eAJKD: Cardiac biomarkers in CKD

Troponin T and N-terminal pro brain natriuretic peptide are potential markers of cardiac injury that are often measured in the inpatient setting. Can these markers be used in the outpatient setting to predict risk of developing ESRD in patients with diabetic kidney disease? Check it out in an exclusive interview on eAJKD. 
Ref:
http://ajkdblog.org/2011/11/29/cardiac-biomarkers-in-ckd-and-esrd-what-to-make-of-them/

CONSULT ROUNDS: Sjogren's Syndrome and Glomerular Diseases?

What is the association of Sjogren's Syndrome(SS) with any glomerular disease..

Well, besides few cases reports scattered in the literature, there are two large case series that highlight this nicely.

In 2001, Bossini et al described the clinical and morphological features of kidney involvement in SS.  Sixteen patients (27%) had laboratory evidence of tubular and/or glomerular dysfunction.  Renal biopsies from nine patients showed tubulo‐interstitial nephritis in six and glomerular disease in three. The three diagnosis were MPGN, mesangiproliferative and membranous. Patients with renal involvement had a significantly shorter disease duration compared with patients without renal abnormalities.

A more recent study in CJASN looked at more number of patients and at least 24 biopsies of SS patients showing mostly tubular interstitial disease but the glomerular disease was a mixed bag: FSGS, mild mesangial sclerosis, MPGN, minimal change disease( 1 case), membranous, were the ones reported. The paper is free access ( look below). Four patients (17%) were diagnosed with lymphoma during their follow-up. Below is a pie chart from the paper that had 24 cases and the distribution on the biopsy. Overall, not a very common thing to see in SS, but glomerular disease is likely.

From CJASN 2009

http://ndt.oxfordjournals.org/content/16/12/2328.full

http://cjasn.asnjournals.org/content/4/9/1423.full

Access educational Tool

The AV fistula first website has developed some really good teaching resources for fistula and graft management and access care.  The videos that are very educational and helpful are the link below:
have a look:
http://www.fistulafirst.org/HealthcareProfessionals/FFBIChangeConcepts/ChangeConcept9.aspx

Image Quiz: What causes this color?

What is your differential diagnosis for "green urine"?

Complement Component Quiz Answers

Question:

Match the following complement components with their function in the complement cascade

C5a	Membrane attack complex
DAF	Initiates the alternative complement pathway
C5b-9	Initiates the classical complement pathway
Factor H	Byproduct of the classical complement pathway
C5	Potent inflammatory mediator
C1q	Membrane bound complement regulatory protein
C4d	Blockade of this complement component is the treatment for PNF
C3b	Deficiency results in atypical HUS

Answers:

C5a – Potent inflammatory mediator

DAF (decay accelerating factor) – membrane bound complement regulatory protein

C5b-9 – membrane attack complex (MAC)

Factor H – Deficiency results in atypical HUS (hemolytic uremic syndrome)

C5 - Blockade of this complement component is the treatment for PNF (paroxysmal nocturnal hematuria)

C1q – Initiates the classical complement pathway

C4d - Byproduct of the classical complement pathway

C3b - Initiates the alternative complement pathway

Post by

Vinay Nair 

eAJKD: Pemetrexed Nephrotoxicity

Pemetrexed is an antifolate agent approved for the treatment of advanced lung cancer.A recent publication in American Journal of Kidney Diseases discusses potential nephrotoxicity of this drug. Kidney biopsy specimens showed tubulointerstitial injury with tubular simplification, shrinkage, loss of brush border, and tubular atrophy in a more advanced case.  eAJKD did an exclusive video blog with the authors Dr. Ilya Glezerman( Renal service, Memorial Sloan Kettering Cancer Center, NY) and Dr.Surya Seshan( Chief of Renal Pathology, Professor of Pathology, Weill Cornell Medical Center, NY)
Check it out
http://ajkdblog.org/2011/11/23/pemetrexed-nephrotoxicity/

Clinical case 47: Answers and Summary

WHICH OF THE FOLLOWING ELECTROLYTE ABNORMALITIES HAS BEEN ASSOCIATED WITH PARAPROTEINS?

