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31 Mar 2018

Autoimmune Kidney Disease – Benefits of an Integrative Medical Treatment Approach.

References:

  1. Sinico RA, Mezzina N, Trezzi B, Ghiggeri G, Radice A. Immunology of membranous nephropathy: from animal models to humans. Clinical and Experimental Immunology. 2016;183(2):157-165. doi:10.1111/cei.12729.
  2. Guleria, A. et al. NMR based serum metabolomics reveals a distinctive signature in patients with Lupus Nephritis. Sci. Rep. 6, 35309; doi: 10.1038/srep35309 (2016).
  3. Lech M and Anders HJ. The Pathogenesis of Lupus Nephritis. J Am Soc Nephrol 24: 1357–1366, 2013. doi: 10.1681/ASN.2013010026
  4. Wu T, Xie C, Han J, Ye Y, Weiel J, et al. (2012) Metabolic Disturbances Associated with Systemic Lupus Erythematosus. PLoS ONE 7(6): e37210. doi:10.1371/journal.pone.0037210

Design:

  1. Literature review.
  2. Sera metabolomic profiling from 22 non-nephritis lupus patients (SLE) patients, 40 lupus nephritis (LN) patients and 30 healthy controls (HC).
  3. Literature review.
  4. Metabolomic study comparing the sera of 20 SLE patients against that of healthy controls.

Practice Implications:

Autoimmune Nephritis (AN) and Systemic Lupus Erythematosus (SLE) are common autoimmune presentations in the integrative medicine setting.  About 50–60% of patients with SLE have nephritis with impaired renal function, and while most AN is idiopathic it may also be co-morbid with many other conditions. AN may develop early in the course of SLE or other triggering disease, but in about 5–10% of cases it becomes clinically apparent several years after the onset of the original illness. Despite advances in effective immunosuppressive therapies (primary standard of care treatment), the treatment of AN and specifically Lupus Nephritis (LN) remains a challenge with considerable morbidity and progressive end stage renal disease requiring kidney replacement therapy.

The reason to review the above four papers as a cohort is partly due to the extreme complexity of not only autoimmunity such as SLE but especially AN and LN.  The other main reason to review this cohort of papers is that the understanding of immunology changes almost daily, and the immunology of SLE and AN / LN is quite complex.  This understanding on the mechanisms of pathology, immune disturbances and disease progression can lead to a better understanding of the natural integrative therapies available to patients suffering from AN / LN.

Metabolomics, immunology and pathophysiology:

Nucleic Acid (NA) derangement is a core factor in AN / LN.  This can be from endogenous NA released as part of the autoimmune response, virally triggered immune NA or methylation deficient NA processing in drug induced SLE and LN.  These NA fragments create direct Toll Like Receptor (TLR) renal inflammation mediated by renal Tumor Necrosis Factor (TNF) alpha and beta.

Infectious states can also aggravate autoimmunity as well as AN and LN.  Although bacterial and viral infections create different immunologic triggers they both can lead to accentuation of AN / LN.

Autoimmune humoral (antibody) immunity responses raise B-cell aggravation of renal tissues as well as triggering Immunoglobulin (Ig) series G, M and A deposits in the kidney.

If all of these triggers were not enough to create a resistant disease state there are de-novo immune complex deposits in the kidney (separate from the aforementioned humoral autoimmune response) that form in the kidneys of patients with SLE who develop LN.

Cell medicated renal damage via cytotoxic T cells and TH-17 positive cells additionally creates damage.

Other metabolomics differences between SLE/LN patients and normal controls include the following (abbreviated in this review for clarity):

  • Altered fatty acid metabolism leading to inflammatory eicosanoids and decreased anti-inflammatory eicosanoid formation.
  • Altered ReDox substrates leading to pro-inflammatory chemistry.  Of note are decreased cysteine, glutathione, choline, Vitamins B5 and B6, Tocopherols and methyltransferases.  This leading to elevated gamma-glutamyl transferase (GGT), slow methylation and overall oxidation.

Implications for natural therapies:

Given the above pathogenic factors and modern understanding of the immunologic and metabolomic imbalances involved the following natural approaches would be the most likely efficacious in the patient with autoimmunity but most critically with AN / LN.  It is crucial that one realizes these supportive measures are necessary as long as the person has autoimmunity with AI / LN, as they are pathologically unable to use the following appropriately.

  • Aggressive support for ReDox balance.  In the case of AN / LN the patient has metabolic forces opposing the “normal” ReDox balance mechanisms and known deficiencies in substrate.  In the February 2015 research review and the Ignite webinar series I went into depth about this subject.  The upshot of all that work is the following need to be replete and balanced to support the pathologically decreased ReDox balance:

o   Glutathione or precursors such as NAC.

o   Ascorbate.

o   Tocopherols or Tocotrienols.

o   Cofactors for these processes including B2, 3 and 5 as well as magnesium, selenium and zinc.

  • Fatty acid balance must also be supported.  Due to the pathological inability to form a balanced eicosanoid output, and an overabundance of inflammatory cytokines from the imbalanced eicosanoids supplementation with Omega-3 fatty acids is critical.
  • Methylation support is critical.  As the methyl cycle is seemingly universally deranged in SLE/LN patients and many with other forms of AN it is critical to include methyl support.  In addition to an assessment of the individual patient methyl cycle genomics support for methyl cycle cofactors and substrate is important.  In addition to the above ReDox supports methyl support would also include active forms of B-12 and Folate as well as vitamin B-6 and choline.  Other supportive nutrients may be required based on the individual genomics of the patient.

In total our understanding of immunology, metabolomics and pathogenesis in autoimmunity and AN / LN has expanded greatly.  This cohort of papers allows a much more specific and efficacious view of potential therapeutic targets.  Understanding that the standard of care in autoimmunity is generally biologic medication management, and that standard is lacking in long term efficacy, the above natural supportive therapies in an integrative medical treatment setting are all the more important.