Nephrology Pearls Courtesy of Hippocrates

A cool article from this month's AJKD describes several of the Nephrology-related aphorisms originally penned by Hippocrates sometime around 400 BCE. These brief, pithy sayings probably represent the earliest attempts to understand the kidney in health and disease and the use of an examination of the urine in diagnosis.

A few of the highlights are shown below. Note that there is still some debate as to what each quote is really referring to.

1. The earliest description of casts? "When small fleshy substances like hairs are discharged along with thick urine, these substances come from the kidneys." Perhaps this describes the recognition of ATN as a cause of acute renal failure.

2. The earliest description nephrotic syndrome? "When bubbles settle on the surface of the urine, they indicate disease of the kidneys, and that the complaint will be protracted." It would be more convincing if he had also described the clinical elements of nephrotic syndrome (e.g., massive edema) but this is not mentioned.

3. On the utility of the bedside urinalysis: "We must look to the urinary evacuations, whether they resemble those of persons in health; if not at all so, they are particularly morbid, but if they are like those of healthy persons, they are not at all morbid." This little nugget is something that we all discover early on in our internal medicine residency: if a patient is admitted with an acute illness (e.g., pneumonia), the presence of concomitant renal failure is a very poor prognostic sign.

4. The earliest attempts at the diagnosis of nephrolithiasis: "In those cases where there is a sandy sediment in the urine, there is calculus in the bladder." A prehistoric "Litholink" test, if you will.

5. The discovery that uric acid-mediated disease is highly dependent on male sex hormones: "Eunuchs do not take the gout, nor become bald...A woman does not take the gout, unless her menses be stopped...A young man [boy] does not take the gout until he indulges in coition." The M:F ratio of gout in premenopausal females and age-matched males is about 8:1, but decreases to about 3:1 in those over 65 years of age.

6. Okay, so the guy's not perfect: "Venesection cures dysuria; open the internal veins of the arm."

Check out the full article if you enjoy this kind of historical stuff; it's really interesting and also offered FREE even for those without an institutional or individual subscription to AJKD.

Utility of Testing For Eosinophiluria

Testing for the presence of urine eosinophils is often performed when the diagnosis of acute interstitial nephritis is suspected.  The landmark paper touting the use of this test is a 1986 New England Journal of Medicine article by Nolan et al in which the use of the Hansel's stain to identify urine eosinophils is first described.  Prior to this, a Wright's stain was used but the Hansel's stain results in a bright orange staining of eosinophil granules that allows them to be much more easily differentiated from other white blood cells.  In this paper, eosinophiluria was noted in 10 of 11 patients with AIN and in 0 of 30 patients with ATN, leading the investigators to suggest that the presence of eosinophils can be used to differentiate between these two common causes of AKI.  

However, a more recent 2008 NEJM correspondence by Andrew Fletcher points out that subsequent studies looking at the utility of eosinophiluria to diagnose AIN are problematic.  The author points out that at his institution, the sensitivity and positive predictive value of eosinophiluria for AIN were 25% and 3%, respectively.  Furthermore, there is a wide variety of other diagnoses that can cause eosinophiluria, not just AIN.  A brief differential diagnosis is as follows:

-acute interstitial nephritis

-renal atheroembolic disease

-bladder Schistosoma infection

-chronic pyelonephritis

-rapidly progressive glomerulonephritis 

The Fletcher letter implies that based on the severe limitations of using the eosinophiluria to diagnose AIN that it not be used at all.  I still use it, though based on these limitations it can probably only be used as an adjunct to make a diagnosis of AIN when trying to differentiate between AIN & ATN, a not uncommon scenario.  Any other opinions out there as to how to best use this test?  

The Acanthocyte

We're all taught that looking for dysmorphic red blood cells on urinalysis is a useful marker of glomerular hematuria.  But how do we define "dysmorphic"?  And how was this association originally studied?  One landmark paper was this 1991 study in Kidney International by Kohler et al.   

The authors initially make the point that the term "dysmorphic red blood cells" encompasses a wide range of RBC morphologies that may be seen in the urine.  This includes discocytes, echinocytes, etc etc (shown below)--all of which are made possible by the deformable membrane of the RBC, necessary for its ability to navigate through very narrow capillaries. 

In the paper, the authors look at the urines of 351 patients with hematuria, 143 of which had biopsy-proven glomerulonephritis and the rest of which had hematuria from other diseases (e.g., AIN, cystic kidney disease, nephrolithiasis, etc.), as well as controls from non-hematuric healthy individuals.  

