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The Essential Role of Vitamin D in Chronic Kidney Disease: Reaching Patients with Hypertension
and Diabetes

Identification and Staging of Chronic Kidney Disease in Patients with Hypertension and Diabetes

Chronic kidney disease (CKD), a progressive and potentially fatal disorder affecting an estimated 20 million Americans, often goes unrecognized and thus untreated until it reaches an advanced stage. Importantly, diabetes and hypertension are the leading causes of reported kidney failure in the United States (United States Renal Data System. Annual Data Report. 2000). “It is important that clinicians assess individuals with diabetes and/or hypertension for CKD, to allow for early intervention and hopefully delay or prevention of CKD progression and associated complications,” said Keith C. Norris, MD, Professor of Medicine; Associate Dean for Research; Program Director, Clinical Research Center; Charles R. Drew University of Medicine and Science, Los Angeles. According to Dr. Norris, an understanding of the staging and monitoring recommendations for CKD is key to early detection and effective treatment.


CKD Morbidity and Mortality
Chronic kidney disease is defined as either 1) a glomerular filtration rate (GFR) of < 60 mL/min/1.73 m2 for 3 or more months, with or without kidney damage or 2) kidney damage for 3 or more months, characterized as a structural or functional abnormality of the kidney with or without decreased GFR and demonstrated by abnormalities by pathology, blood, urine, or imaging tests. The recently released National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines detail the five stages, diagnosis, treatment, and monitoring of CKD (National Kidney Foundation. Kidney disease outcomes quality initiative clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 2002). According to Dr. Norris, routine monitoring and identification of CKD stage is critical to early and appropriate intervention (Table 1).

CKD is associated with a progressive deterioration of kidney function, and an early decrease in vitamin D. This leads to the development of reduced calcium absorption, elevated calcium-phosphate product, and secondary hyperparathyroidism, which are, in turn, associated with increased CKD-related morbidity and mortality. Importantly, persons with CKD have a significantly increased mortality rate. “People who are 35 and undergoing dialysis have the same expected mortality rate as those who are 85 from the general population,” Dr. Norris explained.

CKD-related mortality includes death not only from end-stage renal disease (ESRD), but also from cardiovascular disease (CVD). Indeed, CVD is the leading cause of death in persons with CKD, and CVD-associated mortality is increased 10 to 100 times in persons with CKD (Levey et al. Ann Intern Med. 2003;139:137). Early stages of CKD show albuminuria as well as proteinuria, along with increased coronary heart disease and left ventricular hypertrophy.

As CKD progresses, GFR is decreased and arteriosclerotic CVD is increased (Eknoyan. Am J Kidney Dis. 2002; 39:S1). “Finally, emerging evidence suggests that vitamin D may interact with the renin-angiotensin system, and vitamin D deficiency in persons with CKD may contribute to the development of atherosclerosis, myocardial hypertrophy, and myocardial restructuring,” Dr. Norris noted (Rostand & Drueke. Kidney Int. 1999;56(2):383. Boucher. Br J Nutr. 1998; 79(4):315-27. Erratum in: Br J Nutr. 1998; 80(6):585). Other common comorbidities and complications of CKD include diabetes, hypertension, dyslipidemia, anemia, malnutrition, metabolic acidosis, and renal osteodystrophy.

“Importantly, early CKD is often completely asymptomatic, making identification and monitoring of individuals at high risk essential,” Dr. Norris said.

CKD Risk and Early Detection
Persons at increased risk of developing CKD include those who are older, have a family history of nephropathy, are members of an ethnic/racial minority group (especially African Americans and Native Americans), are obese, or have diabetes and/or hypertension. “Indeed, diabetes and hypertension account for every two of three cases of CKD, and are the leading causes of reported kidney failure in the United States,” Dr. Norris noted (United States Renal Data System. Annual Data Report. 2003).

