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(8) FGF23 vs (9) Cystatin C
These two teams have been knocking on the door of nephrology lab orders for a few years now. Lets look at each more closely.
Two markers have arose in the last decade that have changed the thinking in nephrology. In search for the troponin for acute kidney injury, cystatin C is a front runner at the current time. While urinary markers have been studied, a serum marker is usually easier to measure and very useful in the anuric patient. While many of you know that cystatin C is a potential biomarker for kidney disease, many might not be aware of its role as a predictor of worsening cardiovascular disease and apparently it plays a role in disorders involving amyloid in the brain such as Alzheimer’s disease. Based on large studies, the reference interval is usually 0.57- 1.12mg/dL.
FGF23 is a fibroblast growth factor protein that is responsible for phosphate metabolism. While it’s role in CKD and ESRD is evolving. FGF-23 is a phosphatonin, a hormone that increases renal phosphate excretion. Increased activity of this protein leads to increased renal phosphate wasting and diseases such as autosomal dominant hypophosphatemic rickets and some tumors can over produce this hormone leading to tumor induced osteomalacia. Loss of this protein leads to familial tumoral calcinosis.
(11) suPAR vs (6) anti-PLA2R
The hype in this matchup is palpable. Might as well be a dunk contest.
In 2011, the identification of circulating urokinase receptor (suPAR- serum soluble urokinase receptor) as a cause of focal segmental glomerulosclerosis (FSGS) was reported in Nature Medicine. This received considerable attention in the scientific community. They initially reported that high levels of suPAR was detected in 2/3rds of patients with FSGS. The group who initially described the association also recently published a letter in AJKD describing mother to child transmission of suPAR causing proteinuria. There has been some controversy surrounding this story as some have argued that suPAR is non-specific for idiopathic FSGS. This discovery has led to much speculation and definitive large clinical studies to better understand how suPAR levels can be used to guide therapy are yet to be completed.
The description of the M-type phospholipase A2 receptor anti-PLA2R as the long sought after antigen causing membranous nephropathy was a huge story in 2009 when this was published in the NEJM. Since this time we are beginning to understand more and more about how the detection of antibodies against this receptor can help in the treatment of patients with membranous nephropathy (MN). In the future, the detection of anti PLA2R antibodies may help in parsing out if a patient has primary MN who require aggressive therapy or has secondary disease. Levels of circulating anti-PLA2R antibody may also aid in monitoring disease activity and in assessing response to therapy. A recent review in ACKD can be found here. We are still awaiting properly performed clinical trials to guide us on how identification of this antibody will be useful in clinical medicine. However, there is a lot of potential to benefit patients and guide therapy. This is an exciting discovery for sure.
(13) HIVAN vs (4) MPGN reclassification
The nephropathologists will have a front row seat for this matchup.
HIV-associated nephropathy (HIVAN) refers to the collapsing variant of FSGS. HIVAN was first described in 1984. Mounting evidences showed that that the HIV virus directly causes kidney damage. This was an important event for the field of nephrology. Currently, due to the treatment of HIV, HIVAN is seen less in US but still has a strong prevalence in other parts of the world. This discovery also led to an important form of FSGS discovery or an entity entirely unto its own—collapsing glomerulopathy. This is important as the prognosis of this entity, especially if its primary, is very poor.
MPGN has always been written in textbooks as Type 1, 2 and 3. This classification has been based on electron microscopic findings. Recently, scientists and pathologists have reclassified MPGN based on immunofluorescence (IF) and that has led to a different form of thinking for MPGN. If there is immunoglobulin and C3, there is likely a viral, or paraprotein injury or idiopathic. If there is strong C3 only, then it is more likely to be this new entity called C3 nephropathy (and dense deposit disease would be included here).
(15) MYH9 vs (2) APOL1
We have been waiting for this matchup. They used to be in the same conference until APOL1 decided to be an independent.
One of the mysteries of American nephrology is why there are so many African Americans on dialysis. The facts:
US Population is 13% African American yet they account for 32% of the prevalent dialysis population and 48% of the patients on dialysis due to hypertension. The disparities are seen beyond dialysis to early stages of albuminuria as discussed in this interview with Deidra Crews on eAJKD.
There is likely a social, acquired component but there is also likely a genetic component and in 2008 a candidate gene came up, MYH9. I read the paper and couldn’t understand the technique but I’ve never seen such a small P value.
P = 4 × 10−23
The P value was as small as Avogadro’s number is big (6.02 x 1023). As far as I was concerned, it was the reason for the increase in African Americans with kidney disease. You can hear all the excitement about MYH9 in this Kidney International Podcast.
Well even a P value as small as Avogadro’s number is large indicates uncertainty and that uncertainty was exploited by APOL1. Additional genetic testing indicated that MYH9 was tightly associated with the phenotype FSGS and HIVAN but just to the centromere side of MYH9 was APOL1. APOL1 had a tighter association with FSGS, hypertensive associated ESRD and HIV associated nephropathy than MYH9. And the most convincing part:
- After controlling for APOL1, MYH9 ceased to be significantly associated with FSGS
- After controlling for MYH9, APOL1 remained associated with FSGS
APOL1 is found in 30% of African Americans. APOL1 is so prevalent because of a balanced polymorphism. Having two alleles increased susceptibility to kidney disease but having at least a single allele provided immunity to Trypanosoma brucei rhodesiense and Trypanosoma gambiense, African Sleeping Sickness. The mutation which created APOL1 occurred in Africa 10,000 years ago, the ancestors of Europeans and Asians left Africa 60,000 years before that. Almost no Caucasians or Asians have the mutation.
For more on parasites and the kidney see this interview with Rashad Barsoum.
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