Retroperitoneal leak in PD patient

Ultrafiltration failure is a frequent clinical problem in PD patients. The most common etiologies are: fast peritoneal membrane transport, loss of peritoneal surface membrane and high lymphatic absorption. Mechanical and anatomical etiologies are occasionally seen.

Rule of 4's is used to diagnose membrane ultrafiltration failure: less than 400ml UF using 4.25% bag after 4 hours.

Sudden onset of ultrafiltration failure may occur in the setting of peritoneal leakage. Though sometimes associated with localized subcutaneous edema, it is generally difficult to detect clinically. Retroperitoneal leakage is likely to arise from a tear or a gap in the peritoneum precipitated by an increase in intra-abdominal pressure associated with walking, coughing, straining, or using a high instilled volume (2.5 L or 3 L). Red flags may include history of hernia, pleuroperitoneal communication and large infusion volumes. The acute onset of ultrafiltration failure is another suggestive finding.

Best diagnostic modality is MRI (PD fluid can be used as constrast medium).



Management: involves interruption of PD. But few reports have achieved success by using fast cycles (1hour/exchanges x8) twice a week and leaving abdominal cavity empty between sessions for 4-8 weeks.

Heavy Metal

The excellent drug development blog "In the pipeline" highlighted a fascinating phase 2 trial that is ongoing at the moment. Pentoxifylline is a methylxanthine phsophodiesterase inhibitor that has been used to treat peripheral vascular disease. It is also known to have anti-inflammatory properties and a recent Cochrane meta-analysis suggested that there may be a benefit in patients with diabetic nephropathy and albuminuria. The trial mentioned above is of an analog of one of the active metabolites of pentoxifylline called CTP-499. The clever thing about this molecule is that it is deuterated.

Deuterium is an isotope of hydrogen. Hydrogen typically has a single proton and no neutrons. Deuterium is a hydrogen atom with an added neutron. The thing that makes this interesting to drug companies is that it forms stronger bonds with other atoms than traditional hydrogen. As a result, liver enzymes take longer to break down a drug that has deuterium substituted for hydrogen and thus the half-life of a medication can theoretically be extended. There has been a rush recently to patent various drugs that have been "deuterated" although it is uncertain at this time whether or not this is going to be a successful strategy. There really are few safety concerns - the deuterated hydrogen would eventually form D2O or heavy water in the body prior to being excreted. Although too much heavy water would be deleterious, you would have to drink liters before you would see any adverse effects and the effect of these medications is likely to be minimal.

Does she drink tea?

I was quickly moving along through my busy university clinic, seeing another CKD patient when the nurse came to inform me that the patient’s hemoglobin was critically low at 5 g/dl, while the patient appeared to be just fine. I reviewed the rest of labs just to find out that the iron studies were even more impressive: iron saturation 3% and ferritin 2 ng/ml.

I inquired about the usual suspects - bleeding from various sources - but no luck there (the patient was post-menopausal and denied GI bleeding, later ruled out by EGD and colonoscopy)... Failing to identify a cause of her iron deficiency, I presented the case to my staff who, after reviewing the data, asked me an unusual question: does she drink tea? To my surprise, indeed, the patient admitted to drinking large quantities of black tea. Still puzzled about the link between the two, I jumped onto Google Scholar.

In the renal world, the only time when we talk about tea is when discussing hyponatremia in patients that are on a “tea and toast” diet. So what did I find out? An interesting South African study demonstrated that black tea inhibits non-heme iron absorption by forming iron tannate complexes. This was confirmed by a UK study which showed that black tea was the most potent out of all polyphenol-rich beverages (coffee, cocoa, etc.) in inhibiting absorption of non-heme iron.

Iron deficiency anemia is common in CKD patients, one of the latest mechanisms to be described involves the hepcidin-ferroportin axis (as recently reviewed in JASN). But today I discovered another one!

Posted by Tomoki Tsukahara

Hemoglobin Targets in CKD

For anyone who would like to read a thorough review of the current evidence with regard to Hb targets and the use of ESAs in  patients with CKD and those on dialysis, I strongly recommend the review published in Nature Reviews Nephrology this month. The field of anemia treatment if CKD has changed completely in the last 10 years. Hb targets have gotten considerably lower and the "one size fits all" model is changing into a model based on individualized Hb targets.

