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J Int AIDS Soc. 2013; 16(1): 18596.
Published online Jun 18, 2013. doi:  10.7448/IAS.16.1.18596
PMCID: PMC3687339
Kidney disease in children and adolescents with perinatal HIV-1 infection
Rajendra Bhimma,§1 Murli Udharam Purswani,2 and Udai Kala3
1Department of Paediatrics and Child Health, School of Clinical Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
2Division of Pediatric Infectious Disease, Albert Einstein College of Medicine, Bronx-Lebanon Hospital Center, Bronx, NY 10457, USA
3Chris Hani Baragwanath Hospital, University of Witwatersrand, Johannesburg, South Africa
§Corresponding author: Rajendra Bhimma, Department of Paediatric and Child Health, School of Clinical Medicine, Nelson R Mandela School of Medicine, Private Bag 7, Durban, 4013, South Africa. Tel: 27-31-260 4345. Fax: 27-31 260 4388. (bhimma/at/ukzn.ac.za)
This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org
Received February 19, 2013; Revised April 14, 2013; Accepted April 16, 2013.
Introduction
Involvement of the kidney in children and adolescents with perinatal (HIV-1) infection can occur at any stage during the child's life with diverse diagnoses, ranging from acute kidney injury, childhood urinary tract infections (UTIs), electrolyte imbalances and drug-induced nephrotoxicity, to diseases of the glomerulus. The latter include various immune-mediated chronic kidney diseases (CKD) and HIV-associated nephropathy (HIVAN).
Discussion
The introduction of highly active anti-retroviral therapy (HAART) has dramatically reduced the incidence of HIVAN, once the commonest form of CKD in children of African descent living with HIV, and also altered its prognosis from eventual progression to end-stage kidney disease to one that is compatible with long-term survival. The impact of HAART on the outcome of other forms of kidney diseases seen in this population has not been as impressive. Increasingly important is nephrotoxicity secondary to the prolonged use of anti-retroviral agents, and the occurrence of co-morbid kidney disease unrelated to HIV infection or its treatment. Improved understanding of the molecular pathogenesis and genetics of kidney diseases associated with HIV will result in better screening, prevention and treatment efforts, as HIV specialists and nephrologists coordinate clinical care of these patients. Both haemodialysis (HD) and peritoneal dialysis (PD) are effective as renal replacement therapy in HIV-infected patients with end-stage kidney disease, with PD being preferred in resource-limited settings. Kidney transplantation, once contraindicated in this population, has now become the most effective renal replacement therapy, provided rigorous criteria are met. Given the attendant morbidity and mortality in HIV-infected children and adolescents with kidney disease, routine screening for kidney disease is recommended where resources permit.
Conclusions
This review focuses on the pathogenesis and genetics, clinical presentation and management of kidney disease in children and adolescents with perinatal HIV-1 infection.
Keywords: human immunodeficiency virus, kidney, children, adolescents, anti-retroviral drug toxicity
It is estimated that 3.4 million children were living with (HIV) infection at the end of 2011, 91% of whom are in sub-Saharan Africa [1]. This region accounts for more than 70% of global HIV infections although it has only 10% of the world's population, and thus bears an inordinate burden of this disease [2]. The widespread use of highly active anti-retroviral therapy (HAART), introduced in 1996, has dramatically decreased the incidence of HIV-associated nephropathy (HIVAN) although a clear benefit in non-HIVAN kidney disease has not been demonstrated [35]. In spite of this demonstrated effectiveness, only 28% of children in need of HAART worldwide actually receive it. With the long-term use of HAART, drug toxicity, advancing age and chronic viral infections has resulted in an increase in the overall frequency of kidney diseases in HIV-infected individuals [6,7]. Complications such as end-stage liver, kidney and heart disease are taking on prominent roles in the management of HIV-infected adults [8,9]. Nonetheless, a general lack of surveillance and reporting of kidney diseases in HIV-infected children exists in most developing regions of the world where HIV is highly prevalent [10]. In a large United States cohort, it was estimated that kidney disease complicating HIV infection is now among the ten most common non-infectious conditions occurring in perinatally HIV-infected children and adolescents in the HAART era, with an incidence rate of 2.6 per 100 patient-years [11,12].
