Renal Disease and HIV

HIV and Diminished renal function- from POZ ect

HIV and Your Whole Health

HIV and Your Kidneys

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Weighing a delicate six ounces each—that’s less than 0.5 percent of our total body weight—the kidneys play a number of vital roles. For those living with HIV, this includes breaking down some of the medications needed to keep the viral load low and CD4 counts high. Unfortunately, like other vital organs in the body, the kidneys are not immune to diseases that can impair their ability to function. About 20 million Americans—one in nine U.S. adults—have kidney disease, and another 20 million more are at risk. Studies also show that nearly one third of all HIV-positive people have abnormal amounts of protein in their urine—a sign of potential kidney trouble.

As people with HIV continue to live longer lives thanks to antiretroviral (ARV) therapy, experts reckon that kidney disease will remain a common and potentially serious health threat. Fortunately, much has been learned about HIV and kidney disease in recent years, including the best ways to screen for it, prevent it and treat it.

What do the kidneys do?
Most people have two of these bean-shaped organs (nearly one in 750 people are born with only one kidney). They’re about the size of a fist and are located halfway up the back on both sides of the spine. Often, the left kidney is positioned up to an inch higher than the right kidney.

The kidneys contain millions of nephrons, tiny units made up of blood vessels (glomeruli) and fluid-collecting tubes (tubules), sifting about 200 quarts of blood a day. Over a 24-hour period, they filter the entire volume of blood 30 to 40 times, extracting two quarts of waste products and extra water that’s removed in the form of urine.

In addition to acting as filters, the kidneys keep track of various substances in the blood and, if necessary, release hormones to help replenish missing stock. They produce erythropoietin (EPO) to stimulate red blood cell production, renin to help control blood pressure, and the active form of vitamin D (calcitriol) to maintain calcium levels for healthy bones

What is kidney disease?
When experts talk about kidney disease, they usually refer to "renal function." According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), people with two healthy kidneys have 100 percent renal function, which is actually more than you need. This is why people can survive just fine with one kidney.

If renal function falls below 25 percent, serious health problems can occur. And if it drops below 10 to 15 percent, a person will not live long without dialysis or a kidney transplant.

While reduced renal function has several different causes, there are generally three different types of kidney disease:

• Acute renal failure (ARF): This is when serious damage to the kidneys happens very quickly. An accident might cause this, as can some medications or poisons. In some cases, ARF can lead to permanent kidney damage.

• Chronic kidney disease (CKD): Most kidney problems, including those seen in HIV-positive people, happen slowly. CKD may be "silent" for many years, meaning that it doesn't cause any noticeable symptoms but may still be damaging the kidneys. CKD, left unchecked, can increase the risk of a heart attack or stroke. Routine laboratory testing can help detect CKD in the early stages, before it causes permanent kidney failure.

• End-stage renal disease (ESRD): This is total (or nearly total) kidney failure that cannot be reversed. Patients with ESRD require dialysis or a kidney transplant to stay alive. Of note, a study conducted by Johns Hopkins University in Baltimore suggests that the risk of ESRD among HIV-positive blacks is almost 12 times higher than in the HIV-negative black population—and that the risk may actually be increasing.

What causes kidney disease?
HIV-positive people may face a number of risk factors for kidney disease.

First, it’s important to recognize that some people are naturally at a higher risk for kidney disease. These include people with a family history of kidney disease (for example, if their mother, father or other immediate relative has certain types of kidney problems). Blacks, Latinos, Pacific Islanders and Native Americans also face an increased risk of kidney problems.

Some risk factors, however, can be modified or reduced. These include HIV-related causes of kidney disease, such as certain HIV medications as well as HIV infection of the kidneys. Other modifiable risk factors include high blood pressure and diabetes.

The following reviews the most important modifiable kidney disease risk factors HIV-positive people need to know about.

• Increased blood pressure (hypertension)
  Hypertension, or high blood pressure, is a leading cause of kidney disease. It can also be a sign that kidney health is already impaired. Hypertension can damage the small blood vessels in the kidneys and, in turn, prevent them from properly filtering waste.
  