Two questions remain to be answered fully:
- In patients with CKD, is it the high Hb that is dangerous or is it the high doses of ESAs?
- What do we do with patients on dialysis who are not even achieving the new lower targets despite escalating doses of an ESA

My personal bias is that it is the ESA that is the problem rather than the Hb dose. Observational studies have shown that patients who achieve high Hb targets without the use of an ESA have no increased risk of CVD. ESAs are known to activate the vasculature and potentially increase the production of profibrotic and prothrombotic circulating factors. Patients who require very high doses of an ESA to achieve a particular Hb target are a high risk group and it may be that the requirement for such high doses is a marker of disease burden.

The Normal Hematocrit Study (NHCT) was published in the NEJM in 1998 and reported that there was a non-significant increase in mortality in patients in the high Hb group. However, there was a benefit in terms of QOL in patients with a higher Hb. This study has been criticized before and further analysis of the outcomes has shown that when the patients were followed for a longer period, there was a statistically significant increase in mortality in the high Hb group. Last year, a paper in KI reanalyzed the results of this study and found that this increase in mortality was evident even earlier that had been reported.

There was another fascinating finding in this report. The original study reported quality of life in patients based on achieved Hb levels. Thus, higher Hb was associated with better QOL irregardless of whether or not the patient was in the high Hb group. There was no difference in QOL between the randomized groups. In other words, it wasn't the ESA that was making the difference - there was a difference between those patients who had high Hb levels compared to those who did not reach those levels that was not related to the use of an ESA: patients who are healthier and respond better to an ESA have higher QOL scores! There was a misinterpretation of these results to mean that high ESA doses were associated with better QOL which has subsequently been proved wrong.

There was an accompanying editorial with that KI article that is definitely worth a read and advocates for new standards in the reporting of clinical trials.

Page Kidney

Patient with a history of kidney transplant s/p biopsy 2 weeks prior now undergoing chemotherapy treatment for leukemia develops acute abdominal pain, worsening renal function and hypertension. Renal US followed by CT are shown below:

Renal US with dopplers

Renal US longitudinal view

Abdominal CT with renal tx on right lower quadrant

 

Abdominal CT with red-marked kidney parenchyma

Diagnosis: Page kidney is a condition where extrinsic renal compression from a haematoma or mass results in hypertension and loss of renal function. This condition was initially described by Irwin Page in an animal model with cellophane papers wrapped around the kidney in 1939 and, subsequently, clinically in 1955.Most cases are caused by a subcapsular haematoma following blunt trauma or invasive procedures (eg. renal biopsy). Few cases of spontaneous hematoma have also been reported. Acute renal failure is due to a decreased perfusion of the compressed kidney as a result of pressure exerted by the subcapsular haematoma. In our case, the drop in platelets (4,000) after chemotherapy might have precipitated the bleeding from the previously biopsied site.

Treatment involves relief of the pressure and restoration of blood flow by percutaneous drainage. Nephrectomy is recommended in cases not resolved by interventional nephrology. Conservative course (observation and medical management) has been performed in some case reports.

Which thiazide? - the debate continues

The debate about which thiazide diuretic to prescribe patients with hypertension has been going on for years without resolution and both HCTZ and chlorthalidone have their supporters. This topic has been discussed in the past on the blog with the general sense being the chlorthalidone may be better although the objective evidence was not very strong. Unfortunately, the trial that would answer this for good: an RCT of chlorthalidone vs. HCTZ, will never be done so we have to depend on observational trials, imperfect as they may be, to try and get the answer. The argument in favor of chlorthalidone relies on the longer half-life of the drug which allows once-daily dosing with 24 hour blood pressure control.

An article in Annals of Internal Medicine gives us a little more information to help make an informed decision. The authors reviewed the records of 10000 patients in Ontario treated with chlorthalidone between 1993 and 2010. These were matched using a propensity score to 19000 patients treated with HCTZ and all were followed for a maximum of 5 years. All patients were over the age of 66 at the time of starting the diuretic and patients who had a major CV event in the year prior to entry into the study were excluded. The primary outcome was CV death or a major CV event. The authors believed that they were going to demonstrate a significant benefit for chlorthalidone. The overall results of the study are shown below:

There was no difference in the primary outcome between the two groups. In a safety analysis, the use of chlorthalidone was associated with a threefold higher OR for admission with hypokalemia and almost double the OR for admission with hyponatremia. There was no difference in the risk of all-cause hospitalization. The dose of chlorthalidone available on the formulary in Canada is 50mg daily so the thought was that this difference may be related to the use of higher doses but a post-hoc analysis showed that, irrespective of the dose used, chlorthalidone was associated with a higher risk of hypokalemia and hyponatremia. Looking back, this makes sense. The half-life of chlorthalidone is so much longer than HCTZ that potassium wasting is almost guaranteed. In fact, it has been shown in the past that chlorthalidone causes potassium wasting at much lower doses than HCTZ. Technically, HCTZ should be given twice daily because of the short half-life but it generally is not. I wonder if it was, would you see the same effect on electrolyte concentrations?

