CLINICAL CASE 5

After several weeks of ACEI or ARB use, the plasma aldosterone levels return to pretreatment levels in 40% of patient. What is this phenomenon called?

Aldosterone Escape 66%

Aldosterone Breakthrough 22%

Aldosterone Resistance 0%

Aldosterone Return 11%

Most of you all said Aldosterone escape and that is incorrect. The correct answer is Aldosterone Breakthrough. There is no such thing as aldosterone resistance or return.

A recent editorial in Nature Nephrology from Feb 2010 issue talks about the difference in these two phenomenon( escape vs Breakthrough).  

Aldosterone escape (AE) is as follows: when you have too much aldesterone in your body, there is an initial decrease in urinary sodium excretion, and renal sodium retention is increased.  However, urinary sodium excretion subsequently increases to balance the sodium intake before detectable edema develops. This phenomenon is called AE and is the reason why edema formation is not a characteristic of primary hyperaldo state.  Multiple mechanisms as described in the above linked editorial are responsible for the AE and prevention of edema.

What is Aldosterone Breaktrough( AB): When we uses ACEI and ARBS medication to inhibit the RAAS system, large increase in renin occurs in administration of these medications. People who treat hypertension with a renin or non renin mediated methods are familiar to this concept that renin will increase with ACEI and ARBs initiation, when you check the level in the plasma, its high.  Interestingly after several weeks of using these medication,

the aldosterone level returns to pre treatment levels in 30-40% of patients. This phenomenon is called AB.  Patients who develop this might have worse outcomes and eventually start not responding to ACEI and ARBS.  This editorial suggests that perhaps direct renin inhibitors or Vitamin D might decrease that renin drive and exert a better profile. 

I think we need to know about this novel concept often confused with the escape.

Please look at the following references as well

Bomback et al. Nature Clinical Pract Nephrol 3, 486-492 ;2007

Doorenbos et al. Nature Clinical Pract Nephrol 5, 691-700;2009

We can't really escape from this new breakthrough.

Luminex Technology

We discussed a review article during our transplant clinic morning session about Luminex technology for HLA antibody detection in organ transplantation published in Nephrology 2009; and would like to share it with you.

Pre-formed donor-specific human leukocyte antigen (HLA) class 1 antibodies (DSA) in renal transplant recipients causes hyperacute rejection; there has been an imperative to test all potential recipients prospectively for HLA antibodies to avoid transplanting incompatible grafts.

Since was first developed until recently, the method universally used for antibody detection was the complement-dependent cytotoxicity (CDC) assay. In recent years, solid phase assays have been introduced as methods for HLA antibody screening which have again redefined the definition of pre-sensitization. Luminex is a solid phase assay which consists of a series of polystyrene microspheres (beads), containing fluorochromes. Test is run as shown in the Figure.

Another important concept is PRA (Percent Reactive Antibody); it is the percentage of cells in a random panel which contains all known HLA types; giving positive results with anti-serum. PRA is useful in estimating the probability of a patient receiving a crossmatch-negative kidney.

By referring to this review study, the comparison and advantages of Luminex over CDC:
1-CDC checks for cell death caused by complement fixing antibodies against any cell antigen, while DSA by Luminex checks for the presence of the antibody against HLA type ONLY.
2-Luminex DSA is much more sensitive and can detect Donor-Specific HLA antibodies which in some cases associated with rejection in the presence of negative donor CDC cross-match. Large studies by Gibney et al and Smith et al indicated that a further subset of patients with DSA detectable only by Luminex is at high risk of graft rejection
3-CDC method can detect any Ab directed at the cell surface of a B or T cells; HLA and non-HLA antibodies and these antibodies are complement dependent in causing cell death. Luminex on the other hand detects ONLY the HLA antibodies itself, it doesn’t discriminate between complement fixing or non-compliment fixing HLA-Ab.

The question is: whether those non-compliment fixing Ab are detrimental to the graft and, if not, are we excluding patients from receiving compatible graft by using Luminex tech.
As per Washerman et al C4d+ “complement fixing Ab”, Flow + “Luminex positive” HLA class 1 antibodies graft survival is inferior to C4d -, flow + and flow – patients.

