Useful Autoantibodies in Lupus Nephritis

Quick review of the autoantibodies that may be useful in the diagnosis and management of patients with lupus-related kidney disease:

anti-nuclear antibody (ANA):  as well as know from our internal medicine days:  very sensitive, but not very specific.  In addition to being present in over 95% of patients with SLE, ANA is also frequently positive in scleroderma, dermato/polymyositis, and Sjogren's syndrome among others.  

anti-dsDNA (antibodies against DNA) and anti-Smith (antibodies against snRNPs):  these antibodies are much less sensitive, but also fairly specific.  I have also seen other nephrologists follow anti-dsDNA titers as a means of monitoring disease severity and/or response to therapy.

anti-Ro (SSA) and anti-La (SSB) antibodies:  these antibodies, also frequently associated with Sjogren's syndrome, are noted to be important in the pathogenesis of neonatal lupus.  

anti-RNP antibody:  this autoantibody, also associated with other mixed connective tissue disease, may be linked to flares of lupus cerebritis.

anti-histone antibody:  this tends to be positive in drug-induced lupus. 

anti-phospholipid antibody:  the "antiphospholipid antibody" screen should include detection for both anti-cardiolipin antibodies and lupus anticoagulant.  The distinction between anti-phospholipid antibody-mediated renal injury and lupus nephritis is an important one to make, as the former is a thrombotic microangiopathy which should be treated with anticoagulation therapy, whereas the latter is typically treated with immunosuppressants.  

Finally, although these are not autoantibodies, two of the most useful serologic tests to send in the diagnosis of lupus nephritis are serum complements (C3 & C4):  both of which should be low in the setting of an immune complex-mediated GN.

Use of Hypoglycemic Agents in CKD

Maintaining adequate glycemic control in patients with diabetic kidney disease can be a challenge.  First, it is hypothesized that worsened glycemic control will lead to a greater tendency towards diabetic nephropathy.  Second, individuals with more advanced CKD are more likely to suffer from hypoglycemia.  Finally, many of the drugs which are so useful in maintaining good glycemic control are partially cleared by the kidney, making their use problematic in those with advanced or fluctuating renal disease.  Here is a brief list of some of the medications used to control hyperglycemia and their caveats unique to CKD.

1.  insulin:  insulin is mainly cleared by the kidney; thus, it is not uncommon for patients with diabetic nephropathy to note that their insulin requirements gradually go down as their kidney function gets worse.  Insulin dose must usually therefore be decreased once the GFR dips below 50 mL/min.  

2.  sulfonylureas:  some of these drugs have metabolites which are normally excreted by the kidney which retain secretogogue activity and therefore may cause hypoglycemia in patients with reduced GFR (e.g., CKD 3 or above).  Glyburide and glimeperide are the two main offenders here.  According to KDOQI guidelines, it is okay to use glipizide or gliclazide, which are listed as "preferred sulfonylureas".  

3.  Metformin:  although one of the cheapest and most effective glucose-lowering medications, there are many who believe that metformin should be avoided in advanced CKD (e.g., stages 3-5) based on a risk of lactic acidosis.  This guy, however, disagrees with that assertion. 

4.  thiazolidinediones:  e.g., rosiglitazone, pioglitazone are generally considered safe for patients with CKD in that they are not renally excreted.  However, this class of medications may result in fluid retention which can be an issue in those who are susceptible to edema.  

5.  the "glinides":  this newer class of drugs to treat hyperglycemia includes nateglinide (which should be avoided since an active metabolite is excreted by the kidney) and rapaglinide & mitiglinide, which are considered okay to use in patients with CKD without an adjustment necessary.

6.  incretin-based insulin secretagogues:  this newer class of drugs I personally have never used includes excenatide (which KDOQI says is okay to use) and sitagliptin (which KDOQI recommends a dose reduction by 75%).  

7.  alpha-glucosidase inhibitors:  both acarbose and miglitol are to be avoided in patients with Cr > 2. 

Renal Transplant "Matchmaker" Busted

As has been extensively detailed over the past week, one of the key guilty parties in the large federal sting operation exposing shockingly Sopranos-type corruption throughout the state of New Jersey was this man: Levy Isaac Rosenbaum, allegedly one of the largest illegal organ traffickers in the U.S.

