The Goldilocks Principle on Bilirubin

The impact of hyperbilirubinemia on kidney function continues to be a topic of discussion with two conflicting philosophies: whether bilirubin is nephrotoxic or nephroprotective. To understand the two perspectives, it is imperative to review the physiology behind its metabolism. Eighty-five percent of bilirubin is produced from the breakdown of red blood cells in the reticuloendothelial system as unconjugated bilirubin, and the rest is produced from myoglobin. Unconjugated bilirubin is albumin bound in the blood and delivered to the liver where it enters the sinusoidal circulation (1). There, it is taken up by hepatocytes, made water soluble by conjugation, and subsequently excreted as bile. Excessive production, impairment, or obstruction at any of these steps can lead to either conjugated or unconjugated hyperbilirubinemia and clinical jaundice. After exiting the biliary system, the conjugated bilirubin is secreted in the duodenum and converted to urobilinogen by gastric microfauna. Twenty percent of urobilinogen is reabsorbed systemically and either enters portal circulation or is renally excreted. It is worth noting that urobilinogen production will decrease if the level of defect is prior to duodenal secretion (1).

The nephrotoxic potential of hyperbilirubinemia was first proposed in 1899 after a review of autopsies from patients with jaundice and kidney failure revealed bile pigments in the glomeruli (2). In 1937, Elsom (3) showed the improvement of kidney function with clinical improvement of jaundice in a small cohort, establishing the dogma. Mechanistically, in states of elevated, conjugated hyperbilirubinemia, the glomerular filtration and tubular transport processes may be overwhelmed because of increased oxidative stress, proximal tubular dysfunction, and cast formation (4, 5). In a histological study of 44 patients, bile casts were mostly found in the distal nephron and had significantly higher levels of conjugated bilirubin (6). A large study of over 30,000 patients by Chen et al. (7) showed that higher total bilirubin levels were associated with increased all-cause mortality; of note, liver patients were not excluded, and therefore, there may be an additive effect on the findings.

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On the other hand, bilirubin has also been shown to minimize oxidative stress, highlighting possible nephroprotective effects in vivo and on a population level. In an earlier study, it was shown that conjugated bilirubin can scavenge hypochlorous acid, a reactive oxygen species typically produced by neutrophils, and thus act as an antioxidant (8). Boon et al. (9) performed a more recent investigation into this using an adenine-induced animal model of chronic kidney disease (CKD) in rats. Adenine-induced CKD produced intense oxidative stress, and this study demonstrated that rats with endogenously elevated total bilirubin levels had reduced oxidative stress and less kidney damage. The authors concluded that systemic inflammation and oxidative stress may be attenuated in states of elevated total bilirubin (9). On a population level, a large, retrospective study showed that low total bilirubin levels are an independent risk factor of estimated glomerular filtration rate decline in patients with diabetes and hypertension (10). Interestingly, patients with unconjugated hyperbilirubinemia end stage kidney disease with a uridine diphosphate glucuronosyltransferase 1A1 genotype, similar to Gilbert's syndrome, had reduced cardiac events and all-cause mortality (9). Beyond the kidneys, Cao et al. (11) published a 4-year follow-up of 440 patients with previous myocardial infarction, and they concluded that higher total bilirubin levels reduced incidence of long-term cardiovascular events, providing a secondary risk prevention.

So, who is the winner between the two opposing paradigms? Like many concepts in medicine, the truth likely lies somewhere in the middle. From a basic science standpoint, there appears to be evidence for both nephrotoxic and protective mechanisms, which speaks more to the complexity of how physiology works than provides a definitive answer. Clinical studies showing the toxic effect of elevated bilirubin are inherently biased, as these studies select a highly morbid population with many confounding factors that can lead to kidney injury. Specifically, the large study by Chen et al. (7) did not exclude patients with liver disease. Interestingly, the study by Cao et al. (11) that showed positive cardiac benefits excluded supraphysiological levels of bilirubin and patients with liver, hemolytic, and gallbladder disease.

The second point requiring further clarification pertains to the specific type of bilirubin under consideration. The majority of referenced studies measure “total bilirubin,” thus leaving the impact of conjugated versus unconjugated bilirubin inadequately understood. This poses a challenge when examining studies that suggest nephroprotection. For instance, Stocker and Peterhans (8) demonstrated the antioxidant properties of conjugated hyperbilirubinemia, while Boon et al. (9) discussed the positive benefits of unconjugated hyperbilirubinemia in hemodialysis patients. Consequently, there is a need for well-structured translational studies to determine the potential range at which the benefits of bilirubin become positive; this relationship might even follow a U-shaped curve. It is also possible that both unconjugated and conjugated bilirubin confer nephroprotective effects, but this association requires further investigation. Bile cast nephropathy has been compared to myeloma cast nephropathy, and similar to how light chains can surpass a threshold and induce nephrotoxicity, bilirubin may follow a comparable pattern. Keeping the literature in mind and the clinical course of liver and kidney diseases into account, this might be an example of the “Goldilocks Principle”: an agonistic and antagonistic duality in how bilirubin potentially impacts the kidney.