HemoDoc, From Doctor to Patient

Cholesterol Studies for Dialysis Patients Fail to Control for Important Confounding Variables

By Peter Laird, MD

Joel Topf is a leading nephrologist who posts excellent commentaries on a wide range of nephrology topics on his blog, Precious Body Fluids. In a post from 2009, he described several studies on cardiovascular prevention using proven pharmaceutical agents for this in the general population including aspirin, blood pressure control and statins.

Statins fail again Statins have a tortured relationship with nephrology. Our patients have accelerated atherosclerosis and they die overwhelmingly of cardiovascular disease. So one of my primary jobs is to continually optimize cardiovascular risk factors to save my patients

Control blood pressure, start an aspirin, and maximize the statin are the lather, rinse, repeat of my world.

That said we have little data that this makes a whit of difference, at least in our dialysis patients.

Only the SHARP study has shown any benefit of statins in CKD patients which was published after Dr. Topf's 2009 post.

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial

Findings

4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe&vs619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74—0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%]vs230 [5·0%]; RR 0·92, 95% CI 0·76—1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%]vs174 [3·8%]; RR 0·75, 95% CI 0·60—0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%]vs 352 [7·6%]; RR 0·79, 95% CI 0·68—0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10&000 patients per year of treatment with this combination (9 [0·2%]vs5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%]vs18 [0·4%]), gallstones (106 [2·3%]vs106 [2·3%]), or cancer (438 [9·4%]vs439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%]vs 612 [13·2%], p=0·13).

Interpretation

Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.

There is one common factor that I believe is a fatal flaw in all of the statin trials for CKD patients, the failure to control for the many known non-thrombotic cardiovascular risk factors. CKD patients are much more likely to die from complications related to LVH and disorders of mineral bone metabolism than they are to die from thrombosis of a coronary  artery that we commonly call a heart attack. Sadly, none of the statin prevention trials in CKD patients controlled for these factors rendering their results suspect in my opinion.

The FHN short daily dialysis trial showed a significant reduction in LVH between the control group and treatment group. In addtion, the failed nocturnal FHN study did show significant improvement of mineral bone disease factors. Both of these elements are known cardiovascular risks in the dialysis population.Failure to control for these factors in the CKD population is tantamount to failing to control for smoking or a sedentary lifestyle risk factors in studies of cholesterol reduction in the general population.

We would not accept the results of any study that did not control for those confounding factors in the general polation, yet we readily dismiss the known confounding factors for CKD and dialysis patients. My own personal approach is to reduce my ultrafiltration rates with reduced blood flow rates, increased frequency and duration of dialysis and take my statin for cholesterol control. I cannot produce any study that shows that any of these factors with definitively reduce my risk of death by adopting this approach, but I can show the strengths and weaknesses of this approach from both observational studies and from evaluating the deficiencies of the statin trials in CKD patients.

Perhaps someday, the specific cardiovascular pathology known in the dialysis population will be the basis for future studies on this very important topic. Studying daily nocturnal home hemodialysis patients with a well concieved RCT would reduce if not eliminate the confoudning factors of LVH and poor mineral bone disease control prevalent in the conventional in-center hemodialysis population. In the mean time, taking my statin on a daily basis is and will remain part of my own prevention program. I remain convinced it is the correct approach.

Smoking Increases PTH levels in Dialysis Patients

By Peter Laird, MD

Smoking is a grave health risk for all people, but in those already at risk of cardiovascular disease such as the ESRD population, adding the risks of smoking carries significant risks of complications.  After nearly twenty years of clinical practice, I still advise people I meet that they should consider smoke cessation. Old habits are hard to break, that is my commenting on cigarette smoking. Stopping smoking is not that hard if and when the patient makes up their mind to do so. We can now add one more malady to the extensive list of adverse diseases associated with tobacco abuse, that of increased PTH levels in dialysis patients:

Smoking and hyperparathyroidism in patient with end-stage renal disease (ESRD)