  It's still not clear if HIV-positive people are more likely to suffer from high blood pressure than their HIV-negative counterparts. However, there's little data to suggest that they are less likely to experience it. And with HIV-positive people living longer, thanks to the widespread use of ARV treatment, non-HIV health problems like hypertension become increasingly likely.
  
  It's worth noting that blacks make up 49 percent of the HIV/AIDS cases in the United States And among blacks 20 and older, regardless of HIV status, about 43 percent of men and 47 percent of women have high blood pressure.
  
  Among Latinos, who make up 18 percent of the HIV/AIDS epidemic in the United States, one study documented high blood pressure in 29 percent of the men and 31 percent of the women of Mexican descent.

• Diabetes
  Diabetes is a disease that prevents the body from breaking down glucose (sugar) correctly. This causes glucose levels to remain high in the bloodstream and ultimately damage the nephrons in the kidneys. This can lead to a condition called diabetic nephropathy, a very common form of kidney disease.
  
  HIV-positive people, especially those on protease inhibitor therapy, are at an increased risk of glucose-related problems. In a 2004 report published by the Multicenter AIDS Cohort Study, HIV-positive men on ARV therapy were three times more likely to be diagnosed with diabetes over a four-year period, compared with HIV-negative men.
  
  It's also worth noting that blacks and Latinos are nearly two times more likely to have diabetes than whites of similar age. This increases their chance of developing complications like chronic kidney disease.

• HIV-associated nephropathy (HIVAN)
  A handful of diseases can attack the tiny blood vessels in the kidneys, a notable one being HIV-associated nephropathy (HIVAN). It's caused by HIV infection of the kidneys, which can damage the lining of the glomeruli and tubules. Left untreated, it can lead to ESRD in six to 12 months. HIV treatment can effectively prevent and treat HIVAN.
  
  While it's not really clear how many HIV-positive people suffer from HIVAN, it usually occurs among black men. Low CD4 cell counts and a family history of renal disease are also risk factors for HIVAN.

• Medications
  A small number of medications, including those used by HIV-positive people, list acute renal failure (ARF) as a possible side effect. Experts advise HIV-positive patients with a history of ARF or chronic kidney disease (CKD) to use these drugs with caution—and to have a health care provider adjust the doses.
  
  Medications for opportunistic infections (OIs). Some meds used to treat fungal infections, Pneumocystis pneumonia (PCP) and cytomegalovirus (CMV) are known to rapidly shut down the kidneys in some patients.
  
  HIV medications. The protease inhibitors Crixivan (indinavir) and less frequently Reyataz (atazanavir) can cause kidney stones. Nucleoside reverse transcriptase inhibitors (NRTIs), notably Zerit (stavudine) and Videx/Videx EC (didanosine), have been known to cause a buildup of acid (lactic acidosis) in the blood that can lead to kidney failure and other serious problems.
  
  Another member of the NRTI class that can cause kidney problems is tenofovir disoproxil fumarate (TDF), the active ingredient in Viread and one of the drugs in Truvada, Atripla, Complera and Stribild. TDF can accumulate in the kidney tubules, effectively blocking their function. Fortunately, rates of renal failure have been quite low, on the order of 0.5 to 1.5 percent of tenofovir takers.
  
  Pain medications. NSAIDS, such as over-the-counter Advil (ibuprofen) and Aleve (naproxen), are frequently recommended and used to relieve pain. In some people they can cause an allergic reaction known as interstitial nephritis, which can decrease blood flow inside the kidneys.
  
  Herbal therapies. Finally, some herbal therapies—notably those containing aristolochic acid (found in the flowering plant Dutchman's pipe, formally called Aristolochia)—have been shown to cause kidney damage and may be responsible for some cancers in the urinary tract. In fact, the U.S. Food and Drug Administration recommends that people do not take herbal therapies containing aristolochic acid—including products with the words "Aristolochia," "Bragantia" or "Asarum" listed as ingredients on the label. Click here for a partial list of products to avoid.

