Thiazide Diuretics

There is a good review article in this month's NEJM entitled "Use of Diuretics in Patients with Hypertension" by Ernst and Moser which focuses predominantly on the thiazide class of diuretics. The thiazides are considered a FUNCTIONAL rather than a STRUCTURAL class of medications--that is, not all compounds considered thiazides have the same chemical backbone, but rather they are classified as such based on their common ability to inhibit the sodium-chloride electroneutral transporter in the distal convoluted tubule. The NEJM article breaks down thiazide diuretics into "thiazide-type" diuretics (which are structurally similar, containing a benzothiadiazine group--these include HCTZ and chlorothiazide, for instance) and the "thiazide-like" diuretics (which do not have the benzothiadiazine group--these include chlorthalidone, metolazone, and indapamide).

The hypertension lowering properties of thiazides occur via two mechanisms: an early anti-hypertensive effect is observed as a result of volume depletion, while long-term benefits on blood pressure appear to be due to decreasing vascular resistance, via a mechanism which is not entirely clear.

A few other tidbits about specific thiazide diuretics which may be useful clinically: the half-life of HCTZ is only 9-10 hours; thus, if you really want to inhibit Na reabsorption in the distal nephron it is necessary to dose bid (the traditionally anti-hypertensive dosing is typically given just once daily). Chlorthalidone is unique amongst the thiazides in that it has a very long half-life which enables once daily dosing. Most thiazide diuretics tend to markedly decrease in efficacy at low GFR's (e.g., less than 40 ml/min), though the article states that metolazone is more resistant to this effect than other thiazides, explaining its occasional utility in the diuresis of individuals with the cardiorenal syndrome.

Side effects of thiazide diuretics include hypokalemia, hypovolemia (e.g., orthostatic hypotension), gout flares, a small but measurable increased susceptibility to the development of diabetes mellitus, and rarely causing an allergic reaction to individuals with a severe sulfa allergy.

Happy Thanksgiving

One of the things I was definitely grateful for at this year's Thanksgiving table: I'm not on-call and can spend the holiday with my family! Best wishes to those renal fellows working hard on this holiday.

Poll Results from last week: there certainly appears to be some dissatisfaction with the ABIM Boards exam, with nobody rating it as a perfect test and most feeling that there is at least some room for major improvement. I wonder if the results would be different if the poll was carried out later, after scores come back (I have heard that there is a 90% first-time pass rate...)

New poll on acute interstitial nephritis is on the right...one of the real "gray areas" in nephrology these days.

Transplant Nephrectomy

In my experience, it’s unusual to perform a transplant nephrectomy in a patient who has returned to dialysis in the absence of a ‘hard’ indication such as macroscopic hematuria or severe symptoms suggestive of rejection or infarction. There have been several occasions where I’ve considered transplant nephrectomy for failure to thrive or refractory anemia, but persuading a surgeon that this is necessary can be a challenge. If you’ve ever been in a similar situation, this paper may interest you.

The authors examined all transplant recipients who returned to dialysis over a ten-year period, using the US Renal Data System. This amounted to approx 11,000 people, a third of whom underwent allograft nephrectomy. They found allograft nephrectomy to be independently associated with improved survival; specifically, there was a 32% lower relative risk for all-cause death after adjusting for many factors, including socioeconomic status, comorbidity, donor characteristics and identifiable conditions associated with requirement for allograft nephrectomy. The authors also excluded patients whose transplant lasted less than 3 months, as they would been likely to have an absolute indication for nephrectomy.

Being a retrospective, observational study, one needs to take the results with a pinch of salt, given the possibility of residual confounding and treatment selection bias. Also, there were some important differences in the baseline characteristics between the groups, e.g. patients who received nephrectomy were more likely to be younger, have a higher serum creatinine concentration and a higher serum albumin, suggesting they were better nourished.