According to this article, Rosenbaum was initially suspected to be dealing in human organ trafficking by a UC-Berkeley anthropologist. The actual sting operation involved an FBI agent posing as an individual seeking a kidney for a fictitious uncle who had been on dialysis for two years and was tired of waiting on the transplant list. During a series of meetings Rosenbaum described himself as a "matchmaker", asked for a total of $160,000 for the kidney, and implied that he had brokered many such deals in the past, even providing as references past individuals who had successfully used his kidney matchmaking service. Allegedly, he would obtain his kidneys from impoverished donors from Israel and Eastern Europe, often for a sum of only about $10,000. There are even tales of his threatening reluctant donors at gunpoint when they attempted to back out of a planned donation.

The story suggests that transplant programs may need to be more vigilant in their screening of potential donor/recipient pairs. It's been long suspected that "transplant tourism" takes place elsewhere. The discovery that it is being controlled from within the U.S. is even more chilling.

EAST Syndrome

A relatively recent study by Bockenhauer et al in NEJM reports the identification of a new disease gene in a rare tubulopathy syndrome that sheds light on the physiologic mechanisms of salt transport in the kidney.

The article describes children with an autosomal recessive inherited condition termed "EAST Syndrome", which stands for epilepsy, ataxia, sensorineural deafness, and tubulopathy. Specifically, patients had evidence of renal salt wasting with low-normal blood pressure, resulting in activation of the renin-angiotensin system and a resultant hypokalemic metabolic alkalosis. Individuals also demonstrated significant hypomagnesemia and hypocalciuria. Genetic studies identified the cause of EAST Syndrome: mutations in the gene KCNJ10, a potassium channel which is expressed in all of the affected tissues (brain, inner ear, and kidney) in this disorder. They go on to demonstrate that mice made deficient for KCNJ10 show a similar salt wasting phenotype as in affected humans.

What does KCNJ10 do? The authors propose that this potassium channel sits at the basolateral membrane of tubular epithelial cells where it recycles potassium, which is necessary for maintaining the activity of the Na/K-ATPase. Although rare, EAST Syndrome helps provide greater molecular detail of how the kidney absorbs salt, and suggests that researchers look for polymorphisms in this gene which may explain some of the genetic predisposition towards hypertension and salt handling by the kidney.

Magnesium Therapy in Eclampsia/Pre-Eclampsia

Eclampsia and pre-eclampsia are characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman. One of the major causes of morbidity to both mother & fetus is the occurrence of seizures. Fortunately, decades of experience with intravenous magnesium have led to a generally safe and effective use of this medication as an anticonvulsant. iv Mg is indicated both as a seizure prophylactic agent (in severe pre-eclampsia) as well as for the prevention of recurrent eclamptic seizures.

Generally, iv magnesium is given first as a loading dose (e.g., 6 grams iv bolus given over 15-20 minutes) followed by a continuous infusion of 2 grams per hour. An important caveat to be aware of as nephrologists is that as magnesium is excreted by the kidneys, individuals with acute or chronic renal failure are especially susceptible to hypermagnesemia and its toxic effects. This is not so uncommon, as thrombotic microangiopathy is often seen in women with advanced pre-eclampsia/eclampsia. Up-To-Date recommends giving the full loading dose (6 grams) but a reduced continuous infusion rate of 1gram per hour in individuals with moderately reduced GFR (Cr less than 2.5 mg/dL) and NO continuous infusion rate for individuals with a severely-reduced GFR (Cr greater than 2.5 mg/dL). Although the measured serum Mg concentration does not totally correlate with symptoms, the suggested therapeutic range is between 4.8 - 8.4 mg/dL.

Early magnesium toxicity can be detected as a loss of deep tendon reflexes (typically occuring at levels between 10-12 mg/dL) with more severe symptoms (respiratory paralysis, cardiac arrest) occuring at Mg levels greater than 12 mg/dL. Calcium gluconate can be given as a cardiac stabilizing agent in these instances. Mg therapy may also transiently suppress PTH release and can result in a mild hypocalcemia.

cyclosporine versus tacrolimus

The two calcineurin inhibitors routinely used for kidney transplant immunosuppression are cyclosporine (CSA) and tacrolimus (TAC).  Their mechanism of action is somewhat similar (they both inhibit calcineurin, which under normal circumstances induces transcription of IL-2 in lymphocytes) but they get there by different routes:  CSA binds cyclophilin, and the CSA:cyclophilin complex inhibits calcineurin, whereas TAC binds FK506-binding protein 1a (FKBP1a), and the TAC-FKBP1a complex also inhibits calcineurin.  