What are the symptoms of kidney disease and how is it diagnosed?
Symptoms of kidney disease include:

• The need to urinate more or less
• Foamy urine, caused by too much protein in the blood
• Pink or cola-colored urine, caused by blood in the urine
• Fatigue
• Swollen feet or hands
• Trouble concentrating
• Darkened skin
• Muscle cramps

It's important to remember that some people, especially those in the early stages of kidney disease, do not have any noticeable symptoms. In turn, it is important to conduct lab tests on a regular basis to look for certain abnormalities (these tests are also used to look for kidney disease in people with symptoms). These tests include:

• Urine testing (urinalysis): When kidneys stop working correctly, they start removing healthy protein from the blood, excreting it as waste. Your health-care provider, or the lab that tests your blood, can check for protein by using a dipstick in a small urine sample. Urinalysis is a very common and simple lab test and, depending on your health-care provider, a routine component of HIV care.

• Glomerular filtration rate (GFR) using creatinine measurements: Creatinine, found in the blood, is a waste product created by the normal breakdown of muscle cells. High levels of creatinine don't say much, as levels vary considerably and can be affected by diet. In turn, experts recommend calculations like GFR that use the creatinine measurement along with variables such as weight, age and values assigned for sex and race. The National Kidney Foundation and other expert groups consider GFR to be the best measurement of kidney function. 

• Blood urea nitrogen (BUN): After cells use protein, the waste is converted to urea, a compound that contains nitrogen. Healthy kidneys remove urea from the blood; diseased kidneys have a harder time performing this task. Another simple bood test may determine if levels of urea nitrogen are higher than normal in the blood, which may indicate renal problems.

It's also important to keep an eye out for signs and symptoms of high blood pressure and diabetes, the most common causes of kidney disease. Using a special cuff, your doc can keep an eye out for hypertension and, if necessary, recommend treatment or lifestyle modifications to keep your blood pressure below 130 over 80. Routine lab testing can also help you and your health-care provider keep an eye on your glucose levels in your blood.

Do I need to be checked for kidney problems?
The Infectious Disease Society of America (IDSA) recommends that all HIV-positive people be evaluated for kidney disease at the time of their diagnosis using urine and blood samples. Those at high risk for renal impairment—such as people with high blood pressure, diabetes, CD4 counts below 200, viral loads above 4,000 and hepatitis C virus (HCV) coinfection—should be checked by their health care providers every year, even if they appear to have normal kidney function. Twice-yearly checkups are recommended for high-risk patients who are taking medications that can potentially damage the kidneys, such as Crixivan and meds containing tenofovir DF (Viread, Truvada, Atripla, Complera and Stribild).

How is kidney disease treated?
The IDSA recommends that HIV-positive people who have signs or symptoms of kidney problems be referred to a kidney specialist (nephrologist) for care. Treatment options can vary considerably, depending on the cause (or causes) of a person's kidney disease and any other health issues. Some treatment possibilities include:

• Reduce blood pressure: Medications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are frequently prescribed to bring blood pressure under control in people with kidney disease. Other medications, along with dietary and lifestyle changes (such as exercise), may be necessary as well.

• Manage diabetes: HIV-positive people with diabetes and kidney disease will need to rigorously watch their blood glucose levels and work closely with their health-care providers to keep these levels under control.

• Modify diet: Some parts of a normal diet may speed up kidney failure. It may be necessary to limit protein, cholesterol, sodium and potassium; working with a dietitian or nutritionist can be helpful.

• Stop smoking: Not only does smoking increase the risk of kidney disease, it contributes to deaths from strokes and heart attacks in people with kidney disease.

• Treat HIV: Kidney disease is climbing as one of the most common causes of illness and death among people living with HIV. Antiretroviral (ARV) treatment typically improves kidney function, and it may protect against HIV-related cellular inflammation in the kidneys. This is one of the reasons that the Department of Health and Human Services' HIV treatment guidelines recommends beginning ARV therapy before CD4 cell counts fall below 500.

• Treat HIVAN: IDSA stresses that people with HIV-associated nephropathy should be treated with ARV therapy, regardless of their CD4 count or viral load, once the disease is diagnosed.

• Check medications and their dosages: People with a history of kidney disease may need to avoid some medications, including certain HIV drugs. Doses of medications that are broken down (metabolized) by the kidneys may need to be altered to reduce the risk of side effects and further kidney damage.

