Cisplatin again

In a previous post, we discussed the way the cilastatin prevents imipenem nephrotoxicity by inhibiting dihydropeptidase, a proximal tubular brush border enzyme which facilitates the uptake of imipenem metabolites into proximal tubular cells. This allows imipenem to be excreted unchanged in the urine. In the absence of cilastatin, imipenem would be unusable due to its significant adverse effects on the kidney.

Approximately 40-60% of patients who receive cisplatin develop nephrotoxicity and this is its most common severe adverse effect. The mechanism of this nephrotoxicity is not entirely clear and has been discussed in the past by Emily and Nate. Primarily, however, it is due to proximal tubular cell damage with apoptosis of the affected cells leading to polyuria, a fanconi-type syndrome and ATN.

A paper was just published in KI which looked at the effect of co-administration of cisplatin and cilastatin in rats. The rats were given a single dose of cisplatin and those that received cilastatin had significantly less uptake of cisplatin into the renal cortex and lesser manifestations of renal toxicity. Interestingly, the uptake into the medulla was not affected and the half-life of cisplatin was longer than in the controls. Because dihydropeptidase is specific to the proximal tubule, it did not affect uptake into cancer cells and so anti-tumor activity was preserved. Cisplatin toxicity is the bane of the life of nephrologists working in major cancer centers because, once it has set in, there isn’t much that you can do and it limits the amount of treatment that these patients can get for their tumors. This is a preliminary study and we can’t say that this is the panacea for cisplatin nephrotoxicity but it certainly is promising as well as being a fascinating insight into the mechanisms of renal damage caused by cisplatin.

Bury it!

One of the issues that we come across repeatedly in the clinic is the timing of access insertion. We all want to avoid the use of catheters and so we refer patients early (when possible) for fistula formation. This is a bigger problem when your patient wants to start PD. You don’t want the patient to have the catheter placed too early because then they will be unnecessarily exposed to the risk of infection. At the same time, you don’t want to wait too long and get to the stage where the patient requires urgent HD (and often, once they start HD it is difficult to make the transition to PD). I saw a patient in the clinic a few weeks ago that fits this bill perfectly. He is an otherwise healthy man in his 60s who has a very active life and a full-time job. His creatinine had been stable for 2-3 years but climbed rapidly earlier this year and we thought he would need to start soon. However, his creatinine stabilized again and he is feeling well so we have him in a holding pattern with regard to the PD catheter insertion. Our surgeon suggested implanting a buried PD catheter, a technique that he has just started doing in our institution.

For this technique, the catheter is buried subcutaneously at the time of insertion. Then, when the patient is ready to start dialysis, the subcutaneous portion is externalized and the catheter can be used straight away. This can be done in the dialysis clinic and does not require a trip to the OR. Thus, a catheter can be inserted months (or even years) prior to use and the problem of timing is dealt with very elegantly. Recently, a paper was published which described the experience of the University of Denver where they have been using this technique as standard since 2000. In total, 134 catheters were implanted in that time. The period prior to externalization varied between 2 and 788 days with an average of 40 days. There was no relationship between catheter embedment time and the risk of catheter failure. 90% of catheters worked immediately and of the remaining 13 catheters, 12 were easily corrected laparascopically. Only 1 patient failed this technique and required transition to HD. This seems like a great technique and I look forward to seeing the results here over the next few months.

See also this earlier paper in KI about the experience with the use of buried catheters in Ottawa.

To biopsy or not to biopsy

Diabetes is a common cause of CKD and the prevalence of diabetic nephropathy is increasing. A question that sometimes arises in the clinic is when it is appropriate to biopsy a patient with a presumptive diagnosis of diabetic nephropathy and are there any signs that may suggest that there is an alternative diagnosis. It is reassuring that recent data have suggested that renal biopsies in low-risk patients are associated with a very low risk of adverse consequences but I still don't think that anyone would recommend biopsying all patients who present with diabetes and CKD.