Now, what about those non-compliment fixing antibodies that are detected by Luminex, do they have an effect on the graft?
Smith et al showed that 1 year survival of renal graft of patients with C4d+ DSA was 20%, C4d – DSA was 54%, C4d + non-DSA patients was 91%. The interesting observations are the profound negative effect of the compliment fixing antibody on graft survival and also the reduction in graft survival of the C4d- DSA+

Other significant benefit of Luminex is detecting HLA-class 2 Ab in pre- and post-transplant with high level of sensitivity.

Having the fact that Luminex is far more sensitive than CDC, and at least in many cases detects additional clinically relevant Ab, the question is Can Luminex HLA replace CDC?

Also, keep in mind that on the other hand some patients with CDC-neg and Luminex positive DSA had uneventful post transplant course without evidence of rejection! So, having too much sensitive test can potentially contribute to denying some patients a suitable Graft?!

IN THE NEWS ---> CLASSIFICATION FOR DIABETIC NEPHROPATHY

Recent issue of JASN talks about this interesting topic.
Alas, more classifications to add to our terminology.  This one might be useful. The Renal Pathology Society made a system for DM Nephropathy now.  They divided  diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy were classified as follows: 
Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening.
Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. 
Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. 
Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy.

How useful is this going to be clinically? How many diabetic patients do we biopsy nowadays? This might be useful for prognosticating if we had a biopsy specimen in a patient

Nephrectomy or No Nephrectomy?

A recent study in JASN Feb 2010 issue, a study reports that patients who have failed allografts and who return to dialysis and undergo allograft nephrectomy have improved survival as compared to patients that have retained the allografts. This is going to spring a lot of debate in Transplantation field as it was always thought that if you take out the allograft, you have more chances of making antibodies and you will have a higher risk of rejection.
The authors in this argue that being on low dose immunsuppresion along with dialysis might be more of an infectious and cardiovascular risk and hence worse outcomes.
Its a good paper and a good study to challenge the current notion. But do we take this to practice yet?
Probably not yet, this is retrospective, only medicare patients and a more methodological study needs to be done.
This is going to bring in a lot of debate. Looking forward to see what happens next

CONSULT ROUNDS: ORTHOSTATIC PROTEINURIA

intermittent proteinuria and that lead to a discussion of orthostatic proteinuria?
What is that and is it important?
Orthostatic Proteinuria is an increase in protein excretion in the upright position and normal excretion when supine.
In general, mostly seen in teens and young adults and people who do extensive exercising.
Possible pathogenesis are:-
1. Normal:- as described as early as in 1960s that this is normal and worsened by hemodynamic effects and increased angiotensin II.
2. Glomerular disease:- subtle changes in the basement membrane and possible mesangial cellularity might explain it. The above linked paper postulated that in these patients
3. Renal vessels being effected leading to the Nutcracker syndrome
4. Page Kidney
http://www.ncbi.nlm.nih.gov/pubmed/3965775
http://www.ncbi.nlm.nih.gov/sites/entrez

TOPIC DISCUSSION Risk factors for bleeding post kidney biopsy

Kidney biopsy done by Nephrologist world wide is not a benign procedure. Risks are real and significant retroperitoneal bleed is a major concern in most patients.  Although with US guidance or CT guidance, the risk has been much less in the current era.
What are the clinical risk factors associated which can predict bleeding post biopsy?
The article above lists a few from a retrospective trial done in Ohio State
In this article, the risk of post biopsy bleeding was higher in patients with high Systolic Blood Pressure, Diastolic Blood pressure and MAP. A history of hypertension and high serum creatinine are significant independent risk factors. What about Platelet values or coagulation parameters?
Another study in NDT, talks about if we should stop antiplatelet agents before biopsy and if that makes a difference?  Based on that one study, the risk was unchanged in major complications in both groups but minor complications were more in the antiplatelet group.
Perhaps another thing to keep in mind is patients with amyloidosis, chronic kidney disease and perhaps even antiphospholipid antibody syndrome are at higher risk of bleeding. There is evidence for amyloidosis both ways.  What about patients with SLE? are they at higher risk of bleeding? No one knows?
Any other thoughts on the other potential risk factors, feel free to add.
Other good references are listed below:
http://www.nature.com/nrneph/journal/v5/n10/full/nrneph.2009.147.html
http://linkinghub.elsevier.com/retrieve/pii/S0272638608009906
Image courtesy: MDCONSULT

