Timing of Dialysis Initiation: The Billion Dollar Question

One of the true arts learned during renal fellowship is the timing of initiation of dialysis in outpatients with advanced chronic kidney disease. This a crucial skill to develop as the beginning of dialysis has major implications for the patient's lifestyle, finances and well being. In this regard, the publication of the IDEAL trial (reviewed by Matt and one of our top stories of 2010) was a landmark in helping to guide management in these situations, highlighting the safety of waiting for signs and symptoms of advanced chronic kidney disease rather than pursuing early start dialysis solely based on eGFR in closely followed individuals.

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)

Top nephrology-related stories of 2011

 

2011 proved to be another exciting year in the world of nephrology.  2010 was dominated with big clinical trials (SHARP, FHN, IDEAL), APOL1 gene variants, Propublica article on HD in the US, and medicare bundling.  2011 proved to be a big year in basic science.  Below is a list of the top 10 nephrology-related stories as voted by the readers of RFN. This is by no means a complete list of all of the major news stories.  Feel free to add to this list in the comment section below.  I will summarize each of these studies/stories below in increasing order of votes as received in our year-end poll.

10. FDA approval of belatacept for use in kidney transplant induction therapy (15%)-  In June the FDA approved the use of the selective T-cell costimulatory blocker (anti-CTLA-4) belatacept (Nulojix) for use in kidney transplantation as both induction and maintenance therapy.  This was after the FDA reviewed both the BENEFIT and BENEFIT-EXT trials published in Transplantation in 2010. These trials examined the use of belatacept for induction therapy and as a replacement for calcineurin-inhibitors for maintenance therapy. The hope is that calcineurin-inhibitor based regimens can potentially be avoided in the future as these are associated with a decline in eGFR over time. These trials both showed an improvement in eGFR at 3 years as compared to cyclosporine based regimens with slightly more acute rejection. However, the major concern for belatacept is the increased risk of post transplant lymphoproliferative disease hence it cannot be given to EBV negative patients. Another issue with giving belatacept is that it is given IV at different schedules after transplant which could impart challenges.  Nephron Power has a post about this story.  

9. Success in treating myeloma kidney with bortezomib plus plasma exchange published in NEJM June (17%)- Using plasma exchange to treat myeloma cast nephropathy has been a controversial topic in the field of nephrology. The benefit in clearing free serum light chains with plasma exchange has become an increasingly popular approach. Investigators from the Mayo Clinic published a letter in NEJM in June of this year describing their experiences with using bortezomib in combination with plasma exchange in 14 patients with known or suspected myeloma cast nephropathy.  12 of the 14 patients (86%) treated with plasma exchange had a partial or complete response to the therapy.  6 of the 12 had a complete response with normalization of creatinine after 6 months.  Only 2 were on HD after treatment. These results are encouraging, however a randomized clinical trial will be needed to confirm this.

8. Eculizumab for shiga associated HUS published in NEJM (21%)- The major outbreak of E. coli O104:H4 secondary to contaminated sprouts that occurred in Germany dominated the international news from May to June of this year. About 4000 people were infected and at least 46 died. Nephrologists in Germany were hit with an unprecedented number of patients with hemolytic uremic syndrome (HUS). This coincided with a report published in the NEJM in June of this year which demonstrated the complete resolution of Shiga-toxin-producing E. Coli- HUS in three children treated with eculizumab. This supported the concept that shiga toxin may activate complement directly and direct inhibition of terminal complement complex formation by treating patients with eculizumab. This lead to an ad hoc committee from the German Society of Nephrology to recommend all patients with renal or neurological and hematological symptoms treated with plasmapheresis. If no short-term improvement was seen then they recommended use of eculizumab. This has resulted in wider-spread use and now a clinical trial. This was definitely a positive outcome to a devastating condition.  I'm sure we will see more of this drug in clinical use in the near future.

7. The DOSE study of bolus or drip diuretics in CHF (24%)- This was an interesting study of a common clinical conundrum (Do you give diuretics by bolus or continuous infusion in compensated CHF?) that was published in NEJM in March of this year and discussed on RFN by Finnian. This was a prospective double-blind randomized controlled trial consisting of 308 patients from 26 clinical sites testing 2 questions; how do high-dose (2.5 x home dose) vs. low-dose (home dose) diuretics and IV continuous vs. IV bolus loop diuretic strategies impact the 1.  Efficacy (symptoms) or 2.  Safety (change in creatinine) in patients with compensated heart failure? There were no significant differences between either of these endpoints in either high vs low and continuous vs. bolus diuretic administration. The high-dose group did have more improvement in dyspnea but a higher creatinine level was reached. Read Finnian's conclusion on his blog post.    

