Does she drink tea?

I was quickly moving along through my busy university clinic, seeing another CKD patient when the nurse came to inform me that the patient’s hemoglobin was critically low at 5 g/dl, while the patient appeared to be just fine. I reviewed the rest of labs just to find out that the iron studies were even more impressive: iron saturation 3% and ferritin 2 ng/ml.

I inquired about the usual suspects - bleeding from various sources - but no luck there (the patient was post-menopausal and denied GI bleeding, later ruled out by EGD and colonoscopy)... Failing to identify a cause of her iron deficiency, I presented the case to my staff who, after reviewing the data, asked me an unusual question: does she drink tea? To my surprise, indeed, the patient admitted to drinking large quantities of black tea. Still puzzled about the link between the two, I jumped onto Google Scholar.

In the renal world, the only time when we talk about tea is when discussing hyponatremia in patients that are on a “tea and toast” diet. So what did I find out? An interesting South African study demonstrated that black tea inhibits non-heme iron absorption by forming iron tannate complexes. This was confirmed by a UK study which showed that black tea was the most potent out of all polyphenol-rich beverages (coffee, cocoa, etc.) in inhibiting absorption of non-heme iron.

Iron deficiency anemia is common in CKD patients, one of the latest mechanisms to be described involves the hepcidin-ferroportin axis (as recently reviewed in JASN). But today I discovered another one!

Posted by Tomoki Tsukahara

A Gel Coating Your Hairy Endothelium

To follow up on one of Nate’s posts from 2010, hair grows not only on your skin. He describes a glomerular capillary to be hairy. Glycocalyx, a hairy structure attached to the glomerular endothelium, is a mixture of glycosaminoglycans and proteoglycans. The picture of glycocalyx accompanying that post is quite impressive.

Now we know these hairs are coated with another gel matrix called endothelial surface layer (ESL). ESL, together with glycocalyx, is believed to function as a barrier to prevent protein passage from blood to urine. A recent article addressing this topic was published in JASN.

By using an animal model, the authors showed that loss of ESL increases the sieving co-efficient for albumin and that the degree of albuminuria correlates with the degree of ESL loss (by the way their confocal microscopy images of ESL are pretty cool).

The implication of the study is that it’s not just podocyte or GBM that are responsible for the development of proteinuria; ESL, glycocalyx and endothelium appear to play an important role as well. For example, loss of ESL has been reported in patients with diabetes. Maybe it’s not just on the skin where hair loss occurs.

For those who are interested in this topic, there is a nice review article for further reading.  

Posted by Tomoki Tsukahara

Mg & K

It is well known that hypokalemia does not correct easily if it is accompanied by hypomagnesemia. A medical student I met looked into this topic and found a “Science in Renal Medicine” article. According to this article, one of the mechanisms through which hypokalemia occurs in a hypomagnesemic state is through renal potassium wasting. Several observations have shown that magnesium infusion decreases renal K secretion in the distal nephron.

A study from Nature found that ROMK (aka Kir), one of two potassium channels in the distal nephron, is responsible for the distal renal K wasting in hypomagnesemia. The mechanism is that the intra-cellular free Mg blocks the pore of the ROMK channel and limits potassium secretion in a concentration-dependent manner; therefore low intracellular Mg level increases potassium secretion.

Some renal Mg wasting disorders (e.g. Mg channel TRPM6 mutation) do not always present with hypokalemia. Why is that? The reason is that you need 2 components for potassium excretion. One is increased K permeability of the ROMK, and the other is a driving force to secrete K like increased distal Na delivery or an elevated aldosterone level (via enhanced Na reabsorption in the distal nephron). It seems in these disorders you don’t have the second determinant for K secretion.

Another fascinating renal physiology article! Now we are still confused but have a better understanding of hypomagnesemia in a case of hypokalemia. 

Posted by Tomoki Tsukahara

Honey for the Achilles Heel

In the PD literature, peritonitis has been referred to as an Achilles’ heel because it could lead to catheter removal and PD treatment failure. Topical antibiotics have been used for prevention of an exit site infection (ESI) which may precede and lead to peritonitis.

For this purpose, most centers use mupirocin as their first choice. It has reduced the ESI significantly, but mupirocin-resistant S. aureus and P. aeruginosa ESI have emerged. Then came gentamicin which is superior to mupirocin. However, gentamicin-resistant P. aeruginosa has already been reported… How can we break this cycle?

FOOD was the bright idea! Not any food but a very specific sweet treat – honey. Honey has been applied to wounds since ancient times, but only recently have we come to understand its antibacterial properties: acidity (pH 3-4), high osmolarity (3000 mOsm/kg), H₂O₂, methyl glyoxal, bee defensin-1, etc. In vitro, honey killed bacteria including MRSA, β-lactamase producing E. Coli, ciprofloxacin-resistant P. aeruginosa and VRE! Because of its multiple antibacterial mechanisms, there is a low likelihood that bacteria will gain resistance.

But does it work in vivo? It has been shown that honey heals wounds and maintains sterility. Then, an Australian and New Zealand group tested standardized antibacterial honey (Medihoney) for HD catheter-associated infections and its effectiveness was comparable to mupirocin.

Now the same group is conducting the HONEYPOT study to see its efficacy in reducing the risk of PD infection. This is one of the initiatives to improve the PD technique survival in the region which is lower than in other parts of the world.

The results of the HONEYPOT study are pending, but it would be exciting if honey is proven to be an effective alternative prophylaxis with less chance of bacterial resistance. Penicillin was discovered from fungi. Gentamicin is synthesized by bacteria. Maybe it’s time to ask for honey bees for help.