New drugs for Hepatitis C

The latest AJT report introduces us to a new line of drugs for treatment of Hepatitis C.  The two drugs that are closest to coming to the market are in Phase 3 trials are will be submitted to FDA soon.  They are telaprevir and boceprevir. Protease inhibitors have been discussed in treating hepatitis C for years now and this brings it to the forefront.
Allowing to treat patients prior to liver transplantation might be the most benefit as the interactions post transplants with immunosuppresive medications is always a challenge. We see that in HIV patients who get kidney transplants.
The article summarizes that the future of treating primary Hep C infection or recurrence in the liver graft is going to be a cocktail of medications that will include standard medications like interferon and ribavarin but also protease inhibitors.  Recurrence of Hep c in the transplanted liver is a commonly encountered problem and this might hopefully help in the near future.
Treatment of Hep C might tag behind how HIV is being treated.

CDC HIGH RISK DONORS

What is a CDC high risk donor? A recent article in AJT Feb 2010 issue talked about a study that wanted to see how centers of disease control high risk (CDCHR) status of organ donors affects the recipients and if the organs are being used appropriately.  An observational study showed that after 2 years, the median survival of those kidneys was no different then non CDCHR kidneys.  Labeling these kidneys as CDCHR or high risk resulted in wastage of 41 kidneys per year.

What constitutes CDC criteria for high risk:- a donor who falls under one of the categories:- IV drug user, hemophiliac, prostitution history, high risk sexual activity, exposure to HIV and jail sentencing.  If this information is known, that organ is considered CDC high risk and post transplant care also includes regular checking of hepatitis and HIV viral loads every few months.

Something to ponder on!

TOPIC DISCUSSION: Peritoneal Dialysis First initiative?

The current Feb 2010 issue of Nature Nephrology Review has a great discussion on Epidemiology of peritoneal dialysis( PD). The article discusses why in the entire world hemodialysis (HD) overrides PD as a choice of dialysis modality.
did you know that as of 2008, only 190,000 patients worldwide are on PD vs 1.8 million on HD>
did you know that theses differences are mainly due to non medical reasons,mostly economical?
What I found most fascinating is in Hong Kong, there is a PD first initiative and as a result, there is 81% of the dialysis patients in Hong Kong on PD. So, if you don't try the patient on PD first and show a contraindication to PD, your HD treatment won't be reimbursed. This shows that how an incentive based PD program can make PD a more usable dialysis modality.
In USA, only 7% or so of the dialysis population is on PD. This article nicely talks about the limitations in our country in using this modality and the ongoing lack of education of this modality as less and less patients are on PD in the USA. I am sure if this continues, there might be a time when renal fellows will think of PD like the scribner's shunt.
I think as a community of nephrology, we should make more efforts to offer PD to our patients, teach PD to our fellows well and hopefully come up with more robust reimbursement techniques for PD.
Please read this article, its a great read.
Image courtesy: http://www.kidneydoc.co.za/

CLINICAL CASE 4

Which one of the following is not a cause of elevated serum anion gap?
A. respiratory or metabolic alkalosis   27%
B. hypophosphatemia   36%
C. Metabolic acidosis associated with overproduction or decreased excretion of acid   27%
D. lab error  9%

The correct answer is hypophosphatemia.  This stem arose from a case we saw recently 

of a triple acid base disorder that had metabolic and resp alkalosis and an anion gap met 

acidosis as well.  The ph was 7.89 and the question arose, what are the causes of anion

gap? Can severe alkalemia cause an anion gap? 

