Just Add Water?

There is a popular belief that drinking lots of water is good for one's health. One classic recommendation from doctors to patients--nobody knows where it comes from--is to drink 8 glasses of 8 ounces of liquid beverages daily.

Is this really true? Certainly we are confident that drinking copious amounts of water is a good thing for those who have a history of nephrolithiasis, but are there any medical conditions for which this is true? A review of the literature in a recent issue of JASN by Negoianu and Goldfarb concludes that there is no proven benefit--or at least, there is a dearth of clinical evidence looking at how much water is optimal to prevent various health problems.

What about phrasing the question differently: How much water is too much water? Due to our amazing kidney's impressive power to dilute the urine (in health young folks up to 50 mosm/kg/L), you have to try pretty hard to became hyponatremic as a result of excess free water intake. In 1998, a 28-year-old woman entered in a California radio contest in which individuals were judged based on their ability to ingest large quantities of water without urinating--termed "Hold your wee for a [Nintendo] Wii"--was found dead after ingesting several liters of water over a short period of time.

Biomarkers: The Race for a Better Creatinine

The Panel 7: I remember it was one of the first things I learned in clinical medicine. Na, K, Cl, HCO3, BUN, creatinine and glucose. I know not all countries use the same "grid format" of presenting these numbers as we do in the U.S., but all of them use creatinine as the indicator of GFR which is so useful in interpreting a patient's electrolyte values.

While certainly useful, there is one big problem with creatinine that should be fairly obvious to all renal fellows: it is a relatively late marker of renal injury. By the time the creatinine has risen, there has already been significant renal damage. For some surgical patients in the ICU, immediately post-operatively after a CABG for example, we will start renal replacement therapy even with relatively "normal" creatinines in the 1.3 - 1.4 mg/dL range--if we feel there is a genuine acute kidney injury, as manifested (for instance) by anuria and volume overload. What if there was a blood test which indicated renal damage at the earliest stages of AKI--e.g., a substance whose concentration in the bloodstream (or urine) became significantly elevated before that of creatinine?

This is what the field of biomarkers is all about, and the race is on. Imagine a day where instead of creatinine in the lower right hand corner of the panel 7 there is a different test. An excellent review of the field can be found here, look for the April 2008 edition of the Brigham & Women's "Nephrology Rounds" publication by Won Han. Four of the big biomarkers under investigation currently include neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and cystatin C. Many of them are detected in the urine--with the rationale that the earliest indication of tubular kidney damage would be to look for the presence of proteins expressed by renal tubular epithelial cells in response to ischemic damage in the urine. It could very well be that there is no single "winner" of the best test to detect early renal damage--perhaps different biomarkers can be used to detect injury within discrete regions of the nephron (e.g.,proximal tubular damage versus distal tubular damage), or perhaps different biomarkers will be able to detect different types of nephrotoxin-induced damage (e.g., contrast nephropathy versus sepsis-associated AKI). This is an interesting field with a promising future.

What is Intestinal Dialysis?

We are well-versed in describing to our soon-to-be ESRD patients their options: kidney transplant, hemodialysis, or peritoneal dialysis. However, in many developing countries, these options do not exist, or there may be a significant delay in getting them set up. A different type of renal replacement therapy is intestinal dialysis.

In intestinal dialysis, the diet is supplemented with soluble fibers such as acacia gum, which is digested by colonic flora, thereby increasing the amount of nitrogen that is eliminated as fecal waste. Apparently when acacia fibers are added to a low protein diet in children with advanced CKD who do not have access to dialysis, their serum BUN levels were slightly lower and they experienced a decrease in uremic symptoms. Admittedly, this would appear to be a much less viable option than PD or HD, but in situations of limited resources it may be valuable.

Haas System of Classification for IgA Nephropathy

We are all relatively familiar with the WHO classification system for lupus nephritis, which gives nephrologists a relatively good idea of renal prognosis based on the histologic findings of renal biopsy.

A similar type of system has been developed for IgA Nephropathy known as the Haas system of classification for IgA Nephropathy. Much like lupus nephritis, there is a range of pathologies seen on renal biopsy in patients with IgA Nephropathy, and there is a wide range of prognoses, with many patients going years without any discernable decline in renal function but others which may show a pattern of rapidly progressive glomerulonephritis.

In the Haas paper describing their classification system, the authors took 244 cases of IgA Nephropathy--not including Henoch-Schonlein purpura--and broke down the cases by histologic pattern into 5 subclasses: subclass I (minimal or no mesangial hypercellularity), subclass II (focal and segmental glomerular sclerosis without active cellular proliferation), subclass III (focal proliferative GN), subclass IV (diffuse proliferative GN), and subclass V (any biopsy showing >40% globally sclerotic glomeruli or >40% cortical tubular atrophy or loss). The classification is useful in the sense that there was a statistically significant correlation between IgA subclass and renal survival (with subclass I having the best prognosis and subclass V having the worst prognosis).

Candombe Drumming-Induced AKI

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

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

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

Pseudohyperkalemia

Don't be fooled into dialyzing patients that don't need to be dialyzed! You have to beware of the pseudohyperkalemia.

The most common cause of pseudohyperkalemia of course is due to hemolysis from venipuncture.

There are other, more rare, possibilities however.

In hereditary spherocytosis, for instance, the RBC membrane is susceptible to lysis after collection, and may result in a serum K that is much higher than the in vivo situation.

Familial pseudohyperkalemia is a genetic condition in which RBCs exhibit a leak of K without hemolysis when stored a room temperature (though there is no observed K leak when stored at 4 degrees). Several loci have been identified, but no specific gene has been pinpointed yet.

Extreme leukocytosis (e.g., with blast crisis in various leukemias) may also lead to pseudohyperkalemia.

Finally, there is the phenomenon of "regional pseudohyperkalemia"--the observation that samples which sit around in a cold climate tend to be (on average) very, very slightly more hypokalemic whereas samples which sit around in a warm climate tend to be (on average) very slightly more hyperkalemic.

