CONSULT ROUNDS

We discussed a case of NSAID induced glomerular disease. NSAIDS are a group of drugs that can effect the kidney in many ways possible. Besides the hemodynamic causes of renal injury from NSAIDS, there has been a strong association with Acute interstitial Nephritis.
Another interesting association of NSAIDS is AIN with nephrotic syndrome ( usually seen with membranous or Minimal Change disease) and patients present with frank nephrotic syndrome and even lympadenopathy sometimes.
What is the time from use to disease, usually around 1-2 months for AIN, but could be months or years even. It's been reported that membranous can be on average 39 months after using NSAIDS.
The degree of proteinuria was independent on the amount of immune deposits in the glomeruli. So even if you have two -three immune deposits, you might have membranous Stage I or II but may behave clinically like Minimal Change Disease. The pathology finding is swelling and allergic reaction and activation of lymphocytes.
The most important clinical pearl is that the renal function in AIN and glomerular disease with NSAIDS was strongly associated with the tubular interstitial changes more  and inversely related to the amount of immune deposits in the glomeruli.

TOPIC DISCUSSION: Pseudopheochromocytoma

Pseudopheochromocytoma is a real disease. Dr. Sam Mann from Cornell has written a lot about this disease.  It causes paroxysmal Hypertension.  98% of people with paroxysmal hypertension do not have pheochromocytoma. The cause and management of paroxysmal hypertension remain a mystery, and the subject of remarkably few papers. Patients experience symptomatic blood pressure surges likely linked to sympathetic nervous system stimulation. A specific personality profile( likely of some abuse as a child) associated with this disorder suggests a psychological basis, attributable to repressed emotion related to prior emotional trauma or a repressive (nonemotional) coping style. Based on this understanding, three forms of intervention, alone or in combination, appear successful: antihypertensive therapy with agents directed at the sympathetically mediated blood pressure elevation (eg, combined α- and β-blockade or central α-agonists such as clonidine); psychopharmacologic interventions including anxiolytic and/or antidepressant agents; and psychological intervention, particularly reassurance and increased psychological awareness. An appropriately selected intervention can reduce or eliminate attacks in most patients. Look for this disease in your patients. Its more common than we think.

IN THE NEWS- HIF and Kidney Disease

A recent article in Kidney International talks about the hypoxia inducible factor or HIF and its relation to kidney diseases and anemia.  Based on recent basic science experiments done on AKI and podocytopathies, it has been found that there are different variants of HIF 1 Alpha and 2 Alpha respectively affecting different parts of the kidney.  This paper is one of first basic science papers to localize HIF 2Alpha.  Accumulation of HIF 2Alpha was observed in mainly endothelial and glomerular cells whereas HIF 1Alpha was more in the tubular epithelia. This was more speculative before but now its confirmed.  A large proportion of erythropoetin expressing cells also co expressed HIF 2Alpha.  No co relation with Hif1alpha was found.

Why is this important?  In hypoxic challenges, there is stimulus to produce HIFs and that might be a stimulus for EPO production as well.  Hif is a protein that has alpha and beta subunits,  In normoxemia, Hif Alpha is always synthesized.  However, steady state levels are low as Hif is rapidly ubiquitinated and degraded. This degradation happens via the action of hif with Von Hippel lindau protein (vhL).  In hypoxemia, this interaction is suppressed and you have increased Hif production leading to accumulation in the cells.
This leads to downstream effects of increased Epo and expression of different types of hifs in different parts of kidneys. Hif1 in tubular cells perhaps during AKI
Hif 2 in podocytes and endothelial cells perhaps in glomerular injury
Interestingly , another down stream protein to Hif is VEGF..
A lot of things might be falling into place soon!!
The picture on the left ( Univ of Adelaide courtesy) can explain a lot

B cell agents in Transplantation

A nice review in recent CJASN highlights the use of anti CD20 and other novel b cell agents in transplantation.
The paper actually reviews all of glomerular diseases and transplantation.
Few things about use of B cell agents in Transplantation
1. Use of Rituximab is increasing more and more with desensitizing protocols for ABOI and + DSA patients. Is it a combination of IVIG, Pheresis and Rituximab that really works or is one better than the other, no studies have confirmed that? Although IVIG alone has not been affective.  Hence, it might be an additive effect.
2. Use of anti CD20 in antibody mediated rejection has become an increasingly used agent.  This stems from a simple concept that antibodies are produced by B cells and hence depleting the B cells will deplete the production of antibodies.
3. Bortezomib, has been now used as well in refractory antibody mediated rejection and in biopsies that have enriched plasma cells.  Total IgG were unchanged in those patients treated, so we don't know if this is a one time effect and or long lasting and also there is potential increased risk for infectious complications.
I think we shall see more and more of these agents used for treating transplant patients in the future.
We have to be careful as there are Regulatory B cells and what we are doing to those B cell clones, we don't exactly know!