Acanthocytes (ring-shaped RBCs with blebs of membrane coming off--sometimes described as RBCs with "Mickey Mouse ears") were the best predictor of glomerular disease compared to all other dysmorphic RBC types.  Overall, acanthocytes appeared in 12.4% of all excreted RBCs in cases of biopsy-proven hematuria, and were very rarely seen in non-glomerular disease and controls.  At least 5% acanthocyturia was noted in 75 out of 143 GN patients (giving a sensitivity of 52%) and in 4 out of 187 patients with nonglomerular disease (giving a specificity of 98%).  The sensitivity of acanthocyturia for detecting glomerular disease could be increased by examining more than one urine sample. 

Other types of dysmorphic cells (e.g., echinocytes, etc) were present in glomerulonephritis at greater levels than acanthocytes, but were also commonly found in non-glomerular kidney disease and thus are not specific.  Furthermore, the number of echinocytes, discocytes, and stomatocytes were found to change when the pH, osmolarity, or protein content within a urine specimen was varied, whereas the number of acanthocytes remained relatively constant when these variables were altered.   

Here are some really nice pictures of acanthocytes, employing either phase-contrast microscopy or scanning electron microscopy.

Urine Crystals: Pattern Recognition

One of the easier aspects to taking an examination like the boards is pattern recognition: there are certain images or associations that should be immediate triggers for a particular diagnosis. One good example of this is a knowledge of what different types of urine crystals (causing nephrolithiasis) look like under the microscope. A quick review with examples I swiped from the Internet:

1) Ca-oxalate stones. Crystals of calcium oxalate can take two basic forms. The dihydrate form looks like little square envelopes:


The monohydrate form in contrast looks like elongated rods or sometimes dumbells. Monohydrate crystals are the predominant form of oxalate crystal seen with ethylene glycol poisoning.
Uric acid crystals in the urine are more tricky because they are pleimorphic--they can have many shapes. Some look almost football-shaped; other look more like crystal aggregates. They generally only form in an acidic urine.


Struvite stones are easy--they look like "coffin lids" and are usually found alkaline urine often with evidence of a UTI.
Though uncommon, cystine stones (seen in the genetic condition cystinosis) are hexagonal-shaped crystals. This is pathognomonic.
Finally, different medications can form urine crystals which may have a characteristic shape. One website with a lot of good images documenting many of these drug crystals can be found here.

Evidence for Terlipressin in Hepatorenal Syndrome

There are only limited treatment options for hepatorenal syndrome, and many would argue that treatment of type I hepatorenal syndrome (the bad kind) in the absence of a plan for liver transplantation is a futile effort. Over the past few years, however, there has been evidence accumulating for the use of terlipressin in the treatment of hepatorenal syndrome.

The data derive mostly from Europe, and terlipressin is not yet available in the United States. Terlipressin is an analogue of vasopressin, and is relatively specific for the V1 receptor--recall that it is the V1 receptors in the vasculature which mediate vasoconstrictive effects while it is the V2 receptors in the basolateral membrane of the distal nephron which mediate water homeostasis. 

The largest clinical trial evaluating that safety and efficacy of terlipressin for the treatment of hepatorenal syndrome Type I was conducted by Sanyal et al, in which 112 patients were randomly assigned to either terlipressin 1mg iv q6h versus placebo, plus albumin in both groups. They found that treatment success (defined as a reduction in creatinine <1.5>

Another study by Krag et al took patients with ascites but WITHOUT hepatorenal syndrome and gave them either terlipressin or placebo. They demonstrate that GFR increased substantially in the terlipressin group, providing some further physiologic evidence for this approach.  

I hope this therapy pans out--hepatorenal syndrome is one of those diagnoses I often feel helpless treating, and I'm not 100% sold on the effectiveness of the midodrine/octreotide approach that appears to have been adopted as the "standard of care", without rock-solid evidence in my opinion, at the hospitals I have worked in thus far. 

Tiny Tim: Victim of Renal Tubular Acidosis?

Pictured on the left is Bob Cratchit and his crippled son, Tiny Tim, two beloved characters from Charles Dickens' A Christmas Carol.  In this fun 1992 article by the pediatrician D.L. Lewis, the case is made that Tiny Tim suffered from renal tubular acidosis.  