Heparin Recall Explained

There is an interesting article in the most recent New England Journal of Medicine describing the epidemiology of the now infamous Baxter heparin recall which occurred over the past year or so.

In brief, a Missouri pediatric dialysis unit in January 2008 reported an alarming cluster of allergic-type reactions in their unit which manifested as hypotension, tachycardia, urticaria, and facial edema occurring almost immediately after starting dialysis. Subsequent epidemiologic sleuthwork identified multiple other affected patients throughout the country, and researchers identified Baxter-manufactured heparin as a risk factor for such reactions. Further molecular analysis identified the contaminant as being overly-sulfated chondroitin sulfate (OSCS): recall that the chemical structure of heparin is a heterogenous mix of sulfated proteoglycans; this contaminant is a polysaccharide species which has an unusual sulfation pattern.

Heparin is well-known to cause allergic reactions taking the form of heparin-induced thrombocytopenia (HIT), but immediate allergic reactions such as the one described were previously thought to be extremely rare. The Baxter heparin lots containing OSCS have since been recalled, and according to the NEJM paper, the CDC has stopped receiving reports of such immediate reactions. Of note, a Google Search of the term "Baxter heparin" yields a wide variety of eager law firms, much like the "gadolinium NSF" phenomenon...

List of Diseases Which Recur Following Renal Transplant

Nearly any primary glomerulopathy has the possibility of recurring following a kidney transplant; however, the frequency and severity with which this occurs varies to a large degree.  For instance, evidence of mesangial IgA deposition can be seen in the majority of kidney transplant patients with a prior diagnosis of IgA Nephropathy; however, this does not typically lead to rapid allograft loss and therefore is not so clinically significant.  Recurrent primary FSGS, on the other hand, may occur commonly and with a severity that may indeed lead to graft loss.  The following is a partial list of some diseases with a high rate of recurrence following kidney transplant and their relative rates of frequency, taken in part from a short review in a 2007 Transplant Proceedings issue:

1.  Primary FSGS:  about 40% of cases will recur, many of which ultimately lead to allograft failure.  Plasma exchange and aggressive immunosuppression may be of value.

2.  Primary membranous nephropathy:  about 30% recurrence rate, though its severity is less than that of primary FSGS typically.  Also, de novo membranous nephropathy occurs in 1-2% of all transplants.

3.  MPGN:  type II MPGN has a recurrence rate of about 90%, whereas type I MPGN has a recurrence rate of only about 25%.

4.  HUS:  the D+ type of HUS typically does not recur post-transplant; however, the congenital forms of HUS (e.g. mutations in factor H, grouped amongst the D-type of HUS) recurs frequently.

5.  IgA Nephropathy/Henoch-Schonlein Purpura: recurs about 50% of the time but seldom causes allograft dysfunction.

6.  primary hyperoxaluria:  this disease occurs essentially 100% of the time unless it is performed as a dual liver-kidney transplant.

7.  diabetic nephropathy:  like IgA Nephropathy, pathologic hallmarks of diabetic nephropathy are commonly observed post-trasnsplant, but this damage typically takes years, if not decades, to become clinically significant.

There are probably others, but these are some of the major ones to remember.

The Hatfields, the McCoys, and von Hippel Lindau Syndrome

I saw a patient in my clinic today with the diagnosis of von Hippel-Lindau Disease. She has a Cr in the mid 2's as a result of prior vascular disease as well as being status-post nephrectomy for a renal cell carcinoma discovered several years ago. To review, von Hippel-Lindau (VHL) disease is a rare, autosomal dominant genetic condition characterized by hemangioblastomas of the cerebellum, spinal cord and retina; individuals also have a high rate of nephrology-relevant tumors such as renal cell carcinoma and pheochromocytoma. The VHL gene is a tumor suppressor gene.

What do the Hatfields & McCoys have to do with VHL? In my rapid google search of VHL in the minutes preceding this patient's office visit, I found this interesting hit in which a Vanderbilt geneticist posits that this infamous Appalachian feud between two warring families could in part be due to the fact that the McCoy family is known to carry the VHL disease gene, with multiple affected family members who went public a few years ago. The theory states that pheochromocytomas within affected individuals would lead to an easily-angered and overly-aggressive phenotype as a result of unregulated adrenaline secretion by existing pheochromocytomas. Truth or fiction? It seems a matter of speculation, but a historically fun theory to consider.

cholemic nephrosis?

Amongst the given differential diagnosis for acute renal failure in liver disease is an entity termed "cholemic nephrosis."  It is debatable as to whether or not this actually exists or represents part of the spectrum of hepatorenal syndrome or another unidentifiable cause of ATN.

The idea here is that markedly elevated (e.g., >25 m/dL) concentrations of bilirubin, either conjugated or unconjugated, can result in acute tubular necrosis, even in the absence of apparent portal hypertension or other common causes of ATN.  Individuals with this diagnosis may show bilirubin (yellowish)-pigmented granular casts.  

In support of this idea, isolated rat kidney perfused with high bilirubin concentrations showed evidence of tubular toxicity. 

Tamm-Horsfall Protein

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

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

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

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

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

'Shrooms and Renal Failure

While toxic mushroom ingestions are generally known for their ability to cause acute liver failure, certain varieties of mushrooms can also result in acute renal failure.

One such type of mushroom is Amanita smithiana, (shown at left) which is responsible for causing relatively rapid (e.g. within a few days of ingestion) renal failure. The mechanism is felt to be ATN and there have been several case reports of this type of mushroom ingestion in the Pacific Northwest region of the United States.

Another distinct type of mushroom-induced acute renal failure is those produced by Cortinarius species (shown at bottom). These are found mostly in Europe, and the mechanism of renal injury here is a tubulointerstitial nephritis. As such, onset can be delayed (3 days - 3 weeks) and often less severe than Amanita-induced renal toxicity.