CSA and TAC have an overlapping side effect profile, the specifics of which lend themselves quite nicely to standardized testing...

Both CSA & TAC can cause nephrotoxicity, tremor, headache, thrombotic microangiopathy, hyperlipidemia, hypomagnesemia, and hyperkalemia.

CSA in particular causes excessive hair growth and gum hyperplasia.  

TAC in particular causes hair loss and has a higher rate of NODAT (new-onset diabetes mellitus after transplant).  

Surgery Intern Boy Band

Okay, I'll admit, there's no Nephrology tie-in here. But props to the Mass General Hospital surgical interns for using their undoubtedly sparse spare time to make this ridiculous music video.

Kidney transplant lingo

Continuing with the theme of yesterday's Kidney Transplant post, here are some commonly-used Kidney Transplant Lingo & Acronyms:

CRT/DDKT: CRT = cadaveric renal transplant, which is starting to be replaced by DDKT (deceased donor kidney transplant)--I guess some people find using the term "cadaveric" too grisly.

ECD: expanded criteria donor: ECD kidneys are "suboptimal" kidneys defined as coming from a deceased donor more than 60 years of age, or more than 50 years of age with the following risk factors:

1. a donor history of high blood pressure.

2. stroke as the cause of death.

3. serum creatinine level over 1.5 mg/dL prior to donation.

DCD: donor after cardiac death. These are kidneys donated from deceased individuals who have severe, irreversible brain damage but do not actually meet the criteria for brain death. Typically, the donor patient's family will agree to withdraw life support, the patient will experience cardiac arrest, and the donor kidneys are then harvested for use.

LRRT: living related renal transplant

LURT: living unrelated renal transplant

SPK: simultaneous pancreas-kidney transplant

PAK: pancreas after kidney transplant

"Status 7": when a potential kidney transplant already on the waiting list is deemed temporarily unsuitable for transplant--e.g., if they have an active infection. Patients who are made "status 7" will still accrue time on the waiting list.

We Need More Kidneys!

Example of a paper whose conclusion is summed up quite nicely in the full title:  "Half of Kidney Transplant Candidates Who Are Older than 60 Years Now Placed on the Waiting List Will Die before Receiving a Deceased-Donor Transplant".

The paper is published by Schold et al in this month's issue of CJASN.  Briefly, the authors conducted a retrospective analysis from the national Scientific Registry of Transplant Recipients database and specifically looked at the nearly 55,000 candidates greater than 60 years of age who were listed for a kidney transplant.  They essentially compared the average time to successfully being given a deceased donor kidney transplant to the average time to mortality.  They found that nearly half (46%) of candidates greater than 60 years of age listed recently (2006 & 2007) are projected to die before receiving a transplant.  Patients who were especially at-risk for death before getting a kidney transplant were diabetic (61%), older than 70 years (52%), black (62%), blood types O (60%) or B (71%), highly sensitized (68%), and already on dialysis at the time of listing (53%).  

The study underscores both the significant shortage of cadaveric donor kidneys available for transplant as well as the high mortality rate of elderly patients with advanced renal failure.  

Race & Risk for ESRD

See if you can answer this True or False question:  The increased risk of ESRD in African-Americans is due to the increased risk of hypertension and diabetes seen in this population.  

I think the prevailing view in the past was that this statement is true.  However, according to newer data as described in this month's NephSAP on CKD, the current view is likely FALSE!  

How so?  For one, a 2007 JASN-published longitudinal study looking at the development of ESRD in a cohort of Medicare beneficiaries by Xue et al.  Overall, African-Americans had about 1.5 times the risk of whites of developing ESRD.  However, the subgroup in which there was the GREATEST increased risk of developing ESRD in African-Americans compared to whites was the group in which there was no diagnosis of diabetes nor hypertension (about 3.5 times as likely to develop ESRD).  Thus while hypertension & diabetes are still the leading causes of ESRD overall, these two diseases do not account for all the racial proclivities for developing ESRD.

