HAART and Renal (Kidney) Damage

“Among the 445 patients initiating tenofovir, 51 (11%) developed a decline in kidney function. In multivariate analysis, there was a significant association between decline in kidney function and concurrent use of amprenavir and didanosine, age over 50 years, and lower baseline weight”

“A 38-year-old Caucasian man developed progressive acute renal failure. He was found to be HIV positive in 1988 and received multiple unsuccessful antiretroviral regimens. He subsequently developed a virus resistant to all US Food and Drug Administration-approved antiretroviral agents; his CD4 cell count had been less than 50 cells/µl for more than 5 years, and at the time of renal failure, was 0 cells/µl. Renal dysfunction developed when he was receiving tenofovir, emtricitabine, saquinavir, lopinavir, and ritonavir. Tenofovir was initially suspected as the etiology, but kidney dysfunction progressed (from 1.6 to 8 mg/dl over a 6-month period) despite discontinuation of all antiretroviral agents and other potential nephrotoxic drugs. [The researchers apparently did not consider the possibility that the damage to the kidney was so severe that even stopping the drugs could not reverse it, so they blamed it on a virus instead]”

“The risk of nephrolithiasis associated with atazanavir is not well characterized. The US Food and Drug Administration's Adverse Event Reporting System was searched for reports of nephrolithiasis [kidney stones] in HIV-infected patients taking an atazanavir-based regimen. Thirty cases were identified [note that it's believed that only 1 to 10% of adverse events are reported]. Many patients required hospitalization for management, including lithotripsy, ureteral stent insertion, or endoscopic stone removal. Some cases of nephrolithiasis resulted in atazanavir discontinuation.”

“In a multivariate model any use of indinavir [a protease inhibitor] or tenofovir [a nucleoside analog] was associated with increased odds of CRF [chronic renal/kidney failure], as was cumulative exposure to indinavir or tenofovir.”

“our patient sustained widespread podocyte [kidney cells that are critical for proper filtration] damage while taking HAART. The damage appeared to resolve with the cessation of efavirenz and the addition of irbesartan…Aside from one case of severe hypersensitivity to efavirenz, renal damage caused by efavirenz (or non-nucleoside reverse transcriptase inhibitors in general) has not previously been reported. However, in this case, it appears as though efavirenz directly injured the podocytes.”

“Tenofovir disoproxil fumarate (TDF, viread) is a nucleotide analogue used in antiretroviral therapy (ART) for HIV infection. In addition, it is active against hepatitis B virus (HBV). It is excreted renally and not metabolized. Nephrotoxicity caused by TDF has been reported in a small number of patients…Patient 1, a 39-year-old HIV-positive white man, presented with wasting, Candida esophagitis, marked cerebral atrophy, polyneuropathy, and cutaneous Kaposi’s sarcoma. His CD4 cell count was 168 cells/ml and he also had elevated liver enzymes as a result of alcoholic liver disease. ART was initiated with zidovudine, lamivudine, and lopinavir/ritonavir. Because of anemia requiring repeated transfusions, zidovudine was replaced by TDF. Within 10 days, the serum creatinine level rose from 0.8 to 1.4 mg/dl, serum urea from 40 to 61 mg/dl, and serum potassium from 5.0 to 6.0 mmol/l. After TDF was stopped renal function parameters normalized completely within 10 days…Patient 2, a 69-year-old white man, was diagnosed with advanced HIV infection in 2001. In addition, he had congestive heart failure as a result of arterial hypertension, coronary artery disease, and mitral valve insufficiency. ART was initiated with stavudine, lamivudine and abacavir. One year later stavudine was substituted with zidovudine because of peripheral polyneuropathy. Later, zidovudine was replaced by TDF because of transfusion dependent anaemia. Because of an increase in the HIV viral load ART was changed to didanosine, TDF, and lopinavir/ritonavir according to the results of a genotypic resistance test in 2003. In 2004, lopinavir/ritonavir was replaced by atazanavir/ritonavir because of hyperlipidemia. At this time elevated liver enzymes were noted and were thought to be caused by ART, but therapy remained unchanged because of limited therapeutic options. In spring 2005, an increase in serum creatinine to 1.4 mg/dl and glucosuria of 300 mg/dl were recognized, but the patient’s renal function remained stable until 4 months later, when he developed peripheral edema and ascites. A serum creatinine level of 4.3 mg/dl, serum urea of 71 mg/dl, proteinuria of 2175 mg/l, worsening glucosuria, metabolic acidosis and sonographic signs of liver cirrhosis were noted. ART was stopped and medical therapy optimized. Two months later serum creatinine was almost normal.”

