TOPIC DISCUSSION: The return of "Spironolactone"

The mineralocorticoid receptor antagonists have been forgetten the world of ACEI and ARBCS in past decade. Sometimes, when used for hypertension, have done wonders in many pateints and they come of significant number of drugs.  What is the role of aldosterone in CKD and can the antagnosits retard CKD?
Aldosterone has a potential role in progression of CKD via vasoconstriction, oxidative stress, inflammmation, alteration of filtration barrier and perhaps direct glomerulosclerosis based on some initialy proposed mechanisms.  There is some lab data in certain kidney diseases like diabetic nephropathy, cyclosporine nephrotoxicity, proteinuric nephropathies and esrd even that these antagonists might be of some benefit.

There is growing interest in studing combination of RAAS blockade agents and above agents but concern always is hyperkalemia and that has prevented large trials.  More careful studies need to be done and clinical trials to show effect of these old, cheap but powerful agents that might just work.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21412221

Match the drugs with the toxicity game!

Match the following 15 drugs with likely injuries noted below:

1. Cleistanthius Collinus
2. Conivaptan
3. SSRI
4. Bevacizumab
5. Pamidronate
6. Inteferon alpha
7. Etanecept
8. Hydralazine
9. Star Fruit
10. Zolendronate
11. Sunitinib
12. Omeprezole
13. Melamine
14. Lopinavir
15. Oral Na Phosphate solution

Possible injuries( each drug can have multiple choices)
A. Collapsing FSGS
B. Interstitial Nephritis
C. SIADH
D. Distal RTA
E. Diabetes Insipidus
F. Crystalopathy
G. Thrombotic Microangiopathy
H. Acute Tubular Necrosis
I. Oxalate Nephropathy
J. ANCA associted RPGN
K. Phosphate Nephropathy

CLINICAL CASE and ANSWERS 38

Microfilariae associated kidney disease has been noted. What would one see on the kidney biopsy?

glomerulus revealing sheathed microfilariae in the capillary lumen micro	3 (8%)
mesangioproliferative glomerular disease	2 (5%)
membranoproliferative glomerular disease	4 (11%)
membranous glomerular disease	4 (11%)
granulomatous interstitial inflammation and eosinophils in the kidney	9 (25%)
all of the above can be seen	13 (37%)

Majority of you got this one right.  Two ways microfilariae can cause glomerular diseases: direct physical invasion and second is via an immune mediated process( would included any form of diseases but mainly MPGN, mesangioproliferative and membranous). AIN with granulomas has also been seen. As a result, all of the above are correct.
Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21527949

TOPIC DISCUSSION: Clinical Pearls for electrolytes!

On a recent reading on Sodium and Water physiology, I realized again and again the following points

1. The best way to identify change in Na balance is to examine the extracellular volume status but there are no good ways to do that clinically( orthostatics, axillary sweat, skin turgor, physical exam??). Perhaps the hemotocrit might be the best marker we have.
2. There are no NORMAL values in electrolyte diseases, there are only what is EXPECTED of the kidney to do or the organ to do for the stimuli.
3. Classic one: " The acute discovery of a chronic condition does not make it an acute disorder"- By ML Halperin
4. Hypernatremia and "no thirst" leads to not a pleasant diagnosis to make requiring a MRI of the brain.

TOPIC DISCUSSION: Origins of the 1.73m2 in the GFR formula?

Why is 1.73 m2? and not just m2? and not any other number? Where does this all come from?
Basically, the simple answer is "arbitary".  The 1.73 refers to the standardized body surface area(BSA) used to normalize for all variables for an average 70kg man. Interestingly, this one paper that I reference below taunts the idea of this in a very comical way and shows where this originally came from.  Apparently in 1928, on a basis of just 8 children and 7 adults, the authors found a constant value can be substituted and they said it was 1.73m2- which was the mean of the areas of men and women age 25 from prior medical and acturial tables. So this was based on actuarial data showing the BSA using Dubose formula and then subtracting 1 inch from height in shoes and 5 pounds from weight in clothes and different variables for children and women.  Basically,this was based on american clothing standards and weights in 1920s.
Nothing has changed in using that number in last 80+ years.  The authors of the paper referenced below show that compared to 1920s, current average male weight is 80kg and hence the BSA should be technically corrected by 1.92m2 and not 1.73m2. 
Even if they chose less obese European population, it came to 1.86m2.  Interesting, if we did that, there would be an immediate 9% increase in world GFR per the authors. In general, to get a BSA measurement in the over weight and obese population is a tough task and not easy to measure- for us making GFR a harder thing to measure then as well as almost all measurements of GFR including MDRD correct for BSA and use 1.73m2.

