Wednesday, December 28, 2011
Does this differ from what's been going on in practice for the last 10-15 years? A quick look at the USRDS shows that back in 1996 less than 20% of patients started dialysis with an eGFR of greater than 10 ml/min/1.73m2. In stark contrast by 2009 a full 20% were starting with an eGFR of over 15 ml/min/1.73m2 and greater than 50% were starting above the 10 ml/min/1.73m2 mark.
Why the heck did this happen when uremic signs and symptoms, at least in the IDEAL trial, in general seem to occur at GFRs below 10 ml/min/1.73m2?
A variety of explanations have been put forward (well reviewed by Rosansky and colleagues here and here). A commonly proffered argument is that perhaps uremic signs and symptoms are occurring earlier in our aging and increasingly ill population. However, in a study of 2402 nursing home residents who initiated dialysis, the authors found that seven signs and symptoms commonly associated with declining kidney function, such as volume overload and cognitive or functional decline, accounted for less than one third of all cases of early dialysis initiation including less than half of all cases of early outpatient dialysis initiation, suggesting that dialysis initiation may be primarily prompted by laboratory values in a large number of patients.
Regardless of the reasons, the trend is clear, early start was the rule rather than the exception building through the late 90s into the 2000s.
What has this meant for patients and US societal economic cost? A very nice paper from O'Hare and colleagues tells part of the story, using information from a large integrated health care system in Seattle, the group was able to estimate the rate of eGFR decline prior to the onset of dialysis in a subset of patients. This in turn allowed them to predict how many additional days on dialysis patients spent in 2007 versus 1997 by looking at the mean eGFR at time of dialysis initiation in patients listed in the USRDS and then back calculating (this relied on the assumption that the rates of decline were similar in these groups).
These estimates showed that dialysis was initiated on average of five months earlier in 2007 compared to 1997 and almost 8 months earlier in patients over 75! Doing some back of the envelope calculations the group guessed that early initiation in the US had cost an additional $1.5 billion dollars during 2007. This is slightly higher but similar to the over $1 billion dollar additional yearly cost estimate made using slightly different assumptions by the AJKD editorialists for the economic analysis of the IDEAL trial (this was the US estimate - the IDEAL trial was conducted in Australia and New Zealand).
Given that early initiation of dialysis in asymptomatic closely followed patients has no proven benefit (and may even be harmful if you look at recent retrospective data) part of our charge as emerging nephologists is helping to reverse this expensive and unhelpful trend.
(Photo: Stanford Chapel at Night)
Sunday, December 25, 2011
Thursday, December 22, 2011
Tuesday, December 20, 2011
A nice example of this literature was published this past month in CJASN by a group from Cincinnati examining 3679 diabetic veterans over an average followup of about 5 years looking at how hospital acquired AKI, defined using AKIN criteria, influenced the development of stage IV CKD and mortality. Individuals with less than 3 outpatient serum creatinine measurements or eGFRs of less that 30 ml/min/1.73m2 where excluded from the study.
Hospital acquired AKI occurred in 29% of the cohort and in the vast majority of cases, 88%, was of mild severity (AKIN stage I) with only 12% of cases in AKIN stages 2 and 3. The group was unfortunately unable to capture data on the need for inpatient dialysis. Of those who developed hospital acquired AKI, 23.4% went on to develop stage IV CKD as compared with 10.4% of hospitalized patients who avoided AKI. Hospital acquired AKI was a significant risk factor for the development of stage IV CKD with HR of 3.56.
As with severe dialysis requiring AKI, these less severe cases of AKI were also significantly associated with mortality with 38% of the patients who developed hospital acquired AKI dying by the end of the study period as compared with 24% of the hospitalized patients who did not develop AKI.
Interestingly the group looked at individuals who developed multiple episodes of AKI and with each episode up to 3 there was an approximate doubling of the risk for developing stage IV CKD. It was additionally notable that the hazard ratio for AKI was similar to that of proteinuria, a well known risk factors for CKD progression.
So how should the post hospital followup of these less severe cases of AKI be handled? Some have asked whether these patients should be seen by nephrologists, however given the already strained capacity of many renal clinics this would seem difficult to achieve. More practically, educating housestaff and primary care physicians on the importance of AKI as a risk factor for CKD and encouraging them to refer when CKD becomes present seems more achievable. In addition, in integrated systems such as the VA these patients could be followed remotely and brought into nephrologic care when our services are of value to the patient.
Sunday, December 18, 2011
The course took place on the coast of Maine at the MDIBL, a place with great historical and modern day significance for renal physiology. George Dorr, who founded Acadia National Park with John D. Rockefeller, had the foresight to recognize the potential value of the island for the scientific community. He offered land for two labs, the MDIBL and the Jackson Laboratory (which also continues to operate on the island with tremendous success). The MDIBL is where E. K. Marshall discovered and described active tubular transport in the goosefish in the 1920’s. It is where Homer Smith wrestled with the concepts of clearance, GFR, and effective renal blood flow and worked out calculations based on his studies in marine animals. He did ground breaking experiments in the lab and wrote a number of manuscripts and books in his cottage on the campus describing these fundamental concepts. For 35 years, he spent his summers working at the MDIBL. Roberts Pitts called this time the “Smithian Era of renal physiology”. Homer Smith brought many others to the island to work on renal physiology, and over the years a number of important discoveries have been made at the MDIBL. The lab continues to be a place of excellence, active in research.