According to Dr. Norris, physician assistants and other primary care providers play a key role in the early detection and treatment of CKD. In individuals at increased risk for the disease—such as those with diabetes and/or hypertension—implementation of three simple screening measures is useful: routine assessment of blood pressure; serum creatinine for GFR; and urine analysis of albumin:creatinine ratio for proteinuria (Levey et al. Ann Intern Med. 2003; 139:137). Other recommended laboratory tests include ultrasound, serum electrolytes, and urinary concentration or dilution, and urinary pH. Providing routine screening, along with treatment of modifiable risk factors, allows for effective delay or prevention of disease progression.

CKD Staging and Intervention
In persons who have CKD, the stages of CKD offer multiple targets to treat comorbid conditions and to slow progression of disease (Figure 1). With specific treatment strategies depending on the stage of disease, treatment goals include maintaining normal parathyroid hormone (PTH), serum phosphorus, and serum calcium levels; preventing parathyroid gland hyperplasia; and maintaining normal skeletal function. In addition, long-term strategies are needed to reduce the risk of renal osteodystrophy and CVD-associated morbidity and mortality.

According to Dr. Norris, in patients with stage 1 CKD, clinicians need to confirm the diagnosis, initiate treatment of comorbid conditions, and begin assessing and treating modifiable risk factors. In those with stage 2 disease, clinicians need to assess and monitor progression, act to reduce risk factors, and initiate interventions to protect against CVD and other complications. In patients with stage 3 disease, complications such as anemia and left ventricular hypertrophy begin to emerge. Clinicians should initiate aggressive treatment of complications. In those with stage 4 disease, patients should be prepared for possible dialysis or transplantation. “In patients with CKD, numerous interventions to modify risk factors and treat complications may be implemented. These include diet and exercise, aggressive glycemic control in those with diabetes; aggressive blood pressure control using angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or other antihypertensive agents; aggressive treatment of proteinuria; aggressive management of hyperlipidemia or hypercholesterolemia; and treatment of vitamin D deficiency and secondary hyperparathyroidism,” Dr. Norris explained (Yu. Arch Intern Med. 2003; 163:1417).

In closing, Dr. Norris noted the importance of screening in those at increased risk for CKD, and close monitoring of GFR; calcium and phosphate levels; and PTH levels in patients with CKD. Dr. Norris emphasized that monitoring PTH and vitamin D status, along with consideration of active vitamin D therapy, is important in patients with stage 3, 4, or 5 CKD. “Physician assistants and other primary care providers play a critical role in ensuring adequate screening; early detection; and appropriate treatment of risk factors, primary disease, and comorbidities and complications to prevent CVD, ESRD, or death in patients with CKD,” he concluded.

 

Recommendations for the Initial Timing and Treatment of HIV-Infected Patients

“For those of you in primary care, clinical practice is easier, believe it or not,” said Susan LeLacheur, MPH, PA-C, Physician Assistant at George Washington University, Washington, DC. “Guidelines allow you to easily apply the data from the research to your practice.”

One of the first considerations is when to begin treatment. Aggressive treatment with large doses of medication lead to toxicities. Waiting until there is damage and then treating is not productive either.

Early treatment does have some advantages. It is easier to get viral counts down and protect the immune system. From a public health viewpoint, low viral load means less likelihood of transmission. The disadvantages include having to take medications every day, various toxicities and- since it is not often that the virus is completely suppressed- resistance (DHHS, Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. http://aidsinfo. nih.gov). (Table 1)

The guidelines suggest that everyone with a CD4 count of 200 cells/mm3 and below or who are symptomatic should start treatment. Those with CD4 levels between 200 and 325 should be considered for treatment according to the guidelines, but this is controversial.

“The bottom line is that treatment depends on the patient,” she said. “Medications should be started before the CD4 count drops below 200 because the treatments do not work as well below that threshold and the danger of illness dramatically increases.” One approach would be to use two NRTIs such as zidovudine or didanosine with a non-nucleoside. Efavirenz is generally preferred when using a NNRTI. The NRTIs might be zidovudine, didanosine or stavudine with either lamivudine or emtricitabine used along with efavirenz.