 

The NephSAP summary describes other phenomena which may account for such racial dfiferences.  For instance, living in a neighborhood with a high poverty rate has been shown to increase the risk of ESRD; it is speculated that this may account for some of the increased risk of ESRD in African-Americans.   Recent work identifying polymorphisms in the MYH9 gene may provide a genetic explanation for the increased ESRD risk.  Finally, although not a leading cause of ESRD, HIV Nephropathy often pursues a much more aggressive course of African-American patients compared to their white counterparts.  

Caveats for Using Renal Ultrasound to Diagnose Post-Renal Failure

Most would agree that the renal ultrasound is an invaluable tool in the workup of acute kidney injury. Although the renal ultrasound can give information regarding kidney echogenicity and presence of renal cysts, by and large its predominant utility is in determining the presence or absence of hydronephrosis, a marker for obstructive renal failure ("post-renal" failure when referring to the Holy Trinity of "pre-renal", "intrinsic renal", and "post-renal" categories of AKI).  

However, there are important caveats to the use of the renal ultrasound to effectively rule-in or rule-out obstructive nephropathy.  For instance, false-negatives (e.g., the renal ultrasound does not show hydronephrosis, but there actually is) can occur in the following scenarios:

1.  very early obstruction:  truly acute obstruction (e.g., with a kidney stone, for instance) may take some time to develop enough distension of the collecting system to detect with our current imaging tools.

2.  obstruction in the setting of pre-renal failure:  volume-depleted kidneys may not demonstrate significant hydronephrosis until after volume resuscitation, which expands the collecting system.

3.  large retroperitoneal tumors:  tumors which encase the kidneys may cause obstruction but not allow expansion of the collecting system enough to see hydronephrosis.  

4.  retroperitoneal fibrosis:  this can occur in patients with past extensive GU surgery or prior chemotherapy or radiation therapy and can cause mechanical obstruction without allowing expansion of the collecting system.

In addition, false-positives (e.g., the renal ultrasound is read as "hydronephrosis" but this is probably not pathologic) can occur as well, most notably in pregnancy.  It is also common that hydronephrosis detected on ultrasound is a chronic, long-standing issue and not the main culprit for the present episode of AKI. 

This post is summarized from some basic but well-written handouts by Dr. Joel Topf from Precious Bodily Fluids.  Not a bad idea to print these out and go over cases with a medicine resident rotating on the nephrology consult service...

Sensipar for APKD?

Following on the heels of studies showing a potentially beneficial effect for vasopressin receptor antagonists and rapamycin in the treatment of renal cystic disorders, an article in this month's JASN by Gattone et al suggests another class of commonly-used nephrology-related drug which may be of use: calcimimetics (such as cinacalcet, or sensipar).

The logic is as follows: The growth of cysts in PKD is thought to be driven by low intracellular calcium levels and elevated cAMP levels. The calcium sensing receptor (upon which cinacalcet acts) is activated by binding to serum ionized calcium, and results in a G-protein-mediated decrease in cAMP levels & increase in intracellular calcium concentration. The investigators therefore suggested that cinacalcet might be an effective way to reduce cyst growth in late PKD.

To test their hypothesis, they took a rat model of PKD (Cy/+) and treated them either with placebo or with the calcimimetic R-568, which is similar in function to cinacalcet. Interestingly, rats in the treatment group showed less advanced cyst formation and fibrosis at later time points, suggesting that their hypothesis may be correct. This study is somewhat unique in that it looks at fairly advanced stages of cystic kidney disease, whereas other animal studies have focused on a more prophylactic approach to cyst growth.

Cautious optimism for ADPKD patients--if I were a young guy with the PKD1 or PKD2 gene, I would seriously consider enrollment in one of the ongoing trials.

GI Bleeding in ESRD Patients

While the GI & renal systems are not typically linked together, there are a few aspects to managing a GI Bleed in patients with CKD/ESRD which are somewhat unique.  

For instance, angiodysplasias in the stomach, duodenum and colon (pictured left) tend to occur at a much greater rate in ESRD patients than in the general population and should be included in the differential diagnosis.  Unfortunately, angiodysplasias are notoriously difficult to locate and/or treat.  Bowel ischemia, due to the increased risk of vascular disease in the ESRD population, is also a consideration.  