The spectrum of kidney disease that occurs with perinatal HIV infection in children encompasses chronic glomerular disorders, such as HIVAN and HIV immune complex kidney disease (HIVICK), the thrombotic microangiopathies (including atypical forms of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura), disorders of proximal tubular function and acute kidney injury [13]. Early reports of childhood HIVAN in African-American children were from Miami and New York [14,15], three years after the first description of this condition in adults [3]. The unique histological feature of HIVAN in children is classical focal segmental glomerulosclerosis (FSGS) with or without mesangial hyperplasia in combination with microcystic tubular dilatation and interstitial inflammation [16,17]. Mesangial proliferative lesions secondary to immune complex deposits may also be present in some HIV-infected children with HIVAN [16,17]. All other forms of kidney diseases associated with HIV infection in children are collectively referred to as HIV-related kidney diseases hereafter.
In this article, we review the pathogenesis, clinical presentation and management of HIVAN and other HIV-related kidney diseases, including complications of HAART therapy.
The role of HIV-1 infection of the kidney
HIV viral burden and immunosuppression are well-established risk factors for the development of HIVAN and the main reasons behind the decline in its incidence with HAART [1821]. Consistent with this clinical evidence is the fact that infection of kidney epithelial cells by HIV-1 is now thought to result eventually in HIVAN, and that the kidney is also a reservoir for HIV-1 [22]. What is unclear is how the virus enters these epithelial cells since glomerular podocytes and renal tubular cells do not express CD4 or other co-receptors. Nevertheless, in vitro studies have demonstrated efficient transfer of HIV-1 viral nucleic acid from T-cells to renal tubular epithelial cells. It is also postulated that injured glomerular podocytes undergo proliferation and apoptosis, and that the remaining podocytes hypertrophy and leave bare segments of basement membrane that promotes the development of the sclerotic lesions that characterize HIVAN [22]. A report on the pathogenesis of childhood HIVAN by Ray et al. also discussed the role of productive mesangial cell infection by HIV-1 [23]. Three groups of investigators were able to demonstrate infection of cultured mesangial cells by the virus [2426], while two others were unable to do so [27,28]. Studies have shown that the HIV nef gene is important in the development of the glomerular lesions of HIVAN, in particular the dedifferentiation and proliferation of podocytes, which are otherwise terminally differentiated [2931]. The HIV vpr genes have been implicated in the development of tubular pathology in HIVAN, predominantly through the induction of apoptosis and cell cycle arrests [3235], and the HIV tat gene has been shown to have a potential role in podocyte dedifferentiation [36].
The role of FSGS without an accompanying collapsing glomerulopathy
Histopathological findings of HIVAN vary in children compared to adults. Although collapsing glomerulopathy is a hallmark of the disease in adults, the unique microscopic features of HIVAN in children are defined as the presence of classical FSGS with or without mesangial hyperplasia in combination with microcystic tubular dilatation and interstitial inflammation. Mesangial proliferative lesions secondary to immune complex deposits may also be present in some children [16,37]. The early paediatric literature describes HIVAN without a collapsing glomerulopathy always being present on biopsy [14,15,38]. In two recent paediatric studies [13,18], the percentage of children with biopsy-proven HIVAN that showed a collapsing glomerulopathy with FSGS was 14% and 32.5%. The findings on histology include classic FSGS and mesangial proliferative glomerulonephritis, both of which have been reported by Ray et al. to be consistent with a diagnosis of HIVAN in children [23,37]. The collapsing variant of FSGS is a clinically and pathologically distinct variant of FSGS. Indeed the clinical progression of the two is different, with a rapidly progressive course observed in the collapsing variant that is typically seen with adult HIVAN. In children with HIVAN, most without a collapsing glomerulopathy [39], the clinical course of disease is not as aggressive, with slower progression to eventual end-stage kidney disease [23].