“The decision on which medications to use first focuses on the NRTI,” said Ms. LeLacheur.

Zidovudine’s adverse impact on anemia means that it is probably not a first-line medication in patients who are anemic. Stavudine may cause neuropathies and is strongly implicated in lipodystrophy and other metabolic complications. Emtricitabine is similar to lamivudine and they should not be used together. However, emtricitabine may be a good alternative choice because of its longer half-life.

In choosing an NNRTI, efavirenz should never be used in women who are pregnant or might become pregnant. Nevirapine has a good safety profile in pregnancy and it may help prevent mother-to-child viral transmission, but it does potentially cause hepatic toxicity in women with higher CD4 counts.

Staszweksi, et al. looked at 600 naive patients who were placed on a efavirenz/ lam-ivudine regimen and randomized to either tenofovir+ a stavudine placebo or stavudine+ a tenofovir placebo and followed for 96 weeks. In this cohort, the tenofovir regimen worked equally well with the stavudine. Thus, tenofovir’s inclusion as a preferred option (Staszweski S, et al. 10th CROI, 2003;Boston, MA. Abstract 564b).

The COMBINE study used a zidovudine/lamivudine backbone to compare nevirapine with nelfinavir. The results indicated that the two medications were roughly equivalent. The results were, not however, statistically significant due largely to a small sample size (Podzamczer D, et al. IAS Conference on HIV Pathology and Treatment. 2001. Abstract 7).

The side effect profile may be the deciding consideration when beginning treatment. Both efavirenz and nevirapine can cause rashes, tend to select for class resistance (K103N) with failure, and both can increase PI catabolism complicating therapy. Efavirenz can have central nervous system (CNS) effects, especially vivid dreaming, that are short-lived. Nevirapine can have liver toxicities.

“When you can’t completely get rid of a bug, you’re going to end up with resistance and we cannot completely get rid of this bug,” said Ms. LeLacheur. “Once you lose the ability for either of these drugs to work, you have lost the whole class.”

VanLeth and others looked at two dosages of nevirapine (once-a-day 400 mg or twice-a-day 200 mg dose) versus efavirenz alone and nevirapine+efavirenz. They found that using the two drugs together resulted in higher toxicities. The once-daily 400 mg dose increased hepatic toxicity. This study was underpowered to address efavirenz vs. nevirapine comparisons (van Leth F, et al. Lancet. 2004;363:1253).

Clifford and others studied the CNS concerns of efavirenz. Initial problems with vivid dreams, sleep problems, and the digit-symbol test for eye-hand coordination had all resolved by week 24 (Clifford D, et al. 2nd IAS. 2003;Paris, France Abstract 54).

“There are some caveats to remember when prescribing nevirapine,” noted Ms. LeLacheur. “Women with CD4 counts above 250 cells/mm3 have a greater risk of hepatotoxicity. The greatest risk of potentially fatal events comes in the first six-weeks of treatment. Patients should be monitored closely for 18 weeks as the injury may continue after the drug is stopped.”

The other option for treatment-naive patients is a PI-containing regimen. One of the more widely studied combinations is lopinavir with ritonavir, also known as “boosted lopinavir”.

“Although there are others ways to boost, it is suggested that primary care practitioners stick with ritonavir,” said Ms. LeLacheur. “Boosted lopinavir is recommended for use with lamivudine plus either zidovudine or stavudine.”

There are some new PIs and most of the research compares them to nelfinavir. Fosamprenavir is comparable to nelfinavir overall. However, when you look at viral load, patients with higher loads at the start did better on the newer medication (Rodriguez-French A, et al. JAIDS. 2004;35:22).

Boosted lopinavir also has durability advantages when compared with nelfinavir. The proportion of those taking lopinavir/ritonavir and a nelfinavir placebo with a HIV RNA < 50 c/mL was higher at 96 weeks (p=.001) than those taking nelfinavir with a lopinavir/ritonavir-placebo (Walmsley S, et al. NEJM. 2002;346:2039).

