Analgesic Nephropathy

I saw an interesting case yesterday. A 71 year old male, CKD III with a syndrome suggestive of chronic tubulointerstitial disease (U/A trace proteinuria only, disproportionate anemia, mild cortical thinning on ultrasound, normal-appearing vasculature on ultrasound). He had longstanding, intermittent flank pain which began in his 50's, ascribed to nephrolithiasis, although no stone was ever seen. Anyway, after some probing, he admitted to taking a drug called Vanquish regularly (i.e. daily for over 20 years). I had to look it up, but it turns out to be a compound analgesic (acetaminophen, aspirin and caffeine). I was surprised, as I thought these compounds were off the market, as they are in Europe. So beware, analgesic nephropathy is alive and well in 2009!

Analgesic nephropathy is a slowly progressive form of kidney disease characterized by polyuria and renal colic (due to papillary ischemia and necrosis) in the early stages, progressing to tubulo-interstitial disease, transitional cell carcinoma and ESRD over many years. It became a rare diagnosis following the removal of phenacetin from analgesic mixtures in the 80's, but still accounted for 10% of ESRD cases in Australia in 1990.

Phenacetin, whose main metabolite is acetaminophen, was originally believed to be the cause. But this was challenged by the appearance of cases where phenacetin was not involved. The modern definition of analgesic nephropathy does not mention phenacetin: "a slowly progressive disease resulting from the daily use for many years of mixtures containing at least two anti-pyretic analgesics and usually caffeine or codeine (or both), which may lead to psychological dependence". The diagnosis is made based on pathgnomic appearances on non-contrast CT (reduced renal size, bumpy contours and papillary calcifications) in the appropriate clinical context.

Poll Results & Post-Boards Weariness

First things first:  last week's poll results showed that the majority of individuals were wary of using physician "Pay For Performance" as a strategy towards increasing AV fistula placement rates.  Proponents of this strategy (see editorial by Hakim and Himmelfarb in a 2009 KI article) would argue that linking AV fistula placement to some type of financial reward (or linking lack of AV fistula placement to some type of financial penalty, depending on your viewpoint) is the surest way to increase the AV fistula rate in the overall dialysis population.  Potential arguments against using a physician "Pay For Performance" strategy would include penalizing doctors who take care of patients with a lower success of achieving working AV fistulas and encouraging the placement of unnecessary AV fistulas, to name a few.  

So I took the boards yesterday, and I'm eager to hear what others thought of the exam.  Fair?  Frustrating?  Piece of cake?  My own view:  it's a hard exam, and not only because it requires 8 hours of concentration--like many of these ABIM exams, there are often 2-3 answers which seem like they could be right; the challenge comes in selecting the "Best Answer" according to whomever wrote the question.  Ever wonder how they come up with the questions?  Here is the ABIM's stated policy on how all their exams are developed.  This week's RFN Poll of the Week is Boards related.  

ASTRAL Trial

Another day, another negative study… this is getting painful! The large, randomized ASTRAL trial comparing renal revascularization to medical therapy found no benefit, and substantial increased risk, in the interventional arm.

806 patients with atherosclerotic reno-vascular disease were randomized to undergo revascularization in addition to receiving medical therapy or to receive medical therapy alone. After 34 months of follow-up, there were no significant differences between the two groups in the rates of renal events, major cardiovascular events, or death. There were some marginal positive outcomes in the intervention group, including better renal function (p = 0.06) and statistically significant reduction in blood pressure medications. However, 23 patients in the revascularization arm experienced serious complications, including 2 deaths and 3 amputations.

ASTRAL has been criticized on a few fronts. First, the trial design is based on the “principle of equipoise”. Essentially, the investigators only enrolled patients in whom they were uncertain as to whether they would derive clinical benefit from revascularization. As such, many patients enrolled in the trial had lesions of dubious clinical significance, as more high-risk patients would not have been randomized. As an example, 40% of those enrolled had less than 70% stenosis, and some patients with stenoses as low as 60% were included.

Personally, I feel a bit sorry for the authors here. They set out to answer the specific question of what to do with the incidentally discovered, moderate-grade renal artery lesion in a CKD patient, and are then criticized for designing a trial that excludes patients in whom intervention is very likely to benefit. Critics of the trial claim that many of the lesions chosen for intervention were of unclear clinical significance, but I believe that was exactly the point. It’s not as if the management approach to such lesions has been firmly established. The bottom line with intervention in renal arterial disease is that we are doing a poor job in identifying the right kidney in the right patient, and there is a lot more work to do. ASTRAL is step in the right direction.

kappa versus lambda light chains in paraproteinemias

Antibodies are comprised of the structure noted on the left:  they have two immunoglobulin heavy chains (in blue) and two immunoglobulin light chains (in green), covalently linked with one another via disulfide bonds (in red).  The light chains can be one of two types, either kappa or lambda; each individual B-cell (which synthesize and secrete clonal immunoglobulin) expresses either kappa or lambda, but not both, for the entire duration of its lifetime.  

Light chains play an important role in several nephrologic diseases.  They are small enough to be filtered at the glomerulus, but in normal conditions are reclaimed in the tubule.  When the resorptive capacity of the tubules are overwhelmed with extremely large amounts of light chain--as is the situation in paraproteinemias--then the light chains may appear in the urine, and potentially even cause damage as in the cast nephropathy.  Furthermore, certain light chains may accumulate in the glomerular basement membrane, causing glomerular disease (light chain deposition disease, LCDD), and still other light chains may be the underlying cause of AL amyloidosis.  