There is (as always) a caveat. There may have been some unmeasured confounding. It is uncertain why some physicians may have chosen chlorthalidone over HCTZ. The other formulation of chlorthalidone that is available in Canada is a combination drug with atenolol. As a result, the rates of use of B-blockers was higher in the chlorthalidone group and the rate of the use of ACEi was lower. This is a really interesting study. I have been tending to use more chlorthalidone in my practice over the last few years based on the limited that that were available but I am not sure what the correct answer is now. It should be noted that the UK guidelines now recommend thiazides as a 3rd line therapy for hypertension following CCBs and ACEi.

This is a great interview with the first author of the paper on Medscape which is worth reading.

New potential drug targets in ADPKD

Currently there is no good treatment for the most common inherited cause of ESRD, adult polycystic kidney disease. There have been a number of high profile trials in ADPKD in recent years. These trials have endeavored to show a reduction in cyst growth and GFR decline with everolimus, sirolimus) and most recently Tolvaptan (TEMPO). The longer (2years) and larger (433 patients) of the two mTOR inhibitor trials (everolimus) did show a significant reduction in cyst growth at one year but not in GFR reduction. The shorter sirolimus trial failed to show a reduction in cyst growth or GFR decline. The TEMPO trial was over 3 years, had 1445 patients and did show that the V2 antagonist Tolvaptan slowed GFR decline (reciprocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; p=0.001) and cyst growth, 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0). The jury is still out about the clinical applicability of these drugs and there have been criticisms. For example, tolvaptan is very expensive and would need to be used long term. In the mTOR inhibitor trials some argue doses could have been higher and the lack of hard end points speaks for itself.

However, all is not lost. A potential new drug target in ADPKD was reported by Rowe et al. in Nature Medicine last month. A good overview of the topic can also be found in the same issue.

Using MEF cells from pkd-/- and pkd+/+ mouse littermates they found that growth medium from the pkd-/- cells was more acidic and that the pkd-/- cells had a higher ATP content. To investigate which metabolic pathways might be causing this difference they used NMR spectroscopy and found lower glucose and higher lactate levels in the knock out cells. They then used a mitochondrial ATPase inhibitor to determine the source of higher ATP and found only wt cell had a reduction in ATP with this treatment.  Then the investigators did a real-time PCR analysis on the pkd-/- cells and found an upregulated glycolysis signature. They thus concluded that the pkd-/- cells rely on aerobic glycolysis for their energy demands. This is known as the Warburg effect described in cancer cells (Otto Warburg, a physician-scientist, received the Nobel Prize in Physiology or Medicine in 1931). To see if these in vitro findings translated into in vivo they used Ksp-Cre; Pkd1flox/− mice, which develop early and severe PKD and measured 13C-glucose or 13C-lactate using 13C-NMR. The findings were the same. The authors then used 2-deoxyglucose (2-DG) an analogue of glucose that is unmetabolised. They treated wt and pkd deficient mice this compound and found that the pkd deficient mice had a lower cyst index and lower 13C-glucose consumption as measured using 13C-NMR.

This interesting study proposes that the use of drugs targeting this pathway in combination with other drugs may reduce cystogenesis and progression of CKD in ADPKD. The authors do stress that their summary with regard to human treatments is speculative. In all I think the future is not so gloomy for ADPKD.

Posted by Andrew Malone

Is it time to wake up to online Hemodiafiltration?

