#NephMadness 2024: Animal House Region

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Selection Committee Member: Kelly Hyndman @DrKeeksPhD

Kelly Hyndman is an Associate Professor of Medicine in the Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, at the University of Alabama at Birmingham. She has trained both in comparative physiology and kidney physiology labs and is currently a principal investigator of a basic science lab with research interests in novel mechanisms of fluid-electrolyte balance.

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Writer: Tiffany Truong @CRRTiff

Tiffany Truong is a nephrologist practicing general and transplant nephrology in Seattle, Washington. Her academic interests include transplant nephrology, electrolyte disorders, medical education, and finding creative ways to better advocate for her patients.

Competitors for the Animal House Region

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Image generated by Evan Zeitler using Image Creator from Microsoft Designer, accessed via https://www.bing.com/images/create, January, 2024. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.

“This world is of a single piece; yet, we invent nets to trap it for our inspection. Then we mistake our nets for the reality of the piece. In these nets we catch the fishes of the intellect but the sea of wholeness forever eludes our grasp. So, we forget our original intent and then mistake the nets for the sea…It is not the nets that are at fault but rather our misunderstanding of their functions as nets. They do catch the fishes, but never the sea, and it is the sea that we ultimately desire”

– Martha Boles, Universal Patterns

Anatomy and physiology are often discussed in terms of organ systems, discrete roles assigned to discrete organs. And yet, it is the interconnectedness of the systems which sustain an animal, and it is the specific animal which determines how these systems interact. To discuss nephrology is to consider hemodynamics and blood flow, to examine acid-base balance in concert with gas exchange, to know the kidney as an endocrine organ. When it comes to metabolism, the sum of processes that transform food into energy, that interdependence is especially highlighted as chemical signals are shared by the whole of the organism. Nephrology meets endocrinology in order to meet metabolic demands which challenge a delicate homeostasis, and with the Gila monster and mourning dove, they do so in ways that highlight the intricacy and duality of these systems. After all, adaptations to different environmental demands are not confined to one organ system, but require a coordinated response that is more interdisciplinary than multidisciplinary.

Team 1: Gila Monster

Hidden deep in underground burrows of the Arizona desert, you will find one of only a few species of venomous lizards on the planet – the famed Gila monster. The Gila monster is a slow animal ambling in at only 1.5 miles per hour at its fastest and eating a rare meal of birds, eggs, small mammals, or reptiles. But when provoked, it can mount a ferocious defense. The bite of a Gila monster is notoriously powerful – as it has no fangs, it must clamp its jaws down and chew on its aggravator, releasing into the wound a slow venom secreted onto its grooved teeth.

This venom contains multiple compounds – thrombin-like enzymes often found in snake venoms to induce coagulopathies, hyaluronidase, and phospholipases. In 1980, researchers at the National Institute of Health (NIH) began ‘a systematic search for bioactive agents in insect and reptile venoms’ – a quest that was deemed ‘a fishing expedition’ for the uncertainty of its yield. They quickly discovered that Gila monster venom contained bioactive peptides resembling vasoactive intestinal peptide (VIP) which could induce amylase release in mammals. A decade later, more bioactive peptides were discovered in Gila venom, called exendin-3 and exendin-4. These compounds structurally resemble the hormones glucagon and glucagon-like peptide-1 (GLP-1). Moreover, exendin-4 could bind GLP-1 receptors in mammalian tissues and produce the same physiologic response. To appreciate the significance of the Gila monster and its venom, we must embark on a parallel journey to understand the physiologic role of GLP-1.

What is GLP-1?

It has long been observed that an oral glucose load elicits a stronger insulin response from the body than an intravenous glucose load. This phenomenon, called the incretin effect, is responsible for up to 70% of the overall insulin response after a meal in normal physiologic states, and is mediated by incretins, hormones secreted by the gut. GLP-1 is one of these incretins. GLP-1 is a potent insulin secretagogue which appears to rescue age-related decline in beta-cell function by increasing the number of beta cells, increasing their insulin-secreting ability and their ability to sense glucose. In type 2 diabetes mellitus, the incretin effect is impaired and considered a key pathophysiologic defect leading to glucose intolerance. Infusion of GLP-1 in patients with diabetes improved their plasma glucose levels, both fasting and after meals, without inducing hypoglycemia and with the added benefit of enhancing satiety leading to weight loss. However, the use of GLP-1 as a therapy was limited by its short half-life as it is naturally inactivated in less than 2 minutes by the enzyme dipeptidyl peptidase 4 (DPP-4). 