   
Paraproteins may cause abnormal laboratory findings in 3 ways: 1) through the disease 
process itself; 2) by interacting with the target of an assay; 3) by creating spurious results due to their 
interference with the assay method. Paraproteins have been shown to cause interference with the 
assays of multiple laboratory tests, including blood counts, sodium, calcium, phosphorus, lipids, 
coagulation profiles, iron studies, blood urea nitrogen, creatinine, bilirubin, c-reactive protein, 
glucose, uric acid, lactate dehydrogenase, alkaline phosphatase. 


All the above listed findings have been described with paraproteins except the hypermagnesemia.  Obviously, the most commonly discussed on board questions is pseudohyponatremia but that we don't see that often. Given the burden of light chains, usually one now encounters the others.  See the references below for full primary data on these.  IgM, given its size, is usually the big culprit but igG and igA have also been described.  Paraproteins exert biphasic interference on serum phosphate levels, usually resulting in factitious hyperphosphatemia but occasionally in hypophosphatemia. Pseudohyperphosphatemia may be seen in patients with IgM, IgA, or IgG paraproteins. In addition, hypophosphatemic patients showing falsely “high” levels of phosphate may be labeled as pseudonormophosphatemic, and this may be just as clinically relevant as pseudohyperphosphatemia. Deproteination can usually correct this artifact.

Previous SectionNext Section

Pseudohyponatremia, pseudohypochloridemia, and reduced anion gap have also been described when using the indirect ion-specific electrode method.  Pseudohypercalcemia due to an IgM paraprotein has been reported in two cases in the literature.

Previous Section

Next Section

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/20118906
http://www.ncbi.nlm.nih.gov/pubmed/18251580
http://www.ncbi.nlm.nih.gov/pubmed/21849226
http://www.ncbi.nlm.nih.gov/pubmed/19141380

eAJKD: Sulodexide in Diabetic Nephropathy: Is There a Role for This Novel Agent?

Check out the latest offering from eAJKD:
http://ajkdblog.org/2011/11/22/sulodexide-in-diabetic-nephropathy-is-there-a-role-for-this-novel-agent

Journal Club: Tolvaptan in ADPKD

Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years Experience

CJASN Oct 2011

ADPKD is an inherited disorder resulting in renal cysts, urinary concentrating defects, hypertension, and ESRD. The clinical manifestations include back pain from cyst hemorrage, stones, and infection. Extrarenal manifestations include cerebral aneurysms and can be life threatening .

A recent study evaluated the potential use of Tolvaptan, a V2 receptor antagonist, for the purpose of delaying progression of this disease.  The concept behind its use was based on animal studies that showed suppression of vasopressin by forced hydration or V2 receptor blockade reduced cyst burden and protected renal function.

                Total Kidney Volume (TKV) is a measurable end point that reflects outcomes in ADPKD including pain, hypertension, renal insufficiency, and ESRD. The current study explored if the use of V2 receptor antagonism in ADPKD pts could slow the rate of TKV expansion and decline in GFR.  There was one treatment arm in which all patients carried the diagnosis of ADPKD and were treated with tolvaptan. These patients were randomized in a 1:2 ratio to historical controls obtained from the MDRD and CRISP trials. These controls had ADPKD and were managed with blood pressure control. The treatment and control arms were followed for three years and endpoints included rate of TKV growth and rate of decline in eGFR. Results showed statistically significant differences in TKV growth with the treatment arm showing slower progression. Additionally rate of decline in eGFR was slower in the treatment arm in comparison to controls. However the absolute mean differences in eGFR decline were not significantly different suggesting that over a longer period of time, perhaps that effect would be realized.

                Over the course of the study all treated patients experienced mild side effects consistent with the mechanism of action of tolvaptan. Twelve patients in the treatment arm withdrew and six of them withdrew secondary to side effects which included renal impairment, acute renal failure, benign pituitary tumor, TIA, eye swelling, and subarachnoid hemorrhage with a fatal outcome.

