Glucoretics have arrived: A new class of anti diabetic drugs

The U.S. Food and Drug Administration approved the drug, Invokana, after data showed it was effective in lowering blood sugar in patients with Type 2 diabetes.
Known chemically as canagliflozin, Invokana is a member of a new class of diabetes treatments called sodium-glucose co-transporter-2 (SGLT2) inhibitors that lower blood sugar by blocking reabsorbtion of glucose and increasing its excretion in urine.
To me this sounds like a glucoretic. 

Some of the animal data had shown promise and then these class of drugs came into trials. Preclinical and clinical research has demonstrated that inhibition of SGLT2, the major pathway of renal glucose reabsorption, leads to increased urinary glucose excretion with concomitant reductions in fasting and postprandial plasma glucose levels, HbA1c levels and body mass. In animal studies, the drugs have been correlated with an increase in urinary volume and a reduction in body fat but not water content.They do mention that it is contra indicated in CKD and ESRD patients( well if you don't make urine, this will not be working for sure).

Why is this drug important for nephrologists? Well increased osmotic diuresis can perhaps lead to a pre renal insults, more urinary tract infections( due to the glucorectic effect), perhaps proximal tubular dysfunction or better yet- maybe it gives additional benefit of water loss leading to good blood pressure control. A recent study already looked at the drug's effect on CKD stage 3 patients. It was deemed safe in CKD Stage 3 based on that one study. 

Novel mechanism, lets wait and watch.

Clinical Case 71: Answers and Summary

WHAT IS THE HIGHEST SERUM CREATININE THAT YOU HAVE ENCOUNTERED?

15-20mg/dl	11 (18%)
21-30mg/dl	16 (27%)
31-40mg/dl	12 (20%)
41-50mg/dl	8 (13%)
>50mg/dl	12 (20%)

Only two references I could find reporting high creatinine levels. 

One is Dr Topf's blog PB fluids reference of crt level in 34-37 range. But the highest reported in the literature is 61mg/dl. The poll above shows that 20% of you have seen such high creatinine levels. Disease states that cause such high creatinine likely are to be Rhabdomyolysis and obstruction. But the case reported above was hypertension. Cast nephropathy might be another form of obstructive disease where such high creatinines might be noted. 

Tele-Nephrology? Pros and Cons

Telenephrology may contribute to an effective use of health facilities by allowing patients to be treated in primary care with remote support by a nephrologist. A recent study done in Netherlands showed that telenephrology consultations( done via phone remotely or video conferencing) looked at reduction of in person referrals and response time. Time investment per consultation amounted to less than 10 minutes. Consultations were mainly performed during office hours. Response time was 1.6 days.  Most questions concerned estimated glomerular filtration rate, proteinuria, and blood pressure. The authors concluded that a web-based consultation system might reduce the number of referrals and is usable. Another study done in Russia also shows some promise.  A nice study from Canada showed that a positive response. The analysis of staff hours worked showed almost no increase following the introduction of telemedicine. Telemedicine is therefore feasible for follow-up care of remote chronic kidney disease patients.

Peritoneal dialysis seems to be a place where this might be very useful or home dialysis. Few papers have looked into positive aspects of this form of medicine. Remote monitoring of the patient on peritoneal dialysis offers the benefits of real-time monitoring and recording of the therapy and interactive interface with the nephrology team can allow both acute 'trouble shooting' for problems as well as a means to interact with the patient for their monthly evaluation. This remote monitoring may increase compliance. Recent advances in telemonitoring, remote network access and sensor technologies have made such remote monitoring of peritoneal dialysis therapy a potentially user friendly option. A recent review summarizes the pros and cons of using such techniques.

Other studies have shown otherwise. In France, the experience seemed unfruitful and had to be shut down.

Border Crosser's Nephropathy

A recent article in Renal Failure discusses this novel entity called Border Crosser's nephropathy. Immigrants who were attempting to cross borders in Arizona were wandering for days without food and water and developed AKI secondary to heat exhaustion leading to rhabdomyolysis. The authors term this AKI as Border Crosser's nephropathy. They studied a case series of patients and found that mean days on desert was 4 days and few patients required dialysis. Most CPK were range of 1101 to 447,966IU/L.
Largest CPKs are reported in such patients. This appears to be a risk that we have to keep in mind. Unclear to me if this truly deserves a separate name or can we just call it volume depletion and heat exhaustion leading to rhabdomyolysis leading to ATN.

Nephrology: Name origin

Jean Hamburger from France had named the term " Nephrology" for study of kidney diseases. A pioneer in the field of kidney diseases, Dr Hamburger was a pioneer in the early times of dialysis and transplantation.
A recent memoir regarding his work is published in PEHM

He was a pioneer in nephrology, coined the term intensive care medicine and was a pinnacle for humanism in medicine.  He is considered the father of French Nephrology. If he coined the term- he is the father of nephrology for all of us.

Interesting quote from the paper " Nephrology would have probably been named kidney medicine, under the strong influence of  the American medicine, while the Greek etymology may be seen as a further witness of the strong link between humanities and medicine, of which the whole life of Jean Hamburger is
an interesting example."

Lets celebrate the history of nephrology this month - the National Kidney Month-- or rather World Kidney month with respect to him.

Check out other historical interest blogs.

NephMadness Brackets

Here are my selections for the eAJKD's mega nephrology competition. 

I think PD is an important form of dialysis that is home based and deserves to be offered first and hence PD first. APOL1 is one the most important genetic discoveries of all times. ASN is the most important organization to help with research and progress in Nephrology. A tough battle for most players but I feel that Kidney Transplantation is the winner!  This surgical procedure has been the best thing we can offer our patients!