An elevated gap can be produced by an increase in unmeasured anions or by a REDUCTION in unmeasured cations Usually we see the first kind and rule out MUDPILES ( the known causes of anion gap met acidosis). This leads to overproduction or decreased excretion of acid

Other minor causes are severe hypokalemia, hypocalcemia, hyperphosphetemia and hypomagnesemia. Severe alkalosis can lead to mild elevation in gap as well from three main factors:- volume depletion leading to 

an elevated albumin, increase in number of negative charges as ph is very alkalotic and slight increase in lactate  production as a compensatory response. Lab error is always a possibility

Hence the correct answer is hypophosphetemia as its the opposite that causes an elevated anion gap. A good reference is linked from CJASN

Adrenal Gland Transplantation

The recent issue of AJT Feb 2010 describes a case report of human intramuscular adrenal gland transplantation.
Intramuscular endocrine gland transplantations have been described and we do have cases of that in the renal world of parathyroid glands being retransplanted in the muscles forearms to help continue some function on ESRD patients.  Adrenal transplantation is less common. This case describes a story of a young girl who had adrenal insufficiency and had renal failure and received a renal and adrenal transplantation from her mother.
This is the first case of a successful adrenal transplant for adrenal insufficiency.
Chronic medical treatment for adrenal insufficiency includes steroids and treatment for the transplant also includes steroids, the risk and benefits have to be weighed eventually.
At this point, the authors recommend that adrenal gland allotransplantation is only indicated in patients who already are maintained on immunosuppression for either concomitant or prior solid organ transplants.

IN THE NEWS --->Is BMT Nephropathy really mostly Radiation Nephropathy?

A recent article recently in Biology of Blood and Marrow Transplantation talks about the chronic kidney diseases and thrombotic microangiopathy (TMA) seen post bone marrow transplantation.  Classically, it has always thought to be multi-factorial and calcineurin toxicity being a major part of it.  They are used for GVHD prophylaxis.  In this study, a retrospective analysis of 100 patients was done who had undergone a T cell depleted stem cell transplant( hence not requiring CNIs). Of the 100 patients, 70 were given total body radiation without any shielding of the kidneys and they were compared to 30 patients with no total body radiation. The multivariate survival analysis showed that the exposure to radiation, older age and TMA were risk factors for CKD.  The radiation group had more biopsy proven and clinically diagnosed TMA compared to NONE in the non radiation group.  The incidence of hypertension was also more in the radiation group.
This study shows that in the absence of CNIs, there is TMA, HTN and CKD suggesting the major role of radiation nephropathy in these patients. A shielding of the kidneys should be examined in patients getting stem cell transplants and radiation. Some centers do shielding of the kidneys and some don't. Other studies have shown that the amount of radiation and shielding does make a difference.
A nice review on radiation nephropathy is linked here as well ( Kidney International)

Sad News

Its a great loss to the renal community to loose the founder of Renal Fellow Network- Nathan Hellman, MD,Phd.
He was at Harvard University doing his renal training. His blog was always inspirational for me personally in creating this blog and loved following it till date. Every blog post taught me something. 
A big loss for the education of nephrology. 

TOPIC DISCUSSION: Tamm Horsfall Mucoprotein

Named for two New York virologists, the Tamm-Horsfall mucoprotein (THMP or uromodulin) was first isolated in 1950 by Igor Tamm and Frank Horsfall. Synthesized by cells of the thick ascending limb of the loop of henle, is the most abundant urinary protein in healthy mammals. That being said, it is no surprise this protein is the matrix for tubular casts, and has been shown to have roles in multiple tubular disease states.
The 616 amino acid, 90 kDa protein was first identified by Tamm and Horsfall as a potent inhibitor of viral hemoagglutination in healthy individuals. It is thought to be protective against urinary tract infections by preventing the adhesion of fimbriated E coli to tubular epithelium. The protein has also been implicated in disease states: 
Myeloma Kidney/Cast Nephropathy: Filtered monoclonal light chains bind to the THMP forming obstructing tubular casts 
Rhabdomyolysis: Distal tubule obstruction occurs by binding of myoglobulin
to THMP, which may be enhanced by acidic urine.
Acute Tubular Necrosis: Increased sodium concentration as a result of damage to tubular epithelial cells causes polymerization of THMP and cast formation including the sloughed tubular cells, contributing to tubular obstruction.
Nephrolithiasis: Specifically Calcium Oxalate Monohydrate stones. In an alkaline environment, THMP may prevent crystal aggregation, but in acidic urine THMP viscosity and aggregation increases, decreasing the inhibitory properties thought to prevent this stone formation.
Genetic Disorders: Medullary cystic kidney Disease type 2 and Familial Juvenile Hyperuricemic Nephropathy, (both characterized by hyperuricemia, medullary cysts, interstitial nephritis and progressive renal failure) have genetic defects located close to the human THMP gene. There is speculation that it is an alteration of the structure of THMP that accounts for these disease states.

