Bedside Urinalysis - Blood

All to often now doctors in well-resourced hospitals rely on high tech, expensive and sometimes invasive tests to make a diagnosis. One of the most basic and cheapest tools we have at our disposal is the bedside urine ‘dipstick’ test. What can we learn from such an easy to perform test? 

One urinalysis reagent strip or ‘dipstick’ costs about 14cents (Pinnacle 10SG Urinalysis).

Finnian wrote two excellent blog posts on urine specific gravity and osmolality and on urine albumin and protein measurements using the ‘dipstick’ test. Here’s what else this bedside test can help you with.

Urine dipstick ‘Blood’ test

Heme acts as a pseudoperoxidase and when exposed to the peroxide and a chromagen on the test pad a colour change takes place.

The urine dipstick is a highly sensitive test for the presence of heme in the urine and detects as few as 1 to 2 RBCs per high power field.

The presence of urinary ascorbic acid is one circumstance where false negative tests for hematuria occur. Some manufactures make test strips that can oxidize ascorbic acid to reduce false negative tests.

Semen in the urine can cause a false positive test.

Of course the ‘blood’ panel turns positive due to the heme in free urinary hemoglobin or myoglobin.

Thus the presence of RBCs in the urine needs to be confirmed by microscopic analysis of the urine.

What disorders can we assess with the ‘dipstick’ test for blood/heme?

           

Rhabdomyolysis

Myoglobin is released from damaged muscle along with CK. 

Myoglobin is not avidly bound to protein and is thus rapidly excreted in the urine and has a half-life of about 2 hours. It is also rapidly metabolized to bilirubin so serum levels return to normal within 8 hours.

Thus, a diagnosis of rhabdomyolysis is not ruled out by negative urinary myoglobin.

On must also be aware that there may also be heme or RBCs present in the urine for other reasons during rhabdomyolysis.

Myoglobin appears in the urine when serum levels are above 1.5mg/dl but visible changes in urine colour only occur when serum levels are above 100mg/dl. A clear urinary supernatant usually helps to distinguish myoglobinuria from hemoglobinuria (red supernatant) after centrifugation.

Myoglobin can be detected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL.

Mean peak serum Creatinine Kinase (CK) levels in a large study of rhabdomyolysis was 10,000 to 25,000. 46% of this cohort had AKI. In another study that included only patients with a CK over 5000 AKI was present in 51%.

A good history and physical exam helps makes the diagnosis.

Hemolysis

Again this diagnosis is easy with a good history and physical exam and some basic ‘hemolysis’ lab tests. What can you do while waiting for the lab results?

The urine dipstick will be positive for heme in the urine. In theory there will be no RBCs in the urine and the supernatant will be red without a red cell pellet. However, there are caveats to this, an old urine sample and rarely a very dilute urine sample (low specific gravity – see Finnians post) may cause red cells present in the urine to hemolyze. Urine microscopy should be done to look for presence or absence of RBCs.

Red urine supernatant but negative dipstick ‘blood/heme’?

Rifampin, phenytoin, food dyes, beets (beeturia), rhubarb, senna or Acute intermittent porphyria.

Renal or urological bleeding.

In either of these circumstances urine dipstick tests will be positive for blood.

Hematuria present with proteinuria is suggestive of a glomerular cause. Hematuria with proteinuria greater than 1+ is almost never due to extra glomerular bleeding even when gross hematuria is present. However, massive bleeding can cause proteinuria. Massive bleeding is more likely to occur due to extra glomerular bleeding and the presence of clots and very red or pink urine as opposed to Coca-Cola coloured urine indicates extra glomerular bleeding.

Does that taste bad? - Part 2

Following on from yesterday's post about turtles who may have a taste of urine in their mouths, here's an interesting historical diversion about doctors who, in the past, intentionally drank urine to diagnose disease. An article in Scientific American gave us this picture of a "urine wheel" which, by correlating the taste, smell and appearance of the urine, was a valuable diagnostic tool in the 16th century. The classic diagnosis associated with tasting the urine was of course diabetes but it is by no means the only one. 

Edible geography collected various other urine wheels.

Picture originally from Nature.

Urine albumin and protein measurement

Continuing the theme of must knows regarding urinalysis:

Urine albumin is detected by the urine dipstick via a reaction with tetrabromophenol blue. The reaction produces a colorimetric result depending on the amount of albumin present, which can be semi-quantitated as 1+, 2+ or 3+ by the user.