6. sFLT-1 removal in preeclampsia published in Circulation in August (25%)-  Another exciting development in nephrology is the publication of a pilot study aimed at removing the soluble fms-like tyrosine kinase 1 (sFlt-1) in women with preeclampsia which was published in the journal Circulation in August of this year. Nate originally discussed sFlt-1 role in preeclampia on RFN and it is interesting to see how far research has progressed since then. This study looked at the feasibility and safety of removing sFlt-1 using extracorporeal apheresis in 5 patients with preterm preeclampsia and elevated sFlt levels. The pilot study confirmed that this technique is possible and safe however, it was not able to address whether or not this approach will prolong pregnancy and improve both maternal and fetal outcomes. I'm sure a clinical trial will be forthcoming.

5. Bardoxolone for diabetic nephropathy published in NEJM July (27%)-  The preliminary results from this trial were originally presented at ASN Kidney Week in 2010 which I discussed on RFN in December. The final results were published in NEJM in July and discussed by Gearoid on RFN and Joel on PBF. This was a phase 2, double-blind, randomized, placebo-controlled trial looking at 227 adults with CKD treated with various doses of the oral antioxidant inflammation modulator Bordoxolone or placebo for 52 weeks.  This trial showed improvement of GFR at 24 and 52 weeks compared to placebo.  However, much of this GFR improvement was lost at 56 weeks (4 weeks after stopping the drug). I think these results are provocative, however I am anxiously awaiting the results of the larger phase III clinical trial termed BEACON which is currently enrolling patients.

4. ACT trial of acetylcysteine in contrast nephropathy (30%)-  This trial published in Circulation in August and discussed by Graham on RFN was another long debated clinical question in nephrology- (how do we prevent kidney injury when patients receive iodinated contrast agents?). This trial randomly assigned 2308 patients undergoing an intravascular angiographic procedure with 1 risk factor for contrast-induced acute kidney injury to either acetylcysteine (1200mg twice daily 1 day before and 1 day after the procedure) or placebo. Both groups received normal saline at a rate of 1ml/kg per hour 6-12 hr before and after. They did not find any difference between any of the primary or secondary outcomes comparing acetylcysteine vs. placebo. Read the conclusion and comments from Graham's RFN post. Overall, it appears that  acetylcysteine's days for preventing contrast nephropathy are almost over.        

3. Increased mortality in dialysis patients after 2-day break (41%)- This study published in NEJM in September examines how patients that receive thrice weekly dialysis fare over the 2-day interdialytic interval. This study retrospectively examined the death rates and cardiovascular related hospital admissions on the long 2-day interval vs. other days in 32,065 patients currently undertaking thrice weekly hemodialysis using the USRDS database. They found that indeed the 2-day interval was associated with increased all-cause mortality, infection-related mortality, cardiac arrest, MI, CHF, stroke and dysrhythmia as compared to other days. Evidence is continuing to point towards a more physiological dialysis regimen with daily dialysis. However, this study did not compare thrice weekly to nocturnal or daily dialysis.

2. The lupus nephritis maintenance phase of the ALMS trial published in NEJM November (44%)-  Coming in at number 2 is the much awaited results of the maintenance arm of the Aspreva Lupus Management Study (ALMS) trial. The induction arm of the ALMS study compared Cyclophosphamide to Mycophenolate (MMF) and was published in JASN in 2009 and showed difference between the two therapies in inducing remission in lupus nephritis. The maintenance phase randomized patients that responded in the initial phase to either MMF or Azathiprine. 227 patients were randomized into each group. The patients randomized to MMF had better outcomes as compared to Azathioprine and puts MMF firmly on the map for both induction and now maintenance of lupus nephritis. However, there has been some conflicting data as was reported by the smaller MAINTAIN study that did not show a difference between these two regimens. This was a well conducted clinical trial that adds evidence to a difficult to treat condition. This is a welcome addition to patients with lupus and the nephrology and rheumatology communities.     

1. suPAR as a cause of FSGS published in Nature Medicine in July (54%)-  Coming in at number 1 in the 2011 nephrology poll at 54% of votes received was a basic science article published in Nature Medicine and discussed by Gearoid on RFN exploring the mechanism of focal segmental glomerulosclerosis (FSGS). This study showed that level of serum soluble suPAR urokinase receptor was present at higher concentrations in patients with FSGS. They then showed in 3 different animal models that elevated suPAR was capable of causing proteinuria and foot process effacement. We will see how these findings will be translated to human studies just as the discovery of the M-type phospholipase A2 receptor is for membranous nephropathy.

Again, quite a busy and exciting year in the world of nephrology in 2011. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays.