                This study seems to be a proof of concept that perhaps V2 receptor antagonism may be an avenue for therapy in this disease population. A more rigorous and better designed study is underway with over 1400 ADPKD patients concurrently randomized into a treatment and control arm with long term follow up.    

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21903984

Post by Dr. Ezra Israel
Nephrology Fellow, Hofstra NSLIJ

Frequent Hemodialysis Trials: ASN 2011 update

The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. This trial was launched because it was noticed from small studies that more frequent nocturnal dialysis may help improve outcomes in dialysis patients. A multicenter study headed by Dr. Rocco et al where 87  patients randomized to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea).  NO significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) was found. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Sample size was small which could have been a reason of these negative result.

A sister of this trial was conducted: this time it was morning dialysis ( not nocturnal) but daily vs conventional hd on 245 patients. Compared two groups 6times weekly vs 3times weekly. This was an in-center trial. Average delivered 5.2 days vs 2.9 days in the two arms respectively. The time was shorter in the daily so the total hours were only 20% more in the daily arm overall. However patients in the daily arm still did better compared with the conventional group. Both primary outcomes and secondary outcomes were the same as for the nocturnal trial but they were significantly better for the latter(during the day). The reason for the discordance is being investigated.( of note the nightly dialysis received much more time on dialysis than either daily frequent or conventional)

Final note :

"FHN participants were younger and the racial composition for each study was different from the racial composition of the aggregate US dialysis population. Catheters for vascular access were more common in FHN Nocturnal Trial participants."

Post by

Dr. Azzour Hazzan

Hofstra NSLIJ Nephrology

TOPIC DISCUSSION: SIADH diagnosis

We always struggle to diagnosis this entity in few cases of hyponatremia. Measurement of AVP can prove challenging due to problems of ordering and time it takes to come back. Measurement of copeptin( a 39 amino acid glycopeptide) which is derived from the same precursor peptide as AVP and released in equimolor amounts as AVP might be measurable.  Is that been studied? You bet!

In this one prospective observational study, 106 consecutive hyponatremic patients were classified based on their history, clinical evaluation, and laboratory tests. In patients and 32 healthy control subjects, plasma copeptin concentration and standard biochemical parameters were tested for their utility of diagnosing SIADH.

Plasma copeptin levels were significantly higher in patients with hypo- and hypervolemic hyponatremia compared with SIAD (P < 0.005, respectively) and primary polydipsia (P < 0.001). The copeptin to U-Na ratio differentiated accurately between volume-depleted and normovolemic disorders (area under the receiver-operating characteristic curve 0.88, 95% confidence interval 0.81-0.95; P < 0.001), resulting in a sensitivity and specificity of 85 and 87% if a cutoff value of 30 pmol/mmol was used.  This ratio differentiated between volume-depleted and normovolemic disorders resulting in good specificity and sensitivity in this one study. It did better than copeptin alone as well. Another small swiss study felt that it added very little to the sodium balance information. I guess not much out in the literature. Lets see where this story unfolds and how this becomes real in clinical use.

Ref

http://www.ncbi.nlm.nih.gov/pubmed/18984663

http://www.ncbi.nlm.nih.gov/pubmed/21990032

Complement Component Quiz

Match the following complement components with their function in the complement cascade

C5a	Membrane attack complex
DAF	Initiates the alternative complement pathway
C5b-9	Initiates the classical complement pathway
Factor H	Byproduct of the classical complement pathway
C5	Potent inflammatory mediator
C1q	Membrane bound complement regulatory protein
C4d	Blockade of this complement component is the treatment for PNF
C3b	Deficiency results in atypical HUS

Good Luck
Answers provided in 1 week

Questions by Dr. Vinay Nair
Mt Sinai, Transplant Division
New York, USA

World Kidney Day Crosswords Answers

Kindey F Answers

ASN2011: Dialysis Mortality

SOME TEACHING POINTS FROM ASN 2011 Pre course on Dialysis Care

We all know that mortality is very high for incident hemodialysis and could reach as high as 50%. 

