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...