So how do you decide who to biopsy. It has been suggested in the past that the presence of hematuria was associated with a lower incidence of true diabetic nephropathy while diabetic retinopathy suggested the opposite. A study was recently published in the Journal of Diabetes Investigation which looked at the results of renal biopsies in patients with diabetes. In total, 55 patients with T2DM were included in the study. These were not random patients with diabetes; all of them had a clinical course which suggested that an alternative diagnosis might be present. 30 of the patients had true DN while 25 had no evidence of diabetes. Of these 13 had IgA nephropathy. One patient had a crescentic GN. The duration of diabetes was not a good predictor of the likelihood of DN. This is not altogether surprising when you consider that this is duration since diagnosis and the patients may have had diabetes for signficantly longer without being aware. Poor glycemic control and the presence of diabetic retinopathy were significantly associated with a higher likelihood of DN. No patient in the non-DN group had diabetic retinopathy which again goes to show the usefulness of this examination in stratifying patients with presumptive diabetic renal disease. This goes to show that the advice that we have been getting in the past is good - the absence of diabetic retinopathy should make you suspect an alternative diagnosis.

One interpretation of this study is that patients with atypical presentations and diabetes should have a biopsy because there is a good chance of an alternative diagnosis. Another, more conservative interpretation is that even in patients where there is a high pre-test probability of a non-diabetic lesion, the majority of patients will have diabetic nephropathy and in those that don't the treatment will most likely be the same in any case.

eJournal Club

CJASN eJC Article of the Month, 2012-08-15 Prevalence and Factors Associated with Hyperkalemia in Predialysis Patients Followed in a Low-Clearance Clinic "Pantelis A. Sarafidis, Rochelle Blacklock, Eleri Wood, Adam Rumjon, Shanique Simmonds, Jessica Fletcher-Rogers, Rachel Ariyanayagam, Aziza Al-Yassin, Claire Sharpe, Katie Vinen" Join in the discussion online at ejc.cjasn.org ©American Society of Nephrology

A few months ago, CJASN introduced a new feature called eJournal Club. This is a means by which fellows (and others) can review papers and communicate directly with the authors. The idea is that perhaps these papers could be discussed in local journal clubs and then any questions or concerns that arise could be answered by the authors. It's an interesting idea that to my mind is a big improvement on the traditional model of letters to the editor. At the moment, the paper is chosen by the editors each month but the plan may be for this to change in the future if there is sufficient interest.

This month's paper is a study of the factors that are associated with hyperkalemia in patients attending a low clearance clinic in the UK. The main finding of the paper is that eGFR is the best predictor of the likelihood of being hyperkalemic. In the univariate analysis, patients with hyperkalemia were more likely to have a low serum bicarbonate or be on sodium bicarbonate treatment. However, in the multivariate analysis these were not significant. Looking at the analysis, the cut-off for bicarbonate in the LR was greater than or less than 25 mmol/L while the mean values in both groups were lower. I wonder, if they had run this as a continuous variable in the LR or chosen a lower cut-off for bicarbonate, if it wouldn't have been significant. This is a question that I can now ask the authors. This is free to all - you do not need to be an ASN member or a subscriber but you do need to register your email address with the ASN. The PDFs of the article and accompanying editorial are provided also.

I think this is a great use of new media and we will be referring to it monthly.

Pathology Image of the Month

A 47 year old man with ESRD secondary to a chronic TMA presented 3 months following a renal transplant with a rising creatinine (1.44 mg/dl from a baseline of 0.9 mg/dl). His prograf level had ranged from 5-7. His flow XM was positive although no donor-specific antibody was detectable on a single antigen bead. His H&E stain is seen below.