This topic strikes me as a relatively straightforward subject for a randomized controlled trial. As it stands, these observations would embolden me to push a little harder for a transplant nephrectomy in someone with a ‘soft’ indication, in the knowledge that it does not appear harmful, and may in fact reduce mortality. And in the dialysis population, that’s no mean feat.

A role for polycystins as blood pressure sensors?

One of the hallmarks of autosomal dominant polycystic kidney disease (ADPKD) is hypertension. True, most patients with advanced kidney disease get hypertension anyways--but often the degree of hypertension in ADPKD patients seems to be especially high. Is there something about the function of the polycystin proteins which explains the high blood pressure?

A recent article by Sharif-Naeini et al in this month's issue of Cell claims a pressure-sensing role for the polycystins. ADPKD is caused by mutations in two genes, PKD1 and PKD2, which encode for membrane proteins termed TRPP1 and TRPP2, respectively. It appears these genes function via regulating local calcium fluxes in and out of the cell. Although most efforts to understand TRPP1 and TRPP2 function have focused on renal tubular epithelial cells (since that's where cysts come from), a variety of extra-renal phenotypes are also observed. In this paper, the authors generated mice deficient in TRPP1 or TRPP2 ONLY in smooth muscle cells. Importantly, they found that the balance of TRPP1 and TRPP2 levels was critical for the ability of arterial smooth muscle to maintain appropriate blood pressure. These results imply that function of the polycystins may be different depending on cell type, and suggest a possible mechanism by which ADPKD patients may be especially prone to the development of abnormalities in blood pressure regulation.

Nephrology Oral History Project

Very cool project: The Nephrology Oral History Project. On their homepage you can access interviews with 14 different nephrologists who practiced during the early days of dialysis, as early as the 1950s and 1960s. It's well-organized in that each interview is broken down into labeled snippets, so you can only listen to the topics that interest you the most.

One of the more fascinating topics in these interviews is reading about how much tinkering and troubleshooting was necessary during the early days of dialysis. Access was a major issue; early on, one would cut down to find an artery and a vein in order to perform dialysis; at the end of the dialysis procedure, the vessels were ligated off and therefore those vessels could not be used again. Needless to say, there are only a limited number of arteries available to suppor dialysis, so other techniques were essential. One nephrologist describes making "home-made" catheters simply by cutting the appropriate length of polyethylene tubing and tapering off the end by holding it over a Bunsen burner. Because they couldn't afford real stainless-steel guidewires, they used guitar strings coated in silicone, which were much cheaper.

So: the next time you grab a catheter kit off the shelf and plug in the ultrasound machine, think about all the additional hassle involved in placing a dialysis catheter our nephrology fellow predecessors had to endure!

Kidney Clips

It's the weekend, I need to decompress from the boards. Here's some random kidney-related clips. The first is pretty bizarre.



This next one is pretty basic, but the animation is good.

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...

Metformin-induced Lactic Acidosis

Metformin is the only hypoglycemic agent proven to reduce mortality in Type 2 DM. As such, we really should be making every effort to prescribe it, and keep patients taking it. Unfortunately, mostly due to it's relationship to parent compound phenformin, metformin has developed a reputation for causing lactic acidosis (LA). Prescribing guidelines instruct witholding the drug if there is 'renal impairment'. This is a controversial issue, reviewed here. Here are some points to consider:

- A Cochrane review found no difference in LA rates between those taking and not taking metformin, around 6 cases per 100,000

- The prognosis (or lactate level) does not correlate with metformin levels in cases of LA where metformin has been implicated, but does correlate with the severity of the underlying hypoxic condition.

- A post-hoc analysis of the GOAL-A1C study, showed that 18% of patients taking metformin in the community already had CKD III

- Many patients have received metformin in the presence of an absolute contraindication and the rate of LA is not seen to be increased. One such study includes patients with CI's such as a creatinine > 2.5mg/dL and NYHA IV heart failure.

