Immunological Avalanches in Renal Immune Diseases

Abstract

The complex nature of immune system behavior in both autoimmune diseases and transplant rejection can be understood through the lens of avalanche dynamics in critical-point systems. This paper introduces the concept of the "immunological avalanche" as a framework for understanding unpredictable patterns of immune activity in both contexts. Just as avalanches represent sudden releases of accumulated potential energy, immune responses exhibit periods of apparent stability followed by explosive flares triggered by seemingly minor stimuli. The model presented here draws parallels between immune system behavior and other complex systems such as earthquakes, forest fires, and neuronal activity, where localized events can propagate into large-scale disruptions. In autoimmune conditions like systemic lupus erythematosus (SLE), which affects multiple organ systems including the kidneys in approximately 50% of patients, these dynamics manifest as alternating periods of remission and flares. Similarly, in transplant recipients, the immune system exhibits metastable behavior under constant allograft stimulation. This critical-point dynamics framework is characterized by threshold-dependent activation, positive feedback loops, and dynamic non-linearity. In autoimmune diseases, triggers such as UV light exposure, infections, or stress can initiate cascading immune responses. In transplant patients, longitudinal analysis reveals how monitoring oscillatory patterns in blood parameters and biological age markers can predict rejection risk. In a preliminary study on kidney transplant, all measured variables showed temporal instability. Proteinuria exhibited precise log-log linearity in power law analysis, confirming near-critical-point system behavior. Two distinct dynamic patterns emerged: large oscillations in eGFR, proteinuria, or biological age predicted declining function, while small oscillations indicated stability. During avalanche events, biological age increased dramatically, with partial reversal leaving persistent elevation after acute episodes. Understanding these dynamics has important implications for therapeutic approaches in both contexts. Key findings suggest that monitoring parameter oscillations, rather than absolute values, better indicates system instability and potential avalanche events. Additionally, biological age calculations provide valuable prognostic information, while proteinuria measurements offer efficient sampling for system dynamics assessment. This conceptual model provides a unifying framework for understanding the pathogenesis of both autoimmune and transplant-related immune responses, potentially leading to new perspectives in disease management and rejection prediction.

Keywords: acute kidney injury; critical state; lupus; proteinuria.

Figure 1

A schematic diagram of the pathogenesis of lupus nephritis. Subtle stimuli activate DNA release from circulating cells such as neutrophils (NETosis), which prompts the formation of immunocomplexes with different immunoglobulin isotypes. The immunocomplexes reach the kidney glomeruli, thereby activating the complement system (C3 and C1q) and causing glomerular damage.

Figure 2

A scheme of the idea of immunological avalanche in lupus and kidney transplant. A weak, slow driving force continuously stimulates the immune system, though at a subclinical level. Here, the activation is represented as a neutrophil releasing increasing amounts of DNA, thereby activating antibody production. A feedback mechanism and the pharmacological immunomodulation keep the system at near-critical-point threshold. Under such circumstances, a seemingly small stimulus causes a large “avalanche” with rapid activation of the immune system and organ damage (lupus flare or kidney rejection).

Figure 3

Immunological avalanches in kidney transplant. (A,B) Among the tested variables, proteinuria may be a suitable parameter to predict instability in the kidney graft (note the peaks of large proteinuria changes before the fall in eGFR). Oscillations in the proteinuria follow the power law known for near-critical-point systems (B). Two examples of oscillatory events in eGFR and biological age are graft stability (C) and progressive graft dysfunction (D).

Figure 4

Pathogenesis of IgA immunological avalanches. A weak, continuous driving force, here depicted as a modification of the gut microbiota, stimulates clones of B cells in Peyer’s plaques (gut) to produce modified IgA antibodies. Under the continuous driver, the system operates close to a critical point after which an avalanche occurs: circulating IgA antibodies are then entrapped in the mesangium of glomeruli, inducing hematuria and proteinuria. The use of local anti-inflammatory drugs, such as enteric release budesonide, can induce the system to return to a stable state. “Stability-.activity” refer to the two phases of the immune system, depicted as a mountain. The enteric budesonide moves the system towards the stability region.