Mnemonic for NON-Anion Gap Metabolic Acidosis

As I've mentioned previously on this blog, the "MUDPALES" mnemonic for anion gap metabolic acidosis is one of the most successful medical mnemonic's of all time.

A less successful (and admittedly less useful) mnemonic exists for non-anion gap metabolic acidoses (NAGMA), which I learned as a resident. It's "HARDUP", which stands for the following:

H = hyperalimentation (e.g., starting TPN).
A = acetazolamide use.
R = renal tubular acidosis (Type I = distal; Type II = proximal; Type IV = hyporeninemic hypoaldosteronism.
D = diarrhea
U = uretosigmoid fistula (because the colon will waste bicarbonate).
P = pancreatic fistula (because of alkali loss--the pancreas secretes a bicarbonate-rich fluid).

Practically speaking however, the two main causes you really have to remember for NAGMA are DIARRHEA or RENAL TUBULAR ACIDOSIS, which 90% of the time you can distinguish between based on the history alone. Another way to think about the differential diagnosis of NAGMA is to ask whether or not there is GI LOSS or RENAL LOSS of bicarbonate. If the history does not provide an obvious explanation, one can distinguish between GI versus renal bicarbonate losses by determining the urine anion gap (urine AG = urine Na + urine K - urine Cl), where a positive value indicates renal bicarbonate loss whereas a largely negative value indicates extra-renal bicarbonate loss.

Churg-Strauss Syndrome

There is a patient now on the renal consult service with Churg-Strauss Syndrome. This disease falls under the category of "small vessel vasculitis" and most commonly is thought of as a pulmonary disease, as the characteristic triad consists of allergic rhinitis, asthma, and peripheral eosinophilia. However it may involve any organ system, including the kidney, where it can cause a nephritic urine sediment and kidney biopsy generally reveals a pauci-immune glomerulonephritis. The ANCA titer is usually positive and is typically a p-ANCA (perinuclear) pattern against myeloperoxidase.

This particular patient had a number of features consistent with Churg-Strauss: a long-standing history of steroid-requiring asthma, peripheral eosinophilia, a skin rash (with a biopsy showing extensive eosinophilic infiltrate), mononeuritis multiplex, and acute kidney injury requiring dialysis with a renal biopsy demonstrating a necrotizing vasculitis. She is being treated with pulse steroids and oral Cytoxan.

Acute Phosphate Nephropathy

It has long been known that acute phosphate toxicity--as might be seen in rhabdomyolysis or tumor lysis syndrome--can lead to acute kidney injury as a result of calcium-phosphate deposition in the renal parenchyma and tubules. Interestingly, this problem appears to be increasing as a cause of AKI given the increased use of phosphate-containing bowel preparations (such as Fleet's enema) for screening colonoscopies.

Recent epidemiologic evidence from Khurana et al (Arch Int Medicine, 2008, Vol. 168) supports the idea that phosphate-based bowel cleansing regimens may result in worsening renal function. In a retrospective analysis looking at patients with normal creatinine levels at baseline who underwent colonoscopy with oral sodium phosphate solutions, they found that the GFR went slightly down compared to an age-matched control population. Prior to this, most data in support of phosphate-induced renal damage from colonoscopy preparations suggested that the only individuals at risk were those with pre-existing chronic kidney disease.

It will be interesting to see whether or not this will change clinical practice within the field of gastroenterology; for nephrologists it highlights the importance of asking patients about recent colonoscopies as part of the history-taking in patients experiencing acute kidney injury.

PS: 2 landmarks for the "Renal Fellow Network" today: (1) this is post #100, and (2) we are now the #1 "google hit" when the term "renal fellow" is searched...

History of Dialysis

When discussing the history of dialysis, any renal fellow worth his weight in urine will know that the inventor of the first practical dialysis machine (the "rotating drum" machine shown at left, which consisted of 30-40 meters of cellophane tubing within a stationary 100-liter tank), was Dutchman Willem Kolff, in 1943.

Less well known is who came up with the term "dialysis" in the first place. It was Thomas Graham (right), a Professor of Chemistry in Glasgow, Scotland, who ascertained that crystalloids were able to diffuse through vegetable parchment coated with albumin, which acted as a semi-permeable membrane. He coined the term "dialysis" to describe this phenomenon in 1861, and using this method was able to extract urea from urine.