We investigated the relationship between smoking and hyperparathyroidism in a well-characterized group of 161 nondiabetic dialysis patients. Results: Sixty-four patients (40%) were smokers. Heavy smokers had higher intact PTH (median: 280 pg/mL) and PTH1-84 (188 pg/mL) than light smokers (180 pg/mL and 95 pg/mL) and nonsmokers (169 pg/mL and 95 pg/mL). In a multiple regression analysis, smoking was independently associated with intact PTH (ß=0.29, p=0.002) and PTH1-84 (ß=0.29, p=0.002). Fifty-six of 161 patients (35%) were classified as having hyperparathyroidism. In a multiple logistic regression model the odds of hyperparathyroidism were about 4 times higher in heavy smokers (odds ratio 3.88, 95% CI 1.16-12.92, p=0.027) than in nonsmokers. Conclusion: In dialysis patients heavy smoking is independently associated with high levels of intact PTH and PTH1-84. Further observational, mechanistic and interventional studies are needed to assess the nature (causal or noncausal) of these links in ESRD.

Patients who smoked more than one pack per day were at the highest risk of elevated PTH, although those smoking less than a pack a day had a significantly higher measured PTH compared to controls. Secondary hyperparathyroidism in dialysis patients is further associated with mineral bone disease, poor phosphorus control and increased risk of cardiac anomalies.  The take home message for all smokers and especially those on dialysis is to explore smoke cessation with your health care team. With the calls by many to reduce Medicare spending on both sides of the congressional aisles, it is the responsibility of each individual to not only consider their own health consequences, but that of all patients on dialysis. Being your own best friend when it comes to taking care of yourself on dialysis is also one way to be your brother's keeper at the same time.

The Brave New World of the Renal Bundle

By Peter Laird, MD

We are now a year into the social experiment we call the renal bundle where payments for all dialysis services are bundled into a single payment with disease modifiers and QIP matrices for quality care tied to the final payment. There is no doubt that the abuses of EPO and other separately billable items under the old payment system suffered from an extreme profit motive pushing EPO dosages higher and higher with no clinical benefit and indeed, many would rightly argue, great clinical harm to those at the high dosage end with elevated Hb levels over 12.0. 

CMS.gov: ESRD Payment

Medicare payment to ESRD facilities for outpatient maintenance dialysis services furnished to Medicare beneficiaries with End-Stage Renal Disease (ESRD) is based on a prospective payment system known as the basic case-mix adjusted composite payment system.  The base composite rate covers the costs of the dialysis treatment and certain routine drugs, laboratory tests, and supplies furnished at home or in a facility.  Other items and services, particularly injectable drugs (for example, erythropoietin (EPO), iron sucrose, vitamin D), and non-routine laboratory tests are not included in the composite rate and are billed separately to Medicare.  Separately billable services represent about 40 percent of total Medicare payments per dialysis treatment.  The base composite rate is adjusted by a drug add-on payment to account for changes in the drug pricing methodology that occurred in 2005 and by case-mix factors, that is, age, body size, and a special adjustment for pediatric patients.

Since the implementation of the prospective payment system, several reports are sending a mixed message of this "brave new world" we now know as the bundle. EPO utilization is dropping dramatically as are patients average Hb levels. The biggest news of the renal bundle in 2011 was the decision by CMS to drop the lower Hb target level of 10.0 leaving the door open for providers to adopt the pre-EPO modality of iron supplementation and rescue transfusions. The literature is repleat with the dangers of patients having Hb levels lower than 10.0. PTH levels are rising and uncontrolled secondary hypoparathyroid disease will result in a net increase in the need for parathyroidectomies to control this new epidemic. DOPPS has published an interim report on the effects of the bundle and continue to monitor it effects.

DOPPS reports early trends in dialysis care after the implementation of the ESRD bundle

Anemia management

Trends in all patients: From Aug. 2010 to April 2011, average hemoglobin levels fell slightly (0.10 g/dL). The percentage of patients with hemoglobin >12 g/dL declined from 31.4% to 28.0%. The percentage with hemoglobin <10 g/dL rose from 8.5% to 10.0%, and the percentage with hemoglobin <9 g/dL was stable at ~2.7%. The average prescribed epoetin dose fell by ~3% and the average administered dose fell by 6%-7%, with a notable drop in the higher epoetin dose range. The percentage of patients prescribed injectable iron per month rose from 57% to 78%.