He has a moderate interstitial infiltrate. (A) marks an enlarged, abnormal nucleus with a Cowdry type B inclusion. These inclusions can be seen both in adenovirus infections and in patients with BK nephropathy. (B) marks a lymphocyte in the proximal tubular epithelium – tubulitis. The absence of significant necrosis makes adenovirus less likely and, given the recent history of a renal transplant, the likeliest diagnosis therefore is BK nephropathy.

This image shows immunohistochemical staining for BK (SV-40) in the renal cortex. There is some cytoplasmic staining in surrounding tubules. However, this is non-specific. There is intense staining in the nuclei of infected cells (which are also enlarged relative to the non-infected cells) and this is highly specific for BK-virus infection.

The final image is a EM image of an infected cell. Because BK-viral infection tends to be focal, it is unusual to actually see this appearance on EM. There is the appearance of a crystalline array of viral inclusions and in BK-virus, these tend to the in the range of 40-50 nm in size. In contrast, the inclusions in patients with adenovirus tend to be larger.

(Click any image to enlarge)

More Fruit Please

Current Opinions in nephrology and hypertension has an excellent review this month on the rationale for bicarbonate treatment to slow the progression of CKD. The original data animal data was derived from the 5/6 nephrectomy model where rats fed with an acid chow developed metabolic acidosis and had relatively rapid GFR decline that could be ameliorated by giving the rats sodium bicarbonate. Interestingly, switching them to a low-acid, soy-based diet had a similar effect suggesting that simply reducing net acid intake is just as effective. The same group developed a 2/3 nephrectomy model in rats where they did not develop acidosis but the decline in renal function could still be slowed by treatment with bicarbonate. Current guidelines in humans suggest that patients should be prescribed bicarbonate when the TCO2 is less than 22 but recent studies have suggested that even above this level, patients with a reduced GFR may have net acid retention in the kidney with a potential for consequent renal injury that could be prevented by alkali treatment. This, of course is balanced by the fact that we do not want to give large quantities of sodium to patients with CKD.

One suggestion is to look closer at the diet of patients with CKD. The biggest source of dietary acid is animal protein and reducing meat intake will reduce overall acid intake (in contrast, we all see elderly malnourished patients on dialysis with high pre-dialysis bicarbonate levels that is actually a negative prognostic sign). The DASH diet is high in fruits and vegetables and is already a first line treatment for hypertension. Because it has a high component of fruits and vegetables, it has a high alkali content and could substitute for exogenous bicarbonate treatment in some patients. The trade-off is that it is also high in potassium and this would need to be carefully monitored in patients with a low GFR. The take home for me is that this explains, at least in part, the deleterious effects of a diet high in animal protein in patients with CKD and that we can potentially treat acidosis in these patients without resorting to large quantities of oral sodium bicarbonate. See this previous post on the benefits of bicarbonate therapy in patients with mild CKD.

Combo

Azilsartan medoxomil is a relatively new angiotensin receptor blocker and a study was recently published in Hypertension which compared the combination of two different doses of this drug with chlorthalidone against olmesartan in combination with hydrochlorothiazide for the treatment of stage II hypertension. Both combinations were effective at treating hypertension although the reduction in systolic blood pressures was significantly higher in both azilsartan medoxomil/chlorthalidone arms. There was very little difference between the higher and lower doses of azilsartan medoxomil in terms of effectiveness but there was a higher incidence of adverse effects (mostly dizziness/hypotension or an elevated creatinine) in the high dose group.

This begs the question whether the increased effectiveness of the new combination was due to the effect of the azilsartan medoxomil or the chlorthalidone. Chlorthalidone and hydrochlorothiazide have never been directly compared in a randomized trial and this study is unlikely to ever be done because it simply is not cost effective. However, there is a growing consensus that chlorthalidone is the more effective drug for the treatment of hypertension and prevention of secondary events. Add this to the fact that the majority of patients are on suboptimal doses of hydrochlorothiazide and there is an argument that we should be starting patients primarily on chlorthalidone (if not switching existing patients). To give the authors of this paper their due, they did not gloss over this fact and included a paragraph in both the introduction and discussion about the relative effectiveness of chlorthalidone vs. hydrochlorothiazide and suggested that this could have contributed to the increased effectiveness of their combination drug.

