IN THE NEWS: Remote ischemic preconditioning and prevention of AKI post CABG

Remote ischemic preconditioning(RIPC)  has been used as a protective method from ischemic damage to distant organs.  Application of one or more brief cycles of nonlethal ischemia/reperfusion to an organ or tissue may protect a remote organ or tissue from a sustained episode of lethal ischemia/reperfusion.

In a recent study presented at Europe and published in JAMA,  Zarbock et al examine the effects of RIPC on the rate and severity of AKI in patients undergoing cardiac surgery. In a multicenter trial, 240 patients at high risk for AKI  were randomized to receive either RIPC  or sham control  after induction of anesthesia.

The amazing results showed that AKI was significantly reduced with RIPC (45/120; 37.5%) compared with control (63/120; 52.5%), with an absolute risk reduction (ARR) of 15%. Fewer patients received RRT after RIPC (7 [5.8%] vs 19 control [15.8%]; ARR, 10%) and RIPC reduced intensive care unit stay (3 vs 4 days). RIPC had no significant effect on myocardial infarction, stroke, or mortality.

A recent meta-analysis published in AJKD showed otherwise.  Mostly randomized trials were included ( 13) and total of >1300 patients. There was no differences in levels of post operative AKI and incidence of RRT, in hospital mortality and hospital stay.  A prior meta-analysis had shown similar results as well.

Can we start using this in clinical practice? It is innovative, inexpensive and easily possible.  But long terms risks and harms are not known. Clearly, there is significant risk of AKI post CABG and this might be the only preventive measure that we have that has come close to showing any benefit. 

As suggested by the editorial in JAMA, before RIPC is adopted for clinical use, the potential risks and adverse effects must be considered carefully.  

image source: circres.ahajournals.org

ASN Fellows Survey on Workforce 2015

Nephrology Workforce Annual Fellows report in 2015 is being collected by ASN via a survey. 

This survey, being  performed by colleagues at Geoorge Washington University, will be very useful to understand our workforce related concerns. A prior survey done in 2014 had some alarming results.

See link below at ASN website.
http://asn-online.org/education/training/workforce/home.aspx

The Workforce committee of ASN has spent the last 5 years or more attempting to draw conclusions about fellowship trends and workforce needs from fragmented information. This is one of our few opportunities to gather good data and have it analyzed by those with expertise in healthcare workforce studies.

I think the fellows in the USA should take this opportunity to help out the field of Nephrology. You should try to  must  complete the survey you received from ASN. 

Topic Discussion: Non uremic causes of calciphylaxis

Calciphylaxis, or calcific uremic arteriolopathy(CUA), is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic information is available on calciphylaxis from nonuremic causes.

A review I found in CJASN from 2008 discusses non renal causes of CUA.

Besides renal disease, the non uremic( CKD and ESRD) causes are: the top 4 being the most cases of. The remaining were just 1-2 case reports.  Most of these patients listed below had normal renal function, over 50% had normal calcium and >60% had normal phosphorus levels and 50% had low or normal pth levels. One most keep these causes in mind when ESRD or CKD does not explain the cause of CUA.

Primary hyperparathyroidism
Malignancy( Classically breast, melanoma, gall bladder, myeloma)
Alcoholic liver disease
Connective tissue diseases
Chemo induced protein C and S deficiency
Crohn’s disease
Vitamin D deficiency
POEMS syndrome
Diabetes

NK cell leukemia and lymphomas and renal disease

NK cell neoplasms have a wide range of clinical, morphologic, and immunophenotypic characteristics. Aggressive NK cell leukemia usually affects young patients in their 20-30s with equal sex incidence and shows a rapidly progressive clinical course.  Often they don’t respond well to chemotherapy and prognosis is poor.

Kidney involvement in these cancers is rare but here is what I found?

One case report of a collapsing FSGS published in AJKD in 2011. Initially, in this case, the first biopsy was read as FSGS NOS and then a repeat one had collapsing glomerulopathy.

Another recent case series describes cases of renal diseases seen with all types of non-Hodgkin’s lymphoma.  They describe 20 cases. T/NK cell lymphoma was in 4 cases. 2 of the 4 cases had crescentic GN, 1 had minimal change disease and 1 had infiltrative disease. 

A very early description of minimal change disease has been described in a case report in 1980s of a large granular cell lymphoma.