Personally, I have seen a few severe cases of LA in patients taking metformin that clearly had another precipitant. I do believe that the lactate levels in those cases were higher than I would have otherwise expected. Maybe this is the metformin effect - to aggravate a LA in evolution. Critical illness notwithstanding, I continue metformin down to a CrCl of 30ml/min, but would be interested in hearing what others out there are doing.

General Support for Kidney Allocation Score

Final results of last week's Poll of the Week:  only 13% of individuals said they outright disapproved of the proposed Kidney Allocation Score, the scoring system which has been proposed to replace the current system of determining kidney transplant organ allocation.  

I had discussed on a previous post the motivation behind this plan.  In general, the increasing number of elderly individuals going onto the kidney transplant waiting list has skewed kidney transplant recipients towards older patients.  Critics of the current plan point out that since "waiting time" plays such a major role in determining organ allocation, by the time ESRD individuals are considered for an organ, they have accumulated multiple morbidities which may limit the lifespan of both patient and kidney.  Furthermore, there is also a perception that the current plan does not do a good job of "matching" appropriate kidney donors with recipients:  a young, healthy donor kidney with a projected longevity of several decades might be matched with an elderly diabetic; conversely, a borderline kidney might be matched up with a young recipient who as a result might require a second or even third transplant later down the line.  

The KAS attempts to address these issues, but not surprisingly, it still has its detractors (see this editorial by Hippen in a recent issue of KI).  Critics of the KAS have suggested that the proposed system is "ageist" (e.g., favoring younger patients at the expen

se of older patients), unfair to individuals who have already been "waiting in line" based on the previous system, and furthermore may have unintended consequences--for instance, if younger patients know that they are more likely to get a cadaveric transplant in a short period of time, there would be less incentive for them to obtain a live, donor kidney from a friend or family member which might last longer for that patient AND expand the number of donor kidneys in the societal pool. 

Check out the latest RFN Poll of the Week, this time regarding the Fistula First campaign.  A useful pdf describing the Fistula First's Strategic Plan for achieving their goal of 66% prevalent AVF use, including their position on "Pay-for-Performance" strategies with respect to vascular access, can be found here.  

Classification of Cryoglobulins and MPGN

Cryoglobulinemia is characterized by the presence of circulating antibodies which precipitate at cooler temperatures, and not infrequently leads to renal failure/glomerulonephritis. The stereotypical histologic lesion of cryoglobulinemia is membranoproliferative glomerulonephritis, which takes the appearance on light microscopy of this heavily lobulated glomerulus.

While cryoglobulinemia and MPGN display this link, it is important to realize that each term has its own classification scheme--this can be confusing since both cryoglobulinemia and MPGN each have 3 "Types".

Cryoglobulinemia is classified based on the type of immunoglobulin present in the cryocrit:

Type I cryoglobulinemia is comprised simply of monoclonal immunoglobulins, typically IgM but less frequently IgG, IgA, or serum light chains. Not surprisingly, individuals with Type I cryos typically have a paraproteinemia (e.g., myeloma, Waldenstrom's macroglobulinemia).

Type II cryoglobulinemia is when a monoclonal IgM recognizes and binds to polyclonal IgG's, explaining why Type II cryos are IgM-IgG complexes.

Type III cryoglobulinemia is when a polyclonal Ig recognizes polyclonal Ig. Together, Type II & III cryoglobulinemia are referred to as "Mixed Cryoglobulinemia", and these are the types most commonly associated with hepatitis C.

The MPGN Classification system is as follows:

Type I MPGN is a pattern which can be associated with many different diseases, of which cryoglobulinemia is one. Histologic findings include "tram tracking"/double contours of the GBM, hypercellularity of the glomerular tuft, and a lobulated appearance of the glomerulus. EM may show mesangial and subendothelial immune complex deposits.

Type II MPGN is also known as "dense deposit disease", usually caused by the presence of C3 nephritic factor, and on EM shows ribbon-like electron-dense deposits within the glomerular and tubular basement membranes.