Reference is linked above. AJKD 2003:42:4:658-676.

TOPIC DISCUSSION: Re-evaluating the Role of Immunosuppression in Proteinuria

how does rituximab functions in altering the activity level of the so-called "permeability factor." Definitely an area for research, I was unable to find more than hypothesis. What I came across, however, was this article published in NEJM just over a year ago. The author was struck by the work of researchers who discovered that the influence of calcineurin inhibitors on proteinuric kidney disease goes beyond the inhibition of T lymphocyte signaling by IL-1, which is obviously key in the development of inflammatory disease states that increase glomerular capillary permeability. This action does not necessarily explain calcineurin inhibitors' advantageous role in non-inflammatory conditions including minimal change disease and focal glomerular sclerosis.

The podocyte structure may hold the answer. Synaptopodin stabilizes the actin cytoskeleton of the podocyte and is protected from degradation by phosphorylation. Calcineurin dephosphorylates synaptopdin, subjecting it to degradation by cathepsin L and essentially losing its stabilizing properties. Faul et al showed that the inhibition of calcineurin by cyclosporine A protected against lipopolysaccaride-induced proteinuria in mice, and also demonstrated that activation of calcineurin in the podocyte is sufficient to cause proteinuria by causing degradation of synaptopodin.

This research provides a foundation for new ideas regarding the activity of "immunosuppression" in the treatment of proteinuric disease and novel areas for pharmacologic development.

JOURNAL CLUB: DNA Methylation controls Foxp3 gene expression

A basic science article was discussed at immunology journal club. It discusses the role of T regs and its how they come from naive T cells and what other factors triggers them.
The vast experiments done elegantly in the study concluded the following:
1. TGF-B induces FoxP3 expression in T regs but its unstable in vitro
2. Azacytidine derivatives( demethylation agent) stabalizes foxp3 expression in induced Tregs.
3. The T reg specific demthylated region (TSDR) determines transcriptional activity
4. Azacytidine promotes stable Foxp3 expression in vitro
5. In vivo induced Tregs exhibit stable Foxp3 expression and complete TSDR demethylation
6. Foxp3 Treg generated invivo by targeting of agonist ligands to dendritic cells showed long term survival in the absence of the inducing antigen and exhibited efficient TSDR demythylation.

Besides the specifics of epigenomic imprinting in the mehylation region of the T cell region which might be critical for T cell lineage, this paper I thought highlighted something very alarming. One is that TGF-B is an important promoter of T reg cells. There are drugs out there currently under development that are inhibitory to TGF-B for anti fibrotic effects. Again, we have to think  of these molecules as possible bimodal and perhaps they have different functions in different disease entities.
Second is that the dendritic cells might be important players in the long term survival of Tregs. Since there are studies that show that the patients that has increase Foxp3+ Tregs, those patients post transplant do better.
Perhaps, sustaining that positive effect should be the goal in transplantation. We can perhaps then achieve tolerance. Perhaps!!
This is interesting to me as a clinician as there might be promise ahead for tolerance.
The article source is here.
A review of the Foxp3 T regs is nicely shown in recent Nature Immunology as well
Image source: http://www.scielo.br/img/revistas/abd/v81n3/e10f1.jpg

In the News: The era of epigenetics

Early this month in the TIME magazine, there was an article titled " Why your DNA isn't your destiny"

This is a nice article and puts forth something that we have to all watch out for as clinicians as the face of science is changing. What is epigenetics? It is a science that deals with the epigenome.