A very interesting website describing some of the milestones in nephrology history can be found here.

Lithium as a dialyzable toxin

Lithium is one of the classic dialyzable toxins, as it is very small (atomic # of 3) and elevated Li levels (>2.5 meq/L) may result in tremor, ataxia, vomiting, seizures, or even coma.

However it is somewhat unique amongst toxins in that chronic users tend to have a greater susceptibility to Li toxicity than an individual taking an acute Li overdose for the first time. This is based on the fact that Li has a very high volume of distribution (VOD), and it takes a large exposure (usually over a prolonged period of time) in order to saturate these stores.

Also, as a result of its large VOD, dialysis in instances of Li toxicity may require prolonged periods of time and/or multiple sequential days of dialysis due to a significant "rebound effect."

High Flux versus Hemofiltration

There has been a lot of attention these days regarding increasing "middle molecule clearance", a topic already covered previously here. Certainly it is well-established that buildup of beta-2-microglobulin can lead to a dialysis-derived form of amyloidosis, and it is further speculated that clearance of other "evil humours" of larger molecular weight might have a benefit as well. There are a couple different ways to achieve improved middle molecule clearance: HIGH FLUX DIALYSIS and HEMOFILTRATION. What's the difference between the two?

High flux dialysis refers to using a type of dialysis membrane (these days in the form of many thousand microfibers) which has a larger pore size than older, "low-flux" dialyzers. The mechanism of solute removal still relies no diffusion, however, rather than convection. Although most dialysis centers have transitioned to using "high-flux" dialyzers due to a belief that they are inherently more efficient than their low-flux counterparts, the largest randomized controlled trial looking at high-flux versus low-flux dialyzers (the HEMO Study) failed to show a clinically meaningful benefit of high-flux dialyzers.

Hemofiltration can also result in improved middle molecular clearance; for the same time, blood flow rate, and pore size, hemofiltration improves middle molecule clearance when compared to hemodialysis. The driving force for solute clearance in hemofiltration is hydraulic pressure and the convective clearance which results. Furthermore, some view hemofiltration as being more "natural" than hemodialysis in the sense that the glomerulus works primarily by generation of a pressure gradient.

A recent study (Santoro et al, AJKD 2008) which randomized ESRD patients to either hemofiltration or hemodialysis showed a survival benefit for hemofiltration. However it is notable that the sample size was small, and that the hemodialysis in this study was using low-flux dialyzers. In my opinion, if the authors are trying to prove the superiority of hemofiltration to hemodialysis, they should include high-flux dialyzers in the dialysis arm, as that appears to be becoming standard-of-care.

Hepatorenal Syndrome: Treatment Options

Hepatorenal syndrome (HRS) is thought to be caused by splanchnic vasodilatation with relative renal vasoconstriction. The reversible nature of HRS is highlighted by the observation that patients with HRS who undergo liver transplant usually see a complete reversal of renal failure.
For those who are unable or waiting to receive a liver transplant, however, what are the available treatments for HRS?

The "standard-of-care" at hospitals at which I have worked has become a cocktail of midodrine, octreotide, and albumin; I find this somewhat interesting as there is no randomized controlled trial which supports its use. The most quoted paper (Angeli et al; Hepatology 1999) compared 5 patients who received the midodrine/octreotide cocktail with 8 patients who received dopamine; patients in the midodrine/octreotide group saw a higher rate of improved renal function in a condition which had previously been seen as irreversible by some. With the lack of any competing therapies, this has appeared to become the standard. We use midodrine 5mg po tid which can be titrated up to 15mg po tid and octreotide 100mcg sc tid which can be titrated up to 200mcg sc tid.

Other treatment possibilities include albumin alone (e.g., 25gm tid), other vasodilators (e.g., terlipressin which is apparently used more commonly in Europe), and the TIPS procedure.

Hepatorenal Syndrome: Definitions

Hepatorenal syndrome is a very common consult topic for the 1st year renal fellow. All MDs trained in internal medicine realize that cirrhotic patients are amongst the sickest in the hospital, and one of the reasons for this is the tendency for renal and liver disease to go hand in hand.