Hakim et all showed in a retrospective study in looking at Fersenius data. They looked 10 years back and found out that those with the highest mortality had catheters. One conclusion could be that these deaths could be  infectious complications. It behooves us therefore to prevent these kind of deaths. 

Unfortunately people had these catheters and died despite the fact that thery were followed by nephrologists for more than six months.

Bradbury et al, AJKD, 2009 showed that mortality decreased by 36% and 29% when catheter was changed to AVF, and AVG respectively; and mortality increased by 80% when permanent access was changed to a catheter.

What are some reasons to this suboptimal care: 

Late referal to nephrology, priamary avf failure, patient-induced delays and in-decisions, etc. (NDT)

Patients were reluctant bc of fear of needels and fear of surgery and prior failures of fistulas.

Our job as nephrologists is to prevent these deaths and spend the time and energy to convince patients get AVF or AVG.

Post from

Dr.Azzour Hazzan

Hofstra NSLIJ Nephrology

 

Topic Discussion: Nano Medicine ( ASN 2011)

Nano medicine  was one of the topics presented at ASN 2011. What is that?

Dr.Chan described it very well for us at the ASN meet.

It is the science of application of nano techology principles in biology principals. If one thinks of a single atom, that is called the atomic state.  If we have 26 atoms, that is the bulk state. Anywhere in-between 6-19 atoms, is the tunability state.  Hence in this part of the molecule's structure of growth, it can be used to tube physical and biological properties. That is the nano state of the particle(sub micron size).  The intersection of particles and directed energy is a rich source of novel and useful technology that is only recently being realized for medicine. One of the most promising applications is directed drug delivery.

These particles have tremendous potential for actively disrupting their environment for altering transport properties and unloading drugs.

Nano is actually the same size as DNA and protein. Hence one advantage of such technology is to introduce relevant size particles to specific body parts and have effect( chemo, biology. etc)

Example. Make a particle that is 60 nm and get to the target site of the tumor.  Then can be used for imaging purposes or delivering chemotherapy.  It is in clinical phase trials for invivo cancer, diagnostics as well, and in research phase in cardiovascular diseases, diabetes and pathology.

The limitations are:  delivery is poor- 5percent and the particle can stay in body for MONTHS. 

So toxicity in unclear. 

Nevertheless, nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. Technically,  nano carries can do drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. But not sure if this is clinically able to happen. The leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB).  Finally, direct in vivo imaging of nanomaterials is possible leading to provide real-time tracking of those nanocarriers. 

But this can open up a whole area of research in Renal diseases in terms of podocyte biology and perhaps even renal imaging of certain smaller structures.  

Interesting concept.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/22059114

http://www.ncbi.nlm.nih.gov/pubmed/20199661

ASN2011: Complement related disorders

This ASN, there was a series of talks regarding complement glomerulopathy and the use of certain newer agents for treatment. Dr Licht discussed this in detail in one of the talks.

Bottom line

1. MPGN pattern of injury is seen in complement related glomerular diseases.
2. DDD is now part of C3 glomerulopathies
3. Complement factor H antibodies, complement factor B antibodies have been associated with C3 glomerular disease since they will enhance c3 conversion and eventually affect the alternate pathway.
4. Genetic forms such as mutations in Factor H, CFHR5, C3 polymorphisms were also noted in that case.
5. It is possible that what we used to call perhaps C3 only post infectious GN or resolving post infectious GN was really C3 glomerulopathy.
6. Treatment is plasma exchange as there might be antibody that exists ( if you think there is)
7. Complement inhibition is the key- and the only drug we have is eculizumab ( 4 doses 900mg IV per week and 1200mg per week following that for 4 doses):- but expensive
8. Overall, there is a paradigm shift happening in introduction of these disorders.

eAJKD : Nephrology and the Internet

Check out the new post on eAJKD blog regarding Nephrologists and the Internet

http://ajkdblog.org/2011/11/15/the-nephrologists-and-the-internet/

Journal Club: Blocking complement prevents antibody mediated rejection in positive crossmatch living donor transplantation.