Mineral and bone disorder management 

Trends in all patients: Overall, the average PTH level rose sharply from 337 to 435 pg/mL from August 2010 to April 2011, an increase of 29%. No substantial changes were seen in serum phosphorus or calcium values. The reasons for the rise in PTH are being investigated; large changes in use of injectable vitamin D or oral medications are not yet apparent.

The safety net of the bundle is an ongoing and developing quality indicator payment reduction system for failing to reach the minimum quality standards. Many are now decrying the fact that just measuring the indicators is enough to qualify for payment without actually addressing some of the measured indicators. 

What to Expect from the ESRD Quality Incentive Program

By Steven Fishbane, MD

The Centers for Medicare & Medicaid Services (CMS) published the final rule for the End-Stage Renal Disease Prospective Payment System and Quality Incentive Program (QIP) on Nov. 1. This follows the proposed rule that had been published in the Federal Register on July 8, 2011.

In this article, the focus will be on the ESRD QIP. There were 88 public comments received on the QIP, and the final QIP rule reflects important changes relative to the proposed rule. The greatest changes in the QIP will be for payment year 2014. It is critically important for providers to understand the 2014 QIP because, 1) it contains major changes from previous years and 2) the performance period begins very soon: Jan. 1, 2012. This posting is a summary of the major components of the final QIP rule, with changes from the proposed rule highlighted in italics.

Despite the alleged oversight through the QIP, a distressing essay written by a leading dietitian and posted by Gary Peterson in RenalWeb today depicts the desperate plight that the ESRD bundle is having on the dietitian profession who are admittedly one of the most important clinical partners in preventing complications of dialysis care. It is not only a call to arms for dietitians, but for all concerned about the care of dialysis patients in America. It is most importantly, a call to arms so to speak for all dialysis patients here in this nation as we see many of the improvements of the last three decades in pharmaceutical care slip through the bottomless pit of the ESRD bundle with QIP indices for Hb for instance with no minimum safety zone. Instead, for Hb, the patient is now at the mercy of their provider to consider what is their "healthiest" Hb levels without any guideline to say when low is too low.

Call to Arms

MY FELLOW RENAL dietitian, if ever there was a time to stand up, make noise, and be heard, it is now. We as renal healthcare professionals can no longer sit by in the wings as Medicare and dialysis units make policies that negatively impact our patients’ lives and outcomes. I am outraged by the changes that I have seen in the past year. I am disappointed that policies are made and implemented without thinking about how they will affect those that we serve. I am disheartened that one day, I, a family member, or a friend will have to submit to the suboptimal care that these policies have created. We, as a profession, knew that there would be changes in how we treat our patients when the bundled reimbursement plan came into effect last year. I could never imagine the turn that it would take. . .

Finally, this summer, Medicare released its proposed QIP measures for 2013, which addresses bone mineral management. With the inclusion of phosphate binders into the bundled rate beginning in 2014, Medicare is proposing that units attest whether or not they are following disease markers. There is no proposal at this time on whether the unit is treating the disease. There is no mention of disease marker goal ranges, either minimums or maximums. There is no mention of accountability that medications to treat the disease are being used. I concede that we do not yet know the “ideal” ranges for calcium, phosphorus, and parathyroid hormone, but there is enough evidence to determine levels that we should not exceed without increasing morbidity and mortality in our patients.

Yes, we are entering a brave new world we call the ESRD bundle and to date, the data is not comforting. Prior to the final ESRD bundle rule, CMS had many open meetings and vast input from patients, physicians, health care providers and dialysis patient groups. The QIP was the safety net proposed by CMS to address the concerns of all involved and as congress sat idly by aloof to the outcry by many to intervene for patient safety, instead we entered quietly into this brave new world. If the latest report by the renal dietitians is any indication of where we are heading, then this brave new world may in fact be nothing more than a return to the dark ages of dialysis prior to when advances in pharmaceuticals ended many patients suffering. There is a dark cloud hanging over this nation in our dialysis centers and the QIP blindly measures the faltering indices but has no power to evoke change. A call to arms is our only choice at this point in time. It is no longer a time for complacency among dialysis patients or allied health care professionals. 