Last Revised: January 18, 2016

http://betablog.org/new-research-at-croi-2016-how-prep-changes-kidney-function/

Acquired Fanconi's Syndrome Associated with Tenofovir Therapy

George Mathew, MD¹ and Stephen J Knaus, MD²

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Abstract

Tenofovir (Viread®) is a nucleotide reverse transcriptase inhibitor introduced into the United States in 2001. It is frequently prescribed not only for its efficacy but also for its decreased side effect profile compared with other nucleoside analogs. It is now increasingly recognized as a cause of acquired Fanconi's syndrome (FS) in human immunodeficient individuals. We describe a case of a patient with AIDS, who, after starting tenofovir therapy, developed myalgias, renal failure, and profound electrolyte abnormalities compatible with the classic features of FS. On discontinuation of tenofovir and replacement of electrolytes, the individual improved clinically with normalization of his renal failure and electrolyte abnormalities. With the success of tenofovir in the anti-HIV drug market, practitioners should remain alert to the possibility of the development of FS. Frequent urine, renal, and electrolyte parameters should be measured at regular intervals following initiation of tenofovir therapy.

Keywords: Fanconi's syndrome, tenofovir, renal tubular acidosis, HIV

Tenofovir has emerged as an important member of antiretroviral therapy since its introduction in 2001. In addition, it is now a key component of Truvada® (Gilead Sciences, Foster City, CA), which is a co-formulation of tenofovir and emtricitabine. Ongoing efforts are now focused on adding efavirenz to create a once-a-day pill.

In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5' monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase. It is primarily excreted through the kidney via glomerular filtration and active tubular secretion. Nephrotoxicity owing to tenofovir has been reported in the literature over the past few years.^1–7

A case of Fanconi's syndrome (FS) is reported here in an AIDS patient taking tenofovir. Our case and others reported to date suggest that patients taking tenofovir should be monitored frequently with urinalysis and serum renal panels at least for 18 months after initiation of therapy.

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CASE SUMMARY

A 38-year-old male with AIDS presented with a 3-day history of muscle weakness and myalgias beginning in his lower extremities and spreading proximally to his trunk and upper extremities. He also noted increasing fatigue and polyuria over the past 3 days. Six months before admission, the patient had been initiated on tenofovir, lamivudine, and efavirenz. He responded well to this new antiretroviral regimen both virologically and immunogically as his CD4 count rose from 37 to 287, and an undetectable viral load was noted just 2 weeks before this admission.

Besides a history of HIV detected 9 years back, the patient's medical history was significant for severe peripheral neuropathy secondary to HIV, gastro esophageal reflux disease, and epilepsy. He denied any alcohol, tobacco, glue sniffing, or illicit drug use.

He reported no history of diarrhea. There was no known family history of neurological disease or renal disorders. The patient had no known medication allergies.

Physical examination revealed a cachetic, anxious patient in no acute respiratory distress. His admission temperature was 37°C, blood pressure 110/80 mmHg, and heart rate 80 beats per minute. He exhibited slow motor function, poor fine motor control, and diffuse muscle tenderness in all 4 extremities. He had decreased (4/5) muscle strength bilaterally with normal and symmetric reflexes. The rest of his examination was normal.

In the emergency room, his serum potassium was 1.9 meq/L, serum glucose 92 mg/dL, serum sodium 135 meq/L, serum chloride 107 meq/L, and serum bicarbonate 19 meq/L, with an anion gap of 9 demonstrating a hyperchloremic nonanion gap metabolic acidosis. Serum albumin was 3.9 mg/dL and serum phosphorus was markedly low at 1.2 mg/dL. Other laboratory values of note at admit are as follows: urine sodium 35 meq/L, urine potassium 7 meq/L, and urine creatinine 15 meq/L (urine anion gap 12), with a fractional excretion of sodium 4.1%. A urine analysis showed a urine pH of 5.5, 30 mg/dL of protein, glucose 500 mg/dL, myoglobinuria, and a negative urine Wrights' stain.

Creatinine kinase was elevated at 755 U/L. His serum creatinine had increased to 2.5 mg/dL (1 month back, his creatinine had been 1.3). Complete blood count and serum magnesium was normal; serum protein electrophoresis did not reveal gammopathy, and a urine protein electrophoresis was not conducted.