The role of host genetics
Several studies have identified a genetic basis explaining the increased risk for kidney disease and the occurrence of HIVAN almost exclusively in African-Americans, a population with a four-fold increased risk for end-stage kidney disease [40]. Interest initially centred around genetic variations at a locus near the MYH9 gene on chromosome 22 [41,42]. Later, two independent sequence variants G1 and G2 in the APOL-1 gene adjacent to the MYH9 gene were found to be highly associated with FSGS and HIVAN, with odds ratios of 17 and 29, respectively [43,44]. These risk alleles are present only on African chromosomes. The combined risk frequency of G1 and G2 polymorphisms in the Yoruba tribe in west Africa is 62% and the frequency of either allele in persons of west African origin is 35%, largely operating in a recessive manner. Interestingly, the heterozygous state protects the individual against Trypansoma brucei rhodesiense, whilst the homozygous state confers an increased risk for kidney disease, similar to the protective effect of sickle cell trait against malaria, at the cost of sickle cell disease in the homozygous state [43]. The percentages of one- and two-risk alleles for APOL-1 in self-identified African-Americans in a cohort of children and adolescents with perinatal HIV-1 infection followed in the Pediatric HIV/AIDS Cohort Study are 43% and 13%, respectively [45]. The two identified APOL1 risk alleles were noted to be in strong linkage disequilibrium with the MYH9 risk haplotype, and association between APOL1 and kidney disease remained significant after further adjustment for this and other combinations of the MYH9 alleles. The high frequency of APOL1 risk alleles in African populations do not provide an explanation for the biological mechanisms leading to an increased risk of FSGS associated with these variants [22].
HIVICK is thought to arise either by the trapping or deposition of circulating immune complexes in the parenchyma, or by in situ immune complex formation, described in a detailed report on four patients by Kimmel et al. [46]. These immune complexes comprise various HIV core and envelope antigens including p24 and glycoprotein 41 and 160, respectively, bound to IgG or IgA antibodies that are part of the polyclonal immune response produced against these antigens in HIV-infected patients. Also included in this category are other immune-mediated diseases such as IgA nephropathy, and a membranous or membrano-proliferative glomerulonephritis that may or may not be associated with hepatitis B and C virus infections. A “lupus-like” glomerulonephritis, in which light immunofluorescence and electron microscopic features of lupus glomerulonephritis in the absence of clinical systemic lupus erythematosus, and without the serologic markers that accompany this disease, is also seen in HIV-infected adults and children [47]. Although HIVICK occurs in African-Americans, this entity is more likely to be seen in Caucasians [48], and is not associated with the single-nucleotide polymorphisms implicated in the pathogenesis of HIVAN in African-Americans. HIVICK is not uncommon, and was found in 33% of kidney biopsies in children in a US cohort [18], whereas in South Africa there is a regional bias with HIVICK reported in 7% of paediatric biopsies from Cape Town and a much higher incidence of 51% in Johannesburg [49]. The reasons for the differences in the histological spectrum of the disease from these two regions remain to be explored.
Kidney disease in children occurs at all stages of HIV infection. Anti-retroviral (ARV) agents, antibiotics such as aminoglycosides, antifungals (amphotericin B), antivirals (acyclovir), anti-tuberculosis drugs, anti-inflammatory drugs and combinations of all these contribute to kidney disease.
The spectrum of kidney disease seen in HIV-infected patients is shown in Table 1. Glomerular pathology in children and adults in different countries and populations vary tremendously. In blacks from Africa, America and Europe and Hispanic populations, FSGS with or without collapsing glomeruli and microcystic tubular dilatation are common [23]. In their Caucasian counterparts, mesangial hyperplasia and immune complex-type disease predominates [50]. HIVAN is still the commonest cause of kidney disease in HIV-1-infected children and adolescents in other parts of the world, as evidenced by recent reports from KwaZulu-Natal in South Africa and Nigeria, with a higher incidence in males [13,51]. The exceptions were two studies in adults and children in which HIVICK was equal to or more prevalent [52,53]. Common to both is interstitial inflammation. However, in other adult studies from Cape Town, South Africa [54,55], and paediatric studies from South Africa and other regions of the globe, FSGS was the commonest histological type [13,15,5658]. The incidence and natural history of HIVAN has been dramatically altered by HAART [21,59,60]. Once the commonest cause of kidney disease in adults and children, it is likely surpassed now by renal toxicity arising from ARV treatment in the United States.
Table 1
Table 1
Spectrum of kidney disease in HIV-infected patients
Below we describe the clinical presentation of the most common forms of HIV-related glomerular disease.