Uremic platelet dysfunction, particularly in underdialyzed patients or advanced CKD patients who have not yet started dialysis, can contribute to GI bleeding.  Strategies which can be used to improve uremic platelet dysfunction include the administration of ddAVP (given at 0.3 mcg/kg iv up to two times) or, if bleeding is expected to be more long-term, the administration of conjugated estrogens (5-30 mg iv or po daily x 5 days).

  

PPI's are safe in ESRD patients, but H2-blockers (e.g., ranitidine) need to be adjusted for level of renal function.  The drug sucralfate (carafate) should be avoided as it contains aluminum, and therefore if given for prolonged periods of time can accumulate in the CNS and lead to dementia.  Similarly, the use of bismuth (often used in anti-H. pylori therapy) should be minimized due to its accumulation in ESRD patients.  

Since many patients with ESRD are also on the transplant waiting list, it may also be prudent to transfuse these patients with leukocyte-poor pRBCs in order to minimize the risk of generating alloantibodies that might make finding a negative crossmatch that much more difficult.  

FENa False Positives/Negatives

This post is somewhat basic but it's always good to review, right?

The FENa is one of the most commonly used tools by both nephrologists and non-nephrologists to assess the etiology of oliguric renal failure in a patient.  Classically, a FENa less than 1% is consistent with pre-renal etiologies (and means that more than 99% of the Na filtered is being reabsorbed) while a FENa greater than 1% is consistent with acute tubular necrosis or other types of intrinsic renal failure. 

There are however some specific instances in which the FENa fails.  FENa "false positives" (e.g., the FENa is less than 1% but the patient actually has intrinstic renal failure) in the folllowing conditions.  Contrast nephropathy is notorious for causing a FENa less than 1% despite its not being classified as a true pre-renal etiology of renal failure.  Patients with CHF or cirrhosis/hepatorenal syndrome who develop ATN with clear evidence of granular casts may still retain a FENa less than 1%. Acute glomerulonephritis and rhabdomyolysis may also result in FENa's less than 1%. 

Conversely, FENa "false negatives" (e.g., the FENa is greater than 1% but the patient is actually pre-renal) frequently occur due to one very common cause:  diuretics.  In the face of active diuretic use, a FENa greater than 1% is therefore uninterpretable, and one popular alternative is to assess the fractional excretion of urea (FE-urea).  Since urea is reabsorbed less avidly than sodium, the cutoffs for what constitutes pre-renal and renal etiologies are different:  a FE-urea greater than 35% is consistent with intrinstic renal failure while a FE-urea less than 35% is consistent with pre-renal failure. 

On a previous post I noted the problems inherent in using the FENa is patients with significant chronic kidney disease.  

Genetics of Wilms Tumor

Wilms Tumor--named after the German surgeon/pathologist Max Wilms (pictured at left)--is an embryonal tumor that derives from developing kidney tissue. Wilms was the first to postulate that tumors may arise from precursor cells which arise during development, and indeed study of the molecular pathways active in these "nephroblastoma" shed light on normal kidney development.

There are several genes associated with patients with Wilms Tumor. Here are some of the main ones:

1. WT1 is a transcription factor and considered a tumor suppressor gene. Mutations in WT1 account for between 10-15% of sporadic Wilms tumor. It interacts with p53, a classic tumor suppressor involved in a wide variety of cancers. Denys-Drash Syndrome, a familial and severe form of Wilms tumor, is usually caused by congenital WT1 mutations.

2. beta-catenin is a key component of the canonical Wnt signaling pathway, long known to be a key player in kidney development. Interestingly, most patients with WT1 also have gain-of-function point mutations in the beta-catenin gene which result in increased stability of the beta-catenin protein and subsequent unregulated Wnt signaling.

3. WTX is mutated in a different subset of patients than those with WT1 mutations, and is found on the X-chromosome.

4. BDNF (brain-derived neurotrophic factor): mutations in this growth factor are postulated to result in the WAGR Syndrome--a constellation of symptoms that includes Wilms Tumor along with aniridia, GU abnormalities, and mental retardation.

