Time for a change?

This month's issue of NDT has an interesting debate concerning whether or not clinical laboratories should start reporting CKD-EPI GFR instead of MDRD. The pro side is here while the con side is here. Basically, the argument for changing is that there is less bias in the CKD-EPI equation, it is more accurate at higher GFRs and more accurately classifies patients as stage 3 as opposed to stage 2 (in terms of overall prognosis). The counter-argument is that, although there is a slight decrease in bias associated with the use of CKD-EPI, it is not any more precise than MDRD - this is more a fault of creatinine as a test of renal function rather than a specific problem with the equations. It should also be mentioned that the CKD-EPI equation is not necessarily better in all circumstances - as documented by Leo in this post about renal transplant recipients.

To (perhaps) settle the argument on one side, the moderator of the debate wrote a commentary and came down on the side of changing to the CKD-EPI equation. The argument is that, even if the improvement is slight, we, as a nephrology community, should not settle for something that is clearly inferior in most circumstances. MDRD was developed in a population of patients with CKD and therefore does not accurately reflect GFR in healthy populations. For this reason, in the research community, there has been a move towards more use of CKD-EPI in the recent past as it is more appropriate for epidemiologic research. The switch to CKD-EPI would not require the use of any new analytes - a simple change in coding in the computers reporting results. In fact, a number of organizations have already switched.

Two other things to mention. Neither equation has been properly validated in Asian populations and this needs to be remedied. Secondly, the role for cystatin C-based or combination equations is still uncertain. Cystatin C is a better predictor of outcomes than creatinine but there are many non-GFR determinants of cystatin C that are likely biasing this and are not related to renal function. Also, the cystatin C test is expensive and has not been fully standardized. There may be a place for the combination equation in patients with borderline GFRs (45-60) in whom the diagnosis of CKD is uncertain.

Vitamin D and CV Disease - Part III

For the final part of the series on Vitamin D and cardiovascular disease, we'll focus on the relevant clinical trials. Again, for full attribution, the primary source for this is the excellent review at Nature Reviews Nephrology. Parts 1 and 2 of this series can be found by clicking here and here.

Again, we'll break up the trials into categories:

1. Inflammation: As mentioned before, vitamin D has been shown to have anti-inflammatory effects in animal studies. A number of studies have examined the effect of vitamin D supplementation on inflammatory mediators. One study took ~120 patients with CHF and treated them with cholecalciferol or placebo for 9 months. Levels of anti-inflammatory IL-10 were higher and TNF was lower in treated patients. However, there was no difference in LVEF or mortality between the two groups and about 20% of patients did not complete even 9 months with more dropouts occurring in the vitamin D group. Similar reductions in pro-inflammatory cytokines have been noted in HD patients and patients with diabetes although these studies were too small and short-term to show any clinical effects.

2. Hypertension: Results from meta-analyses have been inconsistent with one study showing a non-significant decrease in BP with vitamin D therapy and another showing a reduction in systolic BP only. Currently, there is insufficient evidence to suggest that vitamin D is effective to treat hypertension.

3. Chronic Kidney Disease: Given the well-described relationship between vitamin D and the kidney, it is unsurprising that there has been a focus on CVD prevention in patients with CKD. Again, the results are inconsistent with some studies showing a benefit in terms of CV risk and others being negative. The PRIMO study examined LV mass index in patients with CKD and looked at the effect of 48 weeks treatment with activated vitamin D. There was no difference in the primary outcome among the two groups. One important point is that, in the past, there was no focus on 25OH vitamin D in patients with CKD due to the perception that it is biologically inactive. This perception is changing and there may be a role for increased 25OH vitamin D supplementation in CKD patients although this role has not yet been fully defined.

4. Cardiovascular Death and stroke: Large meta-analyses have suggested a benefit of vitamin D therapy on all-cause mortality. The results for CV mortality and morbidity are less consistent although a benefit has been shown in some trials. One issue is that most studies do not limit treatment to patients with vitamin D deficiency while subgroup analysis of some trials shows that there is more benefit of therapy in these patients. There are a number of large trials of vitamin D currently ongoing (see table below from this recent review). Hopefully we will be able to get a clearer picture of the benefits of vitamin D therapy in the near future.

Overall, the results of the intervention trials have been disappointing and inconsistent - particularly given the strength of the observational and experimental data. At this point, we still don't know the exact role for vitamin D in the prevention and management of CV disease. There is always the suspicion that unmeasured confounders have an important part to play. The best way to get an answer is by doing well-designed RCTs and perhaps when these ongoing trials are complete, we will have a fuller idea of this role.

