In this analysis using data from the CRISP study, we found a statistically significant association between the interaction of time with caffeine (any vs. none) and ln(htTKV). This interaction term was positive, indicating that the rate of ln(htTKV) growth is higher with caffeine intake. However, the effect size of the interaction was quantitatively very small: 0.6% per year difference in the htTKV among caffeine consumers. Compared to the 4.6% average annual rate of increase in kidney size in non-caffeine consumers, the increased rate of 5.3% due to caffeine was small and unlikely to be clinically important. While the rate of kidney growth in caffeine consumers was higher, the expected htTKV at baseline and throughout the follow-up period showed a trend to be lower than for patients who did not consume caffeine (Fig. 2). Similar to the expected htTKV being lower throughout the follow-up period, the expected mGFR at baseline and throughout the follow-up period was higher for patients who consumed caffeine, although these results were not statistically significant (Fig. 3). The lack of association between caffeine and mGFR has been reported previously, including a meta-analysis that examined coffee consumption and chronic kidney disease in nearly 15,000 individuals [25]. These relationships were generally consistent throughout our sensitivity analyses. Taken together, these findings indicate that caffeine consumption is unlikely to have a clinically significant effect on ADPKD progression.

Fig. 2 Spaghetti plot of ln(htTKV) (on left) and htTKV (on right) over time for each individual patient (randomly jittered to preclude presentation of any individual’s actual data). The final adjusted model is overlayed (Model 2), showing the differences in slope and intercept for patients who reported consuming caffeine and patients who did not report consuming caffeine at baseline Full size image

Fig. 3 Spaghetti plot of mGFR over time for each individual patient (randomly jittered to preclude presentation of any individual’s actual data). The final adjusted model is overlayed (Model 2), showing the differences in slope and intercept for patients who reported consuming caffeine and patients who did not report consuming caffeine at baseline Full size image

The reason why caffeine intake did not accelerate disease progression is unclear. One possible reason might be that the amount of caffeine that reaches the kidney instead of being metabolized in the liver may simply be too small [26]. Only 3% of caffeine is excreted intact [27]. Theoretically it is possible for caffeine to affect renal epithelial cAMP, but only in the patients with very high caffeine intake and high excretion rates of unmetabolized caffeine. In our analysis, patients in the highest category of caffeine intake did not have increased rates of kidney growth or GFR decline. In the majority of caffeine consumers, tissue exposure to caffeine may be too low to significantly increase cAMP in collecting duct cells and thus increase cyst and kidney volume. Additionally, this study examined caffeine intake at baseline only. Since patients with ADPKD are advised to limit caffeine intake, the patients in this study may have consumed less caffeine on average than what was reported at baseline. This could further decrease the amount of caffeine reaching the kidneys intact.

Another possible reason is because of the presumed natriuretic effects of caffeine [28]. Caffeine has been reported to be a potential acute inhibitor of sodium and hence water reabsorption in the proximal convoluted tubule [29]. If this were to be compensated by increased water intake, serum sodium concentration and osmolarity would tend to decrease thus suppressing vasopressin secretion. Vasopressin is believed to accelerate ADPKD progression by acting on V2 vasopressin receptors in cyst epithelial cells to increase cAMP. Tolvaptan, the only approved therapy for ADPKD, is a V2 receptor antagonist and has been shown to slow the increase in kidney volume [30]. As such, caffeine might have a beneficial effect on cellular cAMP levels through suppressing vasopressin levels that might counteract some or all of its effects on phosphodiesterases. However, no studies have shown the effects of caffeine intake on serum sodium concentration, urine osmolarity, urine volume and body fluid parameters in patients with chronic kidney disease. It is also important to note that studies completed on healthy adults have shown no effect of caffeine on these values [31, 32].

Finally, the effect of caffeine may have been masked by the presence of hypertension. Hypertension was a significant risk factor for disease progression in all of our models, and it is well known that acute consumption of caffeine increases blood pressure [33]. The relationship between chronic consumption of caffeine and hypertension is less clear. In some studies, chronic consumption of caffeine did not increase the frequency or severity of hypertension while in others, including one specifically studying ADPKD rats, it was associated with worsening of hypertension [9, 21, 34, 35]. Additionally, it is believed that caffeine exerts a variable response on hypertension due to genetic differences [36]. Thus it is possible that caffeine may exacerbate the deleterious effects of hypertension on ADPKD progression.

There are several limitations of this study. We assessed caffeine intake at baseline. Although caffeine intake is thought to be habitual and is not expected to change over time, some patients in our sample reported varying caffeine intake over time. This could be for many reasons. In 2015, KDIGO Guidelines included a formal recommendation for patients with ADPKD to avoid caffeine intake [8]. While this formal recommendation most likely did not impact this study because this data was collected before 2015, these guidelines reflect the general tendency to recommend that patients with ADPKD restrict caffeine intake. While these factors may have contributed to the results of this study, by analyzing only the baseline caffeine values, we emulated the clinical situation in which information might be limited to a single snapshot of the patient’s environmental and lifestyle exposures.

Another limitation is that CRISP was an observational prospective cohort study and the lifestyle data was self-reported. Additionally, caffeine content from food and the variability of caffeine content in beverages was not recorded in the CRISP questionnaire. As our primary analysis examined caffeine consumption as any vs. none, it may be limited by not including caffeine sources beyond coffee, tea and soft drinks. Finally, because the patients in CRISP were enrolled when they had relatively preserved GFR, the average rate of GFR decline is slow and few patients have reached ESRD so far, thus limiting the power to detect the effect of caffeine consumption on these outcomes.

Our study has several important strengths. CRISP is the largest and longest cohort study of ADPKD with a follow-up time of 14 years. This gave us the opportunity to explore the longitudinal relationship between caffeine and ADPKD progression, as measured by both htTKV and mGFR, over an extended timeframe. Another strength of this study was the availability of information on the intake of caffeinated beverages other than coffee and tea. This is important because beverages such as sodas constitute a significant source of dietary caffeine, particularly in the U.S. population. Finally, all the patients in this study were genotyped for PKD1 and PKD2 mutations, allowing us to adjust for the confounding effect of the PKD genes and allelic effects on both outcomes.

The most important strength of this study is that it used data from the CRISP cohort. The only other longitudinal study of caffeine and ADPKD progression was the study completed by Girardat-Rotar et al. in the Swiss ADPKD cohort [11]. While this study agreed with the conclusions of the Swiss ADPKD study, there are several key distinctions. First, this study had a sample size of 239 compared to the Swiss ADPKD sample size of 151. Second, the Swiss ADPKD study had a median follow-up time of 4.4 years while this study had a median follow-up time of 12.5 years. Third, the Swiss ADPKD study examined only coffee consumption as a caffeine source while this study included caffeinated beverages beyond coffee. Lastly, the Swiss study did not adjust for genotype while this study was able to utilize genetic information.