5. BRCA2: interestingly, mutations in the well-known breast cancer-susceptibility gene can also lead to Wilms tumor.

Location of Culprit Lesion in Acute MI's in CKD Patients

The presence of chronic kidney disease (CKD) portends a much higher mortality in patients who suffer an acute myocardial infarction. There are several potential reasons as to why this might be the case--for instance, the treatment of resultant heart failure may be much more challenging in patients with advanced CKD--but another potential reason is that at the time of presentation their CAD is fundamentally more severe.

A relevant study by Charytan et al in a 2009 Kidney International edition speaks to this issue: they analyzed a cohort of patients who underwent acute myocardial infarction with either the presence or absence of Stage 3 CKD or worse, and examined where the culprit lesion was located with respect to the cardiac vascular anatomy. Interestingly, they found that patients with CKD are much more likely to have lesions which are more proximal than those without CKD. In general, more proximal lesions are generally more severe, as ischemia may occur to a larger region of the myocardium. These results highlight the current thinking that cardiovascular disease in CKD patients may be more aggressive and severe than in the general population, and may even operate by slightly different pathophysiologic mechanisms.

Doing My Part for Kidney Awareness

So it was my Dad's 65th birthday this past weekend, and the kids & grandkids all flew in to Indianapolis to help him celebrate. As my father is also a nephrologist, I wanted there to be a kidney theme to the festivities. As luck would have it, the Indiana branch of the National Kidney Foundation possesses a sweet, human-sized kidney mascot costume named "Billy the Kidney" (a play on the Western hero "Billy the Kid") which the folks at NKF were nice enough to lend. I donned the suit right during the traditional singing of Happy Birthday, and was quite popular for both the nephrologists and non-nephrologists in attendance. Billy the Kidney: rasing CKD awareness one birthday at a time. Happy Birthday, Dad.

The CKD-Epi Equation: An Improved MDRD?

Currently, the most widely-utilized method for routine estimation of GFR (eGFR) is the 4-variable MDRD Equation, in which serum creatinine, age, gender and race are the variables entered into a mathematical formula. eGFR as determined by the MDRD Equation also serves as the basis for CKD Staging. Despite the fact that MDRD appears to be relatively successful as estimating an accurate GFR for patients with CKD Stage 3 and above, there are some increasingly recognized limitations to its use. Most notably, the MDRD Equation is not as accurate for higher degrees of GFR (e.g., GFR > 60 cc/min), and overall tends to overestimate the prevelance of CKD stage 1 & 2 in the general population. In addition, the original MDRD cohort did not contain any patients with diabetic kidney disease or those > 70 years of age, both of which represent a sizeable (and growing) portion of today's CKD population.

To help deal with these limitations, researchers have developed a modified version of the MDRD called the CKD-EPI Equation, recently published by Levey et al in a 2009 issue of Annals of Internal Medicine. Briefly, researchers took a larger and more diverse patient population and measured their GFR using isothalamate clearance as a "gold standard." They then performed a series of statistical manipulations to generate a slightly different mathematical equation than the MDRD in order to arrive at an estimated GFR using the 4 standard values. In particular, they used a mathematical function termed a "spline-knot function" (way beyond my field of expertise) which apparently reduces bias at higher levels of kidney function. Perhaps this equation, with the appropriate follow-up tests & validations, could one day replace the MDRD Equation in routine clinical use, and be more useful at estimating kidney function in individuals with less severe disease.

The Power of Pee

Often, my ideas for blog postings come from reputable journals such as JASN, CJASN, AJKD, Kidney International, NEJM, etc...

But today's topic derives from my regular reading a website I simply can't recommend highly enough...Geekologie. From the July 8th posting, there comes a report that chemists from Ohio University led by Geraldine Botte have succeeded in harnessing the power of urine to drive a hydrogen fuel cell, as recently described in an issue of the Chemical Communications.

Briefly, the authors describe the development of a nickel-based electrode that is able to oxidize ammonia into both nitrogen gas and hydrogen gas, the latter of which could be used to power hydrogen cells. The ammonia is easily derived from urea, the major component of urine. The urine-powered hydrogen car? Don't lose hope.

Rapamycin for ADPKD?