Epigenome is the changes of genetic activity without altering the DNA sequence or the genetic code; but still gets passed down from generation to generation.  These gene expression patterns are orchestrated by the cellular material called the epigenome( sits on top of the genome). Its a turn off and on switch for that particularly gene.

In the RNA world, there is a similar concept of micro RNA as well. It's now a possibility that through these epigenetic marks that environment factors like stress, diet and behavior might be able to change your genetic make up and pass it to the next generation in a speedy fashion rather than the Darwin theory of evolution that takes a long time. I quote from the article a nice saying: " If the genome is the hardware, the epigenome is the software. You're going to have the same chip in there, the same genome, but different software. And the outcome is a different cell type".

This will be important as scientists can use this science in creating markers and possible hints to why some people have disease, some reject and so forth. This might be an interesting are of research that Nephrology can tap into at some point. Apparently, the Epigenomic mapping process in under way.

Great work and something to watch out for in the field of Nephrology as well.

Image source: http://itb.biologie.hu-berlin.de/Events/Workshops/workshop.2007-07-10.1652357222/teaser

Sirolimus and tubular toxicity

The Feb 2010 issue of AJKD talks about a study that nicely depicts the toxicities of Sirolimus.  Since its arrival to the market for preventing rejection, it has met with resistance mostly due to its severe proteinuria.  This paper describes the toxicities of sirolimus - tubules as well as in glomerulus.  Most well know toxicity of this drug is FSGS or severe proteinuria ( sometimes collapsing variant, majority the podocytopenic type of FSGS).  Severe TMA has also been noted with sirolimus use. Most of the reports of sirolimus toxicity are in kidney transplant recipients although there have been 2 reports of proteinuria in a islet cell transplant and BMT patient who had normal kidney function prior to the drug initiation.
This was a single center study done in Switzerland.  But it was open label and randomized prospective trial comparing the tubular toxic affects and rejection outcomes in cyclosporine vs sirolimus group. There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, but the elevation in markers associated with glomerular damag and tubular damage were statistically significantly more in sirolimus group. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy.  On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy. Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy.
Small but nicely done study. Just brings to mind again the utility of sirolimus. Clinically, the KDIGO guidelines have a grade 2C suggestion to use this drug for patients with Kaposi sarcoma, along with reduction in immunosuppresion.
Image source: http://upload.wikimedia.org/wikipedia/commons/d/d4/Sirolimus1.gif

TOPIC DISCUSSION: FIBROTIC DISEASES

The Feb 2010 issue of Annals reviews fibrotic diseases, cellular mechanism and possible treatment options.
This is a good read since we deal with fibrotic diseases a lot and perhaps things are on the horizon for our patients.
Extracellular matrix deposition that becomes abnormal leads to fibrosis in lung, liver and kidney diseases  and other diseases as systemic sclerosis, NSF and GVHD as well.  TGF-B has been identified as a major player in this journey to halt fibrosis.
The article describes the basic two classical and non classical pathways of TGF-B and how downstream it leads to SMAD activation that leads to collagen production and deposition.  Ideas and approaches used so far in mice and some human models is to inhibit TGF-B via the tyrosine kinase inhibition(imatinib), blocking TGF-B production and activation(pirfenidone), inhibition of other kinases involved blockage of Angiotensin II( ACEI, ARBS).
There are some drugs out there already to be used in lung fibrosis. For renal damage and fibrosis, we have yet to see which one will work.  Targeting the tyrosine kinases we have to watch carefully as there might be anti VEGF effect as well and then leading to TMA like syndromes as we are seeing with sunitinib, sorafenib and others as well.  Just like VEGF, is TGF-B a bimodal molecule and perhaps too much and too little is bad for you and altering it will not be without consequences. There is also data that TGF-B is a tumor suppressor in early stages and promote tumor genesis later on.  This has to be kept in mind.  Is it the reason why ACEI and ARB combination can lead to more cancers as noticed recently. Another good article is linked here: It reviews the role of TGF-B in Renal diseases and an oncologic view of the TGF-B is linked here.
Image source: Frontiers in Bioscience 4984-4992, May 1, 2008