Exendin-4 produced by the Gila monster binds GLP-1 receptors, but it is not subject to degradation by DPP-4, which extends its half-life enough to be a feasible therapeutic. This component of Gila monster venom was the basis for a synthetic version of exendin called exenatide, the first GLP-1 receptor agonist created to treat type 2 diabetes mellitus. Ask an expert in the field of venomics, and they will tell you that this was not the first time venom had been used to make medication. They will tell you how the antihypertensive captopril came from the venom of the Brazilian arrowhead viper, how the antiplatelet eptifibatide originated from the venom of the Dusky Pigmy rattlesnake in Florida, and now how the diabetic medication exenatide was gleaned from the saliva of the Gila monster.

GLP-1 and the kidney

Although GLP-1 receptors were originally identified in the pancreas, they have now been reported in many other tissues including the brain, lung, heart and kidney. GLP-1 may even be a key player in the ‘gut-renal axis’, a quick system that regulates the balance of fluid and electrolytes following a meal. Analogous to the incretin effect with glucose loads, it has also been noted that oral sodium loads can be more rapidly excreted by the kidneys than intravenous sodium loads – seemingly independent of aldosterone and atrial natriuretic peptide. GLP-1 may well be a mediator in this process as well, since it is known to increase sodium excretion and urine flow by inhibiting sodium reabsorption in the proximal tubule through inhibition of sodium-hydrogen exchanger 3 (NHE3). GLP-1 can thus act directly on the kidney through promotion of natriuresis and diuresis. 

Seemingly independent of its natriuretic effects, GLP-1 also induces increased glomerular blood flow and filtration rate (GFR), perhaps by direct vasodilatory effects on the afferent arteriole.  Indeed, primate kidneys do express GLP-1 receptors in preglomerular vascular smooth muscle cells and juxtaglomerular cells. Under normal circumstances, this increased GFR is thought to help filter the extra electrolyte load from eating a meal. One might worry then that in patients with diabetes, GLP-1 action would worsen glomerular hyperfiltration. However, in studies of how GLP-1 affects glomerular filtration in diabetes, GLP-1 instead acutely decreased glomerular hyperfiltration paralleled by a reduction in albuminuria. This may be a result of the cumulative indirect effects GLP-1 has in the inhibition of glomerular hyperfiltration in diabetes. 

Other incretin-based therapies, i.e. incretin mimetics like dipeptidyl peptidase-4 (DPP-4) inhibitors, can be useful for glycemic control in diabetic kidney disease due to low reliance on renal clearance. However, they completely lack the luster of GLP-1 receptor agonists’ beneficial renal and cardio-metabolic effects.

While the effects of GLP-1 are diverse and not fully elucidated, it is clear that the improvement in diabetic glycemic control and weight loss alone modifies major risk factors for kidney disease. GLP-1 and the incretin effect have been shifting our perspective about homeostatic mechanisms and what we consider to be an endocrine organ. And without the Gila monster, we would not have had the early treatments that could target the pathophysiology of diabetes in this way, or even had the tools to study this complex system of incretins. In fact, GLP-1-based medicines might be the most impactful therapeutic agents of the 21st century so far!

Return to the Gila monster

Before we leave the Gila monster to scurry from the spotlight of NephMadness, we could not leave the desert without mention of water. Many animals (see hopping mouse) must handle the demands of a dry environment. The Gila monster too has creative adaptations. Its bladder is a water reservoir, able to absorb water into its circulation when food and water are not available. This water-absorbing bladder is a feature shared in other animals needing to conserve water, such as the toad and bear. 

Team 2: Mourning Dove

Image courtesy of Ajit Bhamra.

In contrast to the venomous Gila monster, the gentle mourning dove found throughout North America is a symbol of peace. Known for its soft and distinctive coo, the mourning dove is quite a sweet animal – literally! 

The mourning dove’s plasma glucose is significantly higher than a healthy mammal. At baseline, its plasma glucose ranges 300-330 mg/dL. Despite these high levels, birds like the mourning dove live longer than mammals of equivalent body mass and do not appear to have the oxidative stress that would be expected to accompany hyperglycemia and which are responsible for the microvascular complications we know well in diabetes. Indeed it appears that ‘all birds are seeming hyperglycemic and their blood glucose levels appear to be independent of diet’. This phenomenon of ‘benign hyperglycemia’ is thought to have evolved early in the evolution of bird ancestors away from crocodiles with a ‘genomic revolution’ that drastically altered their metabolic processes in ways we still do not comprehend. 