Haematuria and proteinuria and subsequent development of nephrotic syndrome and chronic kidney disease (CKD) represent the commonest manifestations of HIV-related glomerular disease (Table 1) [13]. CKD in children with HIV infection usually has an insidious onset [49]. The strategy to minimize kidney damage is by screening urine for proteinuria and even microalbuminuria. The mean duration from the onset of proteinuria to developing end-stage kidney disease in children with HIVAN varied from 8 months to 3 years depending on the geographical area and associated AIDS-defining illnesses in untreated patients. Thus, prognosis prior to the introduction of HAART in patients with CKD was very poor [15,37,56,6163]. The reported rate of CKD in HIV-infected patients on presentation varied from 5 to 40% [13,51,53].
Haematuria
Microscopic haematuria, with or without proteinuria was the commonest presenting symptom of kidney disease in two African studies; 75% and 50% with or without proteinuria, thus noting its importance as a sign or symptom in patients with HIVAN and other HIV-related kidney diseases [13,64]. If there is persistence of microscopic haematuria with or without HAART, the patient needs to be evaluated further for the degree of kidney involvement and warrants a kidney ultrasound, serum electrolytes, creatinine measurement and urine microscopy [49]. Once urolithiasis has been excluded and there is no clear explanation for the haematuria, a kidney biopsy must be considered.
Proteinuria
Persistent proteinuria (≥1+ on urinary dipstick testing) is significant. Urine samples must be sent to the laboratory for a urine protein/creatinine ratio (uPCR) and a ratio of ≥0.2 (measured as mg/dL protein divided by mg/dL creatinine) confirms underlying kidney disease, which can be used to monitor response to HAART as shown by Chaparro et al. [64]. In this study, the degree of proteinuria degree of proteinuria was proportional to loss of kidney function and mortality increased with nephritoc-range proteinuria [64]. Severe proteinuria is more prevalent in black African children [13,65,66]. It is also associated with a higher mortality rate, especially in the presence of collapsing glomerulopathy on kidney biopsy [13,51,53,67].
Thus, it is imperative to test for proteinuria in all HIV-infected patients and if persistent, to perform a kidney biopsy. This is borne out by an adult study in which even microalbuminuria correlated with renal parenchymal disease with a prevalence of 36% in HIV-infected black African patients [66]. There are no equivalent paediatric studies showing similar results. In a study from Enugu, Nigeria none of the 154 HIV-infected and 154 HIV-uninfected children screened for microalbuminuria were positive [68]. In another study of HIV-infected non-febrile children without any symptoms of renal disease at Chris Hani Baragwanath hospital situated in Johannesburg, South Africa, the prevalence of microalbuminuria was 25%, but unfortunately none of these patients had a kidney biopsy [69].
HIVAN is the most aggressive kidney disease affecting up to 10% of HIV-infected patients and is the primary form of HIV nephropathy seen in adults [11,12]. The true prevalence of paediatric HIVAN is not known as kidney biopsies have not been performed regularly in all HIV-infected patients with proteinuria [13,15,37,53,56,6163,70] and haematuria, especially persistent microscopic haematuria. The following criteria were used for the diagnosis of HIVAN in children:
  • Persistent proteinuria defined as an uPCR≥0.2 for 3 months or more, in the absence of acute infection especially in children of African descent.
  • Urine sediment with urine microcysts (shed epithelial cells).
  • Highly echogenic kidneys as detected by serial renal ultrasound performed 3 months apart.
  • Black race with a clinical history of nephrotic-range proteinuria with or without oedema or hypertension.
Diagnosis of HIVAN
All HIV-infected children should be screened for proteinuria and microscopic haematuria annually or earlier if indicated. The initial investigations should include blood urea nitrogen, serum electrolytes and creatinine, and urine electrolytes to evaluate for tubulopathies [14]. An uPCR must be done to assess the severity of proteinuria and to determine if nephrotic-range. Urine microscopy is done to determine the presence of microcysts which are clusters of renal epithelial cells forming cyst-like structures [37,56]. Ultrasound examination of the kidneys should be performed to assess kidney size, echogenicity and to exclude any obstructive lesions. Unfortunately, currently available non-invasive diagnostic testing has limited sensitivity and specificity to distinguish HIVAN from other HIV-related kidney diseases. Therefore, kidney biopsy should be performed, if indicated, to confirm the presence of HIVAN, which is presently the only definitive way to diagnose HIVAN [37]. In most United States paediatric centres, children with perinatal HIV-1 infection and kidney disease were not biopsied either because they were felt to be too ill to undergo the procedure, or because of the perception that information gained from the biopsy would not make a significant contribution to the management of these children [15,38,61,62]. To date, HIV infection has not been associated with an increased risk of procedural complications from kidney biopsy [71].