So what's the evidence? Dickens describes Tim's illness as being a syndrome of short stature, asymmetric crippling, and intermittent spells of weakness.  The book also implies that there is some medical treatment available for this illness (which the Cratchits are initially unable to afford given the tight-fisted nature of Cratchit's boss, Ebeneezer Scrooge), and without such treatment Tim would be condemned to death within the year. Fortunately, after his encounters with the Ghosts of Christmas Past, Present, and Future, Scrooge is able to reverse his selfish ways, supplying Cratchit with a much-welcomed bonus with the implication that Tiny Tim will now be able to afford said medical treatments and survive. 

The author of the above article performed a review of available pediatric textbooks within the time frame of the book's setting (1830s-1850s) and determined that the likely treatment regimen for Tim's condition would involve alkali-containing compounds such as sodium bicarbonate and sodium citrate, along with potassium repletion and vitamin D repletion. A distal (Type I) RTA would fit nicely with these symptoms as his crippling could potentially seen as osteomalacia with pathologic fractures (the skeleton can develop severe weakness in the setting of prolonged acidemia), his spells of weakness could potentially be explained by hypokalemic muscle weakness, and his impending death could potentially be explained by the resultant renal failure that could result from chronic nephrocalcinosis, another aspect of RTAs.  

Another possibility would simply be that Tiny Tim suffered from severe vitamin D deficiency and resultant rickets--a relatively common affliction during this time period.

The more recent "real-life" Tiny Tim--the absurdist ukulele player--did not have kidney problems to my knowledge.

Propofol Infusion Syndrome

Though rare, propofol infusion syndrome (PRIS) is a cause of acute kidney injury in the appropriate ICU setting. As we all know, propofol is an intravenous sedative currently favored in the ICU due to relatively short half-life and generally good side effect profile. However under the right circumstances—typically high-dose propofol in conjunction with exogenous steroids and/or catecholamines—it can cause catastrophic and even fatal multi-organ failure. The mechanism of renal failure is a rhabdomyolysis-based mechanism which is postulated to be the result of direct mitochondrial toxicity of propofol occurring within skeletal and cardiac muscle. The syndrome can occur in both adults and children, though is more common in children. In this particular review, the authors suggest that PRIS is a somewhat misleading name in the sense that propofol infusion by itself in a non-critically-ill individual does NOT lead to this severe syndrome; rather, individuals who are already critically ill due to SIRS or neurologic injury are susceptible to a severe propofol reaction in the proper environment. The authors even suggest the more descriptive term, “critical illness cardiac failure and rhabdomyolysis associated with high-dose propofol, catecholamine or steroids,” though this is hardly amenable to a catchy acronym.

Pseudohyponatremia

Hyponatremia can be broadly divided into two fundamental categories:  "true hyponatremia" (in which the serum sodium concentration is truly less than normal), or "pseudohyponatremia," in which the serum sodium concentration is actually normal but erroneously reported as low due to the presence of either hyperlipidemia or hyperproteinemia.

To understand why this is the case, it's first necessary to understand that human plasma is normally composed of 93% plasma water and 7% proteins & lipids. Furthermore, it is necessary to understand that most clinical laboratories measure sodium using an indirect ion-selective electrode (ISE) which involves diluting the original blood sample in a 1:10 ratio and measuring whole plasma sodium based on the assumption that the sample is composed of 93% water. Thus, anything which increases the protein or lipid concentration of plasma will lead to an erroneously low sodium concentration. It occurs more often with hyperlipidemia than with hyperproteinemia, and one example would be in patients with familial hypercholesterolemia where their blood is highly lipemic. 

One way to avoid measurements of pseudohyponatremia is to use a direct ion-sensitive electrode, which measures only the aqueous phase of an undiluted blood sample; however, in most labs this is not done routinely. 

Pseudohyponatremia should also be differentiated from dilutional hyponatremia, in which an osmotic shift of water from cells to the vascular space following mannitol or IVIG infusions results in true (but hypertonic) hyponatremia.

Winter's formula and even simpler

Let's talk about rapid A.B.G. analysis. Just to clarify, I'm talking about arterial blood gases, not the religious rap group "Adopted By Grace" I just discovered existing by googling the phrase "ABG".

I tend to use Winter's Formula for analyzing metabolic acidosis: it's generally simple-enough math I can easily do in my head. To review, Winter's Formula is used to predict the PaCO2 which should result if there is appropriate respiratory compensation for a metabolic acidosis:

predicted PaCO2 = 1.5 x [HCO3-] + 8.