In an exciting pilot study published this month in AJT, Stegall et al. used Eculizumab, a C5 inhibitor, to prevent antibody mediated rejection (AMR) in positive crossmatch living donor transplantation.

High titers of donor specific antibody bind to the cell surface and activate complement through the classical pathway.  Cleavage of C5 precedes the formation of the MAC complex; therefore blocking C5 should inhibit complement mediated cell lysis.  Eculizumab is a monoclonal antibody FDA approved for paroxysmal nocturnal hemoglobinuria with a high affinity for C5.

The authors evaluated patients with donor specific antibody (DSA) described as a B flow cytometry crossmatch with channel shift (semi quantitative measure of antibody strength) between 200 and 450 which was confirmed by Luminex antibody analysis, against their prospective donors.  These patients were either treated with eculizumab (n=26) or a historical control from 2008 - 2010 treated with plasma exchange (n=51).  Both groups received pre-transplant plasma exchange until the channel shift was under 300.  All control patients received post transplant plasmapheresis while only 3 patients in the Eculizumab group received post transplant plasma exchange.  Patients were induced with thymoglobulin.  Protocol biopsies were performed on POD# 7, 14, 28, 90 and 365. 

Eculizumab was dosed as 1200mgs prior to transplantation then 600mgs on POD 1, then weekly for 4 weeks.  At week 4 and 8 weeks crossmatch was repeated and eculizumab was stopped if B cell crossmatch channel shift was below 200.  The primary endpoint of the study was the incidence of antibody mediated rejection in the first 3 months after living donor transplantation. 

Baseline characteristics in both groups including DSA titer were similar.  The incidence of AMR in the first 3 months was 7.7% in the eculizumab group versus 41.2% in the control group, with all cases occurring in the first month.  Graft survival was 100% and 96% respectively.  A similar percentage of patients developed high DSA in both groups during the first 3 months.  All patients in the Eculizumab group had positive C4D staining on protocol biopsy compared to 91% of control patients.    Mean serum creatinine was similar in both groups however, at 1 year 6.7% patients in the eculizumab group had transplant glomerulopathy compared to 36% of control patients.  One patient in the eculizumab group with transplant glomerulopathy was on eculizumab for a full year and lost his graft in 2 years.  One patient has subclinical ACR and one patient developed Burketts lymphoma 2.5 years post transplant.

This study is a truly novel approach to positive crossmatch transplantation, and extends previous reports suggesting efficacy in treating AMR.  While most therapies aim at lowering DSA (plasmapheresis, IVIg, rituximab, velcade), eculizumab simply inhibits the effector pathway of complement.  As the authors point out the study does suffer from limitations.  They included a historical control rather than to perform a randomized trial, and the authors did not evaluate efficacy in donor recipient pairs with a CDC positive T cell crossmatch.  It is also true that despite complement blockade there were patients who still when on to develop AMR and transplant glomerulopathy.  The other obvious question is what will happen 2 or 3 years down the line after eculizumab was stopped?  In addition to therapeutic limitations, the approximate cost of a single dose of eculizumab is about $6,000 dollars making it an extremely expensive therapy.  Regardless of these limitations, this is an exciting study that will hopefully open new doors in treating antibody mediated rejection and facilitate transplantation of highly sensitized individuals.  

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21942930

Post by 

Dr.Vinay Nair

Mt Sinai, Transplant Division

New York, USA

ASN2011: Pearls on Peritoneal Dialysis

From the pre course on ASN 2011, on Dialysis Modalities

The following are different strategies to decrease risk of peritonitis; they are unrelated concepts.

 

1-Russo et al in KI did a multi center Italian study. 353 pts answered a questionnaire. 191 pts had home visits with a score card.  23% were non-compliant with exchange procedure. This was associated with increased peritonitis rates.  So it maybe worthwile retraining Pd patients for 4days yearly to decrease the risk.