Another potentially useful drug to prevent cyst growth in autosomal dominant polycystic kidney disease comes from the interesting observation that kidney transplant patients with native ADPKD kidneys who were given an immunosuppressant regimen containing the drug rapamycin (sirolimus) displayed less cyst growth than those who did not receive rapamycin.

The molecular mechanism of rapamycin is already known: it inhibits a cell signaling pathway known as the mTOR pathway (mTor = "mammalian target of rapamycin"). In support of its usefulness in ADPKD, the epithelium lining cysts (arrow) shows intense staining with an antibody against phosphorylated (active) mTOR, while non-cystic tubules (depicted by the arrowhead) do not show mTOR activity, as shown in this 2006 PNAS paper by Shillingford et al.
We will obviously have to see how rapamycin does in clinical trials. One of the obvious caveats is that this is not a wholly benign medication as observed by many transplant nephrologists, and bear in mind that it would likely be a chronic medication taken to prevent the growth of cysts and resultant ESRD. In the meantime, an article in this month's Kidney International by Gattone et al successfully uses rapamycin to decrease cyst growth in a mouse model of nephronophthisis (the pcy mouse), providing further rationale for this approach.

Sudden cardiac death rates in ESRD patients

The case against Sunday As A Day Of Rest For the Dialysis Unit:  this older study (Bleyer et al, Kidney International 1999) looked at sudden death amongst ESRD patients according to days of the week using data from the USRDS.  Here is the key graph showing mortality rates in ESRD patients by days of the week.  The black bars represent deaths classified as cardiac arrest, the white bars represent deaths classified as "other cardiac" (e.g., myocardial infarction), and the gray bars represent deaths classified as "non-cardiac deaths."   

The most striking feature of this graph is that there is a clear spike in cardiac mortality seen on Mondays, and to a lesser degree on Tuesdays.  The authors go on to show that patients who are dialyzed on a MWF schedule are most likely to have a cardiac death on Mondays whereas patients who are dialyzed on a TuThSat schedule are most likely to have a cardiac death on Tuesdays.  In other words, death is most likely to occur during the long, dialysis-free "weekend".  Patients on peritoneal dialysis in contrast showed relatively constant mortality rates throughout the days of the week as compared to hemodialysis patients.  

There are numerous potential explanations for these findings.  Intradialytic weight gain is understandably higher over a 72-hour period compared to a 48-hour period, and fluid shifts during ultrafiltration might be more liable to result in hypotensive episodes that would be predicted to be particularly dangerous in those with underlying cardiovascular disease.  Potassium or calcium levels may fluctuate more and therefore be more likely to result in arrhythmia.  Overall, the Monday/Tuesday "mortality spike" in ESRD patients appears to reflect the intermittent nature of the currently popular three days a week dialysis strategy, and potentially points to a benefit for a more constant (e.g., daily, 6x/week, PD, etc) dialysis schedule, though this latter point remains a controversial one.

PRES

The MRI above depicts a classic example of posterior reversible encephalopathy syndrome (PRES), sometimes also called reversible posterior leukoencephalopathy, an increasingly-recognized consequence of malignant hypertension.  The whitish areas ("hyper-intense signal") in the bilateral occipital and parietal lobes represent edema in these regions.  PRES has also been reported in other disorders such as eclampsia and lupus.  The lesion is allegedly reversible if the hypertension is appropriately treated.

A recession-proof profession?

How many nephrologists does the U.S. need?

I recently heard a thought-provoking calculation from MGH's Dr. David Steele which helps illustrate a likely shortage in the number of American nephrologists.  The calculation is admittedly a rough estimate, but an interesting thought experiment nonetheless.  

Using the numbers from NHANES, as of the year 2000 there were estimated to be 15.5 million Americans with CKD Stage 3 and 0.4 million Americans with CKD Stage 4.  The ESRD program in the U.S. encompasses about 500,000 Americans.  Let's say that we should try and see all patients with CKD Stage 3 twice a year, all patients with CKD Stage 4 four times a year, and all ESRD patients twice a month as mandated.  Taken together, this calculates out to 45.8 million appointments per year.  Let's be ambitious and say that we work every day that the dialysis unit is open:  6 days of the week, but off on Sundays.  This then comes out to 146,326 visits per day.