Also, as liver failure is still the most common disease associated with toxic mushroom ingestion, hepatorenal syndrome (as a secondary event) must also need to be strongly considered in an individual with renal failure following mushroom ingestion.

Microhematuria in Potential Kidney Donors

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

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

TRP Channels in Nephrology

The TRP (transient receptor potential) family of proteins is a group of related ion channels which is becoming increasingly relevant to the field of nephrologists. The TRPs are cation channels which are responsible for moving Ca2+ and Mg2+ ions across membranes; they were originally found in Drosophila and are named based on the fact that when light is shined on the fruit fly eye, instead of having a sustained photoreceptor response, there is only a transient response.

Examples of TRPs which have become important in Nephrology include:

-PKD2 (the 2nd most common disease gene for ADPKD, which is being renamed "TRPP2" based on the newest classification scheme for the TRP channels).

-TRPV5 & TRPV6 are expressed in the apical membrane of distal convoluted tubule cells and are felt to be responsible for calcium reabsorption at this site.

-TRPM6 mutations have been associated with hereditary hypomagnesemia.

-TRPC6 mutations have been found to cause a subset of familial nephrotic syndrome.

Reverse Osmosis

Reverse osmosis (RO) is a critical aspect of providing the large volume of relatively purified dialysate water to dialysis patients worldwide.  If you've never taken a peek at the water treatment room in your hospital's dialysis unit (it is probably hidden away in a closet or a back room somewhere), I highly recommend it.  Although there are now individual-sized RO units available (for example, for use with home dialysis), chances are your hospital's dialysis unit has a large RO machine (similar to the picture above) installed in order to provide the massive amounts of water needed to power a busy dialysis unit.

Reverse osmosis is the separation process that uses high pressures to force a relatively hypertonic solution through a semipermeable membrane towards a relatively hypotonic solution.  Simply put, the hydrostatic pressure exerted on the high concentration side of the membrane must be greater than the osmotic pressure.  The same principal may also be used for desalination, the conversion of sea water to drinkable fresh water.  

Plasma Exchange Nuts & Bolts

There are many indications for plasma exchange in nephrology:  some common ones include antibody-mediated rejection of a kidney transplant, Goodpasture's, ANCA-associated vasculitis, and TTP--all of which are commonly associated with loss of renal fellows' sleep--that is, you may very well be called upon to start plasma exchange in the middle of the night for one of these conditions.

There are two basic ways to achieve plasma exchange:  the Blood Bank Way (in which plasma is separated from blood cells using a centrifuge) and the Nephrology Way (in which a membrane plasma separator cartridge is installed within a dialysis machine circuit).  They both work, and which one gets the call appears to be highly center-specific.

Here's a quick-and-dirty guide to writing a plasma exchange order, realizing that specific circumstances may well alter what the final order will be:

1.  Estimate plasma volume (=.065 x weight in kg) x (1-Hct).

2.  Decide how many plasma volumes to remove (we typically use 1.5 plasma volumes, which ends up being between 40-60 cc/kg).

3.  Specify what the replacement solution will be:  you need to replace the plasma volume amount removed in a 1:1 fashion; a good default is using 2/3 volume of 5% albumin and 1/3 volume normal saline.  For example, if you remove 4 liters total, you could replace with 2.66 liters of albumin & 1.33 liters of normal saline.  You may have to use some FFP as well (for example, if the coags are elevated or you are doing plasma exchange for TTP).

4.  Specify calcium replacement:  usually 4-6 grams.

5.  Specify anticoagulation:  you can certainly try going it heparin-free, though in my limited experience clotting occurs more frequently than in dialysis.  A 2000 unit heparin bolus, if tolerated, is not a bad idea.

Renal Vein Thrombosis

Renal vein thrombosis is a thrombotic occlusion of one or both renal veins. Its most common cause is nephrotic syndrome, which is a hypercoaguable state though to be due at least in part to loss of the anticoagulant proteins protein C, protein S, and antithrombin III from diffuse protein wasting. It can also be secondary to nearly all other forms of nephrotic syndrome (e.g., minimal chnage disease, FSGS, MPGN) and also lupus nephritis particularly in the setting of a lupus anticoagulant. Renal cell carcinoma is also commonly associated with renal vein thrombosis, and local spread of tumor may also continue into the renal vein clot. A variety of imaging tools (e.g., venography, ultrasound, MRI, etc) are available for diagnosis of renal vein thrombosis but the most common means of diagnosing it currently is a CT scan with iv contrast. Surgical means of evacuating the clot are becoming increasingly rare and the mainstay of therapy involves anticoagulation and correcting the underlying cause (e.g., treating nephrosis with ACE-I/ARB, immunosuppresants as warranted, etc). The idea of giving prophylactic anticoagulation to prevent venous thrombosis in nephrotic syndrome is still a controversial one.

Urine Anion Gap

The urine anion gap is calculated as follows:  [urine Na] + [urine K] - [urine Cl].  

Think about the urine anion gap much as you think about the serum anion gap.  The urine anion gap is really determining unmeasured anions - unmeasured cations.  The major unmeasured cation in the urine is ammonium ion, which is how the kidneys get rid of an organic acid load.  In the setting of diarrhea, the kidney (assuming it is functioning properly) is working to increase acid secretion and therefore there is a large amount of urine ammonium and thus a largely negative anion gap.  In contrast, in a situation such as renal tubular acidosis during which acid secretion is inhibited, the urine ammonium will be low and there will be a positive urine anion gap.

  

This system breaks down some in some instances--for example, in toluene toxicity during which a large amount of an intact, undissociated acid (hippurate) is being secreted without ammonium.  Furthermore, one big knock on regular use of the urine anion gap is that in most cases, the history alone will tell you whether or not a patient's metabolic acidosis has GI versus renal origins.  