Clinical Transplantation: KDIGO Transplant Guidelines

The Feb 2010 issue of Kidney International has summarized the KDIGO clinical practice guidelines for kidney transplant recipients. Its a very brief and to the point summary to standardize transplant care all around the globe. Things we always talked about as transplant physicians and wondered were all discussed and laid down as what should be done and what is the grade of evidence behind it.
For induction, for instance, they recommend( Grade 1B) that an IL2 -RA be used as first line agent and antilymphocyte depleting agent to be used for all kidney transplant with immunologic risk( Grade 2B)
Also, interesting to note that there is Grade2B evidence and they suggest that in patients who are at low immunological risk and who receive induction therapy, corticosteroids could be discontinued during the first week after transplantation. Other concepts on BK treatment, Bone disease, CMV, Cancer and rejection. All are discussed. I think its a good start and an essential read for all of us.

IN THE NEWS- IGA Nephropathy Recent Meeting Report

Recent Kidney International Journal reviews the symposium held on IgA Nephropathy in Italy this last year. 
Few interesting points.
1. The presence of aberrantly glycosylated IgA1 in patients with this nephropathy was again confirmed. This usually happens at the GalNac site on the molecule of IgA.
2. This alteration alters the molecule and possibly could affect the binding to intrinsic mesangial glycoproteins and plasma proteins.
3. Using immortalized B cells from subjects with IgA nephropathy, and normal controls, investigators showed that the aberrant galactosylation in patients is nonrandomly distributed among the glycan residues and that the premature sialylation of the GalNac residues may interfere with the galactosylation of GalNac.  These led to autoantibodies to GalNac.  So, it seems that molecular mimicry from environmental agents maybe involved in the autoantibody response to the neo antigenic GalNac sites on the aberrant IgA.
4. RISK factors to predict IgA post transplant:- prior recurrence of disease and loss of graft from recurrence; rapidly progressive initial disease; use of zero mismatched donors; using a living related donor; lack of treatment with antilymphocyte or anti thymocyte as induction agents; and the presence of IgA deposits on transplant biopsy by zero hour of the transplant.

CONSULT ROUNDS

This week we discussed a case of malignant hypertension with acute renal failure and Thombotic microangiopathy secondary to the severe hypertension.  We discussed in detail Hypertensive Retinopathy. Here are some of the saliant features discussed on rounds. There are different stages of HTN related changes in the retina. The first stage leads to small degrees of arteriolar narrowing and an increase in arteriolar tone due to local autoregulatory mechanisms. As the stages progress, you get more and more narrowing and hyperplasia of the medial wall and sclerosis. Final stages lead to exudative changes leading to retinal ischemia and formation of cotton wool spots, hemorrhages and microaneurysms.  Swelling of the optic disc is the final sometimes noticed on physical exam finding of severe hypertensive urgency.  

How is this different from atheroscloertic changes in the retina? There are four stages and these can also be seen in HTN Retinopathy.  Stage 1 is defined as a broadening of the light reflex from the artery, with minimal or no arteriovenous compression (earliest sign of retinal artery atherosclerosis). Stage 2 is defined as changes similar to those in Stage 1, but more prominent. These narrowings are called AV nicking. In Stage 3, the arteries have a “copper wire” appearance, the arteriovenous compression is much greater, and serious atherosclerotic changes of the retinal arteries are present. In Stage 4, the arteries have a “silver wire” appearance, and the arteriovenous crossing changes are the most severe. Stage 4 is the most severe form of atherosclerosis of the retinal arteries. 
So as Nephrologist or Internists, Do we actively take the time to look at someone's eye? An ophthalmoscopic exam is the least we can do and we should all do that in our hypertensive and diabetic patients because as we do more of these exams, the better we get at picking up more clues and more educated and timely referrals to Ophthalmology. 
A nice review of the Hypertensive Retinopathy is in NEJM. The image to the right is courtesy of MDconsult