Vitamin Supplements: The Dialysis Paradox

By Peter Laird, MD

Vitamin supplements are a favorite of health advocates who help generate the demand in this billion dollar industry, yet recent studies point to the paradox of adverse outcomes from these same supplements in high dosages.   The difficulty of defining the proper role that vitamin supplements play is especially unsettled in dialysis patients who suffer the opposite extreme of documented vitamin deficits as a result of washing out water soluble vitamins during dialysis. Unfortunately, in some instances, the data on supplementing these deficiencies comes at a risk as well.

Vitamin C levels are especially low in dialysis patients according to a recent study looking at dialysis patients undergoing usual in-center schedules compared to extended hours dialysis protocols. Despite the low vitamin C level which borders on the development of scurvy, supplementation of vitamin C also increases oxalate levels even at low dosages of vitamin C which can build up in dialysis patients causing severe effects:

Water-soluble vitamin levels in extended hours hemodialysis

The major finding of this study was the high prevalence of vitamin C deficiency in extended hours hemodialysis patients compared with conventional dialysis patients. This is not unexpected as ascorbic acid is the smallest molecule (MW 176 g/mol) of the vitamins we assayed, and is readily removed by dialysis.²⁴ As the prevalence of more frequent and longer hours (quotidian) dialysis is increasing, the importance of the assessment and supplementation of vitamin C in this patient group is demonstrated.

Traditionally, vitamin C has been used sparingly in patients with end-stage renal failure, as its metabolism generates oxalate. Increased levels of oxalate can cause deposition of calcium oxalate crystals in tissues (oxalosis), with cardiac, renal, and bone manifestations reported historically.²⁷ The appropriate dose of vitamin C for patients with renal failure, as well as the impact of vitamin C dose on oxalate levels has been the subject of much debate. The European Best Practice Guidelines recommends 75 to 90 mg/day;¹⁸ however, this dose may not be sufficient to correct vitamin C deficiency in either extended or CHD patients. For example, a study of 18 conventional patients on 100 mg vitamin C daily found 5 patients had ascorbate levels in the range of deficiency (<0.30 mg/dL).¹⁵ The dose was increased to 500 mg/day for 2 weeks, which corrected the deficiency, and increased the mean plasma ascorbate from 0.69 to 1.82 mg/dL (39–103.5 μmol/L). However, because of a median increase in oxalate levels of 17%, the authors advised against high-dose vitamin C.

The balance between vitamin C levels too high or too low in extended hours dialysis remains a subject of debate with few studies available to guide the individual patient on what is the optimal strategy, truly leading to a vitamin supplement paradox between deficiency or harm from producing excessive oxalate levels with enough supplement to correct the deficiency. This is one area of study that demands a quick resolution since both extremes can cause harm to the patient.  As of yet, there is no consensus on how to proceed.

Vitamin D likewise defies definition of optimal dosage at both ends of the spectrum as well. Low levels of vitamin D can precipitate rickets and is suspected to increase the risk of cancer as well as increasing the risk of death from cardiovascular disease, it brings on cognitive impairment, and may be an important factor in the prevention of diabetes and other health related conditions. Paradoxically, several studies in the female population at risk of osteoporosis showed a tendency to induce vascular calcification with vitamin D supplementation which is likewise demonstrated in dialysis patients as well.

Dialysis patients are especially at risk of vascular calcifications and mineral bone disorders due to the loss of enzymes that activate vitamin D synthesized in the skin by exposure to sunlight.   A recent study suggested that vitamin D supplementation increases vascular calcifications in dialysis patients when phosphorus levels run high:

The dualistic role of vitamin D in vascular calcifications

The current treatment approach of providing vitamin D analogs to patients with CKD often poses a dilemma, as studies linked vitamin D treatment to subsequent vascular calcification. Recent genetic studies, however, have shown that vascular calcification can be prevented by reducing serum phosphate levels, even in the presence of extremely high serum 1,25-dihydroxyvitamin D and calcium levels. This article will briefly summarize the dual effects of vitamin D in vascular calcification and will provide evidence of vitamin D-dependent and -independent vascular calcification.