Albumin first becomes detected by the urine dipstick method when daily excretions are greater than 300mg per day. Therefore, it is insensitive to microalbuminuria (which itself has been independently associated with adverse cardiovascular outcomes).

However, it is important to note that the detection is inherently related to the concentration of albumin in the sample. Therefore, a concentrated urine sample will have a higher reading than a dilute sample, even though the total albumin loss per day may be the same. This speaks to the preference to collect samples in the same way, same time of day etc. for reproducibility purposes. Generally a first morning sample has been shown to have the closest correlation with 24hr urine collections.

In cases of plasma cell dyscrasia that produce large amounts of non-albumin protein, the urine disptick may not give an accurate reflection of the true degree of proteinuria. An older method to detect non-albumin proteins was to add sulphosalicylic acid to the dipstick negative sample and watch for a change in turbidity, indicating the presence of protein. Another useful trick is to compare the urine microalbumin/creatinine ratio and the urine protein/creatinine ratio, looking for a large gap between the two.

Urinalysis - concentration

Here are some simple facts about urine specific gravity, osmolality and their determination from the urinalysis.

Specific gravity
The reference substance for comparative purposes is water, which therefore has a specific gravity of 1.000. The so-called normal ranges are completely dependent on the amount of fluid ingested and solute excreted. Therefore, for example, uncontrolled diabetes mellitus may have a high urine specific gravity (due to the high amounts of glucosuria), as well volume depletion states and proteinuric conditions. Low urine specific gravity may be caused by excessive fluid intake, diabetes insipidus and diuretics, which all cause a relatively dilute urine to be formed.
Proximal tubular injury (e.g. acute tubular necrosis) may interfere with urinary concentrating capabilities, leading to isosthenuria (a specific gravity of 1.007-1.010). This is a set of circumstances whereby the final urine concentration is essentially equal to that of the glomerular filtrate produced at the early proximal tubule.
Note there are potential false elevations in urine specific gravity, many of which are caused by radiographic dyes, which can produce readings >1.03, if measured at a time close to the procedure.

Specific gravity measured by urine dipstick
The reagent strip in the usual urine dipstick actually measures the ionic concentration of urine. The free ions react with a pH indicator in the strip, thereby causing a change in colour, corresponding to the amount of solute present. Obviously, certain molecules may dissociate more freely than others, which can affect how easily they are to detect.

Urine osmolality
Osmolality differs from the specific gravity in that it depends on the amount of solutes, not on their molecular weight. The range of potential osmolality that can be produced by the normal kidney ranges from around 80-1200 mOsm/Kg. In normal circumstances, the approximate relationship between urine specific gravity and osmolality is 350mOsm/kg per 0.01 unit change in specific gravity (e.g. a specific gravity of 1.01 is equivalent to a urine osmolality of 350mOsm/kg). However, this relationship breaks down in the setting of larger molecular weight compounds, like glucose, certain antibiotics and radiocontrast material.

Methylene blue and refractory hypotension

My name is Will Pendergraft, and I just completed the clinical portion of the joint nephrology fellowship between Brigham and Women’s Hospital and Massachusetts General Hospital. I was inspired for the first time by Nate Hellman during my residency at UCSF when I started to peruse this blog. If you have any free time, it’s worth looking back at his very first post from 2008. I am astonished by how he wrote these posts on a daily basis! As a contributor to the blog, my goal will be to provide short and useful, or at least interesting, nephrocentric snippets for first-year fellows.

With that said, I was walking through the cardiac surgery ICU at MGH a few months ago on my way to provide moral support for one of my co-fellows who was placing a difficult dialysis catheter in someone with almost no access, and upon entering the patient’s room, I noticed that the urine in the collection bag was of a Mediterranean shade (see image)! Given that we are differentialists by trade, www.urinecolors.com has a pretty good list of what can cause different urine colors.

The surgical team said they were intravenously infusing methylene blue “to improve the patient’s refractory hypotension,” an idea with which I was unfamiliar, so I sprinted to the nearest computer to look into this more deeply.