These different patterns of paraprotein-mediated disease tend to be mediated preferentially by either kappa or lambda light chains:

In cast nephropathy, lambda light chain is the most common.

In light chain deposition disease (LCDD), kappa light chain is the most common.

In AL amyloidosis, lambda light chain is the most common.

The typical kappa-to-lambda ratio in the normal human is about 65:35 (about 1:9), and this ratio is often altered in the above conditions.  It is especially important to look at the K:L ratio (rather than absolute values of K and L light chains) in patients with altered renal function, as the decreased GFR will directly lead to elevation in both K and L light chains.   

On a related note, Waldenstrom's macroglobulinemia is also a paraproteinemia, but rarely causes cast nephropathy or AL amyloidosis.  Interestingly, renal damage in this condition may well be caused by hyperviscosity syndrome.  

T-MINUS 1 DAYS TO THE NEPHROLOGY BOARDS.  GOOD LUCK TO ALL!

Leptospirosis-induced Renal Failure

T-Minus 2 days to the Nephrology Boards exams! For any of you out there studying, one useful resource is ASN's "NephSAP Core Knowledge Questions", which can be easily reached via the ASN web page. Unlike the main NephSAP questions which tend to ask for very specific details about the content of the NephSAP text (which often involves specific articles or newfangled molecular mechanisms which are unlikely to be tested in the Boards), the Core Knowledge Questions are more general and therefore more Boards-relevant.

Today's topic is leptospirosis, a zoonotic infection caused by the spirochete Leptospira interrogans. Leptospirosis is spread via exposure to contaminated tissue from a variety of mammalian hosts, often rodents (but can also include cattle, pigs, goats, horses, even dogs). While leptospirosis is most commonly found in tropical areas, it nonetheless has a worldwide distribution and can certainly be found within the United States, as evidenced by this outbreak of participants in an Illinois triathlon, who were presumably exposed while swimming in lakewater.

Up to 10% of individuals with leptospirosis will develop acute kidney injury. The mechanism of AKI is still under debate. Some have suggested that Leptospira endotoxin simply results in an inflammatory response, much like gram-negative LPS; usually, AKI occurs in the setting of multi-organ failure and critical illness. Others have suggested that Leptospira endotoxin has tubular toxicity, as evidenced by a high frequency of renal potassium-wasting and hypokalemia noted in these patients. Still others have stated that tubulointerstitial nephritis is the main mechanism of kidney injury in Leptospirosis. In some instances, rhabdomyolysis can be the main cause of Leptospirosis-associated AKI.

Treatment of Leptospirosis-associated AKI includes standard supportive measures, along with the use of antibiotics (either penicillins or tetracyclines are typically used).

Diagnosing Reset Osmostat

The "reset osmostat" is a cause of hyponatremia, sometimes considered a variant of SIADH, in which the kidney retains its ability to appropriately concentrate and dilute the urine; however, the threshold for ADH secretion is reset downward. That is, instead of ADH being secreted with the serum osmolality increases beyond 280-285 mOsm/kg as in most individuals, it is secreted at a lower value.

Diagnosing reset osmostat is a diagnosis of exclusion. Individuals must be euvolemic, and a thorough exclusion of other causes of euvolemic hyponatremia (e.g., hypothyroidism, cortisol deficiency, medications, etc) must take place. A key feature of reset osmostat is that individuals should be able to concentrate and dilute the urine appropriately. Thus, a water challenge should result in a dilute urine (e.g., less than 100 mOsm/kg) and a water deprivation test should result in a concentrated urine. Sometimes, a patient given a diagnosis of SIADH will be proven to be reset osmostat when it becomes apparent that fluid restriction does not successfully raise the serum sodium level.

Reset osmostat classically occurs in neurologic conditions such as epilepsy and paraplegia, in addition to pregnancy, malignancy, and malnutrition. It has also been observed in healthy individuals, such as this 60 year-old man with a chronic sodium level between 125-130 mmol/L; the authors suggest that a 1951 grenade explosion the patient experienced may have caused the osmostat to reset!

Aminoglycoside Toxicity

The aminoglycosides are amongst the most well-known nephrotoxic drugs. Yet due to their efficacy against many organisms, they are amongst the most common antibiotics used. The next time your nephrology service goes toe-to-toe with the infectious disease service in the ongoing battle as to whether or not a patient with CKD should get gentamicin, you can arm yourself with these factoids regarding the mechanism of aminoglycoside toxicity:

Aminoglycosides are a potent tubular toxin; the reduction in GFR which results is therefore thought to be an indirect effect on the glomerulus. The predominant sites of aminoglycoside toxicity are the S1 & S2 segments of the proximal tubule. Aminoglycosides are filtered by the glomerulus, and once concentrated in the urine in these segments occurs, they are known to bind to phospholipids, followed by internalization within the cell via megalin. Once inside the proximal tubular cell, they they are concentrated within lysosomes and cause a stereotypical disorganization of the lysosomes termed "myeloid bodies."

The myeloid bodies are a sign that the tubular cells are functioning poorly, and as a result there is decreased tubular function often manifesting as K, Mg, Ca, PO4, and glucose wasting--almost like a "Fanconi's Syndrome" picture. Overt necrosis of the tubular epithelial cells can also occur, resulting in ATN. Stereotypically, aminoglycoside toxicity results in non-oliguric renal failure which more often than not recovers (after a few weeks) once the drug is withdrawn.

From a pharmacokinetics standpoint, the toxicity of aminoglycosides correlates best with the peak concentration of the drug. Interestingly, in common clinical practice the drug is dosed based on following aminoglycoside trough levels...