Type III MPGN, which is very rare, apparently includes a many of the features of Type I MPGN along with subepithelial deposits.

Understanding nPCR (Normalized Protein Catabolic Rate)

The normalized protein catabolic rate (nPCR) is a formula commonly used to assess dietary protein intake in dialysis patients, as a means towards determining nutritional adequacy, a major problem in many ESRD patients. For example, say you have a patient on dialysis who has a pre-dialysis BUN of 18 mg/dL--reasonably low, right?. This could mean that the patient is a well-nourished individual who is adequately dialyzed. But it could also mean that the patient is malnourished, which is often linked to poor appetite that is linked to inadequate dialysis. The nPCR helps distinguish between these possibilities.

The nPCR is reported in grams of urea nitrogen per kilogram per day, and can be calculated using several methods. One of them is shown here:

nPCR = 0.22 + (.036 * intradialytic rise in BUN * 24)/(intradialytic interval).

For instance, if the pre-dialysis BUN is 70 and the post-dialysis BUN is 18, and the intradialytic interval is 44 hours (e.g., there is an interval of 44 hours from the end of one dialysis until the beginning of the next), then the nPCR is calculated to be 1.24 g/kg/day. As you can see, a large intradialytic rise in BUN is generally indicative of adequate nutrition. Most guidelines specify maintaining the protein intake above 1.0 - 1.2 g/kg/day in dialysis patients, with values less than 0.8 g/kg/day being equated with malnutrition.

If the patient has significant residual renal function, then one must add a term that takes into account endogenous urea clearance. Importantly, these equations are only valid for individuals in steady state, and are not as helpful in the setting of acute illness. Separate equations exist for peritoneal dialysis, since the BUN levels are relatively constant and therefore pre- and post- levels cannot be used to estimate nPCR; rather urea levels in serum and peritoneal filtrate can be compared. Nutritional status can be especially important to assess in patients on peritoneal dialysis, since these patients are at high risk of losing albumin in the peritoneal filtrate. There is a nice discussion of this topic in Up-To-Date ("Protein catabolic rate in maintenance dialysis"), which includes alternative formulas for nPCR that incorporate Kt/V.

Complement Levels & Glomerulonephritis

Although the complement cascade is an essential aspect of the response to infection, it unfortunately can be activated by a variety of means in several types of kidney disease. In common day clinical practice, most of the time we determine complement activity by assessing serum C3 and C4 levels; a decreased C3 level means that the alternative complement pathway has been activated whereas a decreased C4 level means that the classical complement pathway has been activated. This is especially important in the workup of glomerulonephritis of uncertain etiology.

Sometimes, the pattern of C3/C4 levels can give a clue as to the specific diagnosis. Disorders in which C3 is decreased but C4 is not include MPGN and post-infectious glomerulonephritis, indicating a tendency for the alternative pathway to be active moreso than the classical pathway. Activation of the classical pathway will typically result in lowering of both C3 and C4, and therefore disorders in which BOTH C3 and C4 are decreased include lupus nephritis and cryoglobulinemia. These rules may not be perfect, but can potentially give a hint as to the mechanism of inflammation in glomerulonephritis.

Secondary Causes of Membranous Nephropathy

Although the majority of membranous nephropathy falls under the "idiopathic" category, there are a variety of causes of secondary membranous nephropathy. It is quite important to eliminate these entities as possible diagnoses, as the treatment for secondary membranous nephropathy relies primarily on treatment of the underlying cause of disease whereas idiopathic membranous nephropathy often involves the use of steroids and/or cytotoxic agents.

Broadly speaking, the secondary causes of membranous nephropathy can be broken down into 4 general categories:

1. Infection-associated Membranous Nephropathy: hepatitis B and hepatitis C are both associated with membranous nephropathy. Because diseases such as malaria, schistosomiasis, TB, and leprosy are likewise associated with membranous nephropathy, secondary nephrotic syndrome is likely much more common in developing countries subject to these tropical diseases. Syphilis is also on the list.