If the actual measured PaCO2 is lower than predicted, there is a concomitant respiratory alkalosis; if it is higher than predicted there is a concomitant respiratory acidosis.

There are some even EASIER ways to do this calculation however.

SIMPLIFIED WINTER'S FORMULA:
predicted PaCO2 = [HCO3-] + 15. This apparently works for PaCO2 concentrations between 10-40.

There's also something called:
THE THUMB RULE:

Put your thumb over the first digit of the pH on the ABG. The PaCO2 should be the last two digits. For instance, if the pH is 7.30, then the PaCO2 should be about 30mmHg; if the pH is 7.15 then the PaCO2 should be about 15mmHg, etc.

These are very simplified (and personally, I don't think it's that mentally strenuous to go with the more precise Winter's Formula), but potentially handy when rapid clinical decision-making is necessary (e.g., perhaps a resident giving you ABG results in the middle of the night).

Kim-1 Renastick

This month's Kidney International features an interesting report by Vaidya et al which reports on the development of a potentially useful dipstick test able to detect urinary Kim-1, a promising new biomarker for acute kidney injury.

As we all know, the rise in creatinine is a relatively late event in AKI, and the field of nephrology would benefit from tests which detect renal injury at an earlier stage. In this paper, the investigators tested a dipstick test's ability to gauge Kim-1 levels in three different rodent models of acute kidney injury: cadmium toxicity, gentamicin toxicity, and ischemia-reperfusion injury. All three showed a reliable ability of the dipstick test to predict renal injury. An example of gentamicin-treated mice (compared to negative controls) is shown. There are two bands on the dipstick: an upper band (a positive control) and a lower band (Kim-1). You can see that in the urines of mice treatd with the higher concentration of gentamicin there is the appearance of a strong red/pink lower molecular weight band, indicative of elevated Kim-1 levels. The test was also shown to predict AKI in human patients undergoing cisplatin-chemotherapy regimens for mesothelioma. Obviously the characteristics of such a test in a larger population of hospitalized patients will have to be undertaken in a careful fashion before the Kim-1 test can be considered for more routine use, but I like the practical nature of such a test-- incorporation of such a test onto a dipstick sounds easy, and could someday become a routine useful tool for many inpatient nephrology consults.

AAMI...What You Wanna Do?

For a while, maybe longer if I do....

No, I'm not talking about the one-hit wonder song "Amy" by Pure Prairie League...I'm talking about AAMI (the Association for the Advancement of Medical Instrumentation), the organization which regulates water quality within dialysis units.

The municipal water supply derives from both ground water (e.g., below the surface, like wells) and surface water (e.g., lakes and rivers) sources.  A variety of processing steps are typically undertaken--such as the addition of deflocculants such as aluminum, decontaminants such as chlorine compounds, filtering out of particulate matter, and addition of fluoride for the prevention of tooth decay (props to the Precious Bodily Fluids Nephrology blog)--in order to make the water acceptable for drinking.  It is not, however, acceptable for dialysis.  Compared to the 2 Liters of fluid a human typically drinks in a day, the dialysis patient is exposed to between 100-200 Liters of dialysate water, and any impurities which might be present, per dialysis session.  Thus it is essential to regulate and monitor the amount of bacteria and other chemicals with the dialysis water supply.  AAMI is the group which provides oversight of such regulations.  A comprehensive review of current AAMI standards can be found here. 

An example of what happens when these standards are not adhered to occurred during a 1987 incident in a Philadelphia-area outpatient dialysis unit in which high levels of chloramine resulted in an outbreak of hemolytic anemia amongst dialysis patients. Fortunately, no patients died. 

Why doesn't this catheter work?

Dialysis catheters:  the bane of the renal fellow's existence. I'm sure there are some of you who actually like putting in catheters and are quite good at it, and while I will admit that an efficient line placement that goes smoothly puts a smile on my face, troubleshooting dialysis catheters was NOT the reason I went into nephrology in the first place.  Even with the most expertly-placed catheters, it is not uncommon to encounter sluggish flow, even early on in catheter life.

Why do catheters stop working anyways? The most common answer:  fibrin sheaths. The above pictures shows a tunneled dialysis catheter which was removed secondary to poor flows, taken from an article by Peel and Turney from a 2003 NDT issue, which was found to have an extensive fibrin sheath covering the ports on the line and presumably responsible for decreasing flow. There are various options to help treat this: while we frequently reach for TPA, I would imagine that thrombolysis likely work best when there is a thrombus at the catheter tip--and not so much for fibrin sheaths. Pulling back the catheter a few cm (a common maneuver for temporary dialysis lines) may help initially, but the fibrin sheath is still present and may still limit flow. The interventional radiologist has access to tools which allow sheath stripping by the introduction of snares via a 2nd venous access site and passed over the line. 