Though glucose regulation in the avian world generally remains a mystery, a few differences in how hyperglycemia may impact birds has been noted. Firstly, albumin from chickens has been shown to be resistant to non-enzymatic glycation. In addition, birds do not appear to have receptors for advanced glycation products (called RAGE), which are present in mammals and function in innate immunity as well as contribute to cellular dysfunction during hyperglycemia. Birds also have an entirely different insulin-dependent receptor for glucose uptake into cells, GLUT12 rather than GLUT4 in most other vertebrates. Finally, it appears that while insulin primarily lowers plasma glucose in mammals by increasing its uptake into tissues, this does not seem to be the case in the bird. Rather, in the mourning dove, insulin appears to augment glomerular filtration rate, increasing the filtered load of glucose. Researchers suggest that in birds, excretion by the kidneys may also play an important role in glucose regulation.

The ability to tolerate hyperglycemia is not the only impressive feat accomplished by the humble mourning dove. Birds are also known to have an impressive ability to maintain adequate blood flow to perfuse the kidneys even with severe hemodynamic alterations. Blood supply to the avian kidney comes not just from arterial blood, but also from a low-pressure renal portal system coming from veins returning blood from the posterior limbs. Moreover, this portal blood can be shunted either toward the afferent venous system of the kidney or the vena cava, by control of a renal portal valve. This portal blood does not supply glomerular capillaries and so does not contribute to glomerular filtration, but only supplies peritubular capillaries facilitating tubular secretion and reabsorption. In veterinary medicine, this leads to the consideration that drugs injected into the tail of a bird may reach the kidneys before any other organ, leading to potentially more clearance as well as nephrotoxicity. This renal portal system is actually present in most vertebrates (to be fair to the Gila monster), but not in mammals, and control of renal portal blood through valves may be unique to birds.

The kidneys of birds are distinguished in another important way. Among vertebrates, most animals do not have any loops of Henle in their nephrons – only mammals have loops, allowing them to concentrate their urine. Reptiles, amphibians, and vertebrate fish nephrons all lack loops of Henle and will often decrease the number of glomeruli that filter blood when water conservation is necessary and also use other methods to assist with water and sodium homeostasis outside of the kidneys, unlike mammals who rely solely on the kidneys (recall the salt gland in sharks and marine iguanas). Birds, however, have both types of nephrons, those with and without loops of Henle and structurally have a more heterogeneous mix of nephron morphology than either reptiles or mammals. Though only 10-30% of nephrons in the bird kidney have loops, they allow the bird to concentrate their urine unlike reptiles, just not as effectively as mammals. When challenged with a salt load or water deprivation, there is evidence that birds reduce the number of filtering nephrons as reptiles do, but in particular they shut off filtration of those reptilian type nephrons which are unable to concentrate their urine while still continuing to filter through their mammalian-type nephrons which do have loops and can concentrate their urine!

Finally, in contrast to the Gila monster which has a urinary bladder with water reabsorptive capacity, birds do not have bladders at all. Instead, they have a cloaca, a common orifice for the contents of the gastrointestinal, urinary and genital tracts. The gastrointestinal and urinary systems do not just coexist in the cloaca, but work together as urine enters the terminal portion of the gastrointestinal tract. How do they work together? Birds excrete their nitrogenous waste products in the form of uric acid rather than urea as mammals do. The uric acid is bound to protein as a colloidal solution rather than as an aqueous solution from which it could easily precipitate as crystals. The cost then of excreting nitrogenous waste in the mourning dove is the requirement of protein, a heavy metabolic price to pay. Rather than lose all of this valuable protein, birds move this urine from the cloaca into the rectum of the gastrointestinal tract by reverse peristalsis, where that protein is degraded and reabsorbed back into the bloodstream. Extra water can also be reabsorbed from the rectal urine by this mechanism!

The kidneys of the mourning dove are impressive as they can tolerate hyperglycemia and hypotension, take advantage of the functional and morphological heterogeneity of their nephrons in states of water deprivation, and join forces with the gastrointestinal system to excrete nitrogenous waste in a metabolically efficient way.

It is a commonplace bird, the mourning dove, which teaches us about the remarkable diversity of life, the breadth of conditions that may be considered normal and the range of ways that the job of homeostasis can be accomplished. Meanwhile, the rare Gila monster and its venom reminds us that even a single compound can play multiple roles in multiple systems and be effective across different species. In such paradoxical ways, these universal patterns of life emerge, revealing no limit to the number of ways we differ or the number of commonalities we share.

– Executive Team Members for this region: Anna Vinnikova @KidneyWars and Matt Sparks @Nephro_Sparks | Meet the Gamemakers

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on May 31, 2024.

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• Source: https://ajkdblog.org/2024/03/01/nephmadness-2024-animal-house-4-region/