High Salt-Intake and Autoimmunity

The incidence of auto-immune diseases has dramatically increased in the past 50 years and the concern that environmental exposures have contributed to this increase is broadly suspected. However, it is very hard to pin-point to an individual factor. 

Very intriguing observations were just published at Nature linking a high-salt intake to increased auto-immunity. The authors demonstrate that a high-salt diet increased the severity of experimental autoimmune encephalomyelitis (*EAE) - a mouse model of multiple sclerosis . The authors proposed that high salt-intake induces serum glucocorticoid kinase 1 (SGK1), which than promotes IL-23R expression and enhances TH17 ** cell differentiation in vitro and in vivo. SGK1 has has been shown to govern Na transport and salt (NaCl) homeostasis in other cells. Mice lacking this kinase in their T cells have impaired expression of IL-17-family cytokines and of a receptor for another cytokine molecule, IL-23, which stabilizes the TH17 cell phenotype.

Though salt might not be the trigger of autoimmunity, the possibility that high-salt intake might exacerbate auto-immunity is very provoking and would encourage even more the emergent initiation of trials evaluating the efficacy of low salt-diet in the development of auto-immune diseases and other potential diseases related to inflammation, such as coronary heart disease. 

Based on recent computer-generated data suggesting all the potential benefits of lowering salt consumption, this discussion is very pertinent.  

Above the diagram from the Editorial of Nature discussing the findings and below some additional explanations about the mouse model and Th17 cells. One caveat is that effect of high sodium on human cells was only shown in vitro...

* EAE: Experimental autoimmune encephalomyelitis. An animal model of the human autoimmune disease multiple sclerosis. EAE is experimentally induced in animals by immunization with myelin or with peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

** TH17 cells (T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-6, IL-21 and IL-23, as well as the transcription factors RORgt (retinoic-acid-receptor-related orphan receptor-gt) and STAT3 (signal transducer and activator of transcription 3).

Venus, Sjogren's and the Kidney

The Williams sisters put yet another Wimbledon doubles tittle into their trophy case over the weekend.  This, just hours after Serena had won the singles competition.  Pretty impressive.

In reading the coverage I learned that during the last year Venus had been diagnosed with Sjogren's syndrome (I know, I know, old news to those paying attention).  There was no mention in any of the reports that Venus has had any kidney problems, her main issues have apparently been with severe fatigue and joint pains.  Although we usually think of dryness in the eyes and mouth when we hear Sjogren's syndrome there are a number of potential renal tip offs to the diagnosis...

Interstitial (and sometimes glomerular) Disease

Interstitial nephritis - Typically mild but can progress to ESRD in rare cases.  In a Mayo Clinic case series 46% and 25% of patients with Sjogren's syndrome who underwent kidney biopsy had chronic or acute interstitial nephritis respectively.  Only one of the 24 patients biopsied had ESRD and this was from a total case series of 7276 patients (there may have been some additional cases of ESRD lurking in the cohort who didn't get biopsied as they didn't have complete clinical data on all the patients).

Glomerular disease - Less common than interstitial disease but does occur. Associations with MPGN (often in association with cryglobulins), FSGS, Membranous and minimal change have all been reported. 

Tubular defects

Distal renal tubular acidosis - An unexplained distal RTA is a invitation to investigate for Sjogren's.  Patients with distal RTAs are prone to nephrolithiasis (typically calcium phosphate stones) and nephrocalcinosis.  Severe associated hypokalemia can also occur with flaccid paralysis having been described as a presenting symptom.

Although the cause of distal RTAs in most patients with Sjogren's syndrome is unknown a few patients have been described who have an absence of the H-ATPase pump on intercalated cells in the collecting duct.  Another hypothesis is that Sjogren's leads to autoantibodies directed against carbonic anhydrase II thus leading to the generation of less protons for excretion.

Proximal RTA and full blown Fanconi's syndrome have also been described.

Nephrogenic diabetes insipidus - Urinary concentrating defects are not uncommon in patients with Sjogren's.  As an example, in an Italian series 21% of patients were noted to have an abnormal urinary concentrating ability.  The cause of this tubular defect is again unknown but histologically clusters of lymphocytic infiltrate can sometimes be seen around collecting ducts which could theoretically interfere with the actions of ADH.

Hypokalemia - This can occur in the absence of RTA and is thought to be due to tubular damage induced sodium wasting with subsequent increased distal sodium delivery.  In the distal nephron increased sodium delivery drives potassium loss in exchange for sodium.  This effect may be amplified by volume depletion with subsequent increased aldosterone levels which again drive sodium absorption and potassium loss.