I believe that we should always try to give patients as few tablets as possible and as a result, there is a certain logic to combinations of ARB/ACEi + thiazide diuretics. This is the first ACE/ARB that has been combined with chlorthalidone in a single pill and it may be an attractive option for that reason. See this review about the relative benefits of chlorthalidone vs. hydrochlorothiazide (although these authors did not think that the evidence was sufficient to argue convincingly for one over the other), and this previous post by Lisa about the relative efffectiveness of the two drugs.

It's a pity that this study was not done as a direct comparison of two ARBs in combination with chlorthalidone as it would have been easier to judge the relative merits of the drugs without this significant confounding factor.

Myeloma Cast Nephropathy: New treatment possibilities

There are a laundry list of renal complications in multiple myeloma that have been previous reviewed on RFN.  Myeloma cast nephropathy is one of the most frequent, being found in approximately a third of patients in autopsy series.  Acute kidney injury is a common presentation of myeloma cast nephropathy with a variable amount of proteinuria.  As a tubular interstitial lesion with intact filtration barrier lower levels of albuminuria are typically present however large amounts of serum free light chains can be present leading to the classic findings of a negative urine dipstick (which detects albumin) with high levels of proteinuria by quantitative evaluation (stay frosty medical students, your intern is just itching to pimp you on this one).

On light microscopy diffuse tubular damage resembling ATN is seen along with distinctive distal tubular casts (in contrast to light chain fanconi syndrome where intracellular proximal tubular deposits are seen).  These casts often have sharp edges, a tendency to fracture (image on the left) and frequently have adherent neutrophils, monocytes or multinucleated giant cells around their periphery (image on the right).

Two papers from a group in Alabama shed light on the mechanism of formation of these casts and new potential treatment strategies.  It has long been known that the casts are composed of light chains bound to Tamm-Horsfall protein.  What the group first showed is that the CDR3 region on free light chains is the critical determinant of the binding with Tamm-Horsfall protein.

In their more recent paper, they report the development of a competitive inhibitor of the light chain Tamm-Horsfall protein interaction by blocking the Tamm-Horsfall protein binding site.  In a rodent model, in which human serum from patients with multiple myeloma was used to induce myeloma cast nephropathy they demonstrate the ability of the inhibitor to prevent both the histologic changes of myeloma cast nephropathy as well as AKI.

The inhibitor was infused just four hours after the serum containing light chains so future studies will need to examine situations that more closely mimic human disease in which presentation to care is delayed for much longer periods of time.  Despite this, the study adds to our understanding of the mechanisms on AKI in patients with myeloma casts nephropathy and provides a new avenue for investigation of treatment of renal disease in patients with myeloma casts nephropathy independent of chemotherapy.

Images from the recent NephSap Pathology edition.

Conference Review: Renal Biopsy in Medical Diseases of the Kidneys

I'm not a huge conference goer.   I've been to ASN a few times and have made a brief appearance at the Advanced Nephrology for the Consultant down in San Diego but otherwise haven't seen much of the conference circuit.  But when I got the Columbia flyer for the Renal Biopsy in Medical Diseases of the Kidneys a few years ago I knew it was going to be something I'd have to eventually check out.  It features the core of the GN clinical and pathology brain trust lecturing on what they know best: what GNs look like and how to manage them.  Falk and Jennete on ANCA, Appel and D'Agati on SLE, Rennke on, well, anything.  So this summer I finally got myself organized and funded and took the trip out to Manhattan to see the show.