Vitamin D and CV Disease - Part II

In the second post on vitamin D and CV disease (again largely summarizing this excellent review in Nature Reviews Nephrology), we look at the epidemiological evidence for the association of low vitamin D levels and CVD.

1. Hypertension: Data from NHANES showed that there is an inverse relationship between vitamin D levels and hypertension after full covariate adjustment. Subsequently, data from the Nurses Health Study revealed that low baseline vitamin D levels were associated with an increased risk of incident hypertension. In patients with established hypertension, low levels of vitamin D were associated with an increased risk of CV and all-cause mortality.
2. CV Morbidity and Mortality: Multiple large cohort studies have demonstrated a relationship between low vitamin D levels and CV mortality after controlling for traditional risk factors in a wide variety of populations including Europeans and African-Americans. Data from the Framingham Heart Study suggest that a low level of vitamin D was associated with a HR of 1.62 for incident cardiovascular events after about 6 years follow-up.
3. Chronic Kidney Disease: In patients with chronic kidney disease, there is a U-shaped association between vitamin D levels and CV events. However, this relationship is attenuated after adjustment for baseline GFR suggesting that the primary portion of this risk is related to the severity of renal disease (which may be the cause of the vitamin D deficiency). Low levels of vitamin D have been associated with an increased risk of mortality in dialysis patients while also being a predictor of progression to ESRD.
3. Stroke: Low levels of vitamin D have been associated with an increased risk of ischemic stroke in participants from the Nurses Health Study.

Again, it is important to point out that all of these associations do not prove causality and that there is likely a strong lifestyle or other biologic component in these associations that is not being accounted for. Next we'll look at the clinical trials of vitamin D and CVD prevention.

(Image is from Jack Maypole at The Faster Times)

Vitamin D and CV disease

Another excellent review from the people at Nature Reviews Nephrology on the relationship between vitamin D and cardiovascular disease. Some key points:

Low vitamin D levels are associated with an increased risk of cardiovascular disease but, given the inconsistent results seen in trials of vitamin D repletion in high-risk populations, it remains uncertain whether or not vitamin D status is a mediator of disease or a consequence of poor health (decreased exercise and sunlight exposure etc.). There are a number of known pathways associated with vitamin D that could potentially influence cardiovascular risk (these headings are summarized from the NRN paper):

1. RAAS system: As mentioned in a previous post, vitamin D is a negative regulator of RAAS. Renin and angiotensin II levels are elevated in mice lacking the vitamin D receptor (VDR). In humans with low vitamin D levels, increased angiotensin II has been noted although it should be pointed out that patients with hereditary vitamin D resistant rickets (due to a lack of the VDR) do not have elevations in RAAS hormones.
2. Inflammation: Vitamin D has anti-inflammatory effects mediated via the downregulation of IL-6 and TNF expression. Cardiac endothelial cells contain VDRs and vitamin D treatment inhibits TNF activation in these cells. Given the association between inflammation and atherosclerosis, this is a potential mechanism for the putative link between vitamin D deficiency and atherosclerotic disease.
3. Endothelial Function: In vitro treatment with vitamin D downregulates the production of pro-thrombotic proteins in endothelial cells. Vitamin D deficiency has been associated with endothelial dysfunction in human studies but again, the contribution of residual confounding in these observational studies is uncertain and may be substantial.
4. Cardiac Remodeling: Studies in rodents have suggested a role for vitamin D in the prevention of LVH and adverse cardiac remodeling in models of hypertension and cardiovascular disease.

There is growing interest in the association between FGF-23 and CV disease. Treatment with vitamin D stimulates the release of FGF-23 and may be an adverse consequence of the use of supplements in patients with advanced CKD.

Given the amount of vitamin D prescribed in the dialysis world, it is important that we understand the potential consequences and mechanisms of the risks and benefits of this treatment. For appropriate references please see the NRN review. A previous summary of the use of vitamin D in CKD can be found here.

Self-cannulation

Bill Peckham, the author of the excellent patient advocacy and home dialysis blog: dialysis from the sharp end of the needle has been on dialysis since 1990 and home dialysis since 2001 where self-cannulates using the buttonhole method. Last year he posted a video on Youtube that I only came across today. It shows his technique of needle insertion. I have often wondered how patients manage to cannulate themselves at home and this demonstrates it very nicely. I am full of admiration for my patients.

 

Treatment of IgA Nephropathy - Update

Following on from yesterday's update on membranous nephropathy, I thought that this would be a good time to give an update on the treatment of another, very common glomerular disease: IgA nephropathy. IgA has been covered extensively on the RFN before including the history, pathogenesis, diagnosis, features and treatment: collected in this group of posts. This month an excellent review of the treatment of IgA nephropathy was published in Nature Reviews Nephrology which highlights some of the difficulty and controversies in the treatment of IgA.