Bactrim & elevated creatinine

The antibiotic Bactrim is frequently associated with an increase in creatinine shortly after starting it. While Bactrim is a not uncommon cause of acute interstitial nephritis (AIN), the most frequent reason for a Bactrim-associated creatinine increase is actually artifactual one. Bactrim inhibits a particular cationic transporter in the proximal convoluted tubule which is also responsible for creatinine secretion. By doing this, serum creatinine elevates without an acutal decrease in GFR. This is the same mechanism by which cimetidine (Tagamet, also an organic cation) results in an elevated creatinine. For the most part, this mild elevation in creatine is inconsequential and is not a reason for discontinuing the antibiotic.

In addition to an elevated creatinine, Bactrim is also associated with hyperkalemia. The mechanism is felt to be a decreased aldosterone-mediated Na reabsorption via the ENac channel in the collecting duct.

Old Dialysis Video

Check out this video I found of the alleged first-ever home dialysis patient in England. Very civilized, except for the fact that it looks like the patient is using a permanent femoral dialysis catheter--something which would be used only rarely in today's times due to what we know about the dramatically increased risk of infection.

CKD in the Elderly

A current controversy in the CKD community involves definitions of CKD in the elderly. The issue is not trivial: were we to apply the standard KDOQI definitions of CKD staging, using the MDRD equation to estimate GFR, this would lead to a diagnosis of CKD in 47% of the U.S. population! Do nearly half of the geriatric population deserve to be labeled as having a disease of the kidneys? Or should this decrease in GFR be merely considered a normal consequence of aging?

In favor of labeling this decreased GFR in the elderly as abnormal, histopathologic analysis of geriatric kidneys shows evidence of microvascular disease that in a young person would not be seen as normal. Mortality does seem to correlate with GFR, even in the mid-range. Also, from a historical perspective, the idea that hypertension was driving conditions such as stroke and cardiovascular disease was initially dismissed based on how common it was in the general population; the same situation could conceivably be the case here. A good review, from a 2005 NEJM article, is found here.

In opposition to this, Drs. Glassock and Winearls rebuttal in this month's AJKD take issue with the use of the pejorative term "disease" to describe such a large fraction of the nation's elderly, and suggest instead to use the term "age-related reduced kidney function."

cisplatin-induced acute kidney injury

At the Brigham and Women's Hospital & the Dana Farber Cancer Institute, there is an ongoing trial of using pneumonectomy and injected, heated cisplatin into the pleural space for patients with malignant mesothelioma, a condition with an overall poor oncologic prognosis and limited treatment options.  Apparently this technique has had some success, but not surprisingly, it results in many renal consults to the Nephrology Fellow as a very substantial percentage of patients have significant acute kidney injury and many require dialysis.  Unlike standard chemotherapy where cisplatin may be held once renal toxicity has occurred, the injected cisplatin has a very slow, continuous absorption and therefore there is no opportunity for reversal once this sets in.  

The mechanisms of cisplatin-induced acute kidney injury are still being worked out but generally result in tubular toxicity (ATN).  Both necrosis as well as apoptosis appear to be involved, according to this recent KI review article on the topic.  

Cisplatin falls under the category of platinum-containing alkylating agents.  Related drugs include carboplatin and oxaloplatin, which still have some renal toxicity but substantially less than cisplatin.  

mesanagial cells

Mesangial cells--which historically have received less attention than their more "sexy" neighbor cell types of the glomerulus such as podocytes & endothelial cells--are actually quite interesting.  They were originally seen as having purely a "matrix" function--that is, serving as the anchor points for the glomerular capillary walls.  However the evolving view of the mesangial cell is that this cell type has other important functions, including:

-contraction:  mesangial cells derive from smooth muscle cells and may play a role in regulating intraglomerular hemodynamics.

-phagocytosis:  playing a role in the immune system of the kidney.

-synthesis & secretion of growth factors and cytokines.  

-mesangial cells are also capable of producing excess amounts of matrix, which may be important in certain diseases (e.g., diabetic nephropathy, IgA Nephropathy).  

A few other related histological terms:

Mesangial sclerosis refers to an increase in the amount of mesangial matrix, either with or without a concomitant increase in mesangial cellularity.  There is an autosomal dominant form of this disease which may be caused by mutations in the Wilms tumor (WT1) gene.  

Mesangiolysis, in contract, refers to a dissolution of the mesangial matrix and a degeneration of mesangial cells.  Mesangiolysis is seen in a wide range of condition including thrombotic microangiopathies , malignant HTN, diabetic nephropathy, and others.  

Gamblegrams

Heard a very good Renal Grand Rounds yesterday from visiting professor Michael Emmett, currently chair of the Dept. of Medicine at Baylor, regarding the anion gap.

Amongst the pearls I took away from his lecture:

1.  "Gamblegrams" (left), initially created by acid-base pioneer James L. Gamble, are a useful way of analyzing most acid-base disturbances and helping to visualize the anion gap.

2.  In the U.S., the anion gap is [Na] - ([Cl] + [HCO3]) and the normal range is 8-12; in many other countries (e.g., Europe, Australia) the anion gap is calculated as ([Na] + [K]) - ([Cl]+[HCO3]).  The addition of the cation [K] in the equation means that these anion gaps would be slightly lower than those in the U.S.  Keep this in mind when interpreting literature on the anion gap from other countries.

3.  the main difference between an anion-gap metabolic acidosis (AGMA) caused by organic acids (e.g., lactic acidosis, ketoacidosis) and inorganic acids (e.g., hydrochloric acid) is that organic acids are metabolizable to bicarbonate (resulting in an eventual reversibility to the acid-base disturbance) whereas inorganic acids are not, relying solely on renal bicarbonate synthesis to restore homeostasis.  