Clinical presentation of other HIV-related kidney diseases in children and adolescents with perinatal HIV-1 infection
We describe below the presentation of some of the more commonly seen non-HIVAN kidney diseases that may accompany HIV-1 infection in this population.
Acute interstitial nephritis (AIN) results mainly from multiple drugs used in the treatment of HIV infections and its complications. It can occur as a result of HIV infection of the kidney itself, as in 28% of autopsy findings in HIV-infected patients with AIN an inciting agent was not recognized [72]. Known agents causing AIN include non-steroidal anti-inflammatory drugs (NSAIDS), rifampicin and trimethoprim-sulfamethoxazole combinations [73,74]. It has also been reported in patients taking indinavir or ritonavir [57,75,76]. These protease inhibitors (PIs) can also cause nephrolithiasis with flank pain and renal colic [77]. Sulfadiazine crystal formation with resultant tubular obstruction and possibly ureteral obstruction has been described in volume-depleted HIV-infected patients [7880].
Children with AIN from any cause, including HIV-infection, may present with non-specific signs and symptoms of acute kidney injury. More than 30 acute kidney injury definitions exist in the literature and therefore data may not be consistent, but a standardized definition has been proposed by the Acute Dialysis Quality Initiative Group [81] termed the “RIFLE” criteria and this has been modified for use in children [82]. RIFLE (the acronym for Risk for renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and end-stage kidney disease) aims to standardize the definition of acute kidney injury by stratifying patients based on changes in serum creatinine levels from baseline and/or an abrupt decrease in urine output. There may be sudden or insidious onset of nausea, vomiting, and/or malaise. Many patients are asymptomatic. A minority of patients may have proteinuria and gross haematuria may be found in 5% of patients [83].
Discontinuation of the potential causative agent is the mainstay of therapy. In severe cases where there is persistent renal dysfunction, immunosuppressive therapy has been employed. However, the optimal therapy of AIN is unknown, since there are no randomized controlled trials or large observational studies. These complications can be prevented or minimized with ample fluid intake.
Electrolyte disturbances of hyponatraemia/hypernatraemia, hypophosphataemia, hypocalcaemia and hypomagnesaemia are common [13,53]. Hyponatraemia is often seen in HIV-infected children with gastroenteritis [8486]. The syndrome of inappropriate anti-diuretic hormone secretion (SIADH) develops mainly in hospitalized patients [86] usually due to intracranial and respiratory infections such as pulmonary tuberculosis (TB), Pneumocystis jiroveci pneumonia and toxoplasmosis. Hyponatraemia and hyperkalaemia can be caused by adrenal insufficiency due to mineralocorticoid deficiency or hyporeninemic hypoaldosteronism [87,88]. Hypokalaemia due to low body potassium from severe malnutrition and gastrointestinal losses is also commonly seen. This also occurs through renal tubular loss resulting from the use of drugs such as amphotericin B used for the treatment of severe fungal infections. Toxicity from anti-retroviral agents such as tenofovir can cause proximal tubular dysfunction and nephrogenic diabetes insipidus can manifest as glycosuria, hypophosphateemia, proteinuria, acidosis and acute kidney injury [8992]. Therefore, the dosing of nephrotoxic drugs should be adjusted to the estimated glomerular filtration rate in patients with acute kidney injury or CKD [93,94].
Acid-base disturbances are common in children with HIV infection and are due mainly to severe sepsis and drugs [13,94]. Lactic acidosis may possibly be due to drug-induced mitochondrial dysfunction reported with zidovudine, diadanosine, lamivudine and stavudine and which could be present in a mild form in 5–25% of patients [64]. Non-anion gap metabolic acidosis can result from intestinal loss of bicarbonate from diarrhoea or renal losses from drug toxicity, most commonly amphotericin B [73].