Methylene blue was created in 1876 and was first used in humans in 1881 by nobel laureate Paul Ehrlich to treat mild cases of malaria. It now has multiple indications, most notably including reduction of methemoglobin to hemoglobin in methemoglobinemia. Intravenous and oral formulations are easily excreted into the urine turning it blue to bluish-green. Interestingly, methylene blue also inhibits guanylate cyclase, a second messenger involved in nitric oxide-mediated vasodilation; thus, it prevents smooth muscle relaxation. In cases of shock where fluids, standard pressors du jour and steroids are ineffective, methylene blue may be another medication in the anti-hypotensive toolkit. Surprisingly, there are over ten clinical trials with positive results using methylene blue in refractory septic shock, and it is even used by anesthetists and surgeons to treat vasoplegia after cardiopulmonary bypass. The dosing regimen is 2 mg/kg IV once as a bolus followed by continuous infusion. Remember methylene blue the next time you see this shade of urine and be on the lookout for it in the cardiac surgery ICUs.

Posted by Will Pendergraft

Try this in clinic…

It was the usual sort of day in clinic and the team was seeing a middle aged woman with stable diabetic nephropathy and subnephrotic proteinuria. Her blood pressure and blood sugars had been well controlled since the last visit and being good nephrologists her urine specimen was spun and the sediment examined.

The team was shocked to find a packed field shown top left… Which became stranger under polarized light shown to the right…


Some of these objects were sort of hexagonal like cystine crystals but the patient had never had a kidney stone, never had this finding before and was much older than one would expect for a cystinuria presentation. The maltese cross finding was odd as well. Cystine crystals don't have these. The objects didn’t really look like oval fat bodies and the crosses were not the clean symmetric looking ones typically seen in these fat droplets.


The team, perplexed, split up taking the slide to the urinalysis lab to ask the techs if they knew what the heck this was, hitting pubmed and back to the patient to see if there was any funny business with the specimen.


On reconvening the answer was clear: corn starch. The techs instantly said they see it all the time when their gloves contaminate a specimen. Pubmed, gave us a nice case report from NDT Plus and the patient noted having some vulvar irritation and was likely using a corn starch based baby powder which had dropped into the specimen cup.


This is the part you can try at clinic…


To confirm our discovery I dipped one of our powdered gloves in water and then prepared it like a regular urine specimen. Perfect match. Give it a try in clinic next time you have some housestaff or unsuspecting renal co-fellows around.

Differential Diagnosis of Red Urine

Red urine: it's not always hematuria. The first step in evaluating the patient who complains of grossly red urine is to perform a standard urinalysis, focusing on (a) whether or not the dipstick turns heme-positive, and (b) whether or not there are red blood cells visualized on microscopic examination.

We are all fairly familiar with the basic differential diagnosis for heme-positive urine with RBCs visualized on microsopic exam: the presence of dysmorphic RBCs and casts is consistent with glomerular hematuria (e.g., glomerulonephritis) while non-dysmorphic RBCs warrants a work-up for lower-tract hematuria (e.g., nephrolithiasis, bladder cancer, etc.).

However, a heme-positive urine specimen in which RBCs are NOT seen on microscopic exam suggests the possibility of either myoglobinuria (e.g., rhabdomyolysis) or hemoglobinuria (e.g., hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc). A simple way to differentiate between these two possibilities is to centrifuge the patient's blood: the serum fraction will be pink in hemoglobinuria, and clear in myoglobinuria. Myoglobin is a 17kD protein which is rapidly filtered and excreted by the kidney; thus, it should generally not be present in high abundance in the serum. In contrast, hemoglobin exists as a tetramer of 69kD which is bound to haptoglobin, thereby restricting its filtration at the glomerulus and causing the serum fraction to be pink-tinged. Other lab values (elevated CK in the tens of thousands in rhabdo; positive Coomb's test and low haptoglobin in hemolytic anemias) can also be instrumental.

The differential for heme-negative red urine includes some more esoteric diagnoses: acute porphyria, ingestion of beets or certain food colorants, drugs (e.g., rifampin, pyridium, doxorubicin).

Bence-Jones Protein

I had always assumed that the "Bence-Jones" protein--essentially, the demonstration of monoclonal light chains on urine protein electropheresis (UPEP)--was named after two doctors, Bence & Jones.  However I recently found out that actually it was named after a single individual:  Henry Bence Jones, a famous British physician and chemist.  In 1848, he was cited as the driving force for the investigation of an unusual chemical analysis discovered in the urine of a patient with myeloma in a paper titled "On the microscopical character of mollities ossium" (mollities ossium was the name for myeloma, which at the time was thought of as a bone disease based on the osteolytic bone metastases which resulted).  In this paper, he described the appearance of a precipitate which occurred when the urine was heated to 50-60 degrees, disappeared when boiled, and reappeared again when the urine cooled--this substance is now known to be the same urine light chains which result in cast nephropathy.