The patient is the best guide when deciding between using a PI and a NNRTI. PIs have more GI effects and more lipid problems. Patients with diabetes or a family history of heart disease may be better suited to efavirenz or nevirapine. For those with a psychiatric history, the concerns about vivid dreams should probably be considered prior to prescribing efavirenz. Those who are taking many medications for other reasons may not be good candidates for PI treatment because of high levels of drug interactions.

“It does seem from the research that it is better to change from a non-nucleoside to a PI-containing regimen than the other way around,” said Ms. LeLaucheur.

Another option for consideration when PIs or NNRTIs are not appropriate is triple nucleoside regimens. The only combinations considered to be viable are abacavir+ lamivudine + zidovudine or abacavir+ lamivudine + stavudine “Unless using zidovudine in pregnancy to prevent infection of the fetus and not to treat the mother, never let your patients out the door with only one medication,” stressed Ms. LeLaucheur. “There are a large number of other drugs and combinations that the guidelines say should not be considered. Familiarize yourself with them before prescribing.”

Case Studies
John came to Dr. Bowers’ practice in 1996 with a VL of 20,000 and a CD4 count of 362 cells/mm3. They initially decided not to treat. He was stable until September of 2003 when his viral load spiked to 322,000, although his CD4 count was stable at 387.

When seen a month later, his CD4 count had dropped to 89 and VL to 123,170. By November he had developed Kaposi’s sarcoma (KS), had rheumatoid arthritis (RA), and was taking hydroxychloroquine and celecoxib. He had expressed some depressive symptoms, but was not on medication.

“I can’t explain what happened because there were no other changes in his health and he was in a monogamous relationship with no history to suggest exposure to a new strain,” said Dr. Bowers. “So we had to stop following and begin to think about which regimen to start him on. I like to use two NRTIs as a backbone and add either a PI or NNRTI.”

Dr. Bowers was concerned about a NNRTI-containing regimen initially given his high viral load. The sudden explosion of KS increased the desire for greatest potency possible. He settled on atazanavir boosted by adding ritonavir with NRTIs tenofovir and atazanavir.

“You get four HIV physicians on a stage you will get six opinions on starter medications,” said Dr. Bowers. “I chose atazanavir/ritonavir because of once-a-day dosing, which is very important to our patients.”

A month later, the VL was down below 1,000 and T-cell percentage had increased from 9% to 20%. By 12 weeks, the viral load had dropped to 70.

This improvement was short-lived and by March his T-cells had drifted back down to 13% and the VL was 189. At this time, the doctor ordered phenotyping, which came back as wild-type.

The next month, his CD-4 count was 179 and VL 208. His KS was disappearing, the RA has resolved and he felt great. However, the gold standard is that VL should be <50 at six months.

“One option is to intensify the regimen,” said Dr. Bowers. “I am going to add didanosine because of its once-a-day dosing and use an interaction with tenofovir to see if that will help.”

JA is a patient of Ms. LeLacheur. He is newly diagnosed with HIV, has an undocumented history of thrush, a current CD4 count of 275, and VL of 125,000. He has a family history of cardiovascular problems and diabetes and is a smoker.

He is in the range where the decision to treat or not is unsettled. He is concerned about his test results and wants to start treatment immediately.

“He has a strong history of CVD and diabetes in his family and a highly variable schedule,” said Ms. LeLacheur. “So I gave him a combination of zidovudine and lamivudine plus efavirenz. This allowed us to avoid metabolic and lipid problems and maintain twice-a-day dosing.”

He had an urgent care visit with another practitioner a couple of weeks later, was found to have anemia and was sent home with iron and a vitamin. When he next saw Ms. LeLacheur, he was taken off zidovudine for possible medication-induced anemia. In its place, he was given stavudine with lamivudine and efavirenz.

