Of the 559 allograft IgAN patients, 464 patients were included in the current study after exclusion criteria were applied (Fig. 1). Among them, 100 patients were determined to have initial native IgAN as the cause of ESRD, and 11 had other kidney disease, suggesting possible de novo cases. The other 353 patients had unknown primary etiology or only clinical diagnoses for ESRD. Regarding antihypertensive medication usage, there were 272, 38, 33, and 121 allograft IgAN patients in the no medication, single RAASB, single BB/CCB, and combination groups, respectively.
Characteristics of the study population
Significant differences were found between the study groups (Table 1). Although the age and sex distributions were similar between groups, the single RAASB group had a significantly longer duration from transplant to allograft IgAN diagnosis. This group had favorable clinical characteristics regarding higher eGFR values and less frequent coexisting acute rejection when they were diagnosed. On the other hand, a substantially higher portion of patients in the single RAASB group had albuminuria and hematuria at baseline. Other medication usage, including tacrolimus prescription rate among the used calcineurin inhibitors, steroid, or mycophenolic acid, did not differ largely between the studied groups.
Risk factors for 5-year DCGF in the study population
The risk factors for 5-year DCGF in the study population are shown in Table 2. Male sex, presence of T in the Oxford classification, and impairment of kidney function, as reflected by decrease in eGFR, were factors prominently associated with an increased risk of DCGF. Particularly, high-degree albuminuria after 6 months of allograft IgAN diagnosis was associated with very high risk for DCGF, which were even comparable to the categorical eGFR variable of <30 or <15 mL/min/1.73 m2.
Among those who did not require antihypertensive medications, the degree of albuminuria at baseline was not significantly associated with the risk of 5-year DCGF (Additional file 1: Figure S1). However, those with persistent albuminuria or who developed high-degree (≥2+) albuminuria after 6 months demonstrated an increased risk of 5-year DCGF. This association was significant even after adjustment for age, sex, time from transplantation to allograft IgAN diagnosis, and eGFR and MAP values after 6 months (adjusted HR, 6.70 [1.51-29.76]; P = 0.01). Meanwhile, the presence of high MAP was not significantly associated with 5-year DCGF in this patient subgroup, suggesting the relative importance of the high-degree albuminuria after 6 months.
By contrast, those who received antihypertensive medications following the diagnosis of allograft IgAN exhibited worse prognosis than those who did not (Additional file 2: Figure S2). Albuminuria and presence of high MAP demonstrated a significant association with 5-year DCGF risk in this patient group; however, baseline high-degree albuminuria lost its significance in multivariable analysis (adjusted HR, 1.31 [0.77-2.23]; P = 0.32). High-degree albuminuria at 6 months remained a significant predictive factor associated with 5-year DCGF in this subgroup (adjusted HR, 2.77 [1.56-4.90]; P <0.001), also showing the persistent high-degree albuminuria was an important risk factor for DCGF.
Blood pressure and urine dipstick albuminuria according to antihypertensive medications
We analyzed whether differences were present in the urine dipstick results of those with available values both at the time of allograft IgAN diagnosis and after 6 months (Table 3). Compared to the other groups, the single RAASB group had a lower portion of patients with persistent albuminuria or who had developed high-degree albuminuria after 6 months. By contrast, the single BB/CCB group had a higher portion of allograft IgAN patients who developed high-degree (≥2+) dipstick albuminuria at 6 months. Moreover, these differences in changes of albuminuria presence were significant (P for interaction = 0.03) with single RAASB usage even among those who received single antihypertensive medications, showing that RAASB may be better regarding albuminuria reduction than other drug types.
In terms of blood pressure values, the median MAP was the lowest in the single RAASB group; however, the difference was not statistically significant (P = 0.09). In fact, the MAP values became even more similar between the studied groups after 6 months. The changes in high MAP (>100 mmHg) presence (P for interaction = 0.11) or MAP values (P for interaction = 0.28) did not seem to be affected by use of single RAASB. Therefore, we could not identify a significant difference in blood pressure control according to the antihypertensive medication types.
DCGF according to antihypertensive medication categories
Prognosis for DCGF was significantly different between the studied subgroups (Fig. 2). Patients who did not require antihypertensive medications had the best prognosis, as only 8/272 (2.9%) patients reached DCGF within 5 years of their allograft IgAN diagnosis. The single RAASB group demonstrated better outcome than the others, with 8/38 (21.1%) patients developing 5-year DCGF, compared to 15/33 (45.5%) and 52/121 (43.0%) in the single BB/CCB and combination groups, respectively.
The above results were repetitively observed in our regression analysis (Table 4). Compared to the single RAASB group, the no medication group demonstrated better prognosis, while the single BB/CCB and combination groups exhibited significantly worse prognoses. Single BB/CCB usage and its association with worse DCGF among single agent users remained valid when we included the time-averaged eGFR values. When we divided subgroups according to the presence of confirmed native IgAN, the inferiority for prognosis of single usage BB/CCB when compared with prognosis of single RAASB usage was shown only in allograft IgAN with unknown or clinical cause for ESRD (hazard ratio 3.16, 95% confidence interval 1.17-8.57, P = 0.02). On the contrary, in allograft IgAN cases with confirmed native IgAN, the usage of single BB/CCB showed non-significant difference regarding prognosis with the single RAASB usage (hazard ratio 2.40, 95% confidence interval 0.44-13.08, P = 0.31). In addition, within the combination group, the DCGF prognosis did not significantly differ according to RAASB usage (Additional file 3: Figure S3).
Finally, within the single RAASB group, DCGF was significantly better in those without high-degree albuminuria after 6 months from diagnosis (P=0.048) (Additional file 4: Figure S4). Namely, allograft IgAN patients with high-degree of albuminuria after 6 months from their diagnosis demonstrated poor prognosis, with a 5-year DCGF rate of 5/13 (38.5%). By contrast, only 3/21 (14.3%) single RAASB users progressed to DCGF within 5 years in those without high-degree albuminuria after 6 months. Moreover, in our mediation analysis, high-degree albuminuria after 6 months was a partial mediator of the association between the antihypertensive medication subgroups and DCGF (P = 0.008).