First off, however, it is important to be skeptical when somebody tells you that a liver patient's renal failure is due to HRS. HRS is actually the 3rd most common cause of acute renal failure in patients with liver disease, with the first 2 common being pre-renal failure (often 2/2 overdiuresis) and ATN. The diagnostic criteria, as defined by the International Ascites Club, are shown below:

.

1. cirrhosis with ascites

2. serum creatinine >1.5mg/dL

3. no improvement in serum creatinine (decrease to a level <1.5mg/dl)>

4. no current or recent exposure to nephrotoxic drugs (e.g., NSAIDs, iv contrast)

5. absence of parenchymal kidney disease as indicated by proteinuria >500mg/day, >50 RBC/hpf on urinalysis, and/or abnormal renal ultrasonography.

.

In my own experience, hypotension is something that goes hand-in-hand with HRS; if a patient is hypertensive, one should probably entertain diagnoses other than HRS as the cause of AKI. The urine sodium is almost always low unless the patient has recently been on diuretics. Also, hypervolemic hyponatremia is another finding which is commonly linked to HRS. Also, the presence of sepsis or SBP do not exclude the diagnosis of HRS; it is quite common in fact for these to be precipitants, although you need to look at the urine to exclude muddy brown casts/ATN (the urine sediment in HRS is typically bland).

AKI criteria

The study of acute kidney injury has been hampered by a lack of a standard definition.

Some of this is semantics--for instance, the decision to change "acute renal failure" to "acute kidney injury" does nothing to help in our treatment of this high mortality condition, except perhaps for reminding ourselves and the patients that this is hopefully not a reversible process (e.g., that the kidneys have not completely "failed" in many instances).

However, the development of a set of reproducible criteria is essential for research studies which seek to identify potentially new treatments for AKI and to be able to reliably compare results between studies. To this end, two major groups have come up with competing criteria. One is the RIFLE criteria and the other is the AKIN criteria; it remains to be seen which set of criteria (which differ slightly) will be universally adopted.

The RIFLE criteria was put forward by the Acute Dialysis Quality Initiative (ADQI) in 2005. It breaks up patients according to 5 categories (see figure above) using the handy acronym "RIFLE", where R= risk, I = injury, F = failure, L = loss and E = ESRD. There are criteria given based on %GFR loss, how much Cr is elevated above baseline, and urine output, not all of which must be fulfilled in order to classify any given patient.

The AKIN "Acute Kidney Injury Network" criteria were published in 2007 after a meeting in the Netherlands comprised of multiple experts on AKI. They have only three stages of AKI (Stages I-III) which generally correspond to RIFLE stages R, I, and F. The AKIN group claims an advantage over the RIFLE criteria in that it has a lower threshold for definining an individual as Stage I AKI (only 0.3 mg/dL increase OR a 1.5X increase over baseline is required to meet this definition in AKIN; in RIFLE one requires a 1.5X increase over baseline. Both definitions can also be met by urine output criteria as well.) This would seem to be a good idea given epidemiologic studies which show that even small increases in serum creatinine are associated with an increased mortality rate.

Which system will prevail? Only time will tell...

Renal manifestations of rheumatoid arthritis

Renal disease is not uncommon in patients with rheumatoid arthritis, and the differential diagnosis is quite interesting. Here is a list of the major causes, some of which are caused by the RA itself and others of which are caused by the common medications used to treat RA:

-Amyloidosis- of the AA variety, due to a persistently active pro-inflammatory state.

1. -Membranous Nephropathy- a secondary nephrotic syndrome may occur due to RA, or due to treatment with the RA drugs gold and penicillamine.

-Analgesic nephropathy- this can be seen due to the high, chronic doses of salicylates and/or NSAIDs used for the chronic joint pain that is a hallmark of RA.

-Focal mesangial proliferative glomerulonephritis- which may be recognized based on a nephritic urine sediment.

-Rheumatoid vasculitis- this is a rare complication of RA which may affect the small- and medium-sized arteries. It is somewhat similar in its manifestations to polyarteritis nodosa (PAN) and occasionally (though not always) involves the kidneys.

I saw a patient in clinic today with a long-standing history of JRA who a few months back developed RPGN...a renal biopsy had shown a combination between an immune complex GN, endothelial injury likely 2/2 malignant hypertension, and podocyte foot process effacement which was causing nephrotic syndrome...illustrating the fact that patients with RA may be susceptible to other forms of autoimmune disease and may have complex, overlapping diagnoses which are not straightforward.