She saw him again shortly thereafter and labs were back to normal. This time, he mentioned during a review of systems that he had some tingling in his toes. A new vibratory sensation test was compared with one from the initial assessment. There was a demonstrable change in sensation triggering a change in medications.

“We put him on once-daily tenofovir, switched him to a once-a-day dosing of lamivudine and continued the efavirenz,” said Ms. LeLacheur. “He got very nervous about switching medicine so frequently having heard that your first regimen is usually the best. I explained that this was still his first regimen since the drugs were working and toxicities were the reason for the changes.”

Prevention and Treatment of Secondary Hyperparathyroidism in CKD:
The Role of Vitamin D Therapy

“Chronic kidney disease [CKD] affects approximately 20 million Americans. To delay or prevent the development of secondary complications of CKD, including secondary hyperparathyroidism [HPT], the early identification and treatment of disease is essential,” said Joanna Q. Hudson, PharmD, Assistant Professor, Department of Pharmacy and Department of Medicine, Division of Nephrology, University of Tennessee, Memphis. As CKD advances, secondary complications—such as anemia, secondary HPT, and renal osteodystrophy—often develop. One of the earliest complications occurring with a loss of kidney function is that of secondary HPT, with CKD-associated changes in vitamin D metabolism contributing to the progression of this condition. According to Dr. Hudson, “Vitamin D therapy provides an effective therapeutic option in preventing and delaying the progression of secondary HPT and its complications.”

Pathophysiology of Secondary Hyperparathyroidism
In patients with CKD, morbidity and mortality rates are high, with numerous secondary complications developing with progressive loss of kidney function. One of the earliest complications occurring with a loss of kidney function is that
of secondary HPT. According to Dr. Hudson, “Vitamin D deficiency plays a critical role in the development of secondary HPT, a condition that is clearly linked to increased morbidity and mortality in persons with CKD.”

Most of the human body’s Vitamin D requirement is met through casual exposure to sunlight. Exposure of the skin to ultraviolet (UV) rays initiates the conversion of vitamin D precursors to the active form. The first hydroxylation step occurs in the liver as vitamin D is converted to 25(OH)D. This precursor is subsequently metabolized in the kidney via the 1-alpha hydroxylase enzyme to produce the active form of vitamin D—1,25(OH)2D3, or calcitriol. Through its interactions with vitamin D receptors, calcitriol decreases parathyroid hormone (PTH) synthesis, increases calcium and phosphorus intestinal absorption, and stimulates bone resorption. Importantly, persons with CKD can have reduced synthesis of the vitamin D precursor, 25(OH)D. In addition, because calcitriol is synthesized in the kidney, patients with CKD develop active vitamin D deficiency and thus secondary HPT. As renal failure develops, an inverse relationship between phosphorus and calcium is observed. As clearance of phosphorus decreases and serum phosphorus levels increase, serum calcium levels decrease. “It is this decline in serum calcium that acts as the primary stimulus for a compensatory increase in PTH. As the disease progresses, the risk for other serious complications is increased, including hypercalcemia (in large part related to use of calcium-containing phosphate binders), bone disease, and cardiovascular disease (CVD) (Figure 1) (Brown et al. Nephrol Dial Transplant. 2002: 17(suppl 10): 10). “Thus, early management of CKD is critical to prevent progression of secondary HPT and other associated complications,” Dr. Hudson said.

Potential Complications of Secondary Hyperparathyroidism
In individuals with secondary HPT, associated complications can include long-term skeletal disease, renal osteo- dystrophy, and CVD, although more research is needed to further understand this association. Indeed, CVD-related death is increased 10 to 100 times in persons with CKD (Levey et al. Ann Intern Med. 2003; 139:137). “An association between high PTH levels and increased mortality has been observed. In one study, PTH levels above approximately 500 pg/mL were associated with a significant increase in risk of sudden death,” Dr. Hudson said (Ganesh et al. J Am Soc Nephrol. 2001; 12:2131). “An elevated calcium-phosphate product, in excess of approximately 70 mg2/dL2, has also been associated with a significant increase in risk of mortality,” she added (Block et al. Am J Kidney Dis. 1998;31:607).