The annual course brings fellows back to this historical place and places them under the mentorship of a distinguished faculty. Mark Zeidel serves as the course director and every year he brings in a remarkable faculty from across the country to distill fundamental concepts of renal physiology in a historical and comparative context. They do this by dividing the course up into six modules. Each fellow participates in three of the six modules with each module lasting for two days. The modules split the kidney up into functional units beginning with the glomerulus and continuing on through the proximal tubule, the loop of Henle, and the distal tubule. They also covered salt and water homeostasis and renal genetics. On the first day of each module, we worked with the faculty in the lab performing experiments using classic physiology model systems such as the toad bladder, the shark rectal gland, the zebrafish, and the xenopus oocyte. We developed a presentation based on our experiments to share with the group on the morning of the second day of each module. Even though we only work with three of the modules each year, we learned what the other groups were doing through the peer presentations. The afternoons after the presentations were spent exploring the island and Acadia National Park. There were organized outings for hiking, biking, and kayaking. We finished the week with a big lobster bake at a park on the seawall.
I have had the great pleasure of attending the course each of the last two years, participating in all six modules. I told my wife when I got home each time that I felt like a kid at camp. Only instead of the usual camp games, we were playing with kidneys and urine. These were tremendous experiences that I will carry with me throughout my career in nephrology. It was great to meet and work with faculty and fellows from across the country. I came away with an enhanced understanding of physiology and a renewed enthusiasm for all things renal. As you make your schedules out for next year, I would encourage you to consider setting aside some time to attend next year’s course, September 2-9.
Posted by Michael Hovater MD
Sunday, December 11, 2011
Originally Posted by Nate Hellman
Friday, December 9, 2011
Treating hypertension on pregnancy sometimes feels a little like going back in time. As Nate posted previously, the list of anti-hypertensives that are considered safe in pregnancy is relatively short – first line agents include labetalol, hydralazine, methyldopa and some calcium channel blockers, while beta-blockers and diuretics are relatively contraindicated and ACEi and ARBs are definitely contraindicated. ACEi have been associated with a constellation of fetal injuries when used in later pregnancy while a study published in 2006 suggested that they were associated with fetal malformations when used in the first trimester. Given the prevalence of hypertension in the general population and the ubiquity of ACEi, this lead to some understandable anxiety about whether these classes of drugs should be prescribed at all to women of child-bearing potential.
However, two recent studies published in the BMJ and the Journal of Obstetrics and Gynecology have challenged this orthodoxy. The first is a large registry study while the second is a meta-analysis of all studies of ACEi in early pregnancy. These two large studies found that although the risk for fetal malformations was higher than controls with first trimester use of ACEi, there was a similar increased risk associated with the use of any other class of anti-hypertensive and in women with untreated hypertension. There was no excess risk of ACEi over these other groups. This suggests that it is the hypertension itself that is causing the increased risk of malformations rather than any effect of an individual medication. It is important to note that the previously documented association between fetal malformations and the use of ACEi in the second and third trimesters was confirmed in the BMJ study. This indicates that the drugs are not safe for use throughout pregnancy and should be stopped when a woman becomes pregnant. That said, it should bring some relief to mothers who have conceived while taking an ACEi that they have not done any inadvertent harm to their children.
I recommend this excellent editorial on the topic
When recommending OTC medications, it is important to suggest therapies based on patient symptoms, drug interactions and adverse effect profile. Below a summary of safe drugs to use in this population according to symptoms:
Relief of non-productive cough:
Dextromethorphan is a cough suppressant with no reported drug-interactions with immunosuppressant medications. Caution should be exercised in liver transplant patients as dextromethorphan is metabolized by the CYP450 2D6 isoenzyme.
Codeine is typically used as an opioid analgesic but is also used as a cough suppressant in combination products. In patients with low GFR, doses should be reduced (25% - 50% reduction) due to potential for accumulation of metabolites.
Relief of congestion and productive cough:
Guaifenesin is an expectorant with no significant drug-drug interactions, although caution is recommended in renal transplant recipients and in patients with decreased renal function as it is hydrolyzed to a renally eliminated metabolite and high doses of guaifenesin have been rarely associated with urolithiasis.
Antihistamines including diphenhydramine (1st generation) and loratidine (2nd generation) are used for relief of symptoms such as cough, watery eyes, runny nose and sneezing.
Caution should be advised in the following settings: patients on calcineurin inhibitors as antihistamines decrease gastric motility; patients with renal dysfunction due to urinary excretion of antihistamine metabolites (extend dosing interval); liver transplant patients due to hepatic metabolism; and lung transplant patients as antihistamines thicken bronchial secretions and can cause respiratory depression.
