New poll question to jump-start 2010.
Thursday, December 31, 2009
New poll question to jump-start 2010.
Monday, December 28, 2009
Here's a list of some complications of erythropoietin use:
1. Increased thrombotic events. As the CHOIR study and others have now convincingly shown, elevated hemoglobin targets in CKD/ESRD patients are associated with an increased risk of cardiovascular events (the CHOIR study in particular demonstrated a hazard ratio of 1.34 in CKD patients randomized to a high Hgb target compared to a lower Hgb target, using a composite endpoint of death, MI, CHF requiring hospitalization, and stroke).
2. Hypertension: Patients may even experience intradialytic hypertension after receiving erythropoietin.
3. AV graft thrombosis: again, this correlates with the first point, that elevated Hgb concentrations can result in increased thrombotic events.
4. Pure red cell aplasia: rarely, patients can develop anti-EPO antibodies that result in pure red cell aplasia; this was predominantly associated with a form of EPO (Eprex) not marketed within the U.S.
5. Seizures: via a mechanism that appears uncertain.
6. Progression of diabetic proliferative retinopathy: because EPO has some angiogenic activity, it has been suggested to cause worsening of diabetic retinopathy, with some clinical studies appearing to confirm this hypothesis.
Sunday, December 27, 2009
Thursday, December 24, 2009
Wednesday, December 23, 2009
Tuesday, December 22, 2009
Sunday, December 20, 2009
Saturday, December 19, 2009
Some the important differences between mouse and human AKI: First, while the warm ischemia-reperfusion model tends to initially target the S3 segment of the proximal tubule and typically leads to overt tubular necrosis, in human AKI necrosis is not always present, and when it is tends to be patchy and most commonly affecting the distal nephron (in particular: the medullary thick ascending limb and medullary collecting ducts). Second, in clinical practice it is COLD ischemia which is often the mechanism of injury (e.g., surgical procedures in which the aorta is cross-clamped is often performed in the setting of a lowered core temperature, and donated kidneys are typically stored on ice prior to transplantation), rather than warm ischemia. Overall, the authors conceded that the rodent ischemia-reperfusion model has been invaluable, but caution against using it to explain all aspects of human AKI/ATN.
The notion of whether AKI/ATN occurs primarily in the proximal versus the distal tubule is not merely of academic interest. According to one version of the "distal nephron model", the reduced GFR experienced in response to medullary hypoxia is actually an adaptive response: decreasing the metabolic demands of tubular epithelia would decrease hypoxic injury; in a sense one could think of the nephrons as "hibernating" in a low metabolic state until they sense that the hypoxic insult has been removed and they can resume optimal cellular function. If this is true, it might caution physicians from trying to stimulate GFR in patients with AKI, instead encouraging attempts to limit tubular energy expenditure.
Thursday, December 17, 2009
This week's RFN Poll question is a fun one: let's assume Obama's stimulus package includes in its budget funding for a "Mount Rushmore of Nephrology" to be built. This gigantic statue will feature the faces of 4 prominent nephrologists etched into the rock face of a majestic mountain, preferably at one of the national parks in the Western United States. Of all the prominent nephrologists, which four would you choose as being the most influential in the field? Choose from the list of historic figures listed, and feel free to include "write-in votes" under the "comments" section if your favorite nephrologist is not listed. The list I made is admittedly biased towards physicians who have been practicing recently enough that the subspecialty has actually been in existence (e.g., not including folks like Hippocrates), and conversely I tended not to include the current heavy hitters of Nephrology, reasoning that the jury is still out on these folks. Realize that this is for fun, and I'm sure I've made several oversights.
Wednesday, December 16, 2009
As acute rejection rates continue to fall, causes of late allograft loss, such as transplant glomerulopathy (TG), become increasingly important. TG should spring to mind when you encounter a renal transplant recipient who develops heavy proteinuria and progressive allograft failure, usually late post-transplant. The clinical presentation overlaps with that of chronic allograft nephropathy, although proteinuria tends to be greater in TG and patients are likely to have a history of donor-specific anti-HLA antibodies. The pathogenesis is believed to relate to the presence of these donor-specific antibodies, which are often often anti-HLA Class II. These may wax and wane in concentration and, as a result, may not be detected on a single assay but repeat testing is usually successful. C4d staining is typically negative.
Various immunosupressive regimens have been tried, but none are known to be effective. Progressive graft failure and return to dialysis is the usual outcome. Finally, the increasing use of protocol biopsy informs us that ultrastructural changes that predate the TG lesion develop within the first months post-transplant and in apparently well-functioning kidneys.
Tuesday, December 15, 2009
Individuals with complement-associated atypical HUS have a relatively high degree of renal problems, and unfortunately there are few therapies other than standard supportive measures which can be used to help treat it. One obvious strategy for treating this disease would be to target the complement cascade. Enter eculizumab (trade name Solaris), a monoclonal antibody against the complement protein C5 (which if you'll recall your complement cascade is at the nexus of both alternative and classical pathways). Already approved for the treatment of other disorders of complement dysregulation (specifically: paroxysmal nocturnal hemoglobinuria), eculizumab was recently granted "orphan status" in an attempt to aid its testing in clinical trials for patients with atypical HUS.