Another question I have is this:  what happens to the sheath after you remove the catheter? Presumably it is gradually resorbed with time much like a DVT. Still, you have to wonder if persistent sheaths have the ability to cause complications such as emboli or clot. 

Serum Free Light Chain Assay

The dilemma:  there are a subset of patients with some type of paraproteinemia--e.g., light chain deposition disease or amyloidosis, for instance--which are NEGATIVE by SPEP & UPEP.  When there is renal involvement, the diagnosis can potentially be made by renal biopsy. But since we can't always be as invasive as we'd like to be, don't forget about the serum free light chain assay.  

Measuring serum free light chains relies on an assay which quantitates light chains NOT bound to heavy chain. In this 2003 Am J Clin Pathol study by Abraham et al, serum free light chains was found to be much more sensitive than either serum or urine immunofixation, and was successful in identifying several patients with AL amyloidosis who had undetectable paraproteins by SPEP & UPEP. 

Of note, serum light chains are cleared renally--so patients with reduced GFR will have increased values of both kappa and lambda light chain. Thus, for patients with CKD it is essential to look at the kappa:lambda free light chain ratio in order to detect a paraproteinemia. 

Speaking of Ethylene Glycol Poisoning...

If you've never heard the biochemical sleuthwork involved in the legal case of Patricia Stallings, it's definitely worth reading about: a good summary of the case can be found here.

Briefly, it involves a St. Louis-area woman who, in 1989, was sentenced to jail for the alleged poisoning of her baby son after he was hospitalized twice, and eventually died, due to apparent ethylene glycol toxicity. The diagnosis was made due to the presence of characteristic lab abnormalities (anion gap, osmolar gap), crystals deposits in the brain (felt to be oxalate crystals) as well as the documented presence of ethylene glycol--though the lab test used was apparently an older and less reliable gas chromatography method of measuring ethylene glycol in retrospect.

Fast forward several months later, when Patricia Stallings gave birth to a second child while in prison--who developed a similar illness and was diagnosed with a rare autosomal recessive error of metabolism: methylmalonic aciduria (MMA), which causes a chronic metabolic acidosis. The same type of disorder can also occur with severe vitamin B12 deficiency. Geneticists at St. Louis University and Yale University, alerted to the possibility that the first child's death might have been due to this genetic disease rather than ethylene glycol poisoning, re-examined the older blood samples, which were still available. They found that the original samples DID have an abundance of methylmalonic acid, and with a more accurate lab test did not have ethylene glycol. Patricia Stallings was determined to be innocent and subsequently released.

The legal aspects of the case, as it turns out, are just as interesting as the medical aspects: it involves the prosecuting attorney for the case actually initiating much of the detective work after the conviction which helped prove Stallings' innocence.

Wood's Lamp Trick for Diagnosing Ethylene Glycol Toxicity

One of the more common (and potentially successful) suicide attempts is to drink a bunch of antifreeze, which contains ethylene glycol. As we all know, this is typically diagnosed by characteristic lab abnormalities: patients present initially with an osmolar gap, and as the ethylene glycol is gradually metabolized to the organic acid oxalate, it evolves into an anion gap metabolic acidosis.

Another trick for diagnosing ethylene glycol is to use a Wood's lamp--which emits ultraviolet light. Most commercial antifreeze contains a compound which fluoresces under ultraviolet light; this is included so that car mechanics can detect potential antifreeze leaks. Thus, it is theoretically possible to detect a recent ingestion of antifreeze by seeing whether or not a patient suspected of an overdose is fluorescent under uv light. I use the word "theoretical" because there is some literature out there such as this which cast the sensitivity and specificity of uv-fluorescent urine into doubt.

Macroglossia

As you may recall, macroglossia (an enlarged tongue) is one of the many manifestations of amyloidosis, the systemic disorder in which a particular protein is deposited as Congo-red positive aggregations. You may also recall that amyloidosis can be divided into subtypes based on the amyloidogenic protein: for instance, there is AL amyloidosis (caused by deposition of Ig light chain, occuring in various paraproteinemias), AA amyloidosis (caused by deposition of serum amyloid A protein, elevated in inflammatory states), beta-2-microglobulin amyloidosis (caused by deposition of beta-2-microglobulin, usually in the joints, as a consequence of reduced middle molecule clearance in dialysis patients), etc. I learned today, however, that macroglossia is a unique complication of AL amyloidosis.