Happy Holidays

Dr Steele pointed me in the direction of this article from JAMA that was written back in 1927. Although not directly related to the world of Nephrology, it contains advice on building a relationship with your patients and the importance of a proper bedside manner that remains just as relevant today as it was 84 years ago. Even then there was a sense that the younger generation was becoming too caught up in the science of medicine and had lost sight of the "art". So each generation worries about the next... It makes for good reading this holiday season and helps put all of what we do in perspective.

Happy Holidays from RFN

AKI in the hospital: What does this mean for my long term kidney health?

As renal fellows, we are always involved in the most severe cases of hospital acquired AKI that require dialysis. Previously on RFN, we examined the impact that these cases have on the long term risk of ESRD. What we often don't see are the less severe cases of hospital acquired AKI that non-nephrologists feel comfortable managing on their own. There is now a growing body of evidence that these cases have long term implications for kidney function.

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.

The Origins of Renal Physiology, a National Course for Renal Fellows

This fall I attended the fourth annual Origins of Renal Physiology course for nephrology fellows at the Mount Desert Island Biological Laboratory (MDIBL). The course was designed to allow fellows an opportunity to connect with the historical roots of renal physiology and to gain perspective through comparative physiology. The founder of this blog, Nathan Hellman, attended the first course and blogged about his experience in 2008.

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

From the RFN Archives: Plasma Exchange for Catastrophic Antiphospholipid Antibody Syndrome

Interesting case for the weekend: young woman with known lupus, baseline normal kidney function; admitted initially with headaches and "feeling more lupusy than usual", found to have a creatinine of 2.5 on admission with some dysmorphic RBCs on u/a and low complements. Presumed to have lupus nephritis and a biopsy was deferred for several days due to significant thrombocytopenia. When her Cr kept on increasing to the 5's & platelets had improved, a biopsy was eventually performed, and did NOT show lupus nephritis: instead, it showed rip-roaring thrombotic microangiopathy! The patient's lupus anticoagulant is positive, and we are now operating on the assumption that she has renal failure based on antiphospholipid antibody syndrome-induced TMA. How do we treat it?

Catastrophic Antiphospholipid Syndrome (CAPS) describes a rare subset (about 1%) of patients with APLAS who develop significant end-organ damage as a result of widespread thrombotic occlusion. It can cause kidney damage by virtue of thrombic microangiopathy. In addition to treatment with anticoagulants (e.g., coumadin) , steroids, and possibly IVIG, there is also a purported role for therapeutic plasma exchange. There is however a controversy as to what type of replacement fluid should be given: some believe that FFP should be used, as it contains "natural anticoagulants" which may help in treating the underlying condition, while other believe that albumin should be used, using the rationale that the clotting factors, cytokines, and complement activation products present in FFP could worsen the "thrombotic storm" driving the thrombotic microangiopathy. Although the numbers are small, current data seems to indicate that plasma exchange does help in the treatment of this condition with relatively high morbidity & mortality.

Originally Posted by Nate Hellman

Pregnancy and ACE inhibitors

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

Cold and OTCs in Transplantation

Winter season arriving and you might see a couple of transplant patients with colds… Immunosuppressants have the potential to interact with OTC meds used to treat common colds and coughs, which can lead to alterations in the degree of immunosuppression and potentiate adverse effects.

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.

Relief of pain

Acetaminophen is an antipyretic/analgesic, which can be used to relieve fever and pains associated with colds. It is considered generally safe to use in renal transplant patients but caution should be used in patients with liver dysfunction.

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.

Stay warm!

Elsen C. Jacob PharmD, Pharmacy Resident

Steven Gabardi PharmD, BCPS, Organ Transplant Clinical Specialist at BWH

It's that time of year again...

It's time again to compile the top nephrology-related stories of the year. Last years list was a great collection. Help us come up with this years list by voting for the ones that you feel deserve to make it over on the sidebar.

Think we missed a story? Nominate it in the comments to this post and we'll put it up for readers to vote on.

Entrapment

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

Renal disease and HIV

Perhaps the most renowned renal disease associated with HIV infection is the collapsing variant of FSGS. This typically presents with the nephrotic syndrome and has been associated with relatively advanced HIV infection, with low CD4 counts and higher viral loads. HIV infection of tubular cells may play a direct role in the pathogenesis, with some supporting evidence from animals studies in which transgenic mice were created with HIV constructs in their genome – they developed proteinuria and similar histological findings of collapsing glomerular tufts and interstitial disease. Hypertension appears to be less common, possibly due to an association with salt wasting.

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.

The odd couple: the kidney and the colon

The gut posses a staggering number of bacteria. There are more bacteria living in our colons than there are human cells in our bodies. These microbes produce compounds, some of which are absorbed and eventually cleared by the kidney. As such, there are a number of compounds derived from the gut flora that build up in renal failure.


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.