The Latest on FGF23

There has been a lot of buzz surrounding the recent NEJM article by Gutiérrez (a recently graduated fellow from my program!) et al regarding the potential role of measuring FGF23 levels as an important biomarker in patients with ESRD.

FGF23, as detailed elsewhere in this blog, is felt to be the main phosphaturic hormone which regulates in vivo phosphorus balance. In a nest case-control sample consisting of 200 dialysis patients who died within the first year of initating dialysis and 200 dialysis patients who survived their first year of dialysis, it was determined that FGF23 levels were markedly elevated in the group who died within one year.

Obviously, this remains an association and does not imply causality. Indeed, one might postulate that the higher FGF23 group was sicker because they waited until uremic to begin dialysis. However, FGF23 remained associated with a higher mortality even when adjusted for phosphorus level, and the authors suggest that FGF23 may be a biomarker to determine which patients with CKD may be at risk for a high cardiovascular mortality and might benefit from early treatment with phosphorus binders.

Anti-hypertensive Medications in Pregnancy

Managing hypertension in pregnancy is difficult in the sense that there is not a lot of data to guide us. Most of the drugs listed as "safe during pregnancy" are considered so largely based on many years of experience.

With that said, here are a list of medications which can be used, and those which should be avoided:

1st line agents: labetalol, hydralazine, alpha-methyl dopa, and calcium-channel blockers.

some possible side effects : beta-blockers (which are associated with low birth weight) and diuretics.

definitely contraindicated: ACE-inhibitors; ARBs. The classical teaching was that ACE-inhibitors were tolerable during the 1st trimester but needed to be avoided after that; more recent suggests that even 1st trimester ACE-I use is associated with an increased risk of fetal malformations.

What is hepcidin?

What is hepcidin and why is it important to nephrologists?

Hepcidin is a 25-amino acid peptide (see left) secreted by the liver which seems to be the "master regulator" of iron metabolism. It works by binding to the iron channel ferroportin, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells, and degrading ferroportin, thereby shutting off iron transport out of these cells.

In ESRD, hepcidin levels are elevated--probably in part because hepcidin is cleared by the kidneys, and perhaps also because of increased hepcidin expression in the presence of certain inflammatory cytokines. As a result, iron uptake from the gut is diminished (iron can get into the enterocyte via an apical Fe transporter, but can't get out the basolateral surface because it needs ferroportin), and iron is trapped inside of reticuloendothelial cells. This latter phenomenon, "an inability to mobilize iron stores", has long been known to play an important role in the anemia of chronic disease.

One might imagine that hepcidin inhibitors might be a successful pharmacologic intervention for CKD or ESRD patients with anemia.

NSAIDs & the Kidney

NSAIDs are a tricky class of drugs. As an internal medicine resident, I used to prescribe ibuprofen 800mg po tid willy-nilly for my clinic patients with back pain, since I generally had good results using this strategy, and I myself have used it off and on for a variety of athletic-related aches & pains. After a year's worth of Nephrology consults, however, I am much more careful. Nephrologists tend to blame NSAIDs frequently--perhaps too often--but there are a variety of ways in which these medications can lead to acute kidney injury. There are three main mechanisms by which NSAID-induced kidney injury may occur, moving from most to least common in the list below:

1. NSAID-induced hemodynamic injury: Recall that NSAIDs are inhibitors of prostaglandin synthesis. In healthy individuals, prostaglandins do not play a major role in the regulation of renal blood flow; however, in those with underlying renal disease or effective volume depletion (e.g., cirrhosis, CHF) PGI2 and PGE2 preferentially dilate the afferent arteriole thereby augmenting GFR. The addition of NSAID may catastrophically diminish renal blood flow to this group of patients resulting in renal failure.

2. NSAID-induced acute interstitial nephritis (AIN): These patients present with the classic findings of AIN: sterile pyuria, WBC casts, and eosinophils in the urine or blood. Typically NSAID withdrawal is all that is necessary though there remain some who still advocate a short course of steroids.

3. NSAID-induced nephrotic syndrome: this may take the form of either minimal change disease, or membranous nephropathy. The mechanisms by which NSAIDs may cause minimal change disease are presently unknown.