As the authors point out, one of the major difficulties in determining the best treatment (and assessing the comparative effectiveness of therapies) is the heterogeneity in the presentation and prognosis of patients with IgA. It is extremely common, with up to 1.6% of zero-hour allograft biopsies having evidence of asymptomatic IgA. As a result, many patients are diagnosed incidentally and never have any clinically significant disease. One important issue relates to determining who is going to progress. The recently introduced MEST classification came about in an effort to define histological markers in IgA that predict progression. However, follow-up studies have indicated that the only consistent marker of progression was the degree of interstitial fibrosis and atrophy. It should be noted that this classification does not include crescents which are associated with a poor prognosis. Traditional clinical markers of progression include hypertension, increased BMI, smoking and, most importantly, persistent proteinuria of >1g/24 hours.

The treatment of IgA depends on the clinical presentation. Patients with normal blood pressure, normal renal function and no proteinuria can generally be watched in the clinic with no specific treatment and, in fact, it is debatable if these patients should be biopsied in the first place. The figure below (originally from JASN and reproduced in NRN) provides a suggested algorithm for the management of patients with IgA depending on the stage at presentation.

It is important to state that the only treatment that has been consistently been shown to be beneficial in patients with IgA is RAAS blockade.The role of corticosteroids is controversial and the current KDIGO guidelines suggest the use of steroids only in patients who have been on optimal therapy for 3-6 months, have persistent proteinuria >1g and have an eGFR of >50 ml/min/1.73m2. Low dose steroids are of no benefit and the use of higher dose steroid regimens is associated with significant morbidity so this recommendation comes with significant caveats. Other immunosuppressants including cyclophosphamide, MMF and azathioprine have been trialed in IgA and despite some encouraging results in open-label and retrospective studies, prospective studies have failed to show a consistent benefit. However, there are ongoing RCTs that will be reported in the next 12-24 months that may finally give us the definitive answer with regard to these agents.

Tonsillectomy, more commonly performed in Japan, is not recommended, either by these authors or in the KDIGO guidelines. Fish Oil may be of benefit in patients with persistent proteinuria >1g but is probably of limited use in other groups. One of the limitations of the studies of fish oil in IgA is that they were generally performed prior to the widespread use of ACEi and it is uncertain if they add any additional benefit to these agents. Again, the dose needs to be sufficient (supranormal doses).

Finally, crescentic IgA is a different entity that generally is associated with rapid progression. It is only diagnosed when more than 50% of glomeruli have crescents; the presence of a single crescent in one glomerulus should not prompt the institution of aggressive immunosuppressive therapy. Again, there are no RCTs that demonstrate a benefit of cyclophosphamide but there are some retrospective studies that have shown some effectiveness. That said, in the presence of rapidly progressive disease and active glomerular inflammation, the recommendation is that a combination of steroids and cyclophosphamide should be used.

Update on Membranous Nephropathy

U Penn established an annual one-day seminar in nephrology symposium. This year was titled “New Horizons in Nephrology: Updates in Glomerular Disease”.

Dr. Beck from Boston University gave the update on membranous nephropathy (MN). Previously, we discussed his article in the NEJM in detail, and today we will go over some key points and updates:

• 75% of MN is considered primary (idiopathic).
• IgG4 subclass is predominant in idiopathic MN.
• Anti-PLA2R is highly specific for primary MN
• Co-localization of PLA2R and IgG4 within immune deposits on biopsy.
• The majority of patients with primary MN have circulating autoantibodies against PLA2R.

There is a clear association of anti-PLA2R with disease activity.

- Positive in nephrotic state.

- Declines prior to the decrease in proteinuria.

- Absent in remission.

- Returns with (or prior to) relapse.

- Associated with recurrent MN

Methods of testing:

- Western blot

- Indirect immunofluorescence test

- ELISA : Will likely be the test of choice. Available in Europe, not yet in the US.

Treatment:

- Do NOT use corticosteroid monotherapy or MMF monotherapy for initial therapy of MN.

- No single definitive immunosuppression could be easily identified.

Current Initial therapy :

• Ponticelli regimen: methylprednisolone 1g/d iv x 3 doses followed by oral prednisone 0.5mg/kg/d in months 1,3,5; oral cyclophosphamide (2mg/kg/d) in months 2,4,6.
• Alternative initial therapy for those who refuse or have contraindications to cyclophosphamide is Calcineurin inhibitor (CNI) for at least 6 months.
• Stop if no remission in 6 months.
• If remission is attained, reduce dose every 1-2 mo by 50% and continue for at least 12 months 

Posted by Tarek Alhamad

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