4.  One weird (and not terribly common any longer) cause of acidosis:  pseudohyperchloremia bromism.  Several decades ago, bromide was a common over-the-counter sedative.  Because the laboratory test which detects chloride has an even greater sensitivity for bromide ions, individual with bromide toxicity can actually present with a NEGATIVE ANION GAP!  Bromides are less available now, with the exception of the acetylcholinesterase medication Mestinon bromide (pyridostigmine), which is still used to treat myesthenia gravis.  

Why does hypomagnesemia result in refractory hypokalemia?

We've known this medical factoid since we were medical students: you can't successfully replete a potassium-depleted patient if they have low magnesium levels. But what is the mechanism by which this occurs?

One possible explanation is put forth in a 2007 JASN article by Huang and Kuo. In this paper, the authors suggest that magnesium regulates the activity of ROMK, the renal outer medullary potassium channel, providing a rationale for how low Mg levels lead to low K levels. ROMK is the inwardly rectifying K channel on the apical surface of the distal nephron which is required for the backleak of K+. When there is high intracellular Mg2+, it will block the ROMK channel pore and prevent K+ from effluxing. Conversely, a low intracellular Mg2+ would allow for high ROMK efflux activity and therefore result in K+ wasting. The authors are cautious to state that additional factors (e.g., high aldosterone levels, increased Na uptake, etc) may also be required to result in clinically significant renal K+ losses.

TGF-betas & diabetic nephropathy

The TGF-beta family of proteins has wide effects on nearly every tissue of the body--it is one of the key players in a mammalian development and homeostasis.  It also has particular relevance to renal pathophysiology as one of the central mediators of diabetic nephropathy.

The TGF-betas are secreted peptides.  They interact with receptors (a family of transmembrane serine/threonine kinases) which upon binding leads to activation of a family of proteins known as the Smads, which regulate gene expression.  

The evidence that TGF-beta is involved in diabetic nephropathy is abundant.  For one, TGF-beta is overexpressed in glomerular and tubulointerstitial compartments in rodent models of diabetes.  In addition, TGF-beta stimulation results in a gene expression program that involves key elements of the fibrotic pathway--with fibrosis being the "common final pathway" not only for diabetic nephropathy but other forms of chronic kidney disease as well.  Also, treatment of diabetic mice with neutralizing anti-TGF-beta antibodies helps prevent matrix expansion and renal functional decline.    Perhaps modification of this pathway might be a good pharmacologic target for preventing progression of CKD in teh future...

Scoring System for ATN vrs pre-renal AKI

One of the earliest time-saving tricks I learned as a Nephrology fellow was to always ask the covering housestaff to have a specimen of piping hot urine waiting for me at the time of the initial consult:  I was trained to do a urinalysis on all patients on whom I am called to see.  While I have been impressed with its usefulness of several occasions, there is surprisingly little standardization for the technique, and not a lot of literature providing objective criteria for diagnosis.

A recent study in C-JASN by Perazella et al looked at the ability of the urinalysis to distinguish between ATN versus pre-renal AKI on 267 consecutive inpatients with AKI in the Yale-New Haven Hospital system on whom a renal consult was called.  Participating nephrologists were asked to assess a cause of either "ATN", "pre-renal", or "other" at two different time points:  (1) just after history & physical but before microscopy diagnosis, and (2) after patient discharge or death.  As biopsies were not done in this study, the 2nd & final diagnosis--based on clinical judgement--was the "gold standard."  The urinalysis itself was carried out in a standardized fashion and a scoring system based on the number of casts or renal tubular epithelial cells (RTECs) was developed.

Not surprisingly, patients with a high "urine sediment score" (indicating many casts or RTECs) had a high rate of ATN as a final diagnosis while those with lower scores were more likely to have pre-renal AKI as a final diagnosis.  While this is not groundbreaking, what is worthwhile about this study is that (a) they prove that the urinalysis is a valuable tool for diagnosis by showing that a significant number of patients had their diagnosis changed following urinalysis, and (b) they tackle this problem in a systematic fashion.

What is DOPPS?

DOPPS is an acronym which stands for "Dialysis Outcomes and Practice Patterns Study." It is one of the largest prospective study of ESRD patients worldwide and is comprised of a random sampling of dialysis patients in a random sampling of dialysis units in multiple countries, including the United States. DOPPS-related research has led to dozens of peer-reviewed publications and will undoubtedly involved in many more.

One example of the usefulness of DOPPS research has been settling the question of whether non-white minority groups do better on dialysis than whites. Multiple previous epidemiologic evidence had shown an apparent survival advantage of such minority groups compared to whites. However, using the DOPPS database and a careful multivariable proportional hazards analysis, researchers determined that in fact there is no significant survival advantage on dialysis for any major ethnic group; the reason that African-Americans appear to last longer while on dialysis than whites is in part explained by their lower age and decreased comorbidities upon starting dialysis.

Fabry's Disease

Fabry's Disease is an X-linked disease caused by a mutation in the alpha-galactosidase A gene, resulting in the accumulation of glycosphingolipids within lysosomes. In the kidney under electron microscopy, this is manifested as the presence of multiple round "onion-skin" inclusion bodies (see EM on the left).

It presents clinically with renal failure (preceded by proteinuria, lipiduria, and variable hematuria), cutaneous angiokeratomas (see below), painful paresthesias of the hand (acroparesthesias), and early CAD.

As it is X-linked, it occurs mostly in boys; however, females may have a mild form of the disease.

In recent years, the biotech company Genzyme has developed an injectable form of the missing enzyme, marketed under the trade name "Fabrazyme." Although successful, it comes at a cost of approximately $170,000 a year for a single patient, a significant barrier to many patients without insurance.

Glomerular Basement Membrane

The glomerular filtration barrier is traditionally thought of as being comprised of 3 layers: (1) the fenestrated endothelium, (2) the glomerular basement membrane, and (3) the podocyte foot processes.