First, a few general comments.  Staying in Manhattan is expensive.  Like $400 a night expensive.  The conference had a block of rooms reserved at hotel called the Lucerne for $200 a night.  I procrastinated and called the hotel after the deadline listed in the flyer and was politely told that all the rooms were gone and I could now book one for $440 a night if I was interested.  I declined and luckily had a family member take mercy on me and allowed me to stay with them on short notice.  If that hadn't come through I was ready to book a room through Airbnb which, if you haven't used it, is a cool site where you can find locals renting out space in their homes for cheap.

Second, it is hot and humid in Manhattan in the summer. Crazy hot. Bring wardrobe accordingly. I scuttled between air conditioning on the subway, lecture hall and my hosts place the whole week (I know, soft Californian behavior).

Third, take advantage and see Manhattan. I channeled my inner intern and skimped on sleep to hit the conference then experience the city.  Well worth it.

As for the conference it is certainly one of the best I've ever been to.  It's truly education focused, the talks are given in series rather than parallel like some of the big conferences so you're never at risk for missing anything.  The speakers are, for the most part, amazingly clear and avoid the common sin of nerding out on their own particular pet projects but rather focus on big picture relevance.

It's fun watching the older and younger members of the team interact as they clearly like each other and have a great back and forth.  You also get a sense of how some of the younger faculty like Glenn Markowitz, Andrew Bomback and Leal Herlitz are coming into their own and making their marks on the GN world.

The group aren't afraid to give their opinions when it gets to the grey areas.  Who doesn't want to hear how Gerry Appel manages not so clear cut cases of Lupus Nephritis?

Lots of path slides, which for those like myself about to take boards, is great review.  The faculty clearly take pride in their lectures and are up-to-date current in their lectures with recent literature incorporated.  Lots of interested cases discussed.  Very nice syllabus with all slides included.  If they want to kick up their game they could go for online access to high res versions of the path slides - though many of them you can find in the recent NephSap renal path edition.

My inner intern unfortunately caught up with me on the last day and I missed Saturday morning and had to catch a flight out before the path and case workshops in the afternoon.

My only gripe would be the daily supplied lunch - terrible.  I bailed and braved the heat to find something good to eat, which was actually a lot of fun.  All in all a wonderful conference that I highly recommend.  I kept up a pretty good twitter feed of pearls from the first three days of lectures which you can check out here.

A unified view of abnormal sodium regulation in the nephron

Summer has come to the northern hemisphere and it is time to praise our kidneys for all the hard work of preserving the intravascular volume. Although only 30% of Na reabsorption takes place in the distal nephron, this is the place for most common genetic diseases causing abnormal sodium handling:

What are the responsible proteins for these diseases?

1. Bartter syndrome: Na reabsorption decreases via NKCC2 due to defects in NKCC2, ROMK and basolateral Cl channels or from an overactive basolateral CaSR.

2. Gitelman syndrome: Na reabsorption decreases due to a reduced number of NCCs on the luminal membrane.

3. Pseudohypoaldosteronism type 1: Na reabsorption decreases due to the defects in ENaC or mineralocorticoid receptor.

4. Liddle syndrome: Na reabsorption increases due to a higher number of ENaCs on the luminal membrane (they are spared from ubiquitination).

5. Gordon syndrome: Na reabsorption increases due to a higher concentration of NCCs on the luminal membrane (defects in WNK4 or overactive WNK1). More recently, mutations were discovered in the genes encoding KLHL3 and CUL3 proteins.

CUL3 is a component of ubiquitin ligase and KLHL3 is its partner (expressed in the DCT). It is speculated that the defects in these proteins may change the distribution of NCC.

Is this clinically relevant?

In Gordon syndrome, these mutations can occur de novo and are encountered more frequently (47% for KLHL3 and 32% for CUL3) than those involving the WNK kinases (13%). It appears that they are under-diagnosed and some of the cases of RTA type 4 with hypertension could be caused by them!

50 years after Bartter syndrome was described, the work on mechanisms responsible for abnormal Na regulation in the nephron continues…

Posted by Tomoki Tsukahara MD