Don't forget about nonpharmacological therapies, which can be safely utilized to provide relief for cold symptoms: saline sprays, vaporizers and humidifiers.
The following medications are NOT recommended: Pseudoephedrine, Phenylephrine, Oxymetazoline and NSAIDS (Advil, Aleve, Ibuprofen, Motrin, Excedrin, Midol). Patients should be informed to carefully read product ingredients as combination therapies could contain these agents.
Thursday, December 8, 2011
Think we missed a story? Nominate it in the comments to this post and we'll put it up for readers to vote on.
Wednesday, December 7, 2011
An 18 year-old girl with end stage renal disease secondary to focal segmental glomerular sclerosis had a double cuff flex neck peritoneal dialysis (PD) catheter uneventfully inserted in order to begin dialysis. Ten days after this procedure, following successful post-operative catheter flushes, she presented with new, intermittent, sharp, right-sided abdominal pain with catheter flushes. Over the next week, she went on to experience progressive peritoneal filling difficulties that required curtailing planned treatments. She was otherwise asymptomatic and, when not on dialysis, reported feeling well. An abdominal x-ray revealed that her catheter had migrated into the right flank, and her dialysis treatments did not improve after recombinant tissue plasminogen activator or an intensified bowel regimen. Her PD catheter was capped, and she was instructed to present for surgical repositioning of the catheter the following day.
In the operating room, the peritoneal catheter was found to be in the right lower quadrant as expected and initially appeared to be surrounded by only inflamed omental remnants. Further dissection of the omentum away from the catheter, however, revealed multiple dense adhesions, including a small loop of bowel and a markedly inflamed appendix, encircling the PD catheter. These adhesions were lysed, freeing the PD catheter from the appendix. After a pause to discuss these findings with her mother, the surgeon proceeded to perform a previously unplanned appendectomy. The PD catheter was relocated to the pelvis and flushed with ease.
This case highlights a rare but previously documented cause of PD catheter obstruction: appendiceal entrapment. However, this case has a few significant differences from the literature. First, and most notably, the patient’s pathologically-confirmed appendicitis did not present with signs or symptoms consistent with this disease (fever, localized abdominal pain, elevated WBC). Catheter obstruction and malposition were our only clues, and even en route to the OR, both the medical and surgical teams believed this to be a simple case of catheter malposition, perhaps with an element of omental adherence. Second, this case questions the current literature’s suggested management of surgical peritonitis, which centers around catheter removal and dialysis interruption. HS’s catheter was left in, and her pain, catheter flows, and dialysis treatments dramatically improved post-operatively. Perhaps the most important lesson that I take away from this case, though, is to quickly consider the more rare surgical causes of PD catheter obstruction and even peritonitis when conventional medical treatments fail.
Posted by Matt O'Rourke
Sunday, December 4, 2011
In addition there are many other renal diseases that can be associated with HIV infection, its treatment or associated conditions. An interesting review can be found here.
Below are some of the differentials on that long list:
Many of the anti-retrovirals have been associated with nephrotoxicity in various forms. Further information can be found on previous posts.
Similarly, various antibiotics and other anti-microbials used to treat or prophylaxis this population must be kept in mind (e.g. Bactrim, amphotericin, pentamidine etc.). Another potential problem over the longer term is the diabetogenic potential from various protease inhibitors.
Co-infection with other diseases, particularly HBV and HCV should be investigated. This opens a whole other list of differentials in terms of renal disease – e.g. membranous associated with HBV and syphilis; cryoglogulin and membranoproliferative disease associated with HCV. An immune complex mediated disease with predominance of IgA has also been described, as have various forms of lupus like clinical cases.
One other rare consideration is thrombotic thrombocytopaenic purpura, which may result from HIV induced endothelial injury.
Just some of the differentials to keep in mind when asked to see a patient with kidney disease and HIV infection.
Thursday, December 1, 2011
Two examples of such compounds are indoxyl sulfate and p-cresol sulfate which are produced by colon microbes from tryptophan and phenylalanine/tyrosine, respectively. In the ongoing search for the medley of true uremic toxins (remember that urea, produced from protein metabolism in the liver is at worst only mildly toxic) compounds such as indoxyl sulfate and p-cresol sulfate are potentially toxic candidates.
In an interesting study recently published in JASN a group from Stanford examined the profile of plasma solutes in normal subjects and dialysis patients with and without colons. As expected, HPLC assays revealed that indoxyl sulfate and p-cresol sulfate were nearly absent in dialysis patients without colons in contrast to solutes like urea that were present in equal amounts in both the colon intact and absent groups.
In addition, mass spectroscopy revealed a number of other known and unidentifiable solutes in significantly higher concentration in the dialysis patients with colons when compared with normal subject and dialysis patients without colons. This suggests that we are just at the beginning of understanding the contribution of the colonic microflora to uremic toxicity.
As suggested at the end of the JASN article, a deeper understanding of our micorflora's contribution to uremic toxicity could allow us to explore the health benefits of reducing the production of toxic solutes by nutritional, probiotic, or pharmacologic means.