Focusing on (2) the glomerular basement membrane (GBM), this structure is typically 330-460 nm in thickness and can be further subdivided into 3 additional layers: (a) the lamina densa (LD, in figure, the middle lyaer), (b) lamina rara interna (LRI, in figure, the "subendothelial layer" closest to endothelium), and (c) lamina rara externa (LRE, in figure, the "subepithelial layer" closest to the podocytes.). In terms of molecular components, the GBM is comprised of type IV collagen, heparin sulfate proteoglycan, and laminin.

Important diseases of the GBM specifically include Alport's Syndrome, thin basement membrane disease, and anti-GBM (e.g., Goodpasture's) Disease to name a few.

Toad Skin-Induced Hyperkalemia

Why is there a picture of a toad on the Renal Fellow Network?

In reading the most recent edition of ESRD/Dialysis "NephSAP" (the ASN's periodic review of relevant nephrology-themed literature), I learned about an unusual cause of hyperkalemia: toad skin. In Southeast Asia, toads may be used as food, and in some Chinese traditional medications toad venom extract may be an ingredient. Toad skin in particular is particularly rich in bufadienolides, molecules which are similar in structure to digitalis, and thereby induce toxicity due to inhibition of the Na-K ATPase. Individuals with toad-skin toxicity may present with arrhythmias and hyperkalemia and CKD/ESRD patients would be especially susceptible to these effects. In addition to standard treatments for hyperkalemia, this can be managed with high-dosage administration of digoxin-specific Fab fragments, much like digoxin toxicity.

Hemoglobin A1c in Dialysis Patients

The Hemoglobin A1c has proven to be one of the most utilized and helpful tests in the management of diabetes. Instead of relying on random blood sugars to adjust a diabetic's insulin regimen, the HgbA1c (which increases in the setting of poorly-controlled diabetes due to increased glycosylation of hemoglobin molecules in red blood cells, which have a half-life of 120 days) provides a more long-term and balanced view on glucose control.

However, there are some serious caveats to its use in dialysis patients. Because erythropoietin-stimulating agents will increase the proportion of young RBCs in the circulation, the HgbA1c significantly underestimates glucose levels in diabetic patients. This appears to be true across a wide range of glucose concentrations. It is probably more accurate to rely on serial serum glucose readings to help manage insulin regimens for ESRD diabetics, and there is also some data on the use of glycosylated albumin in the monitoring of this population. As diabetes is now the most common cause of ESRD in the U.S. and many patients rely on their nephrologist as their primary care doctor, this is an important finding.

Preventing Ototoxicity with Aminoglycoside Therapy

Ototoxicity--which can occur via both auditory and vestibular mechanisms--is one of the major side effects of aminoglycoside use, particularly in dialysis patients. A recent paper looked at N-acetyl cysteine (NAC) as a potential strategy for preventing ototoxicity in dialysis patients.

In this study, HD patients who were being treated for catheter-associated bacteremia were randomly assigned to either 600mg of NAC versus placebo. Of the 40 patients who received gentamicin for > 2 weeks, those who received NAC had a 42% reduction in ototoxicity as assessed by serial audiometric evaluations.

Given the relatively low cost and low side effect profile of NAC, it seems reasonable to use this strategy for preventing aminoglycoside-induced ototoxicity. Of note, NAC has proved to be quite a versatile drug--already being used as a mucolytic agent, a drug which allegedly prevents nephrotoxic injury from iv contrast, and as an invaluable tool for treating Tylenol overdose.

Potter's Syndrome/Sequence

Potter's Syndrome--perhaps more accurately referred to as Potter's Sequence as it refers to the pathophysiologic consequences of lack of kidney function in utero--is characterized by absence of renal function, oligohydramnios, pulmonary hypoplasia, and a characteristic "Potter's facies", in which there is a flattened nose, recessed chin, prominent epicanthal folds, and low-set abnormal ears. In addition to other serious cardiovascular, ophthalmologic, and skeletal malformation, Potter's Syndrome also occurs frequently with sirenomelia (a.k.a. "mermaid syndrome", as pictured in the X-ray above.

Any form of severe renal dysfunction in utero can be the root cause of Potter's Syndrome. More common causes include bilateral renal agenesis, autosomal recessive polycystic kidney disease, and congenital obstruction/hydronephrosis. When the kidneys do not produce urine, there is oligohydramnios (since fetal urine production accounts for the majority of amniotic fluid during the 2nd and 3rd trimesters of pregnancy). Since amniotic fluid is also responsible for proper alveoli expansion, these patients commonly get pulmonary hypoplasia and potentially serious respiratory problems at birth.

The syndrome is named after pathologist Edith Potter, who initially characterized this sequence of events.

DRIVE Study

There are numerous reasons as to why an ESRD patient might be "EPO-resistant", and perhaps the most obvious one to exclude initially is iron deficiency: you can't make more red blood cells if you don't have enough iron (pictures in lump metal form on the left). Generally speaking, iron deficiency is traditionally diagnosed by having a low MCV, a transferrin saturation less than 20%, and a ferritin level <200.>

However, there is some confusion as to what to do with patients who are EPO-resistant despite having apparently "adequate" iron stores based on the values above. Using ferritin as a marker for iron stores has some caveats associated with it, as ferritin is upregulated during inflammation and thus may underestimate the degree of functional iron deficiency in a dialysis patient.

With this mind, the makers of Ferrlicit designed the DRIVE study, in which dialysis patients with a low Hgb (<11.0g/dL), high ferritin (500-1200 mg/dL), and low transferrin saturation (<25%) were randomized to receive (or not) 1 gram of iv iron administered over dialysis sessions. Both this trial as well as the follow-up DRIVE-II study reported that the iron-treated
group developed higher Tf-sat's and a reduced EPO requirement, suggesting that in some patients an elevated ferritin is not a good marker for iron deficiency. Although the authors report no significant safety issues in the iron-treated group compared with the control group, there is still some concern about the use of continuous iv iron in patients with chronic
inflammation.