So in summary, NK cell neoplasms likely are related to cause some glomerular involvement-likely podocytopathies such as minimal change to FSGS. Cases of crescentic GN have also been described.

Topic Discussion: Metformin and CKD

The package insert of Metformin says

“Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 2 I .5 mg/dL [males], 2 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS). “

This is dated back when this drug was introduced decades ago.  Most physicians withhold this very useful agent in most patients with a crt >1.4mg/dl.  But cautious use have been tried by many in advanced CKD and there are not many cases of lactic acidosis. 

This well done study in JAMA by Inzucchi et al reviewed over 800 publications on this topic of CKD and use of metformin from 1950 and 2014 and looked at major studies, case series and retrospective data.

What did they find?

1.       Lactate level was normal in patients with GFR of 60-90ml/min and even in patients with GFR of 30-60ml/min

2.       Most cases of lactic acidosis occurred in setting of a “second hit”- such as volume depletion, sepsis, AKI. Etc

3.       The rate of lactic acidosis in patients taking metformin was same as lactic acidosis in patients not taking metformin

4.       What did they recommend: 

Not to initiate metformin in patients with GFR< 45cc/min
Contraindicated in patients with GFR <30cc/min

5.       They recommended max doses based on GFR:

If GFR >60- max dose 2550mg per day

If GFR 45-59- max dose 2000mg per day

If GFR 30-44- max dose of 1000mg per day

Maybe it’s time we liberalize our guidelines to use metformin in CKD. Look what the Australians and Canadians are doing.  

Detective Nephron Strikes Back

Next venture of Detective Nephron as he takes on a case of hypophosphatemia.
http://www.asn-online.org/publications/kidneynews/archives/2015/KN_2015_05_may.pdf ( check out page 16-17)

Topic Discussion: Do B regulatory cells exist and do they help in transplant tolerance?

Recently, David Rothstein from Pittsburg gave an amazing grand rounds on B regulatory cells in NYSN in New York. Here are some notes on what I learnt.

B cells can influence T cell differentiation but B cells are effector cells themselves.  B cells also are responsible for antibody production. Do B regulatory cells exist?

Koichi et al showed in an elegant manner that certain subset of B cells in mice produce IL-10 and they might have regulatory function. In addition, IL-10 production was restricted to this CD1d^hiCD5⁺ B cell subset, with IL-10 production diminished in Cd19^−/− mice. Thereby, CD1d^hiCD5⁺ B cells represent a unique subset of potent regulatory B cells per authors in that study.

Ding et al in JCI showed that B cells that had the IL-10 production also had a TIM-1 marker.  What is TIM-1.  T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4⁺ T cell effector differentiation. TIM-1 was expressed by a large majority of IL-10–expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1d^hiCD5⁺.  They showed that with a  low-affinity TIM-1–specific antibody that normally promotes tolerance in mice, actually accelerated (T cell–mediated) immune responsiveness in the absence of B cells. TIM-1⁺ B cells that had IL-10 expression  could directly transfer allograft tolerance.  What is possible is that TIM-1 is an inclusive marker for IL-10⁺ Bregs.

Could these be the cells that induce tolerance in transplant patients?

Yeung et al answered this question in mice. B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1^Δmucin) are unable to produce IL-10 in response to specific ligation with anti-TIM-1. TIM-1^Δmucin mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both  baseline and induced IL-10⁺ Bregs, since a single transfer of WT TIM-1⁺ B cells can restore long-term graft survival.

That’s in mice studies. It is impossible to measure TIM-1 in humans as percentage of these cells might be just <1%.

To make things more exciting, there might even exist a subset of regulatory plasma cells that produce IL-35. So is IL-35 producing cells also a type of B regulatory cells.

No one is aware of a disease entity that exists that is a Breg deficiency. IPEX syndrome is a Treg deficiency syndrome. One study has looked at kidney transplant human samples in JASN and using Breg data. 

Cherukuri etal. examined the cytokine profiles of human samples and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. What was important was the  ratio of IL-10/TNF-α expression, a measure of cytokine polarization, as an indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. So, B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.  This is an amazing start. Hope to see more of this work to help us figure out the holy grail of transplant- tolerance!!

Interestingly, in a study done in NEJM where rituximab was used to deplete B cells as induction agent in transplantation, there were more rejection episodes in that arm.  Perhaps there was too much B reg depletion?