IN THE NEWS --> IgA with ANCAs

The Feb 2010 issue of AJKD describes an interesting entity of IgA Nephropathy with ANCA presenting with crescentic disease on biopsy.  This is interesting since IgA deposits are so common worldwide, why can't someone have 2 glomerular processes at the same time.  They studied 8 patients with crescentric IgA associated with ANCAs (MPO and PR3) against 26 patients with pure IgA crescentric disease without ANCAs.
Not to their surprise, they found that the first entity was more aggressive but the 8 patients with ANCA and IgA responded to aggressive immunosuppresive therapy much better than the 26 with just IgA disease. This is an interesting read and perhaps points out a possible new entity of an aggressive IgA disease. They noticed no significant improvement in kidney function in the ANCA negative patients with RPGN IgA disease.  Its possible that those patients were not that aggressively treated as an ANCA positive disease might have been treated.  An aggressive IgA with creascents should also be treated as an RPGN regardless of ANCA or no ANCA.
Image source: CIN  2003( 3rd Congress of Nephrology in Internet)
Something to watch out for.

JOURNAL CLUB: Pirfenidone Is Renoprotective in Diabetic Kidney Disease

Past Journal Club we discussed the potential effect of Pirfenidone(PFD) in halting the progression of Diabetic nephropathy. this paper was published in Jasn April 2009.
Characteristic morphologic lesions of DN include glomerular hypertrophy, thickening of the basement membrane, and mesangial expansion. Several interventions, such as tight glycemic control and antihypertensive therapy, especially angiotensin converting enzyme inhibitors (ACEIs) and angiotensinII receptor blockers, have been shown to slow the progression of established disease. Nevertheless,DN remains a major long-term complication of both types 1 and 2 diabetes. the mechanism of DN is multi factorial as we know. inflammation,fibrosis, hemodynamic effects both in the mesangial cells and matrix as well as as in the podocytes, are some elements which are involved in this very complex cascades of disease process. and this study tried to examine the possible benefits of PFD in halting the progression of DN through inhibiting TGF-B production and therefore antifibrotic and possibly anti-inflammatory effects. Pirfenidone (PFD; 5-methyl-1-phenyl-2-(1H)-pyridone) is
a low molecular weight synthetic molecule that exerts dramatic antifibrotic properties in cell culture and various animal models of fibrosis. it has been shown to improve pulmonary function tests in patient with IPF post Lung transplantation.
To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria.
the idea is intriguing because it opens up the possibly of treating this disease through different mechanisms. however, this study although shows that PFD did decrease the production of TGF-B, it did so in cell cultures and only mesangial cells were involved. Also there was no clinical parameters such as BP, and GFR. and more importantly there was more protinuruia in the PFD treated mice. and this is obliviously not a welcome effect.
SO we would want more studies, preferably in the Podocytes. as well clinical outcomes.
for the complete article go to J Am Soc Nephrol 20: 1765–1775, 2009. ISSN : 1046-6673/2008-1765.
posted by Ezra Hazzan MD on feb 5, 2010.

IN THE NEWS- CKD and Proteinuria

A recent study from Canada in the latest issue of JAMA Feb 3, 2010 talks about the inclusion of proteinuria in CKD staging.  The current staging system of CKD puts more emphasis on GFR and the lower the GFR, the worse the outcome. Proteinuria has been noted to be marker of kidney damage as well( this is now also in debate).  A community based cohort study done of adults for mean follow up of 35 months showed that the risks for all cause mortality, heart attacks, progression to  kidney failure associated with a given level of GFR were independently increased among patients with higher levels of proteinuria.

At this point, if there is a patient with GFR Of 80ml/min and 3+ proteinuria, they would get assigned Stage I, even though their risks of death and need for dialysis might be 2-10 times higher than otherwise similar patient in Stage 3 with no proteinuria.  They propose subdividing stage 3 in parts ( proteinuria, no proteinuria, so forth)

It's an observational study and it brings a good point back to the table. Is our classification system good? Does it help identify more risk patients? Do we need to include more parameters besides GFR? What about albumin as well?