There has been a lot of interest recently in online Hemodiafiltration (olHDF) with multiple studies  published in the past year. It is a technique which has gained favor in Europe (albeit with a lack of hard evidence) while being not utilized at all in the US for various reasons. HDF involves the addition of convective clearance, hemofiltration, to the diffusive treatment of hemodialysis (HD) which gives better clearance of middle sized uremic toxins. Very large volumes of plasma water are ultrafiltered using a high flux dialyzer with replacement solution needed to maintain fluid balance. As a large volume of fluid is infused directly into the patient, this infusate needs to be ultrapure with low levels of pyrogen and microbial contamination. The development of online generation of ultrapure replacement fluid, directly from the water treatment plant, has facilitated the roll out of olHDF in Europe. Safety concerns have also been addressed. Previously reported benefits, apart from middle molecule clearance, have included better phosphorous removal, improved intra-dialytic blood pressures, lower levels of EPO resistance, improved quality of life among others but hard outcome data has been lacking until recently. The past year has seen the publication of 3 randomized controlled trials examining olHDF versus conventional HD.

CONTRAST Study

The Convective Transport Study randomly assigned 714 patients to either olHDF or low flux HD. There was no difference between the groups in the primary outcome of all-cause mortality after a 3 year follow-up. However, in post-hoc analyses, receiving high dose olHDF (>22L of convective volume per session) was associated with a lower all-cause mortality compared to low flux HD (HR 0.62).

Turkish olHDF Study

This study randomized 782 patients to olHDF or high flux HD. The composite endpoint of all-cause mortality and nonfatal cardiovascular event rate was not different between the groups after a 2 year follow-up. However, again in a post-hoc analysis, a higher delivered dose of convective clearance (>17.4L, the median clearance) was associated with a lower risk of overall (RR 0.54) and cardiovascular mortality (RR 0.29).

Spanish olHDF Study

The latest study set out to deliver a high dose of replacement fluid and they succeeded (median convective volumes approximately 23L). They assigned 906 patients to either continue their current modality (mostly high flux HD) or switch to olHDF. The primary outcome of all-cause mortality occurred 30% less frequently in the olHDF group (p=0.01) after approximately 2 years.

Verdict: My previous experience with olHDF involved using it in an ad-hoc basis for patients with uremic symptoms despite ‘adequate’ KT/V urea or in patients with long dialysis vintage (extrapolating results from the HEMO study as high flux HD is a form of low dose HDF). Many European Nephrologists have presumed outcomes would be better but with very little data to back that up. We now have 3 RCTs suggesting a relationship between high dose olHDF and improved mortality. In our dialysis patients with such high mortality and with few interventions proven to impact this over decades, these results should be appreciated by the Nephrology community. It is at least time to reconsider the barriers to its use.

Posted by Paul Phelan

Bad Odor

Cystinosis is an autosomal recessive disease caused by a mutation in CTNS, which encodes the lysosomal transporter of cystine. This leads to intracellular cystine accumulation which leads to renal, neurological and cardiac damage. The treatment for this condition is life-long cysteamine. Back in 2011, we reported on a new formulation of cysteamine that is given just twice daily (rather than q6 hours) and is associated with a lower incidence of side effects including halitosis and body odor. There was a higher incidence of GI side effects in patients treated with the new drug. The halitosis occurs because a proportion of the drug is converted to dimethylsulfide and this can appear in expired air. The reason why the new formulation is associated with less halitosis is because, although serum drug levels are the same as with the older drug, the total dose is reduced so there is less overall conversion to the offending metabolites. This is welcome news for patients given that the drug should be started before age 5 and the halitosis and body odor cause major social problems for patients which can result in non-compliance.

Yesterday, the FDA approved cysteamine bitartrate ER (Procysbi) for the treatment of cystinosis. Essentially, this is an enteric-coated delayed-release version of the drug that is largely absorbed in the small intestine. The major issue, of course, is cost. The traditional form of the drug costs about $8,000/year while the new formulation will cost approximately $250,000. That is an enormous difference for a drug which does no more than reduce side effects. However, when you read this New York Times article on procysbi, you can better understand why the parents of these children think that this is entirely worth it.

According to the same article, it is estimated that by 2018, spending on orphan drugs will account for about 16% of overall spending on prescription drugs. This is bound to lead to conflict between insurers, patients and the manufacturers when trying to decide who to treat and who will pay. Is it worth $242,000 every year for a drug to be given twice, rather than four times daily? The problem, of course, is that this is the only way that the company can recoup the cost of development because there are so few patients with the disease - approximately 300 in the US. It should be remembered, of course, that the ulitmate cost of non-compliance in this case is very high - dialysis, transplantation and loss of future earnings so the cost calculation is not as simple as I suggested above. This is a debate that is certainly going to continue over the next few years.