Mount Rushmore of Nephrology Announced

The readers have spoken and it is time to announce the results of the hypothetical "Mount Rushmore of Nephrology":  the four Nephrology Pioneers whose contributions have mattered most, and deserve to have their imagery preserved forever on a big slab of rock.  The four highest vote-getters over the week were:

1.  Willem Kolff (inventor of dialysis)

2.  Belding Scribner (access pioneer, founder of 1st outpatient HD unit)

3.  Homer Smith (pioneer of renal physiology)

4.  Joseph Murray (Nobel-winning surgeon who performed 1st kidney transplant)

A few comments on these choices.  First, the top two leading vote-getters were both dialysis-related--which is indicative of the dominant role that dialysis has played in the evolution of nephrology, a field which was early on founded more on issues such as electrolyte abnormalities and medical diagnosis using the urine sediment rather than renal replacement therapy.  Second, I debated as to whether or not to put Joseph Murray on the list--he is, after all, a surgeon rather than a true nephrologist, and to some degree I was hoping that John Merrill would have been the representative for the field of transplant nephrology instead.  Then again, Homer Smith ("Father of Renal Physiology") also may not be considered by some to be a "true nephrologist" since he was not an M.D.--he was really a basic scientist/physiologist. Who knows, perhaps in another 50 years, the list might look different.

Check out the latest poll question on the right.  For those renal fellows working on Christmas Eve/Christmas Day:  may your pager be silent for as long as possible!  

Angiojet as a Cause of AKI??

The Angiojet Rheolytic Thrombectomy System is a medical device currently used to re-establish blood flow in a variety of settings. Briefly, a catheter is introduced into an area of thrombosis and a saline stream is directed towards the thrombus of interest. These saline jets generate a localized low pressure zone via the Bernoulli principle, leading to breaking up of the thrombus. The saline and clot particles are then sucked back into the catheter, avoiding potential embolic complications.

Angiojet has been primarily used for removing thrombus from arteries--for example, in acute myocardial infarction or acute graft thrombosis, for instance. It's also been useful in restoring flow in some dialysis accesses. More recently, however, efforts to use Angiojet in the treatment of venous clots--such as DVT or pulmonary emboli--have been attempted.

At a recent Renal Grand Rounds, one of the fellows presented an interesting case of a patient who developed acute renal failure shortly after undergoing attempted Angiojet therapy for a pulmonary embolus. In addition to a rising creatinine and oliguria, the patient developed red, heme-positive urine with only a few red blood cells, and labs reflecting intravascular hemolysis. Although it is not yet rigorously defined as a cause of acute renal failure, others have reported an association between Angiojet and AKI. It is possible that the Angiojet procedure is more likely to result in hemolysis if thrombectomy is attempted in a large, open space (e.g., for treatment of DVT/PE in a larger vein), as there have generally not been such complications when Angiojet has been used in restoring flow to arteries where the area of thrombus is relatively localized.

It will be interesting to see if there are further reports of this type of AKI with Angiojet.  I purposely put TWO questions marks in the title since I fully admit that much more work needs to be done in order to actually prove causality.  

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).

Cardiovascular Complications of Kidney Disease

Question: Who is the most important medical subspecialist for a patient with CKD to have regular contact with? Is it the nephrologist? A case could be made, relying purely on mortality statistics, that it's actually the cardiologist. CKD/ESRD leads to a wide range of cardiovascular complications. A quick review:

1. Hypertension: it is rare to find the ESRD patient WITHOUT hypertension. Along with a high rate of essential hypertension afflicted the general Western population, ESRD patients are at the additional disadvantage of having to deal with hypervolemia and sodium retention, which can made BP very difficult to control. Common ESRD medications such as EPO is also associated with high blood pressure, as is secondary hyperparathyroidism.

2. CHF: Both systolic and diastolic dysfunction are commonly associated with CKD/ESRD; in particular, there is a very high rate of LVH (both concentric and eccentric LVH). Furthermore, patients with AV fistulas or severe anemia can develop high output CHF.

3. CAD: CAD is exceptionally high in the CKD/ESRD population, though the mechanism of cardiac ischemia is posited by some to be discretely different from the standard "rupture of an atherosclerotic plaque" model which has been studied primarily in non-CKD/ESRD populations. Although serum troponin levels may be slightly elevated in CKD/ESRD patients simply because it is cleared less efficiently, even small elevations of cardiac troponins in these patients are associated with poor outcomes. Many hypotheses have been put forth regarding the increased CV risk associated with dialysis; the currently favored ones include abnormal calcium-phosphate metabolism, chronic inflammatory state, dyslipidemias, the accumulation of hypothetical cardio-toxic uremic toxins, and the high rate of association between CKD and diabetes.

4. Arrhythmias/Sudden Cardiac Death: The dialysis unit is a great place to uncover underlying EP abnormalities: there are non-physiologic fluid shifts, rapid changes in electrolyte concentrations, and the patient is being closely monitored.

5. Pericardial Effusions: Both uremia and dialysis itself can be associated with pericardial effusion. Main intervention: intensify dialysis.