“We present a series of 40 patients who developed hypokalemia [low potassium levels which can result in kidney failure] associated with tenofovir [a nucleoside analog AIDS drug]. Identified risk factors included concomitant ritonavir or didanosine use, a lower weight and longer duration of tenofovir use. Recovery or improvement was seen in the majority of patients (66%) after the discontinuation of tenofovir; however, four deaths occurred. The associated consequences of tenofovir-related hypokalemia may be profound and life-threatening.”

“A total of 61 patients were screened of whom 24 were found to be ineligible. This left 37 eligible patients of whom 2 were excluded…Prior to indinavir exposure the cohort had a mean serum creatinine of 82 (12.7) µmol/L, corresponding to an estimated creatinine clearance of 84 mL/min. At baseline for the present study the serum creatinine concentration was 149 (27.7) µmol/L, representing an estimated creatinine clearance of 46 mL/min, and a mean (SD) percentage reduction of creatinine clearance from pre-indinavir exposure of 44 (14) %. After indinavir dose optimization the mean serum creatinine returned to 135 (29) µmol/L, representing an estimated creatinine clearance of 53 (15) mL/min. The mean change in creatinine clearance from study baseline to endpoint was 6.6 (10) mL/min (P = 0.001). At baseline the majority of patients had Grade 2 pyuria (48.6%) [discharge of pus in the urine] and at study end the majority (51.4%) had Grade 1 pyuria (P = 0.09)…we have demonstrated an association between the use of pharmacokinetically guided indinavir dose reductions and amelioration of indinavir-associated renal toxicity, at least in the short-term.”

“kidney disease has emerged as a leading cause of death among HIV-infected patients in the HAART era. This study compared the incidence and predictors of acute renal failure and mortality before [1995] and after [2003] the widespread introduction of HAART, and described the impact of acute renal failure on mortality in a contemporary cohort of patients with HIV infection who were hospitalized in New York State. HIV infection was associated with an increased risk of acute renal failure and in-hospital mortality both before and after the widespread introduction of HAART. Among patients with HIV infection, acute renal failure was a strong predictor of in-hospital mortality in the HAART era. In addition, chronic kidney disease and acute or chronic liver disease were strongly associated with both acute renal failure and in-hospital mortality among patients with HIV, suggesting a need for more aggressive management of chronic kidney disease and hepatitis virus coinfection in the setting of HIV…The unexpected increase in incidence of reported acute renal failure in the HAART era may reflect a combination of factors related and unrelated to HIV…it is possible that both comorbid disease [other conditions] and medication nephrotoxicity [kidney damage from antiretroviral and other medications] play a more important role in the HAART era.”

“Twelve weeks after initiating a tenofovir-containing HAART regimen…[several signs of kidney damage were noted, and two cases with clinical symptoms]…Patients with the above findings should be monitored carefully for renal tubular toxicity.”

“61 patients were enrolled in the study…Twelve (20%) patients underwent IDV [indinavir] dose reduction, mainly because of nephrotoxicity (nine of 12 patients)”

“Patients on tenofovir showed a lower mean glomerular [kidney] filtration rate estimated by creatinine clearance or cystatin C clearance compared with control patients. In total, 24 patients on tenofovir versus five control patients had proteinuria greater than 130 mg/day.”

“We report here seven cases of HIV patients with renal colic [kidney stones causing extreme colic-like pain], cholangitis [infection of the bile ducts, often caused by kidney stones] or parotitis [inflammation of the parotid glands] while receiving LR [Kaletra=Lopinavir+Ritonavir] in association with other antiretroviral therapies…Delay between the beginning of LR and the occurrence of lithiasis [kidney stones] was 8-16 months.”

“We describe a patient in whom disseminated intravascular coagulation (DIC) developed within 6 days after starting abacavir for the treatment of HIV infection [resulting in kidney failure and liver abnormalities]”

“Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones...Our cohort study of the prevalence of indinavir nephrolitihiasis [kidney stone formation] included 155 patients with HIV for 5,732 patient-weeks...At 78 weeks 43.2% of patients had stones...The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported.”

“Reports about the glomerular [filtration portion of kidneys] diseases due to these drugs are rare [but one is reported in this paper]”