Urinary tract infections
There is a higher prevalence of urinary tract infections (UTIs) in HIV-infected patients [53,57] ranging from lower tract involvement to pyelonephritis. UTIs in these patients seem to be due more to malnutrition than from immunosuppression due to HIV infection [95]. To prevent kidney damage, it is important to diagnose and treat UTIs appropriately. In a group of 60 children with HIV and renal involvement studied in Johannesburg, South Africa, 23% had UTIs [49]. The investigation and treatment of UTIs in HIV-infected children is based on standard guidelines used for management of HIV-uninfected children with UTIs [95].
Pulmonary and disseminated TB should be excluded in HIVAN. Nourse et al. demonstrated in four of their HIV-infected children with proteinuria as well as granulomatous lesions on histology compatible with TB, that proteinuria resolved on anti-TB drugs alone prior to the introduction of HAART [67]. TB was also a predominant finding in an adult Indian autopsy study in patients with AIDS [96]. The prevalence of TB in a cohort of 60 children at the Chris Hani Baragwanath Hospital was 33% [53]. The impact of other viral infections such cytomegalovirus (CMV), hepatitis B and hepatitis C on HIVAN has not been fully explored. One study of renal pathology in HIV-infected adult patients described CMV infection of the kidney as a cause of acute renal failure [97]. Hepatitis B virus resistance to lamivudine has been noted in kidney transplant recipients on HAART regimens containing lamivudine [98]. In patients with hepatitis C virus co-infection, clearance of the virus with interferon-ribavirin therapy should be attempted early, especially prior to transplantation, as immunosuppression exacerbates hepatitis C infection in kidney allograft recipients making management of HIV and hepatitis C virus co-infection particularly difficult [99].
Once kidney involvement is detected by renal dysfunction, proteinuria and/or haematuria, HAART needs to be commenced as soon as possible in accordance with WHO guidelines [100]. If already on HAART, it may be that their HIV disease is not well controlled, as evidenced by CD4 depletion and/or a high viral load, both being risk factors for HIVAN. In such a situation, appropriate resistance testing can guide subsequent HAART regimens. Associated infections such as TB, if present, must be appropriately treated. HAART is commenced after exclusion of tuberculosis to avoid immune reconstitution inflammatory syndrome (IRIS); however, ARVs may be started before TB is excluded in sick children [5,101103]. This possibly arrests the rapid progression of kidney disease.
NRTIs are excreted in the urine unchanged, and therefore decreased dosing is often required in CKD stage III and above [104]. The threshold for dose reduction varies for different NRTIs; most NRTIs generally require dose adjustment at creatinine clearance below 40–60mL/min/1.73m2. The dosing for zidovudine is only reduced at creatinine clearance <15mL/min/1.73m2 whereas the dosing for abacavir remains unchanged at any level of kidney function [94]. Due to this variability, it is challenging to prescribe fixed-dose combinations of NRTIs in patients with reduced kidney function. Most non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, fusion inhibitors, integrase inhibitors, and the β-chemokine receptor (CCR5) antagonists do not require dose modification with CKD [105,106].
HAART itself can cause acute kidney injury and progressive nephropathy [107110]. Some patients with normal kidney function at baseline still progress to CKD despite HAART [111]. Thus, patients on HAART who show progressive kidney disease or signs of acute kidney injury must undergo a kidney biopsy. This also applies to those in whom potentially nephrotoxic drugs are being used and whose kidney function fails to improve upon discontinuation of the drug [112].
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blocking agents (ARB) can be used as an adjunct for decreasing proteinuria provided the patient does not have a depleted intravascular space, often due to severe gastroenteritis, fluid loss from tubulopathy and/or severe nephrotic syndrome [13,15,56]. The introduction of HAART and angiotensin II blockade reduces progression to end-stage kidney disease [94,113]. However, to date, no completed randomized controlled trials or quasi-randomized controlled trials have been done providing evidence for treatment of HIVAN using ACE inhibitors or ARBs as adjunctive to HAART, although in most centres this is presently the standard of care [102,114]. Diuretics need to be used with caution as these agents can exacerbate intravascular volume contraction, further worsening the decline in glomerular filtration.