Sevelamer Carbonate

Renagel (sevelamer hydrochloride) is one of the most utilized phosphate binders in the U.S., though its superiority compared to other (and cheaper) phosphate binders remains controversial. One of the theoretical benefits of using Renagel is that it should not contribute to hypercalcemia, a possible side effect of the common calcium-containing phosphate binders (e.g., calcium acetate, calcium carbonate), which could possibly contribute to the increased vascular calcification seen in ESRD patients.

One of the drawbacks of using sevelamer hydrochloride--particularly in advanced CKD patients who have not yet reached dialysis--is its tendency to cause a metabolic acidosis, based on the hydrochloride moiety which forms the salt. To get around this, the drug company (Genzyme) has manufactured another form of sevelamer, this time conjugated to carbonate. The drug (sevelamer carbonate) is being marketed under the name "Renvela". We'll see how it works.

Know Your K's

The constant "K" pops up in many forms in nephrology, particularly in the realm of dialysis, as each dialysis membrane has its own characteristic K values.  

There is first and foremost the Kt/V equation, the currently accepted standard for determining dialysis adequacy.  K here is the dialyzer blood water urea clearance, and in practice one calculates the Kt/V for dialysis patients by measuring their blood urea concentration both before and after dialysis.

Next we have the K(oa), the dialysis mass transfer area coefficient, which describes the efficiency of a given dialyzer in terms of its ability to remove solute.  The K(oa) may be thought of as the maximum possible clearance by a dialyzer at infinitely large blood and dialysate flow rates.  K(oa) values are traditionally reported in cc/min; standard dialyzer K(oa) values are typically 500-700 cc/min with "high efficiency" dialyzers (not to be confused with "high flux" dialyzers--see below) having K(oa)'s > 700 cc/min.

The K(uf) is the ultrafiltration coefficient, and it describes the ability of a given dialyzer to remove fluid at a given transmembrane pressure gradient per unit time.  Dialyzers with a high K(uf) (e.g., >20 cc/hr/mmHg)  are considered "high flux" dialyzers, and these may be especially helpful in patients with large intradialytic weight gains.  

What's in Nephrocaps?

We prescribe them with abandon to our CKD and ESRD patients...Nephrocaps, Renavit, whatever you want to call it.  How many nephrologists do you think are able to name all the ingredients in this vitamin-containing tablet?

The not-so-secret ingredients:  nephrocaps consist of vitamins B1 (thiamine), B2 (riboflavin), B6, B12, folic acid, niacin, pantothenic acid, biotin, and a small dose of vitamin C.  

You will note that these are all water-soluble vitamins.  The fat-soluble vitamins (A,D,E, & K) are generally not a problem in ESRD patients (with the obvious exception of vitamin D, whose activated form is produced in the kidney) as the body has adequate stores of these and in fact supplementation with vitamin A, for instance, can cause toxicity.  ESRD patients are often deficient in water-soluble vitamins for a number of reasons:  poor oral intake, restricted protein diet, and the fact that many of these are dialyzed off during treatment.  Nephrocaps are designed with these losses in mind.  

Abatacept

A relatively new immunosuppressant agent--originally approved for treatment of refractory rheumatoid arthritis but now gaining steam as an anti-rejection medication for kidney transplant recipients--is abatacept (marketed under the trade name Orencia by Bristol-Myers-Squibb. Its mechanism of action is based on the idea of T-cell costimulation, a pathway which will likely be the target of further immunosuppressive drugs of the future.

Under normal conditions, full T-cell activation requires (a) binding of the T-cell receptor to the antigen-MHC complex on the antigen-presenting cell, and (b) a costimulatory signal--with two of the important molecules responsible for this signal being CD28 (expressed on T-cells) and B7 protein (expressed on antigen-presenting cells). Abatacept is a fusion protein comprised of an IgG fused to the extracellular domain of CTLA-4 (essentially a subtype of CD28, which binds to B7). The addition of this soluble B7 binder outcompetes the endogenous costimulatory interaction, and as a result, T-cell activation is prevented.

What is the "crit-line"?

Not all dialysis units use "the crit-line", and its utility remains somewhat controversial. As an example, in our fellowship program, one of our hospitals (Mass General Hospital) believes in the use of the crit-line, whereas the other (Brigham and Women's Hospital) does not.

What is the "crit-line" and how is it useful? The crit-line is a device built into dialysis machines which monitors absolute hematocrit and oxygen saturation. It works by attachment of a small cuvette to the arterial side of the dialyzer which, via optical measurements, determines the hematocrit concentration. Assuming that the red blood cell mass stays constant during dialysis (e.g., in the absence of blood transfusion), the hematocrit will change only as a result of changing blood volume, a characteristic that may be very useful in determining fluid status. Thus, as fluid is being removed, the hematocrit will increase and vice versa. The readout on the screen is that of percent blood volume change. If the crit-line goes down rapidly (as in the cartoon) you might be concerned that you are being too aggressive with the ultrafiltration rate, and you may need to increase that patient's dry-weight. In contrast, a crit-line which stays relatively constant throughout the dialysis treatment suggests that there is still fluid available for removal, and that patient's dry-weight may need to be lowered.

The benefit in using crit-line monitoring is therefore to avoid intradialytic hypotension and to help determine dry weight. It can also be used to determine access recirculation, and there is recently some suggestion that it may help in more accurate EPO dosing.