I have learned this, and many other renal factoids, at this year's Massachusetts General Hospital 2009 Nephrology Update. It's free for me (since I'm a fellow at MGH) and about 5 minutes from my house, and a way to force myself into doing at least a little bit of review for the Nephrology Boards. In any case, I have a whole list of new blog topics for the coming weeks...

Gestational Diabetes Insipidus

Changes in the regulation of serum osmolarity is just one of the many chances that occurs during the normal physiologic response to pregnancy.  Beginning with the first trimester, the plasma osmolarity level, serum Na, and osmolarity thresholds for the thirst and ADH responses are decreased by about 10 mosm/kg, a phenomenon which generally lasts through term.  

Later on in pregnancy, however, levels of circulating ADH actually decrease--due to production of the enzyme vasopressinase, which drastically enhances the turnover of ADH.  In most cases, the presence of vasopressinase counterbalances the decreased threshold for ADH secretion.  However, in individuals with gestational diabetes insipidus--a rare disorder in which vasopressinase production is excessive--can develop polyuria, polydipsia and excessive thirst, usually manifesting during the third trimester.  

Gestational diabetes insipidus, if severe, can be treated with DDAVP--a synthetic peptide analogue of ADH (pictured above) which is resistant to endogenous vasopressinase activity.

Minimizing risk of infertility in cytoxan-treated patients

One of the major side effects of cyclophosphamide (Cytoxan) in both men and women is gonadal failure and resultant infertility.  While there is markedly less risk with the doses typically used for the treatment of glomerular disease than, say, the massive doses used for chemotherapy, there is still a concern that long-term exposure to Cytoxan can have fertility implications.  

One potential strategy to minimize the risk of infertility in women is to use the hormone leuprolide, a gonadotropin release hormone (GnRH) agonist.  The idea here is that although leuprolide initially triggers a surge in LH & FSH, prolonged exposure leads to decreased LH & FSH levels, and this will eventually result in oocyte quiescence.  There is some data to support its use in the delaying of premature ovarian failure in women with lupus with long-term Cytoxan exposure in this paper by Somers et al.  Of note, it typically takes several weeks for leuprolide to work, so it is not necessarily a good option in individuals with rapid renal deterioration in whom starting Cytoxan is a priority.  

In men, the risk of infertility with Cytoxan is less well-defined than with women, but sperm banking may be a convenient option.

Structure & Function of Other Animals' Kidneys

Here's a very brief overview of the kidneys of animals (other than humans). All vertebrates have kidneys and the functional unit of the kidney in all species is the nephron.  Freshwater fish--like the zebrafish--have a kidney which is kind of like a long tube.  In zebrafish embryos (as discussed previously in another post) the kidney starts out as a structure called the pronephric duct, which consists of a single nephron, and as the fish becomes an adult develops into the adult mesonephros which contains multiple nephrons.  The function of the freshwater fish kidney is predominantly to create a dilute urine that osmolar homeostasis. 

The frog kidney must be able to adapt to both freshwater and land conditions--thus the frog kidney must be able to create both a dilute and a concentrated urine, depending on the environment to which the frog is exposed.

Snakes live in a dry environment and therefore their kidneys must retain water.  Snakes metabolize nitrogenous wastes into uric acid, which can be excreted in an insoluble form using very small amounts of water.  

The bird kidney also eliminates waste via uric acid.  The whitish pasty component of birdshit is in fact a uric acid paste that represents the renal waste product, which is usually mixed in with the brown stuff (the feces from the GI tract).  

Mouse kidneys are similar to human kidneys in that they use soluble urea, rather than insoluble uric acid, as the waste product.  

Aggrenox for Maintaining AV Graft Patency?

A very significant percentages of ESRD patient admissions derive from clotted dialysis access--the "lifeline" dialysis patients require in order to survive on dialysis. Any maneuver or treatment which is successful in preventing, or even delaying, access thrombosis would be welcomed throughout the Nephrology community.