Renal Side Effects of HIV Medications

The treatment of HIV infection has been radically changed with the development of HAART--highly active antiretroviral therapy. Fortunately for nephrologists, these medications are relatively safe from a renal standpoint.

There are two notable exceptions to be aware of.

The most relevant is the medication tenofovir, a NRTI which has been reported to cause renal failure which can lead to dialysis-dependence. The mechanism is unclear but there is some degree of tubular toxicity e.g. ATN. Other tubular pathologies have been reported with this medication including Fanconi's syndrome and nephrogenic diabetes insipidus. The trade name of tenofovir is Viread, and is tenofovir is sometimes given as part of a "combined" pill (Truvada or Atripla) containing tenofovir and 1-2 other antivirals as part of a cocktail.

The other relevant HAART drug nephrologists should be aware of is indinavir (Crixivan), a protease inhibitors. It has been shown to precipitate and result in nephrolithiasis in some patients, and therefore these individuals are instructed to increase their water intake.

Urine eosinophils

Eosinophils in the urine can be detected by applying a Hansel's stain to the urine sediment. The presence of >1% eosinophils of the total urine WBCs constitute a positive test. In general, the same things which cause +urine eosinophils may also show elevated serum eosinophils, and in my limited experience it is the presence of SERUM eosinophilia which is more convincing that urine eosinophils.

While most often sent to help weigh in on whether a patient with acute kidney injury has acute interstitial nephritis, the differential for positive urine eosinophils is fairly broad. In addition to AIN, they may also be seen in atheroembolic disease, parasitic infection, pyelonephritis, or Schistosoma hematobium infection.

The Cryocrit

Whenever you recommend that "cryoglobulins" be drawn on a patient, it is important to realize that the specimen must be collected in a very specific way. It cannot be simply "added on" to a specimen already drawn.

Cryoglobulins are named as such because they are antibodies which precipitate in the cold. In order to test for circulating cryos, a blood specimen must be drawn and immediately placed at 37 degrees. Once the blood has clotted (the test cannot be performed for patients on heparin), the sample is then centrifuged at 37 degrees, and the serum is placed at 4 degrees. Every day, the sample is checked for for turbidity; once cloudy the sample is centrifuged to give a quantitative value to the "cryocrit." Some cryoglobulins take up to 5 days to precipitate.

The "poor man's cryoglobulin" test--and faster in terms of turnaround time--is a rheumatoid factor with complement levels (C3 and C4 are both typically low in cryoglobulinemia).

Unusual Causes of Anion Gap Metabolic Acidosis

The "MUDPALES" acronym, which details the main causes for anion gap metabolic acidosis (Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Alcohol, Lactic acidosis, Ethylene glycol, Salicylate toxicity), is one of the most successful medical acronyms of all time.

There are a few other causes of anion gap metabolic acidosis which are less common but still worthy of note:

Propylene glycol is the vehicle in which iv Ativan is given; patients who are given massive amounts of iv Ativan (e.g., during treatment of delirium tremens for instance) may experience an anion gap metabolic acidosis.

-D-lactic acidosis may occur with intestinal overgrowth syndromes, as bacteria may produce D-lactic acid (as opposed to endogenous L-latic acid production), which is not able to be metabolized by the liver.

-certain drugs may cause lactic acidosis, such as nucleotide reverse transcriptase inhibitors (NRTIs) used in the treatment of HIV which may cause mitochondrial toxicity; metformin, linezolid, and isoniazid may also cause lactic acidosis.

-5-oxoproline accumulation, a rare but perhaps underdiagnosed condition in which accumulation of the organic acid 5-oxo-proline, a byproduct of the gamma-glutamyl acid cycle which is responsible for the replenishment of the antioxidant glutathion, occurs. This may be either genetic (caused by mutations in 5-oxo-prolinase or glutathione synthetase) or acquired (due to Tylenol ingestion, classically in elderly malnourished women).

NSIAD (not NSAID)

A subset of pediatric patients with a clinical and biochemical profile consistent with SIADH (the syndrome of inappropriate ADH secretion)--that is, euvolemic hyponatremia with an inappropriately elevated urine osmolarity--have low to undetectable levels of ADH. What's going on?