Pure Red Cell Aplasia

One of the rare but serious side effects of recombinant erythropoietin therapy is the possibility of pure red cell aplasia, an autoimmune condition in which antibodies against erythropoietin result in T-cell-mediated destruction of erythroid precursors.  It may be recognized by an escalating EPO requirement and need for transfusions despite adequate iron stores.  It has been reported much more frequently in Europe (with a formulation called Eprex, not used in the U.S.) and is thought to be at least partially due to the practice of subcutaneous administration there rather than in the U.S. where intravenous EPO therapy, for reasons of reimbursement, is the rule.  The diagnosis of pure red cell aplasia requires a bone marrow biopsy which demonstrates a lack of erythroid precursors with a preservation of megakaryocyte and myeloblast lineages; in a recent case at our hospital one of the major manufacturers of EPO products was contacted and performed an assay looking for EPO-specific antibodies.  Being a rare condition, there is limited data on how best to treat acquired pure red cell aplasia, but standard practice currently consists of withdrawing EPO and giving a course of immunosuppressive therapy with Cytoxan and prednisone.

  

There are other causes of pure red cell aplasia:  a genetic condition (Diamond-Blackfan Syndrome) as well as other forms of acquired disease, which include leukemia/lymphoma, viral infection (e.g., hepatitis C, HIV, parvovirus B19), or drugs.  It may also be a prodrome to a full-blown myelodysplastic syndrome.  

Pre-Eclampsia & HELLP!

The pre-eclampsia story (which I have mentioned previously on this blog) is one of the triumphs of basic nephrology research over the past few years, and apparently the folks at the ASN thought so as well, as Dr. S. Ananth Karumanchi received the Young Investigator Award this year.  He gave a very nice overview of this story at his talk.  To summarize:  most women with pre-eclampsia have high levels of sFlt-1, a VEGF receptor antagonist elaborated by the placenta.  When transferred to pregnant rats, purified sFlt-1 recapitulates the thrombotic microangiopathy phenotype, proving that sFlt-1 is not only correlative but also causative.  Intriguingly, Dr. Karumanchi presented data showing that routine blood samples from pregnant women several weeks PRIOR to their diagnosis of pre-eclampsia showed elevated sFlt-1 levels.  This suggests that an assay for sFlt-1 could well be used for early identification of women who will go on to develop pre-eclampsia.  

One missing piece to the puzzle, however, was that sFlt-1 injection in rats did not seem to produce any liver pathology.  How does one explain the existence of the related HELLP Syndrome (HELLP = hemolysis, elevated liver enzymes, and low platelets) with this supposedly unifying theory for pre-eclampsia?  It turns out that another circulating protein produced by the placenta--soluble endoglin--may be responsible for this.  Circulating endoglin levels are higher in individuals withi HELLP, and co-njection of both sFlt-1 + soluble endoglin into animals leads to both endothelial and liver damage.  

Rheos Implantable Blood Pressure Device

The private company CVRx has developed an interesting method under investigation for blood pressure control in highly refractory hypertensive patients.  The approach consists of a surgical implant of electrodes at the carotid sinus; stimulation at the sinus results in a baroreceptor reflex which is predicted to decrease blood pressure.  While not yet commercially available, a feasibility trial in which 10 patients with refractory hypertension were implanted with such a device showed an average reduction in systolic blood pressure of 41 mmHg with no significant hypotension or major safety issues.  

The suggestion of surgery to correct high blood pressure is certain to be controversial, but in the future this might be a viable option in selected patients in whom medications are unable to control blood pressure.

Did Mozart Die of Kidney Disease?

What's a picture of Mozart doing on the Renal Fellow Network?

Fellow renal fellow Lisa Cohen gave a presentation on nephrotic syndrome at our Renal Grand Rounds and discussed evidence that Mozart, who died at the young age of 35, also had nephrotic syndrome. Consistent amongst the impressive literature trying to determine the cause of the young composer's death are reports of his having massive anasarca at the time of his death. While there are certainly multiple etiologies of anasarca, the fact that he was allegedly able to sing lines from his famous "Requiem" on his deathbed suggests that he was neither encephalopathic nor dyspneic, favoring a renal cause of anasarca rather than a hepatic or cardiac one.

Theories of what caused his fatal illness are broad: suggested possibilities include post-streptococcal glomerulonephritis (he apparently had a serious febrile illness as a child), a congenital urinary tract malformation (he had a history of recurrent UTIs and also had an ear malformation--sometimes associated with congenital renal anomalies), Henoch-Schonlein purpura (he had a concurrent rash during his fatal illness), renal tuberculosis (T.B. was a major cause of disease in this era, both pulmonary and otherwise), heavy metal poisoning (there are rumors that his competitor Salieri once admitted to poisoning Mozart out of jealousy), and other primary nephrotic syndromes. Obviously this differential diagnosis is broad and we are unlikely to answer this question definitively, but it is tempting to speculate not only on the nature of his disease, but also on the further musical works he might have written had he been born in the modern era of kidney-aiding medications and renal replacement therapies.

This post is complementary to a previous posting on this blog regarding famous individuals with nephrotic syndrome.

Humanized Mouse Model for Minimal Change Disease

Identifying the "permeability factor" for patients with FSGS or minimal change disease has been one of the "holy grails" of nephrology, and our inability to identify such a factor has not been for any lack of trying.  One of the obstacles in studying this disease is the lack of good animal models to study it.

A French group published a 2007 JASN article describing a mouse model of immune-mediated nephrotic syndrome which perhaps gives us some mechanistic insight into the cause of the disease.  In this paper, researchers took CD34+ T-cells from humans with steroid-resistant nephrotic syndrome.  They then injected these T-cells either (a) intraperitoneally, or (b) intraosseously--that is, directly into the bone marrow.  In the case of intraperitoneal injections, the existence of circulating "humanized" T-cells could be demonstrated, but they eventually went away over time as the engraftment was not permanent.  These mice did not get proteinuria.  In the case of intraosseous injections, these T-cells could be demonstrated to engraft permanently, albeit at a low frequency.  Interestingly, these mice developed significant albuminuria and foot process effacement, suggesting that this could be used as a mouse model of disease.  

What is particularly interesting about this experiment is the idea that the "permeability factor" is transferable only with T-cell precursors--and not with peripheral T-cells.  So perhaps the permeability factor comes from the bone marrow, rather than activated T-cell responses...