A recent NEJM article by Dixon et al suggests that a combination of aspirin and dipyridamole can improve access patency rates by a modest but significant amount. The study looked only at arteriovenous grafts (AV grafts), which have a higher rate of thrombosis than arteriovenous fistulas by comparison. It was a randomized control trial in which patients were randomized to either placebo or 25mg ASA/200mg extended-release dipyridamole twice daily within a day or two of successful AV graft surgery. The primary outcome here was loss of primary unassisted graft patency--that is, did the graft stay patent without requiring any intervention such as thrombectomy. One strength of the study is that graft patency was quantitatively defined in terms of changes in blood-flow rate at dialysis and/or angiographically-defined stenoses.

The most important finding of this study was that the incidence of graft patency at 1 year was 23% in the placebo group and 28% in the dipyridamole-aspirin group. Another way of expressing this data was that the addition of dipyridamole-aspirin resulted in a hazard ratio of 0.82, with a confidence level that just barely missed crossing 1 (0.68 - 0.98) . Thus, the authors claim that this treatment resulted in a modest but significant improvement in graft patency.

The decision to use dipyridamole-aspirin on a regular basis in dialysis patients with AV grafts would also have financial repercussions. The authors point out that the cost of dipyridamole-aspirin (marketed under the name Aggrenox by Boehringer Ingelheim) is between $500 - $2,200 per year per person. Of note, the manuscript also notes that although the drug company supplied drugs for the study, they were explicitly not included in the study design or analysis, as the study was sponsored primarily by the NIDDK.

5-Oxoprolinuria as a Cause for Metabolic Acidosis

One of the rare (but potentially underdiagnosed) causes of anion gap metabolic acidosis is acquired 5-oxoprolinuria due to excessive Tylenol ingestion.  To explain how this works, you need to familiarize yourself briefly with the gamma-glutamyl cycle, a series of enyzmes and reactions involved in the metabolism of glutathione, an amino-acid derivative which appears to be important in the prevention of oxidative injury.  This cycle is shown below, taken from a 2005 AJKD paper by Humphreys et al.

  

You can see that acetaminophen inhibits glutathione.  Normally, glutathione performs a type of negative feedback control on the cycle by inhibiting gamma-glutamyl cysteine synthetase.  Without glutathione, then, this feedback inhibition is removed, and there is an upregulation of this enzyme, resulting in increased amounts of gamma-glutamyl cysteine, which itself is a precursor to the organic acid 5-oxoproline.  One of the key aspects of diagnosing this disorder, aside from having a clinical suspicion in the setting of anion gap metabolic acidosis without another explanation, is the detection of 5-oxoproline in the urine.  The disorder appears to be more common in elderly women or individuals with multiple comorbidities, in whom glutathione levels may already be low.  Although there is not much data in support of it, it makes sense that Mucomyst (N-acetyl cysteine, which augments glutathione levels) might work.

From the genetics angle, there are some pediatric, congenital causes of 5-oxoprolinuria which not surprisingly involved defects in enzymes of the gamma-glutamyl cycle (in particular, mutations in glutathione synthetase and 5-oxoprolinase have been identified in these patients). 

Nature versus Nurture in Deceased Donor Kidney Transplant Pairs

A recent paper in the most recent issue of JASN by Louvar et al asks the "nature versus nurture" question of deceased donor kidney transplants. Using data from the US Renal Data System (USRDS), the investigators looked at over 19,000 recipient pairs who received kidneys from the same deceased donor. Their goal was to determine the relative importance of donor characteristics ("nature") versus transplant center characteristics ("nurture") on deceased-donor kidney transplant outcomes.

To be brief, they the study had two major findings. First (the "nature" component), a recipient was more than twice as likely to develop delayed graft function when the recipient of the contralateral kidney also developed delayed graft finding. Not surprising--if one kidney sucks, the other one is likely to suck. Second (the "nurture" component), for pairs transplanted within the same center, there was an additional 42% risk for delayed graft function compared to pairs transplanted at different centers. That is, certain transplant centers are associated with a greater chance of delayed graft function than others. On this latter point, it's important to point out that some transplant centers tend to take higher-risk patients (e.g., desensitization protocols, ABO mismatches, 3rd- or 4th- transplants, high PRAs, etc) than others, so it may not be totally fair to use such center-specific data as "rankings" of transplant care quality.

Branching Morphogenesis

If a picture is worth a thousand words, then a movie is worth a thousand pictures, right?

What is this video of exactly?  This elegant work comes from the lab of Frank Costantini and colleagues at Columbia University, who developed a transgenic mouse line which expressed green fluorescent protein (GFP) under the control of the Hoxb7 promoter, leading to expression of GFP in the ureteric bud & developing collecting system, but not the surrounding mesenchyme which will give rise to the glomeruli and proximal nephrons.  They are able to grow the kidney as a tissue explant--that is, they surgically remove the kidney and grow it in a dish so they can closely examine its development. 