6. Valvular Abnormalities: in particular, valvular calcifications can result from abnormal calcium/phosphate metabolism. These patients tend to do poorly with valvuloplasty procedures.

7. Pulmonary Hypertension: it is important to be aware of pulmonary hypertension in the patient with CKD/ESRD as it may make the patient ineligible for renal transplantation if it is too severe.

Ischemia-Reperfusion Models

The study of AKI/ATN has relied heavily on one particular animal model: the warm ischemia-reflow model (often referred to as "ischemia-reperfusion injury"), in which one of the renal arteries is transiently ligated off for a set period of time while body temperature is maintained, then opened up and allowed to reperfuse the kidney. A recent review in Kidney International by Heyman et al addresses some of the limitations of this model, mostly in terms of differences between the mouse model of ischemia-reperfusion and the typical human AKI/ATN we experience clinically.

Some the important differences between mouse and human AKI: First, while the warm ischemia-reperfusion model tends to initially target the S3 segment of the proximal tubule and typically leads to overt tubular necrosis, in human AKI necrosis is not always present, and when it is tends to be patchy and most commonly affecting the distal nephron (in particular: the medullary thick ascending limb and medullary collecting ducts). Second, in clinical practice it is COLD ischemia which is often the mechanism of injury (e.g., surgical procedures in which the aorta is cross-clamped is often performed in the setting of a lowered core temperature, and donated kidneys are typically stored on ice prior to transplantation), rather than warm ischemia. Overall, the authors conceded that the rodent ischemia-reperfusion model has been invaluable, but caution against using it to explain all aspects of human AKI/ATN.

The notion of whether AKI/ATN occurs primarily in the proximal versus the distal tubule is not merely of academic interest. According to one version of the "distal nephron model", the reduced GFR experienced in response to medullary hypoxia is actually an adaptive response: decreasing the metabolic demands of tubular epithelia would decrease hypoxic injury; in a sense one could think of the nephrons as "hibernating" in a low metabolic state until they sense that the hypoxic insult has been removed and they can resume optimal cellular function. If this is true, it might caution physicians from trying to stimulate GFR in patients with AKI, instead encouraging attempts to limit tubular energy expenditure.

IgA Nephropathy Treatment Poll Results

The results of last week's poll on IgA Nephropathy are in:  90% of individuals correctly identified that the only treatment shown in randomized controlled trials to consistently benefit patients with IgA Nephropathy is ACE-inhibitors and/or ARBs.  The response was pretty divided beyond that, however, with a variable number of individuals (37% in all) opting for a trial of immunosuppression.   In retrospect, I'll admit that the question was not perfectly worded: whether the patient has already been treated with ACE-I/ARB therapy was not really clear.  If the patient is just recently diagnosed with IgA Nephropathy, a case could be made to avoid immunosuppression initially and to see whether or not ACE-I/ARB therapy alone could suppress proteinuria and hypertension to acceptable levels.  According to this review in Brigham & Women's "Nephrology Rounds" from 2007, a trial of steroids or possibly even more aggressive cytotoxic therapy (e.g., cyclophosphamide) could be attempted in an individual with these lab parameters who is not responding to conservative therapy.  A majority of folks said they would use fish oil, a topic which has been covered previously.  

This week's RFN Poll question is a fun one:  let's assume Obama's stimulus package includes in its budget funding for a "Mount Rushmore of Nephrology" to be built.  This gigantic statue will feature the faces of 4 prominent nephrologists etched into the rock face of a majestic mountain, preferably at one of the national parks in the Western United States. Of all the prominent nephrologists, which four would you choose as being the most influential in the field?  Choose from the list of historic figures listed, and feel free to include "write-in votes" under the "comments" section if your favorite nephrologist is not listed.  The list I made is admittedly biased towards physicians who have been practicing recently enough that the subspecialty has actually been in existence (e.g., not including folks like Hippocrates), and conversely I tended not to include the current heavy hitters of Nephrology, reasoning that the jury is still out on these folks.  Realize that this is for fun, and I'm sure I've made several oversights.  

Transplant Glomerulopathy

As acute rejection rates continue to fall, causes of late allograft loss, such as transplant glomerulopathy (TG), become increasingly important. TG should spring to mind when you encounter a renal transplant recipient who develops heavy proteinuria and progressive allograft failure, usually late post-transplant. The clinical presentation overlaps with that of chronic allograft nephropathy, although proteinuria tends to be greater in TG and patients are likely to have a history of donor-specific anti-HLA antibodies. The pathogenesis is believed to relate to the presence of these donor-specific antibodies, which are often often anti-HLA Class II. These may wax and wane in concentration and, as a result, may not be detected on a single assay but repeat testing is usually successful. C4d staining is typically negative.

Various immunosupressive regimens have been tried, but none are known to be effective. Progressive graft failure and return to dialysis is the usual outcome. Finally, the increasing use of protocol biopsy informs us that ultrastructural changes that predate the TG lesion develop within the first months post-transplant and in apparently well-functioning kidneys.