It turns out that activating mutations in the V2 vasopressin receptor can account for this phenotype. This condition has been termed "NSIAD" for nephrogenic syndrome of inappropriate antidiuresis", which is not to be confused with our long-standing enemies, the "NSAIDs" (non-steroidal anti-inflammatory drugs, which are themselves a cause of SIADH). In NSIAD, pituitary ADH secretion is appropriately low, but there is high aquaporin activity at the renal collecting ducts based on constitutive V2 receptor activity. Not surprisingly, these patients are resistant to treatment with the new V2 receptor antagonists, the so-called "vaptans" (conivaptan and tolvaptan).

Interestingly the gene is on the X chromosome, which might predict that the disorder should be inherited in an X-linked fashion (e.g, boys only). Due to the gain-of-function nature of this mutation, however, the disease can affect both girls and boys.

Loss-of-function mutations in the same gene logically result in nephrogenic diabetes insipidus.

NODAT

The acronym NODAT stands for "new onset diabetes after transplant". Diabetes is one of the many complications which occur in the post-renal transplant setting. The reasons for this are manifold. Transplant recipients who require long-term steroids will obviously have an increased susceptibility to diabetes and metabolic syndrome. In addition, cyclosporine inhibitors--tacrolimus moreso than cyclosporine--appear to have some direct beta-cell toxicity, as well as predisposing to hypertension and hyperlipidemia which often go hand-in-hand with the diabetic phenotype. Finally, improved renal function leads to increased insulin clearance by the kidney, and previously diabetic individuals who were previously insulin-independent may require exogenous supplementation in order to meet their insulin needs.

Collapsing Variant of FSGS

The collapsing form of FSGS is a histologic variant which is characterized by mesangial hypercellularity and resultant collapse of the glomerular capillaries, as illustrated in the photo to the left. Its identification is important for prognostic reasons as it is known to progress much more rapidly than garden-variety FSGS (average time to progression to ESRD 13 months from diagnosis as compared to only 65 months). Not surprisingly these patients often have profound proteinuria.

The differential diagnosis of collapsing glomerulopathy is limited, but should include HIV ("HIV Nephropathy"), parvovirus B19 infection, hepatitis C infection, therapy with the bisphophonate pamidronate, lymphoproliferative disease, and certain autoimmune disease (e.g., lupus, Still's disease, etc). The Collapsing FSGS also occur in an idiopathic form, which is interestingly much, much more common in blacks than in whites.

Rituxan Dosing

Rituxan is seeing a lot of use these days. Although technically only having formal indications for rheumatoid arthritis and non-Hodgkin's lymphoma, it is being used for a number of off-label indications, and in general the results seem to be overall encouraging. In terms of renal disease, Rituxan is being used for the treatment of membranous nephropathy, lupus nephritis, ANCA-associated vasculitis, and antibody-mediated rejection of kidney transplants, among other things.

There are two major Rituxan dosing regimens in use. One common regimen is to give 375mg/m2 iv every week for 4 weeks.

It's often more convenient to give another regimen, which is 1000mg iv x 1 then another 1000mg 2 weeks later.

The duration of giving further "maintenance" Rituxan is not well worked out--overall the medication is still relatively new--but one common way to do it is to give 1000mg iv every 4 months.

Since the antibody is against the CD20 molecule on B-cells, you can perform a CD20 blood count to see whether the drug is having an effect--in general it is quite efficacious.

Beta-2 Microglobulin Amyloidosis

The two major forms of amyloidosis are AL amyloidosis (in which light chains form the amyloid deposits) and AA amyloidosis (in which a variety of inflammatory molecules may adopt a beta-pleated structure to deposit as amyloid.

A specific subset of AA amyloidosis which is secondary to dialysis is beta-2 microglobulin amyloidosis. Beta-2 microglobulin (B2M) is an 11.8 kD protein which is a subunit of the MHC Class I molecule and is normally filtered and catabolized by the kidney. In the absence of renal function, large serum concentrations of B2M may build up and deposit, specifically synovial membranes, tendones, and bone. This leads to a stereotypic syndrome of carpal tunnel syndrome, flexor tenosynovitis, and other musculoskeletal manifestations which may be quite debilitating.

The GOOD NEWS is that this disease is not seen nearly as much as previously. It is hypothesized that the use of high flux dialyzers--which have a larger pore size than previously favored dialyzers and therefore would allow for the clearance of middle molecules such as as B2M--has made B2M amyloidosis a thing of the past.