According to this brief biography of Henry Bence Jones, he published on a variety of topics including renal calculi and gout, and was an early proponent of the urinalysis (both urine microscopy as well as chemical analysis of the urine) in diagnosis.  He was also apparently the physician for Charles Darwin, and published the then-definitive biography of the physicist Michael Faraday.   

New Urine Test for Appendicitis

Traditionally surgeons have relied on a well-honed abdominal exam, combined with abdominal imaging usually in the form of an iv-contrast CT scan, to make the diagnosis of acute appendicitis. Nevertheless, there remain significant instances of "false negatives" (usually a delay in diagnosis due to real episodes of appendicitis not picked up on imaging, occasionally resulting in appendiceal rupture) as well as instances of "false positives" (individuals who undergo appendectomy due to suspected appendicitis, but turn out to have no local inflammation on biopsy).

In order to improve the rapidity of diagnosis of appendicitis, Kentsis et al sought to identify new urine biomarkers which could conceivably help, as described in a recent issue of Annals of Emergency Medicine. In brief, their study subjected 12 urine specimens--6 from patients with appendicitis and 6 from patients without appendicitis--to mass spectrometry. They identified a list of several potential biomarkers which were elevated uniquely in appendicitis. They then attempted to validate selected markers in 67 children admitted for suspected appendicitis, 25 of which eventually turned out to have true appendicitis. The most promising candidate was leucine-rich alpha-2-glycoprotein (LRG), which demonstrated near-perfect sensitivity & specificity for predicting appendicitis early on.

I think the study is relevant to nephrology to the extent that substances specific to disease processes other than the kidney can be detected in the urine: "the urine is the window to the soul." It also is another example of how this cool "high-throughput"-type technology will continue to lead to the identification of new useful diagnostic tests relatively quickly.

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.

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.

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.

Albuminuria Screening for the General Population?

An article by van de Velde et al in this month's JASN describes the results of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a cohort study in which the ability to predict the need for renal replacement therapy based on albuminuria screening of the general population was performed. The study looked at over 40,000 individuals from the Netherlands over a wide range of ages, health and disease who had urine albumin measured. They found that a severely elevated urine albumin (>100 mg/L) is associated with a hazard ratio of 37 of needing RRT over a 10-year period, while a more modestly elevated urine albumin (between 20-100mg/L) is associated with a hazard ratio of 3 of needing RRT. While renal failure certainly occurred more commonly in those with standard risk factors (e.g., diabetes, vascular disease, early-onset hypertension), the authors demonstrate that between 40-50% of patients with albuminuria detected on screening did not have one of these risk factors. They conclude that aluminuria screening for the general population would be a good idea to identify those at risk for worsening renal function, particularly because a treatment known to slow the progression of proteinuric CKD (ACE-I/ARB therapy) is now readily available.

In the same issue, there is also an accompanying editorial in which the author disagrees with the above conclusion, suggesting that screening the entire population for proteinuria would likely not be cost-effective and would only rarely prevent the need for RRT.

Loin Pain-Hematuria Syndrome

The loin pain-hematuria syndrome occurs when glomerular hematuria occurs in conjunction with renal colic, in the absence of glomerulonephritis or a worsening of renal function.  It is not a common disorder, though appears to be more common in women than in men.  It appears to lie along the same continuum as thin basement membrane disease, as a substantial number of patients with loin pain-hematuria syndrome who undergo biopsy demonstrate irregularities (either too thick or too thin) in the glomerular basement membrane; in thin basement membrane disease, however, there does not seem to be a predilection for females and hematuria is typically painless.  Approximately 20% of patients with suspected loin pain-hematuria syndrome who undergo biopsy are subsequently found to have IgA deposits--thus biopsy is warranted if the diagnosis of loin-pain hematuria syndrome is suspected.  The pathophysiology of loin pain-hematuria syndrome is postulated to be based on irregular basement membranes, which will occasionally rupture and result in glomerular bleeding.  When the bleeding is significant enough, it could conceivably result in swelling of the renal capsule and resultant pain.  A decent review can be found in this 2006 KI article.  

Routine Urinalysis Screening?

Is it a good idea to screen the pediatric population at-large for hematuria and proteinuria?  

This is  a controversial topic, as generally speaking isolated hematuria or isolated proteinuria are almost always benign findings in pediatric populations, and overly-aggressive work-up (e.g., renal biopsy) in all individuals with these abnormalities would likely result in measurable morbidity.