Fanconi's syndrome was suspected in this patient given the presence of a hyperchloremic nonanion gap metabolic acidosis, hypokalemia, hypophosphatemia, glucosuria, and proteinuria. Suspecting that FS was due to tenofovir, it was stopped. The patient was aggressively rehydrated with intravenous fluids. He required replacement with 100 mEq potassium chloride twice daily for 2 days to keep potassium above 3 mEq/L for the first 5 days of hospitalization. Phosphorus was also replaced orally.

The patient's muscle weakness, myalgias, and dyspnea improved dramatically in the first 12 hours of hospitalization, with normalization of his creatinine kinase. The patient's renal function also improved during hospitalization, and upon discharge on hospital day #7 his creatinine had stabilized at 2.2 mg/dL. He was sent home with oral potassium and phosphorus supplementation. Two weeks after discharge, he had follow-up blood tests, which showed that his serum creatinine was 1.5 mg/dL, potassium 3.1 meq/L, and serum bicarbonate 25 meq/L. A repeat urine analysis showed a pH of 6.5 with mild proteinuria and glucosuria. A year after discharge at follow-up, his urine analysis had completely normalized. He is currently doing well, with no long-term sequelae resulting from his renal failure.

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DISCUSSION

Fanconi's syndrome was first described by Lignac in 1924 and further defined by Fanconi in 1936 in children presenting with rickets, growth retardation, and glucosuria. Heritable FS is transmitted as an autosomal recessive trait and occurs in 1 in 40,000 births. Cystinosis is the most common inherited condition associated with FS, but galactosemia, Wilson's disease, tyrosinemia, and hereditary fructose intolerance may all cause FS. Acquired causes include multiple myeloma, light-chain deposition disease, renal transplantation, and medications, a topic that will be further discussed later. Multiple myeloma is the most common cause of FS in adults and causes renal injury by incomplete obstruction of renal tubules by monoclonal light chains.⁸

There is a high concentration of mitochondrial organelles that populate the proximal tubular cells. This is needed to satisfy the high-energy requirement for driving sodium-potassium pumps. Inherited mitochondrial disease affecting the kidney most commonly takes the form of proximal renal tubular dysfunction (PRTD), otherwise known as FS.

This is characterized by a generalized defect in proximal tubular function with subsequent aminoaciduria, glucosuria with normal serum glucose, and phosphate wasting.⁹

The acidosis that occurs in patients with FS is due to defective bicarbonate reabsorption in the proximal tubule. The amount of filtered bicarbonate decreases until a new threshold is established and all filtered bicarbonate is then again reabsorbed, resulting in a persistent metabolic acidosis.¹⁰ Hypophosphotemia also occurs secondary to poor proximal tubular reabsorption. Severe hypokalemia alone or in conjunction with hypophosphatemia can lead to spontaneous rhabdomyolysis and there are other reported case reports of renal tubular acidosis presenting with rhabdomyolysis and muscle weakness.^11,12

Polyuria occurs in FS because of osmotic diuresis of glucose and a concentrating defect in the distal tubule and collecting ducts, which may be worsened by hypokalemia.⁸

On a cellular level, it has been proposed that disruption of the Na-K-ATPase pump on the basolateral membrane of the proximal tubular cell could inhibit active transport into the peritubular capillaries. Another theory is that active transport may remain intact but the permeability of the proximal tubule is increased, thereby significantly enhancing back-diffusion of solutes.⁹

In the case presented in this article, the most likely factor causing the patient's FS was a drug. A search of the literature reveals that several drugs apart from tenofovir have been implicated in causing FS, among them aminoglycosides, ifosfamide, cisplatin, streptozocin, mercaptopurine, tetracycline, and valproic acid.¹³

Most importantly, for this case, certain antiretrovirals have been implicated in causing FS, namely cidofovir, adefovir,⁹ and 1 case of didanosine.¹⁴

Tenofovir was initially introduced in the United States in October 2001. It is closely related to the nucleotide reverse transcriptase inhibitor adefovir, which is no longer being used for the treatment of HIV but is in use at a lower dose in hepatitis B virus therapy. Adefovir was associated with PRTD in approximately 50% of HIV-infected patients in a large multi-center trial.¹⁵