  

Let's also say that there are 6000 nephrologists in the United States--probably an underestimate of full-time clinicians, but let's choose 6000 as the denominator.  In order to provide optimal nephrology care to the U.S. population of CKD and ESRD patients, each nephrologist would have to see almost 25 patients per day, 6 days a week.   This calculation does not allow for the growing population of kidney transplant patients, acute kidney injury consults which must be seen by a nephrologist, complex patients who must be seen with greater frequency, and the possibility of an expanding population of CKD given rising rates of hypertension and diabetes in our society.

In sum, based on these calculations, one can make a compelling case that there is a shortage of nephrologists in the U.S.  

Why Do U.S. ESRD Patients Do So Poorly?

The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an important longitudinal study of ESRD patients in multiple countries, and is the source of much respected epidemiologic data on dialysis patients worldwide. Interestingly, the DOPPS estimated the crude 1-year mortality rate of ESRD patients in the U.S. to be a whopping 21.7%, which compares quite poorly to the rates in Japan (6.6%) and Europe (15.6%). This difference persists even after controlling for comorbid conditions. An editorial in this month's JASN by Foley and Hakim tries to tackle this touchy topic of American inferiority in the ESRD setting in an organized fashion.

A 2006 cross-sectional study by Yoshino et al using an international WHO mortality database helps to get at this question by noting a close correlation between all-cause mortality rates and cardiovascular mortality in the general population and showed that this correlation is even stronger within dialysis patients. This, it appears that at least some of the reason that U.S. ESRD patients do poorly is because of the relatively high rate of cardiovascular disease in the general population here.

There remain, however, other variables between countries which could also potentially explain the difference in mortality. U.S. patients tend to spend less overall time on dialysis than in Japan, for instance, and the U.S. also performs poorly in terms of having a low percentage of patients who begin dialysis with catheters as opposed to AV fistulas. Dialysis units in the U.S. are often staffed by a high percentage of dialysis technicians who have less formal training than dialysis nurses, which are required in greater numbers in Europe. I have also suspected that in the U.S. we may tend to dialyze the very elderly or the very ill with greater frequency than in other countries, which would obviously tend to make our numbers look worse. Explaining the mortality discrepancy likely has a complex answer, but it makes sense to try and figure out what aspects of our dialysis care might be improved to help lessen the mortality difference.

Some Cool, Geeky Science-Type Kidney Web Resources

Two very interesting web sites for those involved in the study of mouse as a model organism for the study of kidney disease and kidney development:

The first is the Genitourinary Development Molecular Anatomy Project (GUDMAP) site, which contains a useful database of thousands of genes' expression patterns in the developing kidney.   

The second is the EureGene Kidney Atlas, part of the European Renal Genome Project, which contains databases for kidney gene expression, phenotypes of mouse knockout lines, and some nifty images of the developing kidney at different stages.  

Exciting NEJM Membranous Nephropathy Article

A landmark paper on membranous nephropathy was published by Beck et al in the most recent issue of NEJM. Ultimately we will have to see if the finding is reproducible, but based on the data presented this represents a major breakthrough in understanding the pathogenesis of membranous nephropathy and nephrotic syndrome.

There has long been strong evidence in support of a circulating factor which causes podocyte injury and resultant nephrotic syndrome. Additional evidence from the neutral endopeptidase story further suggested that an autoantibody directed again some podocyte antigen might be the culprit. In this issue, the researchers demonstrate that in 70% of patients with idiopathic membranous nephropathy (but 0% of patients with secondary membranous nephropathy or other forms of proteinuric kidney disease such as FSGS or diabetic nephropathy) contain an autoantibody against the podocyte antigen phospholipase A2 receptor. Furthermore, the autoantibody's presence appears to correlate with disease activity, suggesting a possible pathogenic role.

The work has a number of implications. First, it suggests that membranous nephropathy is indeed a separate disease than FSGS and other distinct forms of nephrotic syndrome. The common final pathway for proteinuria is the same (podocyte injury), but the ways in which to get there is likely different. Second, it suggests that detection of serum antibodies against phospholipase A2 receptor may be a useful part of the diagnostic workup for nephrotic syndrome--perhaps even making biopsies unnecessary--and perhaps could be used to follow disease activity in response to various therapeutic maneuvers. That is, this test may well become the "ANCA" of membranous nephropathy.