Nephrotic Syndrome Trivia Question

Nephrotic Syndrome Trivia Question: Name two different athletes, both with nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS).

Answer: Most people are aware of Alonzo Mourning, the NBA center who was diagnosed with FSGS which forced his temporary retirement and then amazing comeback after having received a kidney transplant. He actually won a championship while playing with the Miami Heat as Shaquille O'Neil's backup at center, and looked in great shape while doing it. The other NBA player is now-retired Sean Elliott, famous for hitting some clutch shots with the San Antonio Spurs, also diagnosed with FSGS and also has received a kidney transplant.

Primary FSGS--not secondary FSGS--is a disease which is notorious for recurrence in the allograft which may lead to premature graft loss. I am not aware as to whether 'Zo or Sean had primary or secondary FSGS, or whether or not they have had any issues with recurrent proteinuria, but the fact that both ex-basketball stars still have their kidney transplants bodes well.

Another famous individual who is thought to have been afflicted with nephrotic syndrome is 2-time Nobel Prize Winner Linus Pauling, though this was never biopsy-proven and he fortunately experienced a remission, which he attributed in part to following a scrict low-protein diet.

Gleevec for Nephrogenic Systemic Fibrosis?

Nephrogenic Systemic Fibrosis (NSF) has recently been linked to the gadolinium-based contrast used for MRI imaging in patients with advanced stage (e.g., Stages 4-5) CKD and ESRD. This appears to be most true for the agent gadodiamide (Omniscan) but there are some suggestions that all gadolinium-based agents carry some unacceptably high risk in this patient population.

There is certainly no consensus yet as to how to treat NSF, but things which have been tried and may work in a subset of patients are prednisone, thalidomide, and photopheresis. In addition, a group headed by Rheumatologist Jonathan Kay at Massachusetts General Hospital is initiating a clinical trial using imatinib mesylate (Gleevec) to treat NSF based on some positive responses in a few patients. Gleevec was initially designed to inhibit the tyrosine kinase activity of the bcr-abl gene fusion product which is constitutively active in most forms of chronic myelogenous leukemia (CML). Apparently Gleevec does have some activity against endogenous tyrosine kinases which is postulated to lead to decreased secretion of critical basement membrane components thought to be involved in the fibrotic reaction which occurs in NSF.

Urinoma

Time for some "Renal Radiology Rounds."

The case involves a 77 year-old man with a history of severe benign prostatic hypertrophy. He had been advised to have a TURP in the past but had repeatedly declined. He was hospitalized for nausea, vomiting and R flank pain without hematuria occurring over a week's time, and it was noted that his creatinine had elevated from its baseline of 1.3 to 7. A CT scan on arrival showed the following:


Uploaded on authorSTREAM by nathanhellman

This patient had developed a R-sided urinoma, which is simply a collection of urine which results from rupture of the collecting system due to high pressures from obstruction. It is more typically seen in renal transplant patients post-operatively at the site of the surgical anastamosis between the recipient and donor collecting systems; non-surgical cases of urinomas such as this one are more rare. The patient had a decompressive Foley catheter placed and an IR drain placed to remove the fluid collection. The fluid's creatinine level was higher than serum level, indicating urine as the source. He experienced a post-obstructive diuresis with a lowering of his creatinine following these interventions.

The Hemodialysis Prescription

This is probably fairly basic to many renal fellows already, but the Hemodialysis Prescription is an integral part of any nephrologist's routine.

The hemodialysis prescription should specify the following:

1. The dialyzer being used. These days, most dialysis units are using high-flux dialyzers in order to improve middle-molecular clearance.

2. The time on dialysis. This generally ranges anywhere between 2.5 to 4.5 hours, though there are patients who will require more or less dialysis than this. Increasing the time on dialysis is probably the single-most important change that can be made in order to increase the efficiency of dialysis.

3. The potassium bath concentration. I was taught the "Rule of 7's": the patient's K plus the dialysate bath K should equal approximately 7. For example, if somebody presents with a K of 5.2, put them on a 2 K bath; if they present with a K of 3.3, put them on a 4 K bath. The lowest K bath I've ever used is a 1 K bath and I don't think there's any reason to use anything higher than a 4K bath.