"Is it a time to change or is 1.73m2 going to live longer than all of us like it has been!!"

 Re:f:
http://www.ncbi.nlm.nih.gov/pubmed/17445062
http://www.ncbi.nlm.nih.gov/pubmed/16693840
image source: wikipedia.com

Prolia or Xgeva, Denosumab and The Renal world!

Bisphosphonates are established treatment for metastatic bone disease in many cancers.  Recently the RANK ligand inhibitors had come into the picture for treatment of osteoporosis under the name of Prolia. Osteoclasts are activated in part by a signal made by osteoblasts called RANKL (receptor activator of NFkB ligand), which binds to its receptor on osteoclasts( see figure below). Denosumab(Prolia) is a monoclonal antibody against RANKL. It thus prevents activation of osteoclasts and the initiation of resorption. Denosumab is given every six month subcutaneously. A trial called the Freedom trial( listed below in references) enrolled over 7800 women between the ages of 60 and 90 with a T score on their dexa scan between -2.5 and -4.0, denosumab prevented the radiological evidence of vertebral fractures, as well as reduced the risk of hip fractures, non vertebral fractures. It also increased bone mineral density at the lumbar spine and hip.  The side effects were not many. No patients with ESRD were included, but there were a fair amount of CKD stage II, III and IV patients in the trial and in those subgroups, fractures were less as well in the Prolia arm. Following that, three recent randomized trials also showed denosumab under the trade name Xgeva showed non inferior to bisphosphonates in prostate cancer and breast cancer and metastatic cancer to bone and myeloma patients in terms of skeletal related events and preventing bone lesions. And perhaps even preventing hypercalcemia of malignancy???

The studies are interesting and apparently renal monitoring is not needed.  Compared to zoledronic acid(comparison agent), no renal monitoring is required for these agents.  It appears at closer look at the trials that the renal events were similar in both with no significant statistically. 
For us these trials might be important to follow as perhaps this agent might be something that might be used in the near future and we have to monitor for any renal side effects. Besides, it causes significant hypocalcemia in normocalcemic individuals as a common side effect. Hence, it might be an interesting agent to consider in treatment of malignancy associated hypercalcemia. A more recent trial in the US on using this agent that included few myeloma patients as well showed non inferiority to bisphosphonates. Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab.  Osteonecrosis of the jaw occurred at similarly low rates in both groups. Renal adverse events and elevations in serum creatinine were more in the bisphosphonates arm.

Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.
Let’s keep a close watch for it. For now, it is expensive and can only be given as an outpatient basis in the oncology clinics.


Check out the references below:
http://www.ncbi.nlm.nih.gov/pubmed/21411557
http://www.ncbi.nlm.nih.gov/pubmed/19671655
http://www.ncbi.nlm.nih.gov/pubmed/21353695
http://www.ncbi.nlm.nih.gov/pubmed/21060033
http://www.ncbi.nlm.nih.gov/pubmed/21343556
http://www.ncbi.nlm.nih.gov/pubmed/20682374
Image sources: medscape.com, cancergrace.org,
  

Alemtuzumab for Induction- the 2011 update

A recent NEJM May 2011 article has one article that compares use of Alemtuzumab and early steroid removal to Basiliximab and Thymo.  Its a nicely done randomized controlled trial that is multi centered.
On face value:- appears that rate of biopsy confirmed acute rejection was lower in the alemtuzumab group in the low risk patients when compared to basiliximab and similar to thymo when compared in high risk groups.

Few points from the trial:
1. All were steroid sparing making things not standard around all programs
2. The infection events were statistically more higher in the Alemtuzumab group especially in the low risk population
3. WBC count was also <3000 in the treatment arm
4. Cancer, renal injury other complications were similar
5. Rate of late rejection (after 12 months) was higher in both low and high risk groups compared to standard treatment
6. If steroids were withdrawn, and infections were more in the alemtuzumab group, wonder what the rate of infection would have been with steroids!

Till further studies, looking ahead. Awaiting to see what the transplant community thinks

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21591943
http://www.ncbi.nlm.nih.gov/pubmed/21591949