2. Disease-associated Membranous Nephropathy: it is well-known that MN may be see in lupus ("WHO Type V Lupus Nephritis") either alone or in combination with other lupus-related pathologies. A variety of the other conditions associated with MN are also autoimmune diseases (e.g., rheumatoid arthritis, Sjogren's syndrome). Diabetes mellitus and membranous nephropathy have also been linked, as has sickle cell disease.

3. Drug-induced Membranous Nephropathy: the classic offenders are gold, penicillamine, NSAIDs, and captopril, though there are case reports for many others.

4. Malignancy-associated Membranous Nephropathy: although there appears to be a increased relative risk of solid tumors and lymphomas in patients with membranous nephropathy as compared to the general population, this association is still somewhat poorly defined and remains controversial. Many would simply recommend age-appropriate cancer screening (e.g., mammogram, screening colonoscopy, etc) in the patient with newly-diagnosed nephrotic syndrome without any other evidence for malignancy rather than a large-scale imaging workup.

Serum Amyloid P prevents renal fibrosis

Congratulations to my colleague at the Brigham, Jeremy Duffield, who made the cover of Science this week for demonstrating human Serum Amyloid P (hSAP) potently inhibits fibrosis in two independent models of renal fibrosis. hSAP is a naturally circulating soluble pattern recognition receptor, and radio-labelled SAP is used clinically to identify sites of amyloid deposition in systemic amyloidosis. In the studies, hSAP was given to mice with either unilateral ureteric obstruction or unilateral ischemia reperfusion mediated kidney injury. In both cases, hSAP potently suppressed fibrotic collagen protein and collagen gene expression in a sustained fashion, preventing the development of interstitial fibrosis. hSAP acts by binding danger molecules at sites of tissue injury, causing the complexes to be cleared by the Fcγ family of receptors on macrophages. This results in suppression of inflammatory and fibrotic gene and protein expression in monocyte-derived cells, via an interleukin-10 dependant mechanism.

These findings raise the possibility of using hSAP as a therapy for kidney diseases with a prominent fibrotic component, such as diabetic nephropathy or chronic allograft nephropathy. A recombinant form of human Serum Amyloid P, PRM-151 (rhSAP), is already in phase 1 trials.

Results of Kidney Biopsy Poll

The results from last week's Poll of the Week are in, and in general, a majority of individuals (64%) felt that their training programs  did a good job of teaching them the art of the renal biopsy, while a significant minority (36%) felt that they were ill-equipped to perform biopsies at the end of their fellowship experience. Interestingly, there was an identical breakdown of those who felt that nephrologists' renal biopsy skills are still relevant (64%) compared to those who felt that it's okay to leave the biopsies up to the interventional radiologists (36%).  Here is another way to look at the results:

 

A 2008 CJASN article by Drs. Berns and O'Neill ("Performance of procedures by nephrologists and nephrology fellows at U.S. nephrology training programs") states that virtually all nephrology fellowship programs provide training in renal biopsies, with about half of those training programs providing the fellow with instruction in hands-on renal ultrasonography.  Interestingly, the number of biopsies required for "certification" in each program varies widely, from only two to up to fifteen, and very few professional guidelines exist which specifically address what should constitute adequate training for kidney biopsy.  

Check out the latest Renal Fellow Poll of the Week on the left, which has to do with the newly-proposed Kidney Allocation System (KAS).  Because the Poll widget only allows the question to be rather short, I had to radically simplify what the plan proposes--I openly acknowledge that the plan is more complex than making it "easier for younger patients to get transplants, but harder for older ones", so to read a more detailed description of precisely what the KAS plan is, you can click here.  

