Post Hoc Analysis of HALT-PKD Data Examines Patterns of Kidney Function Decline

An estimated one in 400 to 1000 individuals in the United States and more than 12 million worldwide are affected by autosomal dominant polycystic kidney disease (ADPKD). The predominant causative genes are PKD1 on chromosome 16 and PKD2 on chromosome 4. For patients with PKD1 genotype, mean age at onset of end-stage renal disease (ESRD) is 56 years; for patients with PKD2 genotype, mean age at ESRD onset is 73 years.

Kidney cysts begin to develop in utero and grow throughout life; however, glomerular filtration rate (GFR) generally remains normal until the fourth or fifth decade. Earlier studies demonstrated that when GFR begins to decrease, the decline is rapid and leads to ESRD within 5 to 10 years. In the MDRD (Modifications of Diet in Renal Disease) Study, patients with ADPKD had fast decline in measured GFR of 5.8 mL/min/1.73 m2 per year.

According to Godela M. Brosnahan, MD, and colleagues, there are few data on a detailed examination of individual patterns of decline in estimated GFR (eGFR). Utilizing data from the HALT-PKD (Halt Progression of Polycystic Kidney Disease) trials, Dr. Brosnahan et al. conducted a longitudinal post hoc analysis to test the hypothesis that GFR decline in ADPKD is not always linear and rapid, and that periods of stability can occur even in advanced cases. Results of the analysis were reported in the American Journal of Kidney Diseases [2018;71(5):666-676].

The current analysis included 494 HALT-PKD Study A participants and 435 HALT-PKD Study B participants. The Study A participants were younger and had preserved eGFR compared with Study B participants who were older and had reduced eGFR. Eligible participants had >3 years of follow-up and seven or more assessments of eGFR. Relevant measurements were longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. Outcomes of interest were the probability of linear and nonlinear patterns of decline or of stable eGFR calculated for each participant form a Bayesian model of individual eGFR trajectories.

Study A

During mean follow-up of the 494 Study A participants, 62.5% (n=309) were classified as linear progressors, 21% (n=108) as nonlinear progressors, and 15.6% (n=77) as nonprogressors.

Some baseline characteristics, i.e., age, sex, baseline eGFR, and left ventricular mass index, were similar across the three groups. However, compared with both groups of progressors, the nonprogressors had significantly smaller total kidney volume (TKV) and height-adjusted TKV, higher renal blood flow, and lower urinary albumin excretion. The nonprogressor group also included a higher proportion of low-risk cases and a lower proportion of high-risk cases. Mean slopes for annual TKV increase for linear progressors, nonlinear progressors, and nonprogressors were 6.4% (95% confidence interval [CI], 6.0-6.8), 6.3% (95% CI, 5.6-7.0), and 4.8% (95% CI, 4.0-5.7), respectively (P=.006 between groups).

During the trial, blood pressures were similar in the three groups; the number of medication steps required to achieve the blood pressure goal was slightly lower in the nonprogressor group. By definition, decline in eGFR was significantly greater in progressors compared with nonprogressors, who had no significant change in eGFR. Mean slopes for linear and nonlinear progressors were –3.5 (95% CI, –3.2 to –3.7) and –3.7 (95% CI, –3.3 to –4.0) mL/min/1.73 m2 per year (P<.001 between groups). There was no association between age and rate of eGFR decline in linear progressors.

Sixty-two percent of nonprogressors had the PKD1 genotype and 84% had a family history of ADPKD. Patients in the progressor groups had slightly higher rates of acute kidney injury (AKI), but gross hematuria and hospitalizations were equally common in all three groups, with no obvious temporal relationship between those events and steeper eGFR slope.

 

Study B

Mean follow-up for the 435 participants in Study B was 5.4 years. During that time, 81% (n=352) were classified as linear progressors, 13% (n=58) as nonlinear progressors, and 6% (n=25) as nonprogressors.

With the exception of age, the three groups were similar in baseline characteristics; nonprogressors (14 men, 11 women) were older than progressors. There was no significant difference in muscle mass estimated by daily creatinine excretion; blood pressures and number of medication steps needed to achieve the blood pressure goal were also not different. Because none of the nonprogressors achieved an end point, they remained in the trial significantly longer, whereas >50% of progressors did reach an end point.

Nonprogressors had a nonsignificant decline in eGFR. Mean slopes for linear and nonlinear progressors were –3.9 (95% CI, –3.8 to –4.1) and –3.8 (95% CI, –3.3 to –4.2) mL/min/1.72 m2 per year (P<.001 between groups). Among linear progressors, there was an association between younger age and faster progression; a 10-year decrease in baseline age resulted in a 0.86 mL/min/1.73 m2 per year steeper eGFR slope (P<.001).

Two-thirds of the nonprogressor group had the PKD1 genotype. Of those, one-third had a truncating PKD1 mutation, but weak nontruncating mutations were more common. Seventy-six percent of nonprogressors had a family history of ADPKD.

Participants in the nonlinear progressor group experienced episodes of AKI; frequency of hospitalizations was similar in the three groups. There was no temporal relationship between those events and steeper eGFR slopes observed.

The relatively short observation time (5 to 8 years) and limited data on individual clinical events were cited by the authors as limitations to the study. Also cited was the absence of magnetic resonance imaging in Study B and the use of eGFR as opposed to measured GFR.

In summary, the researchers said, “This is to our knowledge the first large analysis of individual patterns of eGFR decline in ADPKD. Loss of kidney function is not always linear and rapid; prolonged stabilization of GFR can occur even in advanced disease. Future trials evaluating the effect of treatment on eGFR will need to recognize that eGFR slopes in ADPKD can have varying configurations and can change in 13% to 22% of patients without apparent cause.”

Takeaway Points

  1. Results of earlier studies of autosomal dominant polycystic kidney disease (ADPKD) indicated that loss of kidney function commonly followed a steep and relentless course.
  2. In a recent study, researchers tested the hypothesis that decline in glomerular filtration rate (GFR) is not always linear and rapid and that even in advanced disease, periods of stability can occur.
  3. Study results found that a substantial fraction of patients with ADPKD experience prolonged intervals of stable GFRs; there was an association of lower body mass index with more stable kidney function in early disease.