's height and the depth, height and width of the kidneys as measured by any imaging modality (MRI preferred), can be used to calculate height-adjusted total kidney volume (htTKV). The Mayo Clinic ADPKD imaging classifications (A-E) are then used to risk stratify patients for developing rapid eGFR loss and ESKD.

Mayo classification classes are based on htTKV growth per year. Patients tend to stay on their trend lines and repeat imaging isn’t typically recommended unless there’s a significant change in the clinical course associated with an unexpected change in eGFR. However, there can be variability in htKTV due to differences in imaging techniques. Patients with higher risk of CKD progression (Mayo class C-E) may benefit from medical treatment. Tolvaptan (a V2-receptor vasopressin antagonist) has been shown to slow, but not entirely halt, the rate of htTKV. Tolvaptan has also been shown to slow the rate of eGFR decline in patients with rapidly progressive disease.

Let’s look at the evidence for the use of vasopressin antagonists in ADPKD.

TEMPO 3:4

Tolvaptan slowed the increase in htTKV and decline in eGFR versus placebo over a 3-year period in patients with ADPKD. Patients who received tolvaptan had a higher frequency of adverse events related to increased aquaresis (thirst, polyuria, nocturia, and polydipsia as a result of the excretion of electrolyte-free water). There were higher discontinuation rates in the treatment arm due to adverse events (15.4% versus 5%), including the risk of liver toxicity. 

REPRISE

The REPRISE study included patients with ADPKD and CKD 3b/4 (eGFR of 25- 44 ml/min). Tolvaptan resulted in a slower decline than placebo in eGFR at 1-year follow-up.

The decline of eGFR, even in patients with severe CKD was slowed by tolvaptan (eGFR −2.34 ml/min in tolvaptan group versus −3.61 ml/min in placebo group; difference, 1.27 ml/min/1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). 

OVERTURE

OVERTURE was an observational, longitudinal study that included 3409 ADPKD patients from 20 countries. Patients were followed for 12-36 months. Higher baseline measured htTKV was once again confirmed to be associated with worse ADPKD-related clinical outcomes including abdominal girth, albumin-to-creatinine ratio and eGFR decline rate. Higher htKTV was also associated with worse scores on multiple measures of patient-reported quality of life, productivity, physical function, and healthcare utilization. It was also noted, the relationship of htTKV to eGFR decline was attenuated in subjects at low risk of rapid progression (Mayo class 1A–1B). This finding is consistent with data from the Mayo Clinic that htTKV has an inverse correlation with patient age at ESKD. In patients at low risk of ESKD, the risks of tolvaptan may outweigh the benefits. 

SGLT2 inhibitor overview

SGLT2 inhibitors block glucose reabsorption in the proximal tubule of the kidney, promoting glucosuria and reducing hyperglycemia. Beyond glycemic control, they reduce intraglomerular pressure, inflammation, and oxidative stress which contributes to their benefits in patients with proteinuria (with or without diabetes), CKD, and heart failure. 

Proteinuria, a marker of kidney damage, is a key target in CKD management. Studies have consistently shown that SGLT2 inhibitors reduce albuminuria by lowering glomerular hyperfiltration, presumably via tubuloglomerular feedback. Patients treated with canagliflozin (CREDENCE) with type 2 diabetes and CKD demonstrated a 30% reduction in albuminuria compared to placebo. Even in non-diabetic CKD, the DAPA-CKD trial reported a 31% reduction in albuminuria with dapagliflozin, suggesting benefits independent of diabetes status. Additionally, SGLT2 inhibitors have shown remarkable efficacy in slowing CKD progression. In CREDENCE patients with type 2 diabetes and CKD (eGFR 30–90 mL/min/1.73 m²), canagliflozin reduced the risk of kidney failure (dialysis, transplantation, or sustained eGFR <15 mL/min/1.73 m²) by 34%. In DAPA-CKD, dapagliflozin reduced the composite endpoint of sustained eGFR decline, ESKD, or renal death by 39% in patients with CKD (eGFR 25–75 mL/min/1.73 m²), with or without type 2 diabetes. This trial was stopped early due to overwhelming efficacy. Finally, heart failure (HF) often coexists in patients with CKD. Dapagliflozin (DAPA HF) reduced the risk of worsening HF or cardiovascular death by 26% in patients with HF with reduced ejection fraction (HFrEF), regardless of diabetes status. In EMPEROR-Preserved, empagliflozin became the first therapy to show benefit in HF with preserved ejection fraction (HFpEF), reducing HF hospitalization or cardiovascular death by 21%.These findings have led to updated guidelines (e.g., KDIGO 2024) recommending SGLT2 inhibitors as first-line therapy in CKD patients with proteinuria, with or without diabetes.

Selective clinical trials of SGLT2 inhibitors in CVD and CKD. Colbert G, et al. Therapeutic and clinical risk management, 2023.

SGLT2 inhibitors have shown benefits in a wide variety of patients with kidney and cardiovascular diseases, with impressive improvements in patient outcomes. Prior studies of SGLT2 inhibitors in ADPKD animal models had yielded conflicting results in cyst growth and eGFR decline. Now this class of medications is being tested in human patients with ADPKD to determine if the benefits to retard progressive kidney disease might be more universal. 