Tenofovir disoproxil fumarate is the first and only nucleotide reverse transcriptase inhibitor approved for the treatment of HIV in combination with other antiretrovirals. Data from numerous clinical studies have highlighted tenofovir's convenience, potency, safety, tolerability, and unique resistance profile. It has a much-touted decreased mitochondrial toxicity and superior efficacy as compared with nucleoside analogs,¹⁶ supporting its use in all stages of HIV infection. The number of patients on tenofovir has increased exponentially. As a stand-alone molecule and as a component of Truvada®, tenofovir has become the second most widely prescribed antiretroviral agent.¹⁷

The use of adefovir and cidofovir has been limited because of nephrotoxicity. Tenofovir has been favored for its excellent safety profile, particularly its lack of nephrotoxicity. Two randomized, double-blind studies have described renal tolerance of tenofovir and have found that there was no significant difference between tenofovir (75 to 300 mg/day) and placebo in incidence of renal insufficiency, glucosuria, hypouricemia, and hypokalemia.¹⁸ However, the first case of FS and renal failure due to tenofovir was reported in December 2002.¹ Then, in April 2003, 4 more cases were reported in France in 2 separate publications.^2,3 Karras et al. described 3 cases similar to the case reported here. These patients had had HIV infection for several years and had received other courses of antiretroviral therapies before starting tenofovir. All these patients had normal baseline renal function, but a slight increase in creatinine was noted a few weeks after initiation of tenofovir. However, the drug was not stopped at that time. Then, several months (6 to 11) after initiation of tenofovir therapy, the patients experienced a rapid decline in renal function and classic signs of FS. Discontinuation of antiretroviral therapy led to normalization of proteinuria, acidosis, hypokalemia, and hypophosphatemia in less than 2 weeks. Improvement in renal function was noted in 1 patient but the other 2 had a persistently elevated creatinine, which indicates that there may be some partially irreversible renal damage.³

Prolonged renal dysfunction has also been reported by Rifkin, who noted that renal dysfunction can be reported as far out as 18 months with tenofovir-based therapy.¹⁹

Argument against the association of tenofovir and higher rates of nephrotoxicity is made by an elegant cohort and case control study performed by Jones et al.,²⁰ showing no significant increase in renal dysfunction in patients taking tenofovir compared with other antiretroviral drugs. In a study of 4,183 HIV-positive patients, 1,175 were identified as having a creatinine over 1.2 mg/dL. A comparison of antiretroviral-naive patients and patients exposed to tenofovir and nontenofovir-containing regimens surprisingly revealed a lower rate ratio and probability of developing a creatinine value >1.2 mg/dL in patients exposed to tenofovir (rate ratio vs no antiretrovirals = 0.22, 95% confidence interval [CI]: 0.07 to 0.69; P <0.001), with no significant difference between antiretroviral therapy regimens, corrected for duration of therapy. Of the 1,058 individuals on tenofovir, 84 (8%) patients had a creatinine value >1.2 mg/dL subsequent to exposure, with an alternative cause of renal failure in 75 (90%) of these individuals.

However, it is important to note that the focus of this article is to highlight the unique association of FS with tenofovir. No other currently prescribed anti-HIV therapy has been linked to the development of FS consistently.

Our patient had been taking tenofovir for 6 months before presentation. A close review of his serum potassium and creatinine shows evolving hypokalemia and declining renal function during this period (Figure S1). With the discontinuation of tenofovir, his metabolic abnormalities gradually resolved.

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CONCLUSION

This case and the other cases reported to date suggest that tenofovir causes FS, and that this may become more problematic with more widespread use of the drug. The possibility of irreversible renal damage also suggests that patients given this drug should be followed more closely in the 12- to 18-month period after initiation of tenofovir therapy and should have a urinalysis, serum creatinine, and potassium performed on a regular basis following initiation of therapy. Raising the awareness of clinicians with regard to the potential for this side effect is important so that patients with this side effect can be discovered early and switched to an alternate antiretroviral therapy.

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Supplementary Material

The following supplementary material is available for this article online at www.blackwell-synergy.com

Figure SD1 Serum Creatinine and Serum Potassium Trends in a Patient on Tenofovir Therapy.

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