TREAT Trial

The TREAT trial was one of the bigger stories to emerge from this years ASN. This was a large, multicenter trial of darbepoeitin (Aranesp) vs. placebo in 4000 predialysis CKD patients with type 2 diabetes and anemia. The two groups did not differ in the two primary endpoints of all-cause death or cardiovascular event and death or end-stage renal disease and on the plus side, compared with placebo, treatment with Aranesp did result in some improvement in fatigue, less need for red-cell transfusions and a reduction in cardiac revascularization. However, there was also a significantly increased risk of fatal or nonfatal stroke (5% versus 2.6%; HR 1.92, 95% CI 1.38 to 2.68), which was not explained by systolic blood pressure.

The Aranesp group was treated to achieve a target hemoglobin of 13 g/dL, which is higher than I generally aim for, and it may be that a more restrictive dosing strategy could mitigate the risk of stroke. Even still, these findings create a lot of uncertainty and unease as to how best manage anemic CKD patients in the clinic.

As a footnote, this study also lends fuel to the growing literature on ESA’s driving the progression of cancer. In patients with a history of malignancy at baseline, cancer death was an order of magnitude more common in the darbepoetin group (7.4% versus 0.06%, P=0.002).

The Uroplakins

We are taught that water is freely diffusable via cell membranes--even in the absence of aquaporin function, there are usually some water molecules which traverse the lipid bilayer.  However, there are tissues within the human body which must be extraordinarily tight:  two that come to mind are the thick ascending limb of the nephron, as well as the bladder epithelium.  How does the epithelium comprising these "water-tight" barriers obtain these characteristics?  

The epithelium lining the bladder (a.k.a. "the urothelium") is one of the tightest epithelia in the body:  the bladder must be capable of holding urine for long periods of time without leakage, and furthermore serves as an important barrier for toxic substances filtered by the kidney.  The urothelium's water-impermeable properties can be explained in large part by a family of proteins called the uroplakins.  The uroplakins form tiny, hexagonal arrays of particles--visualized best by electron microscopy (see figure taken from this excellent recent KI review by Wu et al)--which comprise structures called "urothelial plaques" that overlie the plasma membrane of superficial umbrella cells of the urothelium.  It is thought that these plaques are tethered to the lipid bilayer, limiting the movement of phospholipids and therefore limiting water permeability.  Interestingly, mice deficient in uroplakins show increased water permeability.  

The uroplakins also appear to play a role in urinary tract infections; the uroplakin Ia/Ib glycoprotein is the means by which some strains of E. coli adhere to the urothelium.  

On the mechanism of thiazide-induced hypocalciuria

Back from the 2009 ASN Meeting in San Diego!  I'll admit to a few lapses in blogging, but the meeting kept me pretty busy.  Thanks to everybody who stopped by the Renal Fellow Network poster and their encouraging words.

The 2009 ASN Homer Smith Award went to Rene Bindels, a master physiologist from the Netherlands who has made great advances in our understanding of renal calcium and magnesium handling via the Trp channels.  Amongst the highlights of his Saturday morning talk was a good explanation for why hypocalciuria results from thiazide diuretic treatment.  

The hypocalciuric effect of thiazide diuretics is well-known:  we frequently put patients prone to develop calcium nephrolithiasis on thiazides with this effect in mind, and patients with Gitelman's Syndrome (caused by mutations in the thiazide-sensitive Na channel, NCC) also have significant hypocalciuria.  There were two general mechanisms postulated to account for this.  Either:

(1).  blockage of NCC results in increased active Ca uptake via TrpV5 channels in the distal tubule, or

(2). thiazide-induced hypovolemia results in enhanced passive Ca uptake in the proximal convoluted tubule.  

The generation of TrpV5 knockout mice provided an opportunity to see which of these possibilities was correct.  Interestingly, these mice still developed hypocalciuria when given thiazide diuretics, indicating that hypocalciuria does NOT require TrpV5 (that is, the 2nd explanation above is true while the 1st explanation is not).  Just another example of how the physiology in one segment of the nephron strongly influences the ion uptake in another segment.