Monday, December 14, 2009
Sunday, December 13, 2009
The differential diagnosis of syndromes involving hypokalemia, metabolic alkalosis, and hypertension
1. Liddle's syndrome. Autosomal dominant condition caused by a gain-of-function mutation in the epithelial sodium channel (ENaC) which results in increased Na+ reabsorption.
2. Licorice ingestion and the Syndrome of Apparent Mineralocorticoid Excess (SAME). Ingestion of large amounts of licorice (or licorice-containing tobacco or gun) can lead to inhibition of the enzyme 11-beta-hydroxysteroid dehydrogenase, which converts cortisol into the cortisone in aldosterone target tissues (e.g. collecting ducts). Since cortisol has an equal affinity for the mineralocorticoid receptor compared to aldosterone, it would act as the primary mineralocorticoid if it were not converted into the inactive cortisone. The compound in licorice that is responsible for this enzyme inhibitory activity is glycyrrhetinic acid, which also has some mild mineralocorticoid activity. The mechanism is similar in SAME, in which one has mutations in the 11-beta-hydroxysteroid dehydrogenase enzyme that prevent proper conversion of cortisol into cortisone.
3. Renal artery stenosis and renin secreting tumors. Both of these etiologies are the result of elevated production and secretion of renin leading to hyperaldosteronism.
4. Adrenal hyperfunction. This category includes causes of primary hyperaldosteronism, including adrenal adenoma, adrenal hyperplasis, and adrenal carcinoma.
All of these conditions essentially result in or mimic hyperaldosteronism and can be partly differentiated on the basis of the response of the renin-angiotensin-aldosterone system to the disease processes:
Liddle's -- low renin, low aldo
Licorice and SAME -- low renin, low aldo
Renal artery stenosis and renin-secreting tumors -- high renin, high aldo
Adrenal hyperfunction -- low renin, high aldo
Saturday, December 12, 2009
There are other health problems already associated with anabolic steroid use--these include gynecomastia, dyslipidemia, testicular atrophy, decreased fertility rates, some forms of hepatotoxicity, neuropsychiatric disorders, and developing a massively enlarged head a la disgraced baseball player Barry Bonds. It seems as if kidney disease can now be added to the list.
As a caveat, however, the authors also point out that there are potential other explanations for how bodybuilding might be linked to FSGS. These individuals were typically on regimens consisting of complicated cocktails of steroids, growth hormone, insulin, protein shakes, diuretics, and other supplements whose content is not carefully regulated. Therefore it remains possible that a substance other than anabolic steroids is the common nephrotoxin amongst these individuals. Furthermore, it's already known that elevated BMI in obese patients can result in secondary FSGS; perhaps their increased lean body mass itself drives the process. High protein diets may expose podocytes to unusually high serum protein levels; could this contribute to toxicity?
One final tidbit I learned from this article: individuals who take creatine supplements (another baseball reference: this is one of the few substances that home run guru Mark McGwire has admitted to taking) may have a falsely-elevated serum creatinine based on the fact that creatine is coverted to creatinine. This limitation can be overcome by measuring a full creatinine clearance in which a 24-hour urine creatinine and simultaneous serum creatinine are used.
Thursday, December 10, 2009
Wednesday, December 9, 2009
Tuesday, December 8, 2009
Monday, December 7, 2009
#1 = acute renal failure.
#2 = polycystic kidney disease.
#3 = passing a stone.
#4 = "taking a leak" (in case you can't tell, the vegetable my daughter is handing Billy the Kidney is a leek. Yeah, I know, that's one bad joke.)
Sunday, December 6, 2009
Thus, it's important to know the dialysis billing codes. Despite its central importance, the details of billing weren't really emphasized to me during either my residency or my fellowship training. Here are a few of the important billing codes and important billing issues related to nephrologists, focusing primarily on the relevant "CPT" (or "Current Procedural Terminology") codes for dialysis. If there are any seasoned nephrology vets out there, please feel free to make comments or clarifications, as I'm just personally discovering the coding game:
- Inpatient Dialysis Codes. The main issue to be aware of here is that in order to get reimbursed for supervising a dialysis session, the attending physician must be physically present while the patient is undergoing the dialysis procedure. Seeing the patient beforehand and writing out the prescription is not enough--you have to be present while the patient is hooked up to the machine. I have been advised to write something like, "The patient was seen and examined while on dialysis," as well as being careful that your date & time on the note is consistent with the patient's time on dialysis. Obviously, this applies only to attendings and not to fellows. The standard inpatient hemodialysis code is the "90935". If you see a patient in the morning and then their status changes such that they now require dialysis, you can still get credit for the procedure by billing a "90937" (again, as long as the nephrologist is present for part of the dialysis procedure). A separate set of codes ("90945" for single visit and "90947" for multiple visits) is used for other dialysis procedures such as peritoneal dialysis; I believe this code can also be used for coding CVVHD.