 

2-Diverticulitis may be associated with increased peritonitis rates. 

 

3-Hypokalemia and constipation can cause peritonitis; Bacteria in the colon migrate across the visceral peritoneum and enter the peritoneal cavity which is filled with dialysis fluid which inhibits immune function.

 

4-We should use prophylaxis medications for GI procedures to decrease risk of infections.

 

5-Fix all hernias before starting PD. On exam, one needs to have patients stand to uncover hernias and leaks. Umbilical hernias may be the smallest but have the biggest risk of incarciration.

 

And one more interesting tit bit of information was a new way of reporting Peritonitis instead of N of months between episodes;  is to use the number of infections per year and this will help compare centers to each other and also get a sepecific bug rates internally and within centers. 

Post by 

Dr.Azzour Hazzan

Hofstra NSLIJ Nephrology

ASN2011: CPC- Adenovirus Nephropathy

One of the highlights of ASN is always the CPC conference. This year the case was a transplant case with viral nephropathy and the nephropathy was Adenoviral origin.

Adenovirus nephropathy

Adenovirus is an important virus to consider in the differential of post kidney and BMT transplant nephropathies.  The urinary subgroup is 34 or 35 and the incidence is < 1% causing nephropathy.

Can see hematuria, testicular tenderness, and subjective complaints.

The kidney biopsy usually has ATN or AIN or abscess.  The viral particles are mostly in the epithelial cells unlike CMV which can infect endothelium and epithelium.  In the EM, there are 70nm non enveloped bodies noted.

Treatment is decreasing immunosuppresion or cidofivir ( nephrotoxic) but may have to be used.

A diagnosis that we should keep in mind when thinking of viral etiologies of nephropathies post transplant. 

Take a look at this recent JASN article.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21436288

ASN2011: late breaking trials: RESCUE TRIAL

A trial was presented about looking at Sirolimus(SRL) in primary prevention of skin cancer in kidney transplant recipients.  Patients with history of known skin cancer who had received a kidney transplant were randomized to continue their current CNI based regimen or change to a SRL based regimen.
Use of SRL based regimen showed a 67% risk reduction of skin cancer. Data on post CrCl and proteinuria was not presented. It shows again and again to use that SRL is a very good cancer preventive agent but can it prevent acute rejection episodes and proteinuria is not clear. Data from Canada in mice studies discussed earlier in the Onco Nephrology pre course by Dr. Susan Quaggin shed light on the mTOR pathway. It appears that if the mTOR pathway is completely knocked out in mice, they developed collapsing FSGS and ESRD in 3-4 weeks. Clinically, perhaps SRL doesn't do a complete blockade and hence we don't get such drastic findings but here and there we do hear about the significant proteinuria from SRL.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21610495
http://www.ncbi.nlm.nih.gov/pubmed/21792049

ASN2011: Late Breaking Oral Presentation: FISH Trial

Dr Lok from Canada presented the findings of the FISH trial that looked at use of 4gm of fish oil as a primary preventive for AVG stenosis.  The primary outcome was native potency and they did a randomized controlled placebo based trial.  It was a large group of patients and it was a well designed trial.

Unfortunately, the primary outcome was negative and there was no statistical significance of native potency prevention. But the secondary outcomes such as rate to thrombosis, number of interventional procedures, and cardiac events( MI and CHF) were statistically significant in the fish oil group.  

Also, the rate of corrective interventions was more in the placebo arm. Interestingly, there was no difference in cholesterol, TG and LDL in both groups. But HTN mean SBP was less in the fish oil group post intervention.  

A nice trial, but negative results. But there is some suggestion here that fish oil might be helpful in preventing cardiac events. This is the largest cause of death in ESRD patients. Something to follow up on as the research gets published

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/17848497

ASN Kidney News 3 day podcast from ASN

History of Nephrology: First ASN

It was 1967 ( first ASN ever)
Some words of wisdom and pride from Dr. Grantham, John Peters Award Recipient
"Nephrology is the best kept secret of internal medicine"