The bigger question at debate is also:- is non nephrotic range proteinuria all bad? is it really a marker of kidney disease? Those are questions at debate even now among nephrologists 

CLINICAL CASE 3

CASE 3: A 20 yo white male with one year of nephrotic syndrome, slow onset, and slowly rising creatinine to 2.0mg/dl and hematuria. A kidney biopsy done shows mesangial proliferation, EM with mesangial deposits, IF :3+ IgG, C1q,kappa and lambda, DIAGNOSIS?

Tip Variant Focal Segmental Glomeruloscelrosis	0 (0%)
Membrano-proliferative GN	1 (11%)
C1Q Nephropathy	6 (66%)
Mesangio-proliferative GN	1 (11%)
Light Chain Deposition Disease	1 (11%)

The best option is C1Q Nephropathy.  This disease falls in the spectrum of Minimal Change and FSGS.

Classically, you see mesangial proliferation in most cases and the IF will be positive for just C1q, C3 and IgG.
EM will now show anything except mesangial deposits. It clinically can behave like any other immune complex disease.  Lupus has to be ruled out and other infectious causes leading to a concurrent immune complex disease have to be treated or ruled out.  The prognosis is usually not bad. From the Columbia series, 75% of them with C1Q nephropathy had stable renal function and 50% had complete or partial remission.  Only 2 patients progressed to ESRD. In other studies, the outcome was more like FSGS rather than MCD.

So they are more likely to progress to ESRD.  Most present with renal failure, nephrotic range proteinuria or hematuria. There are no treatment trials. Most people would treat it like MCD with 1mg/kg of Prednisone for 12 weeks and see what response they get. 

Positive Cross Match, Desensitization

The recent AJT Report talks about fighting the positive Cross Match or desensitization.  Currently, many centers are using the combination of pheresis and low dose IVIG or high dose IVIG and rituximab is thrown in once in a while as well.  The value of rituximab is still questioned.  No one really knows how it is working in some and not in others.
There are few new agents:- one is bortezomib, a proteasome inhibitor that has shown some data in treating antibody mediated rejection.  There are some centers using one cycle pre and one cycle post transplant as densitization technique.  This has become a concern for many as people are starting to use it for indications that have not been systematically tested.  The side effect profile of this drug is not trivial. It includes peripheral neuropathy, pyrexia, anemia, leukopenia  and GI side effects.
Finally, the latest player in the market is eculizumab ( complement protein c5 inhibitor).  It has worked in some centers to treat antibody mediated rejection. Is it a good idea to use it for desensitization. Its early to say.

Lets wait and watch.

CONSULT ROUNDS: Post Bone Marrow Transplant Thrombotic Microangiopathy(TMA)

Someone presents to you withclinical signs of TMA 3-4 weeks following a BMT.  TMA after a stem cell transplant doesn't follow the classic route of HUS or TTP but is more syndromic of TMA( low platelets, microangiopathic anemia, low haptoglobin, elevated LDH, renal failure, some proteinuria and hypertension)
The etiology is anything that can be damaging to the endothelium ( Calcineurins, other chemotherapy agents, total body radiation, GVHD or the primary cancer returning back with a TMA component)
The presentation may involve the kidney as the primary site. The acute TMA kidney biopsy will resemble that of pre eclampsia with or without mesangiolysis and intraglomerular and renal arteriloar thrombi and double contouring as well if there is chronic TMA ( MPGN pattern of injury).
Risk factors for TMA post transplant include female race, cytoxan high dose induction, TBI without shielding and CNI and sirolimus use.
Many people consider chronic TMA in post BMT patients a radiation nephropathy and TBI as the major risk factor and the damaging the endothelium.  Does pheresis help in this instance? Less likely as its more of a direct insult on the endothelium and not really an antibody mediated that can be removed with pheresis.
Left image courtesy: Kidney International