I have included it to illustrate the principle of branching morphogenesis:  a developmental program that is responsible for the highly branched collecting system of the mammalian kidney, which in the human kidney can ultimately will contain hundreds of thousands of nephrons.  How does the ureteric bud know when to start branching?  How does it know when to STOP branching?  What decisions control which cells get to branch and which one stay behind to form, say, the calices as opposed to the collecting ducts?  This model enables these researchers to ask cool developmental biology questions such as this.  This work has broad relevance to developmental biologists, and not just those interested in the kidney--other epithelial tissues such as the lung, breast, and salivary glands for instance appear to use a similar program of branching morphogenesis.  

Dialysis in the Elderly

The rate of patients >75 years of age initiating dialysis has grown substantially in the U.S. over the past two decades.  This has to do with several factors, including improvements in medical technology enabling people to live long enough to develop advanced CKD, but also an increasing expectation for aggressive medical care late in life.    In the U.S., the fact that the Social Security Act in 1972 pays for dialysis in all individuals also plays a role in this statistic.  The "Precious Bodily Fluids" blog recently posted an extensive review of the subject in power point presentation form.  

But how do elderly patients do once they have started dialysis?  The answer is complex--and not surprisingly it depends on the patient.  According to several studies, age itself is not a preclusion for starting dialysis--some patients > 90 years old can even do well provided their functional status is reasonable going in.  It turns out that the degree of comorbidity a patient has is a much better predictor of how they will do on dialysis than age alone.  

As an example, in this 2007 NDT study by Murtagh et al, the investigators performed a retrospective analysis of 129 patients > 75 years of age who were referred to a multi-disciplinary pre-dialysis care clinic.  They compared patients who chose dialysis with those who chose "conservative care"--which involved the decision to NOT begin dialysis but rather attempting to control their symptoms with blood pressure control, diet, etc.  The primary outcome measured was survival after reaching a GFR of <>

The top graph (A) shows the Kaplan-Meier curve describing patients WITH ISCHEMIC HEART DISEASE as a comorbidity.  You can see that the survival advantage in the dialysis group compared to the conservative care group virtually disappears.  In the bottom graph (B) is charted patients WITHOUT ischemic heart disease--and shows a robust and obvious survival advantage in the dialysis group.

These factors should ideally be discussed in educating elderly patients about the advantages and disadvantages of starting dialysis.  Patients >75 years of age with Stage V CKD and underlying ischemic heart disease should know that their likelihood of dying with or without dialysis is virtually the same.  Obviously, every patient is different and deserves to make their own decisions about end-of-life care.  But perhaps we should be adopting an evidence-based model similar to what some (not all) oncologists use--in which patients who do not meet a certain performance status are often not even deemed suitable to receive aggressive chemotherapy, with the knowledge that it has the potential to do more harm than good.

3 Key Facts Regarding Catheter-Related Bacteremia

The following "3 Key Facts Regarding Catheter-Related Bacteremia" are taken from Eliot Heher's "MGH Nephrology Handbook" distributed to nephrology fellows every year which I find very helpful:

Fact #1:  Fever and chills are highly predictive of positive blood cultures in dialysis patients with tunneled cuffed catheters:  In this article by Krishnasami et al, 76% of the time blood cultures end up being positive in this instance.  

Implication:  All dialysis patients presenting with fever and a tunneled dialysis catheter should receive empiric antibiotic therapy while blood cultures are cooking in the lab.

Fact #2:  A significant minority of catheter-related bacteremia episodes result from GNRs (30-40%), with the majority arising from Staph species which are often methicillin-resistant.  Mixed bacterial and fungal infection are much less common.

Implication:  Empiric antibiotic therapy must include coverage for both GPCs and GNRs (e.g., vancomycin 1gm iv x 1 & gentamicin 1mg/kg iv x 1 given towards the end of dialysis).

Fact #3:  Systemic antibiotic therapy without additional catheter management fails to clear infection in about 70% of cases, according to this 1997 AIM article by Marr et al.  

Implication:  Some type of catheter management for catheter-related bacteremia should be attempted in addition to antibiotics.  Options include (a) removing the catheter (the safest option in terms of preventing bacteremic complications such as endocarditis), (b), changing the catheter over a guidewire, (c) or attempting catheter preservation using the "antibiotic lock" technique.