“Given the morbidity and mortality associated with CKD and secondary HPT, early and aggressive intervention in patients with any level of kidney dysfunction is warranted,” Dr. Hudson said. Dr. Hudson recommended that all clinicians review and follow the recently published National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, which outline the screening, diagnosis, staging, treatment, and monitoring of CKD and associated complications (National Kidney Foundation. Kidney disease outcomes quality initiative clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 2002).

The prevention or treatment of secondary HPT involves early and aggressive intervention to control serum phosphorus levels, maintain serum calcium within normal limits, prevent hypercalcemia, maintain target PTH levels, and prevent parathyroid gland hyperplasia. According to Dr. Hudson, treatment should include dietary restriction of phosphorus, use of phosphorus-binding agents, prudent use of calcium- containing binders, and vitamin D therapy. Because many persons with CKD are deficient in 25(OH)D and cal-citriol, supplementation may be necessary. In persons with stage 3 and 4 CKD and elevated PTH levels, monitoring of 25(OH)D is recommended and supplementation with a vitamin D precursor agent should be considered. In those with more advanced CKD, supplementation with active vitamin D, or a vitamin D analog, may be needed to regulate calcium, maintain normal bone metabolism, and prevent secondary HPT.

The Role of Vitamin D Therapy
The recent National Kidney Foundation K/DOQI guidelines on bone metabolism and disease recommend earlier consideration of vitamin D therapy in persons with CKD. “The challenge in providing vitamin D therapy is maintaining calcium, phosphorus, and PTH levels without oversuppression of PTH and subsequent development of adynamic bone disease,” Dr. Hudson explained. For this reason, differences in the currently available vitamin D analog agents should be considered for individual patients. In a study of patients with CKD who received either calcitriol or paricalcitol, both agents achieved effective suppression of PTH. However, there were fewer episodes of hypercalcemia in paricalcitol-treated patients compared with the calcitriol group (Sprague et al. Kidney Int. 2003;63: 1483).

Importantly, emerging evidence suggests that active vitamin D therapy may provide benefits beyond the control of PTH, calcium, and phosphorus levels. One study, for example, analyzed vitamin D levels in patients with known risk of coronary artery disease. “The results showed that lower vitamin D levels were associated with increased coronary calcification and total vascular calcification scores,” Dr. Hudson explained (Watson et al. Circulation. 1997;96:1755).
In addition, a large retrospective analysis of patients undergoing hemo-dialysis showed a 16% survival advantage in those receiving paricalcitol over those receiving calcitriol (Figure 2). In addition, the 2-year survival rates were significantly greater in patients who switched to paricalcitol (73%) than those who switched to calcitriol (64%) (Teng et al. N Engl J Med. 2003;349:446). “These promising data indicate the need for further study into the potential cardiovascular effects and survival benefits of active vitamin D therapy, along with comparison trials of individual vitamin D analog agents,” Dr. Hudson said.

Monitoring Recommendations
According to Dr. Hudson, the National Kidney Foundation’s K/DOQI guidelines provide clear stage-specific recom-
mendations for monitoring persons who are at increased risk for or who have CKD. “The research shows that few patients with CKD undergo assessment of PTH or vitamin D metabolite levels, despite the finding that calcium-containing phosphates binding agents and vitamin D therapies are associated with reduced mortality rates in the first year of dialysis,” Dr. Hudson noted (Winkelmeyer. Kidney Int. 2003;63: 1836).

The speaker emphasized the need for physician assistants and other clinicians to follow the National Kidney Foundation guidelines, and monitor patients for 25(OH)D, for calcitriol, and for PTH levels. “As clinicians on the front line of primary care, physician assistants can play a pivotal role in ensuring patients who are at increased risk for CKD undergo routine screening, and that those who have CKD are promptly diagnosed, treated, and monitored for CKD and secondary HPT status,” she concluded.


 

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