- Outpatient Dialysis Codes. A list of the major outpatient dialysis codes can be found here; they are generally submitted monthly: the main ones for adult dialysis are "90960" (for 4 face-to-face visits per month), "90961" (for 2-3 face-to-face visits per month), and "90962" (for a single face-to-face visit per month). Separate codes exist for patients who are dialyzed for only a few days out of the month, or for supervising home hemodialysis ("90966").
The process of nephrology billing is sufficiently complex that the Renal Physicians Association offers full-day "Coding and Billing Seminars" around the country. The discussion above does not even go into the intricacies of billing for individual injectable medications or all the important disease-specific codes (e.g., ICD-9 codes for CKD, hypertension, etc) which are routinely encountered in outpatient clinical practice.
Saturday, December 5, 2009
A more novel link is reported in this month's JASN: a manuscript by Betjes et al describes an association between ESRD patients with CMV-positivity and those with EPO resistance. It turns out that individuals infected with CMV have an altered profile of T-cells: they tend to have high percentages of CD4+ T-cells which lack the co-stimulatory molecule CD28, whereas patients who are CMV negative contain very small (less than 5%) numbers of these cells. These CD4+ CD28- cells apparently are very pro-inflammatory, capable of secreting large amounts of IFN-gamma and TNF-alpha, which the authors cite as a plausible mechanism to explain why CMV-positive dialysis patients tended to have higher EPO requirements (12,000 units versus 6,300 units per week) than CMV-negative dialysis patients.
The study is potentially significant in that it implicates a common virus in aspects of the chronic inflammatory state known to be associated with poor outcomes in CKD and ESRD, and even points towards antiviral medications as a potential therapy for preventing some of the cardiovascular complications of ESRD. Of course, the big caveat is that the association does not necessary reflect causality; for instance, it may be possible that "sicker", more chronically-inflamed dialysis patients may simply be more susceptible to acquiring CMV seropositivity.
Friday, December 4, 2009
These agents work by inhibiting the SGLT2 glucose transporter found in the S1 segment of the proximal tubule, responsible for 90% of glucose reabsorption in the kidney. They work by causing dose-dependant renal glycosuria, lowering both plasma glucose levels and insulinemia in animal models. Agents have the suffix -gliflozin, and examples include dapagliflozin and sergliflozin. Here's a recent review.
Interestingly, humans with loss-of-function mutations in SGLT2 live into adulthood, but experience systemic hypotension with markedly elevated renin levels, hypernatremia and metabolic alkalosis. This seems to be driven by renal sodium wasting occurring in association with glycosuria. These phenomena could also possibly occur as side effects of these drugs. Whether this side effect is a blessing (through improved BP and volume control) or a curse (through an adverse interaction with ACE inhibitors) remains to be seen. But with over 20 prototypic agents in the drug development pipeline, we'll definitely be hearing more about them.
Thursday, December 3, 2009
Wednesday, December 2, 2009
- they're metabolized by hepatic glucuronidase to 6-glucurinides (e.g. morphine 6 glucuronide or M6G)
- these metabolites are renally excreted, increasing the half-life to 6 times that of the parent compound in ESRD
- peak toxicity may not occur for over 6 hours (or at 6 am while you're on call) as M6G occurs in both hydrophilic and lipophilic forms, and it takes time for the latter to cross the blood-brain barrier and acculmulate in the CSF. Opiate toxicity should be your first thought in any hypoventilating dialysis patient.
The worst offenders are codeine and morphine, and to a lesser extent oxycodone and hydromorphone. Not all opiates behave like this though, and the following three are probably safest:
- Fentanyl has no active metabolites and appears to be well tolerated.
- Tramadol is a non-narcotic analgesic with some effects at the mu opioid receptor. It's usual half-life is 5 hours, increasing to ten in ESRD. Max. dose of 50mg bid. Watch out for serotonin syndrome with SSRI's
- Methadone does not appear to accumulate at all in renal failure, as observed in drug addicts with CKD and ESRD, and appears safe to use.
Tuesday, December 1, 2009
(1) the urge to move the legs, usually with unpleasant sensations.
(2) the appearance of symptoms during inactivity or rest.
(3) relief of symptoms with movement.
(4) worsening of symptoms in the evening or at night.
The mechanism of RLS is unclear, but many signs point to (a) the dopaminergic system (dopamine agonists, such as ropinirole, have been observed to successfully treat some individuals with RLS), and (b) iron status (iron supplementation also appears to have some benefit in treating RLS in individuals with depleted iron stores--a problem which may be accentuated in dialysis patients). In addition, there is some suggestion that inadequate dialysis may be a cause of RLS; this study by Kim et al showed that pre-dialysis BUN is associated with RLS symptom severity.
Thus the workup for dialysis patients with RLS symptoms should include an assessment of dialysis adequacy, review of anemia/iron labs, review of the medication list for drugs which have been associated with RLS (certain antidepressants and antipsychotics have been implicated), and any evidence of a positive family history of RLS.