Clinical Case 70: Answers and Summary

A 31 Y OLD MALE WAS FOUND TO HAVE 6MM KIDNEY STONE INCIDENTALLY ON RENAL SONOGRAM? WHAT DO YOU DO NEXT?

Urology referral

  10 (18%)

Observe with no further imaging

  20 (37%)

Stone workup

  14 (25%)

Start Potassium citrate

  1 (1%)

Observe with frequent imaging yearly

  9 (16%)

What do you do with a 6mm stone incident finding? Varied answers from majority saying do nothing and observe and second highest saying stone workup and then urology referral. One study of 107 such patients for a mean of 32 months. The likelihood of developing symptoms was approximately 32 percent at 2.5 years and 49 percent at 5 years; the risk was lowest in patients who had no history of previous stones.  Wait and watch approach may be a reasonable in asymptomatic patients with small, non-infected calculi, without evidence of obstruction. Based on stone experts, certain asymptomatic patients, depending upon their occupation (airline pilots, frequent business travelers) or having anatomic consideration( solitary kidney, diversions) should consider undergoing evaluation and treatment to reduce the risk of recurrent stone formation or growth of existing stones with perhaps options that we listed above. Tough question and practices might be varied depending on nephrology or urology. Not much data to support either way. 

BK nephritis in the non renal transplant setting

BK nephropathy got it's fame in kidney transplantation. Why can't this entity exist in native kidneys?
While reports have been seen following stem cell transplantation, no study had looked at this question till recently. A recent study in NDT presents 8 cases of BK nephritis in a native kidney setting.

The settings were:

1. HSCT
2. TB
3. Other hematologic malignancies
4. lung transplantation

What is interesting is that HIV patients don't get BK? Or there are scare reports. One study did find that HIV patients do shed BK virus. But most studies have found that they don't co exist. Some have suggested that they share the same co receptor.  Why don't we get full blown BK nephritis in this setting?- is it the altered immune setting or is it the one of the HAART meds that are protective ( and potentially a treatment for BK). Here is one case report in the literature.

eAJKD's #Neph Madness

Welcome to Neph Madness: the ultimate Nephrology competition of the best accomplishment in Nephrology. 

March Madness and Kidney Awareness Month leading to the NephMadness.
Blend it with NCAA Men's tournament and we shall crown the next champion- the greatest nephrology advancement
Check out the next 2 weeks in eAJKD for the winner

Play along the fun game and in the midst- learn the history of Nephrology!!.
http://ajkdblog.org/category/nephrology-madness/

Medical student perspective on Nephrology

Happy World Kidney Day!  The theme this year is kidney attack or Acute Kidney Injury. In the US, the nephrology community is facing a different form of attack.  There is a nephrology workforce angina.
While we have postulated what could be the reasons for many residents not choosing the field for variety of reasons, two medical students( American and German) in a recent editorial highlight their reasons and concerns regarding the field of nephrology.

Two medical students celebrate nephrology with it's wholesome experience. Medical students need to see the entire nephrology experience ( and not just inpatient) and need to have knowledge of the gratifying longitudinal experience of nephrology.
Let's take a pledge this World Kidney Day

1. To showcase nephrology( both inpatient and outpatient) to medical students around the world
2. To showcase the positive research opportunities in this field of medicine
3. To showcase them that nephrologists are good teachers and make great clerkship faculty cohorts
4. To showcase them the best organ of the human body

Topic Discussion: Renal injury biomarkers

Finding a troponin for renal injury has been the quest for the last 10 years for many researchers in Nephrology. A recent article in AJKD nicely summarizes this quest in a core curriculum review. The lead author is from the renal fellow network.

Some key points:
1. Most biomarkers that have been discovered in the recent years have been mainly looking at proximal tubular injury and glomerular permeability.
2.While creatinine and albuminuria are always considered conventional, it was interesting to see that they included cystatin C as a conventional marker as oppose to novel. Clinically, doubt the use of this marker has blossomed yet.
3. Most common settings most of the newer markers have been checked are: post cardiac surgery, intensive care unit settings and contrast nephropathy
4. The best part of the paper is the discussion of urinary versus serum biomarkers and how in certain cases urinary markers could be most helpful but there could be contamination. Serum biomarkers are excellent to have during anuric settings but are they specific for kidney injury?
5. There are many tables that are good to review to go over most of the new markers that have been evolving in the last 5 years.

Kidney TREKS: ASN's new venture for medical students

A product of the ASN workforce committee's efforts to increase interest in nephrology is Kidney TREKS- the medical student course in physiology that could potentially spark interests among budding nephrologists. Regardless of the choice of specialty these students choose, attending this spectacular course will enhance their understanding of physiology and science. Also, for more references and details check the ASN trainees page.

In the News: LG3 and the Transplanted kidney

Antibodies have always been the biggest concern in transplantation. During vascular rejection, there is endothelial cell damage. The apoptotic endothelial cells release a fragment of perlecan referred as LG3.  

A recent study in the AJT identified a novel antibody that may be playing a role in vascular form of antibody mediated rejection. The authors call this anti-LG3, an antibody that some patients produce to attack a protein that plays an important role in vascular repair and regeneration, LG3. In these patients, the secretion of LG3 by the new kidney stimulates the activity of these antibodies which attack and injure the blood vessels of the transplanted organ, and the normal healing process of the transplanted organ is impaired. Patients who experienced vascular rejection had elevated anti-LG3 titers pre and posttransplantation compared to subjects with interstitial form of rejection( cellular) or stable graft function significantly respectively.  The authors also confirmed these findings with mice data. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling. One prior animal study showed similar findings. 

Do we have a new marker for potential vascular rejection? What is the data on LG3 in other forms of endothelial injury namely CNI induced TMA or other forms of endothelial damage? Then again, the perlecans are altered in certain genetic diseases that don't quite fit the role they play in transplantation.