Certainly dietary guidelines for dialysis patients include eating several servings of fruits and vegetables every day which contain many of these vitamins as well as taking a daily vitamin specifically designed for dialysis patients.  Data on the efficacy of this recommendation remains scant. Vitamin D is an important element in improving anemia as is Vitamin C, but at what cost. The balance between deficiency and too many vitamin supplements remains for future studies. In the mean time, for those taking vitamin D or its analogs, one key noted in the study above is keeping phosphorus levels in check.  Likewise, there is hope that extended dialysis schedules may be able to remove the excess oxalate from increased vitamin C supplements but this remains unproven to date.

Until we have the studies available, discuss the risks and benefits with your medical team of vitamin supplementation which in the case of dialysis patients is mandatory to avoid the known consequences of severe deficiencies, control your phosphorus, eat a diet complemented with fruits and vegetables, exercise regularly which is perhaps the best "vitamin" we have, and do all things in moderation including vitamin supplements. Sometimes too much of a good thing is actually harmful. 

Combined Aerobic and Resistence Training Improves Diabetes Control - Is this a model for CKD Patients?

By Peter Laird, MD

Exercise is an important adjunct in the treatment and even the prevention of Type II diabetes.  An interesting study in the Journal of the American Medical Association revealed that it is not only the amount of exercise that is important, but also, the combined effect of both aerobic and resistence training:

Effects of Aerobic and Resistance Training on Hemoglobin A_1c Levels in Patients With Type 2 Diabetes

Conclusions: Among patients with type 2 diabetes mellitus, a combination of aerobic and resitance training compared with nonexercise control group improved HbA_1c levels. This was not achieved by aerobic or resistance training alone.

A related article in the New York Times expands upon the details in an interview with the lead author, Dr. Timothy S. Church, director of preventive medicine research at Pennington Biomedical Research Center at Louisiana State University.:

After nine months of observed exercise, participants who did the combination training lowered their blood level of the glucose marker HbA1c to 7.3 percent from 7.7 percent, on average, a drop that corresponds to a significantly reduced risk of heart disease, Dr. Church said. The improvements in the other exercise groups were not significantly different from those in the non-exercise group.

Dr. Church said he was surprised but added that the findings made sense. “Diabetes is the failure to control the amount of sugar in your blood, and the biggest user of blood sugar is skeletal muscle,” he said. “The healthier your skeletal muscle, the more blood sugar it’s chewing up and taking out of the blood.”

It is likely that this information will apply not only to patients with diabetes, but the general population as well as renal disease patients who have the added burden of overcoming sarcopenia, wasting of the muscles.  The metabolic potential of increasing skeletal muscle as an adjunct to medical therapy is an area that needs further investigation.  I have often wondered whether large muscle mass improves control of phosphorus since that is a major component of muscle activity. A simple study would be weight training in dialysis patients to see if it impacts phosphorus control.  In fact, a rather interesting study from the recent ASN connects PTH elevations to the presence of metabolic syndrome.

Metabolic Syndrome in CKD Patients May Be Linked to PTH

When taken as a continuous predictor, each standard deviation increase of natural log transformed PTH was associated with a 26% higher odds of having metabolic syndrome.  The association of PTH with metabolic syndrome was not modified by age or gender.

Taken together, it would be prudent for some young investigator to make their Renal Fellowship research project a simple cross over study of patients with elevated PTH and CKD and use the intervention of aerobic and resistance training to see if this intervention improves PTH and PO4 as well.  In the mean time, I will continue to use exercise as a key component to my own mineral-bone metabolism which I have long believed helps keep my PO4 normal even without any binders at all. The metabolic potential of active skeletal muscle training should be explored further not only for diabetic patients, but CKD patients as well.