Posted by Tomoki Tsukahara

Less is More

Despite the fact that the kidney ultrasound is generally obtained as one of multiple recommendations when evaluating AKI, the benefit of kidney ultrasound is not clear. The post-renal causes of AKI are not very common. It adds to the cost and can subject patients to unnecessary work-ups by revealing incidentalomas. How often, then, is the ultrasound useful? 

In order to assess the prevalence of the post-renal AKI and determine a cost-effective use of the ultrasound, a single-center case-control study was conducted.

Their conclusion is that the prevalence of hydronephrosis requiring stenting or nephrostomy placement was only 0.4% in the low-risk group. The number to screen to find a case of urinary obstruction was 223. At what cost? In our institution the kidney ultrasound without Doppler costs $600. It costs $133,800 to find one case.

Who is the low-risk group patient? Based on the multivariate analysis, a patient was considered low-risk if he or she did not have a history of hydronephrosis and had no more than one of the following:

1. Recurrent UTI

2. Diagnosis to suspected obstruction (BPH, abdominal or pelvic cancer, one functional kidney, neurogenic bladder, pelvic surgery)

3. Non-African American

4. Absence of:  exposure to the following medications (ASA, diuretics, ACEI or IV vancomycin), congestive heart failure, or pre-renal AKI.

The study has limitations. Not all AKI patients were studied. The cases requiring non-surgical interventions were not counted. If we would have to implement this strategy, we don’t know what the cost of missing some cases of obstruction would be.

However, the implication is that we should not routinely order kidney ultrasound on every patient with AKI, particularly those in the low-risk group. In this era of cost constraint on medicine, less is usually more…

Or, here is what you can do. If your place has an ultrasound on the floor, with a little training you can have a quick look at the kidneys just to rule out obstruction in low risk patients. You acquire one more diagnostic skill, your students have one more fun on round, and your hospital saves significant amount of money!

Posted by Tomoki Tsukahara

A Quest for a Pot of Gold

In the quest for better solute clearance, two divergent paths were taken on each side of the Atlantic. The US nephrology community has concentrated more on low weight molecules. The European counterpart has focused on both low and middle weight molecules.

The European endeavor has led to the evolution of the on-line hemodiafiltration (HDF), combining HF and HD. A water-permeable filter allows middle molecule removal by convection. Dialysate then supplements low molecular weight solute removal by diffusion. Production of the replacement fluid from dialysate in the circuit (thus called “on-line”) cuts the cost.

Since Fresenius’ Online Plus™ came out in 1998, on-line HDF has gained popularity in Europe and other continents. In the US? Not so much, but we may see it more as it was just cleared by FDA for the market this April.

The idea of middle molecule removal sounds physiological. But is there really any advantage?

It has been suggested that the on-line HDF may reduce intra-dialytic hypotension, improve nutritional status, and decrease ESA (erythropoiesis stimulating agent) requirement. But what about the hard end points (all-cause mortality and cardiovascular outcomes)?

In the recent CONTRAST study, 700 patients in the Netherlands, Canada, and Norway were randomized to on-line HDF or low-flux HD. The surprise? There was no CONTRAST between the two groups… The CONSOLATION was a minimal survival benefit among those who received top-quartile convective volume.

Did this disappoint the nephrology community? Yes, to some extent. In a recent CJASN editorial, Dr. Kuhlman from Germany pointed out  that in Europe the advantages of on-line HDF over conventional HD have been “somehow taken for granted”.

Did this put an end to on-line HDF? The answer is no. A couple of more European studies are on their way, so is the research to solve technical challenges. This is a never ending journey, even if it may end up with the quest for a pot of gold at the end of the rainbow.

Posted by Tomoki Tsukahara

A unified view of abnormal sodium regulation in the nephron

Summer has come to the northern hemisphere and it is time to praise our kidneys for all the hard work of preserving the intravascular volume. Although only 30% of Na reabsorption takes place in the distal nephron, this is the place for most common genetic diseases causing abnormal sodium handling:

What are the responsible proteins for these diseases?

1. Bartter syndrome: Na reabsorption decreases via NKCC2 due to defects in NKCC2, ROMK and basolateral Cl channels or from an overactive basolateral CaSR.

2. Gitelman syndrome: Na reabsorption decreases due to a reduced number of NCCs on the luminal membrane.

3. Pseudohypoaldosteronism type 1: Na reabsorption decreases due to the defects in ENaC or mineralocorticoid receptor.

4. Liddle syndrome: Na reabsorption increases due to a higher number of ENaCs on the luminal membrane (they are spared from ubiquitination).

5. Gordon syndrome: Na reabsorption increases due to a higher concentration of NCCs on the luminal membrane (defects in WNK4 or overactive WNK1). More recently, mutations were discovered in the genes encoding KLHL3 and CUL3 proteins.

CUL3 is a component of ubiquitin ligase and KLHL3 is its partner (expressed in the DCT). It is speculated that the defects in these proteins may change the distribution of NCC.

Is this clinically relevant?

In Gordon syndrome, these mutations can occur de novo and are encountered more frequently (47% for KLHL3 and 32% for CUL3) than those involving the WNK kinases (13%). It appears that they are under-diagnosed and some of the cases of RTA type 4 with hypertension could be caused by them!

50 years after Bartter syndrome was described, the work on mechanisms responsible for abnormal Na regulation in the nephron continues…

Posted by Tomoki Tsukahara MD