In favor of routine screening are some studies from Asian populations where urinalysis screening has been more routinely adopted--specifically, this study from Korea and this study from Taiwan--which demonstrate that the rate of pediatric ESRD dropped from 19 per million to 8 per million following these interventions, much of which could be explained by a drop in glomerulonephritis-induced kidney injury.  

In the United States, the American Academy of Pediatrics currently recommends that urinalysis be performed only when there is a specific complaint.  

Candombe Drumming-Induced AKI

Hope everybody is having a happy holiday season--even those nephrology fellows (not myself, fortunately) who are required to staff the dialysis unit in lieu of spending time with family and friends.

An unusual cause of acute kidney injury I recently read about was reported in a recent 2008 issue of C-JASN: glomerular hematuria caused by excessive candombe hand drumming.

Candombe hand drumming is a popular form of music in Uruguay. During a carnival-type festival termed "las llamadas", several individuals will engage in vigorous hand-drumming for several hours. Interestingly, some individuals will report rust-colored urine, and a subset of these individuals will present with a reduced GFR significant enough to require temporary dialysis. Hematuria in affected individuals tended to show dysmorphic red blood cells, suggesting a glomerular source of hematuria. Furthermore, the mechanism suggested by the authors is extravascular hemolysis as a result of repetitive trauma to the hands as a result of drumming--which is suggested by the elevated post-drumming levels of LDH, low levels of haptoglobin, and relatively normal levels of CK & myoglobin to rule out rhabdomyolysis as a significant contributor to renal injury.

Tamm-Horsfall Protein

It took me until just recently to realize this, but the Tamm-Horsfall protein and uromodulin are two names for the same gene.  

As we all know, Tamm-Horsfall protein (discovered by Tamm and Horsfall in 1950) is the most abundant protein in normal urine and forms the transparent matrix of hyaline casts.  It is synthesized as a membrane protein which is attached to the apical membrane by a GPI-anchor facing the tubular lumen; when cleaved off it is excreted in the urine.  Casts only form in the distal tubule & collecting duct, not in the proximal tubule.  What is its function?

1.  Tamm-Horsfall protein acts as a constitutive inhibitor of calcium-based stone formation.   Mice deficient for Tamm-Horsfall protein show an increased tendency towards nephrolithiasis.

2.  Tamm-Horsfall protein acts to prevent urinary tract infection.  There is some data that certain strains of E. coli may be bound by Tamm-Horsfall protein; once cleaved this could represent a means of eliminating the organism from the urinary tract.

3.  Mutations in Tamm-Horsfall protein cause the autosomal dominant disorder medullary cystic kidney disease type 2 (MCDK2) as well as the disorder familial juvenile hyperuricemic nephropathy (FJHN) . This is a pediatric-onset disease characterized by hyperuricemia, gout, and progressive renal failure.  Interestingly it appears that the pathophysiologic mechanism here is that mutations in this gene lead to defects in protein folding and intracellular deposition of mutant Tamm-Horsfall protein.  

Microhematuria in Potential Kidney Donors

The key aspect of the workup for a potential kidney transplant donor is ensuring that donation does not result in future health problems for the donor. For the most part, this boils down to determining whether or not the potential donor is at risk for future kidney injury. For some conditions this is an easy decision to make (e.g., in a family with ADPKD where the potential donor's PKD1/PKD2 genotype status is known), but for other conditions the decision becomes a tougher one.

One such example is asymptomatic microhematuria in the potential kidney transplant donor. How does one work this up and what are the recommendations? Potential causes of persistent microscopic hematuria include subclinical IgA Nephropathy, Alport's Syndrome, thin basement membrane disease, PKD, urologic malignancy, subclinical nephrolithiasis and/or hypercalciuria/hyperuricosuria, AV malformations & fistulas, and (in endemic areas such as the Middle East) bladder schistosomiasis. A 2007 Kidney International paper by Vadivel et al reviews the subject, and suggests that all potential donors with microscopic hematuria should undergo a detailed family history (to rule out IgA Nephropathy & Alport's, which are contraindications to donation; thin basement membrane disease is considered okay provided there is no family history of renal compromise), urine culture (to rule out chronic infection), 24-hour urine studies (to rule out stone disease), urine cystoscopy & cytology (to rule out malignancy), and a CT scan with iv contrast (to look for stone disease and malignancy). Furthermore, the authors suggest that if the above workup is inconclusive for cause, a renal biopsy should be performed. Obviously, a detailed discussion regarding the risks/benefits of donation with the potential donor is warranted with every patient, but is particularly relevant with this subgroup.