4. The calcium bath concentration. More recently the trend has been to use a Ca bath which is slightly lower than physiologic concentrations--2.5 mEq/l--in order to minimize the risk of vascular calcification which is thought to accelerate cardiovascular disease. Patients with hypercalcemia may be placed on a Ca bath of 2, and patients who are immediately status-post parathyroidectomy should be placed on a Ca bath of 3 or 3.5 to avoid symptomatic hypocalcemia from "hungry bone syndrome."

5. The Blood Flow (Qb). We often write for a blood flow rate of "best" which is ideally between 400-450 cc/min, though ultimately it's the dialysis nurse who will determine the optimal rate of flow, as not all fistulas or catheters are able to sustain such high flows. The higher the flows, the better the clearance. Patients just starting out on dialysis should be run with a lower Qb (e.g., 250 cc/min) which is gradually increased over the course of the first 3 sessions.

6. The Dialysate Flow (Qd). The rate of dialysate flow can be easily varied but plays a relatively minimal role in the determination of clearance efficiency. We typically use a Qd of 500 cc/min when somebody is initiating on dialysis and a Qd of 800 cc/min for an established dialysis patient.

7. Address Anemia. This should include whether the patient meets requirements for Epogen or iv iron therapy.

8. Address Bone Metabolism. This should include addressing the patient's calcium, phosphorus and PTH levels; whether they are on the appropriate dose of phosphate binders, and whether they need any pharmacologic titration of their PTH level in the form of calcitriol, vitamin D analogues, or cinacalcet.

9. Any additional medications which need to be given at dialysis (e.g., antibiotics) should also be addressed.

10. Any dialysis-related complications (e.g., intradialytic hypotension, cramping, etc) should also be addressed.

Cystinosis versus Cystinuria

Don't confuse "cystinosis" with "cystinuria": they are different diseases, both genetic and both involving the amino acid cystine--but with decidedly different pathogeneses.

Hereditary cystinosis is an autosomal recessive disorder caused by mutations in the CTNS gene, which encodes a lysosomal transporter of the amino acid cystine. Without this transporter, cystine accumulates in the lysosomes of proximal tubule cells, eventually leading to cell toxicity. Patients (which typically present in infancy) may have Fanconi's Syndrome and progressive deterioration of renal disease which usually leads to ESRD. Other identifying clinical characteristics of cystinosis include corneal depositis, hypothyroidism, growth retardation, and hypophosphatemic rickets.

Hereditary cystinuria, on the other hand, is an autosomal recessive condition in which there is a mutation in a dibasic amino acid transporter which is expressed at the apical surface of the tubular lumen. There are two genes, SLC3A1 and SLC7A9, which have been identified thus far. Without the ability to reabsorb basic amino acids, the urine becomes quickly supersaturated with cystine which may precipitate out as pathognomonic hexagonally-shaped crystals (see picture). The main clinical consequence of this phenomenon is an increased susceptibility to stone formation and its resultant complication (e.g., obstruction, pain). Other dibasic amino acids--namely, lysine, arginine, and ornithine--are also found in high concentrations in the urine, but unlike cystine they are freely soluble and do not cause problems.

sFlt-1 & Pre-eclampsia

One of the most exciting new advances in the field of pre-eclampsia has been the relatively recent discovery of the role of sFlt-1 in pre-eclampsia.

sFlt-1 (which stands for "soluble Fms-like tyrosine kinase) is a circulating protein which is able to bind to and inhibit vascular endothelial growth factor (VEGF). It was initially noted that there is an increased level of sFlt-1 in the blood of pregnant women with pre-eclampsia which rapidly goes away following delivery. Furthermore, injection of sFlt-1 into pregnant rats results in hypertension, proteinuria, and endothelial dysfunction causing a thrombotic microangiopathy pattern of injury (all the cardinal features of pre-eclampsia), implying that the elevated sFlt-1 levels are not just associative with pre-eclampsia but also causative (see Maynard et al, JCI 2003). The current model is that VEGF is required for maintenance of a healthy endothelium; the release of sFlt-1 by placental cells inhibits VEGF activity and thereby deprives endothelial cells of this necessary stimulus.

One might therefore be able to treat pre-eclampsia by designing inhibitors of sFlt-1, or perhaps by overwhelming the inhibitor with exogenous VEGF.