IgG-4 associated kidney disease

We heard a very interesting presentation today on autoimmune pancreatitis and concurrent systemic disease. The pathogenesis is felt to be related to IgG-4 producing plasma cells, and has now been linked to numerous systemic disease manifestations. The case in question had possible associated autoimmune hypophysitis, leading to presentation with a central diabetes insipidus picture.

These conditions first came to light following the description of autoimmune pancreatitis and recognition of the association of this disease with various other organ system involvement. The lesions in the affected areas had in common a dense infiltration of IgG-4 plasma cells and T lymphocytes. Involvement has been described in the liver, pancreas, gallbladder, kidneys, retroperitoneum and salivary glands as well as many other tissues.

In terms of renal involvement, the most commonly reported lesion is that of tubulointerstitial nephritis, again with a characteristic infiltration of IgG-4 positive plasma cells. Nodular lesions have also been described, which in many cases can be confusing for primary or secondary malignancies. Of note, sometimes these lesions can be FDG avid, and light up on PET scans, further confusing the picture with malignancy. Membranous nephropathy with IgG-4 positive deposits has also been described. Finally, retroperitoneal fibrosis may also predispose to obstructive nephropathy.

Diagnosis involves biopsy of the affected tissue with demonstration of IgG-4 positive plasma cells. Serum IgG-4 levels should also be requested and, if elevated, have a sensitivity for disease presence of ~70-95%.

Most successful reported treatments have been with corticosteroids, usually starting high and tapering to a lower maintenance dose. There is limited experience in relation to the duration of treatment with steroids or use of steroid-sparing agents in this condition.

Hepatorenal Disease - Beyond the syndrome

In general, when we are asked to evaluate a patient with liver disease for the development of acute renal failure, the three top differentials are usually: true hepatorenal syndrome, a prerenal picture (often 2/2 overdiuresis) and ATN. Cholemic nephrosis can also be considered but it usually requires very high bilirubin levels. These causes were previously discussed on prior blogs. However, I wanted to focus on some more atypical etiologies that we should keep in our list in case things don’t look as straight forward.

The first key point is to always carefully look at the urine on microscopy and quantify the proteinuria. The latter is important since some conditions that have proteinuria do not show on dipstick (not related to albuminuria), like AL amyloidosis, which can also be a cause of liver disease.

The presence of active urine sediment opens a whole new list of differentials, which can be narrowed down by using the primary cause of liver disease as a starting point:

1) Alcoholic cirrhosis: Mesangial IgA deposition associated with chronic liver disease, is the most common form of secondary IgA nephropathy. An imparied removal IgA-containing complexes by the Kupffer cells in the liver is thought to predispose to IgA deposition in the kidney. Despite the frequency of glomerular IgA deposits in advanced liver disease, most adults have no clinical signs of glomerular disease. It is unclear why some patients are predisposed to renal manifestations while others are not.

2) Viral hepatitis (HBV or HCV): might lead to variable glomerular lesions. It is important to add complements and cryo to your workup.

• MPGN: (low C3 and C4) Renal manifestations range from hematuria to nephrotic syndrome. In some cases, its associated with mixed cryoglobulenemia (positive Cryo and low C4). Cryos picture tends to be associated with purpura, arthralgia and lymphadenopathy.

• Membranous nephropathy (normal complements): thought to be related to HBeAg and anti-HBe deposition on subepithelial space.

• Secondary polyarteritis nodosa (vasculitis): typically occurs within 4 months after the onset of HBV infection (also cases with HCV) and has similar clinical features as the idiopathic form - systemic symptoms (fever, weight loss, fatigue) + Skin signs (purpura/livedo reticularis) + neuropathy + GI symptoms (pain/bleeding) + HTN.

Don’t forget about potential drugs used for treatment of hepatitis that can be nephrotoxic to the tubules (e.g. adefovir)

3) If an auto-immune disease is the cause of liver failure, like primary sclerosing cholangitis (PSC), you have to think about a possible concomitant auto-antibody process. Interestingly, more than 75% of patients with PSC have either ANA or pANCA. A small proportion also have either anti-GBM or anticardiopilin antibody (antiphospholipid syndrome). Finally, more than 90% of patients with PSC also have ulcerative colitis. The latter may predispose to secondary amyloidosis (amyloid A deposition 2/2 chronic inflammation) or its treatment with sulfazalazine (type of NSAID) might lead to AIN or nephrotic syndrome.

Overall, just be thorough in your evaluations and don’t let the routine of patient care limit your differentials.

Picture: Chihuly amazing work on glass that is being exposed in Boston now! Truly outside the box.