The Study

To date tolvaptan is the only medication approved to treat ADPKD with rapidly declining kidney function. Patients with ADPKD were specifically excluded from previous trials of SGLT2 inhibitors. This was done because SGLT2 inhibitors are proximal tubule diuretics (due to forced glucosuria resulting from sodium-glucose transporter blockade) and may increase serum vasopressin, or its surrogate copeptin. Increased vasopressin has been shown to promote cyst growth and worsen ADPKD, thus the use of a vasopressin antagonist (or increased volume intake) is used to effectively retard progression. Because of the concerns of SGLT2 inhibitors in ADPKD patients, it was determined that the authors would examine the use of dapagliflozin exclusively in patients already receiving tolvaptan therapy.

Outpatients from several centers in Japan were recruited from this study from December 2021 through March 2024. Adult patients who were diagnosed with ADPKD and receiving high dose tolvaptan (> 60 mg daily for 3 months) with an eGFR >25 ml/min/1.72 m2 were eligible. Patients on tolvaptan had already met the criteria of a TKV >750 ml with an annual growth rate of > 5%. Patients with diabetes or already on SGLT2 inhibitors prior to the study were excluded.

Due to concerns about the safety of dapagliflozin in patients with ADPKD the study was conducted as an open-label trial. To decrease the number of patients needed to be recruited a cross-over design was adopted. Patients received dapagliflozin 10 mg with tolvaptan or just tolvaptan for 6 month intervals in a counterbalanced fashion.

Fig.1 Crossover flow chart. Uchiyama K, et al. KI Reports, 2025.

Patients had bloodwork done every 1-2 months. Patients also underwent CT or MRI at six month intervals to assess TKV. Adherence to dapagliflozin, but not tolvaptan, was monitored by the treating nephrologist.

Outcomes

The primary outcome was the rate of eGFR decline calculated by linear regression models. Given the known decline in eGFR when initiating SGLT2 inhibitors, chronic slope (1-6 months) was used rather than total slope (from baseline). Japanese population based eGFR equations, including both creatinine and cystatin C, were used to calculate eGFR. Secondary outcomes included changes in TKV and body weight, plasma vasopressin levels, and 24-hour urine volume, osmolarity, and albuminuria.

Results

Thirty patients were randomized into 2 groups of 15 to receive dapagliflozin for the first six months or second six month interval. Three patients were lost to follow-up leaving 13 patients in group one and 14 patients in group 2.

Fig.2 Consort flow diagram. Uchiyama K, et al. KI Reports, 2025.

Baseline characteristics did not differ significantly between groups, except for TKV and htTKV which were higher in group 1 (1414 [993-2369] vs 1012 [914-1126], p =0.08 and 822 [575-1381] vs 624 [516-675] p =0.07 respectively). Because of the crossover design, differences between groups had minimal effect on outcomes.

Table 1. Demographics and clinical characteristics. Uchiyama K, et al. KI Reports, 2025.

Primary Outcome

The slopes of eGFR decline were significantly flattened during the periods in which patients received dapagliflozin. The carryover effect of discontinuing dapagliflozin was negligible. Linear mixed models confirmed that eGFR (cr-cys) estimated marginal mean was greater during the periods when patients received dapagliflozin at both 4 and 6 months.

Fig. 3 Mean change in eGFR (cr-cys) equation during the whole study period in groups 1 and 2, linear mixed models. Uchiyama K, et al. KI Reports, 2025.

Secondary outcomes

The 6 month change in TKV was significantly attenuated by dapagliflozin. Not surprisingly, body weight changes were significantly smaller and vasopressin levels were higher in patients receiving dapagliflozin. Urine osmolarity, but not volume, was higher in patients receiving dapagliflozin. There was no effect on albuminuria, however, all patients had under 150 mg/d at baseline. Finally, systolic (but not diastolic) blood pressures were lower in the dapagliflozin group. 

Table 4. Effect of dapagliflozin on secondary outcomes. Uchiyama K, et al. KI Reports, 2025.

Safety

There were 2 COVID infections (3 total) and 1 kidney cyst infection in patients on dapagliflozin. There were no recorded episodes of hypoglycemia. Cyst hemorrhage, subarachnoid hemorrhage and hospitalizations were not recorded during the study period.

Conclusion

SGLT2 inhibitors, by altering intraglomerular pressure, have been shown to be beneficial to a number of patients with chronic kidney disease of varying severity. Although there are physiologic concerns about the use of SGLT2 inhibitors (increasing vasopressin), and because the exact mechanism of renoprotection by SGLT2 inhibitors hasn’t been elucidated, their benefits still might outweigh their risks in high-risk ADPKD patients. In this first-of-its-kind study in human patients with ADPKD the authors used significant caution and close follow-up in an attempt to show benefit or harm from dapagliflozin. Special precautions were used to select a population of ADPKD patients with severe disease who had already qualified, and were actively using tolvaptan. The authors did observe a rise in serum vasopressin levels in patients on dapagliflozin, but also an improvement in eGFR slope over the short term. Although the study participants had a high risk for CKD progression based upon ADPKD criteria, they specifically did not have diabetes nor significant albuminuria. The crossover design was also beneficial, as there was a slight imbalance (non-significant) in TKV between the groups, but eGFR decline was improved in both groups upon initiation of dapagliflozin. This trial did not look at dapagliflozin as a monotherapy or in patients with less severe ADPKD who did not qualify for tolvaptan. Longer randomized control trials with more heterogeneous groups, given the number of genetic variations and phenotypes seen in ADPKD, will have to be done before SGLT2 inhibitors can be emphatically recommended for patients with ADPKD.