Steroid therapy has, in the short term, been shown to improve kidney function and proteinuria in HIVAN and in children treated for lymphoid interstitial pneumonitis; long-term effects of steroids on HIVAN are unknown. In resource-limited countries with a high prevalence of TB this could potentially cause exacerbation of, and overwhelming infection with TB, particularly when compliance is always an issue [49]. Also, in the absence of HAART, corticosteroids have not been shown to prevent the progression of HIVAN in children [15,38,56]. Steroids are therefore not currently recommended for the routine management of HIVAN.
The effects of other immunosuppressive agents such as cyclophosphamide, cyclosporine, azathioprine, mycophenelate mofetil, tacrolimus, are not known, but some have been utilized in a selective manner in certain patients [62].
In summary, co-morbidities such as UTIs, hypertension and electrolyte and acid-base disorders need to be treated aggressively. Avoidance of nephrotoxic drugs and combinations of ARVs that cannot be adjusted according to the patient's estimated glomerular filtration rate will help prevent further kidney damage.
Infants with perinatal HIV-1 infection are started on combination ARV therapy as soon as the diagnosis is established and will remain on medications for the rest of their life, given the current state of our knowledge on the treatment of HIV. It is therefore critically important to understand the toxicity profile of these drugs in order to be able to use them effectively and safely. Unfortunately, there is a paucity of data on such toxicity in children. A comprehensive review by Jao and Wyatt has described kidney toxicity reported with all classes of ARVs, except for the integrase inhibitors and the CCR5 antagonists [106]. Most PIs have, on rare occasions, been associated with the development of urolithiasis. This toxicity is notably most commonly reported with the use of indinavir. Crystalluria occurs in 20%, and nephrolithiasis in 3% of patients on this PI. Indinavir has also been reported to cause sterile pyuria and interstitial nephritis, as well as haematuria, renal colic, papillary necrosis, acute kidney injury and CKD. Due to the frequency of crystalluria and haematuria and the lack of a convenient paediatric formulation, this drug is rarely used in children and adolescents. The dose of atazanavir is now established in the paediatric population [115] and, along with the combination of lopinavir/ritonavir (Kaletra®), is a frequently used PI in children. Although cases of nephrolithiasis and interstitial nephritis have been reported with its use, the incidence of such toxicity is very low [116,117]. Similarly, the NNRTIs are metabolized by the hepatic cytochrome P450 system and have minimal nephrotoxicity, with rare reports of minimal change disease and urolithiasis with the use of efavirenz, and acute hypersensitivity reactions with the use of nevirapine. Lamivudine, didanosine and abacavir are nucleoside reverse transcriptase inhibitors (NRTIs) for which there are rare reports of Fanconi syndrome, and for the latter two, nephrogenic diabetes insipidus [118122].
Tenofovir is one of the most widely used ARV agents in the United States. Until recently, it was used only in children ≥12 years, provided their body weight was≥35 kg. It is now available as a powder and a low-dose tablet, and in 2012, received approval for use in children ≥2 years of age. It causes proximal renal tubular toxicity [123] and has been investigated far more extensively than other ARVs in order to better understand its renal safety profile. With acute tubular injury, there is reduced glomerular filtration rate, presenting as acute kidney injury [124]. The initial presentation of chronic tubular toxicity is the appearance of proteinuria, with glycosuria, phosphaturia and uricosuria, resulting in a complete or partial Fanconi syndrome [125]. In adult randomized controlled clinical trials, nephrotoxicity was observed in 1–2% of individuals [126]. It has been argued, however, that this is an artificially low estimate due to rigorous screening prior to participation in such studies. Cohort studies may better reflect the true renal safety profile of tenofovir in clinical care. There are few such studies in HIV-infected children and adolescents, and these are described in Table 2. They have shown results ranging from 86% proteinuria to no evidence of impaired glomerular or tubular function. One prospective double-blind placebo-controlled study showed no toxicity, while a recent large prospective cohort study showed a 2.5-fold increased risk of proteinuria with use of tenofovir for >3 years [134]. Thus, findings have been inconsistent.
Table 2
Table 2
Recent pediatric studies of tenofovir toxicity in children and adolescents with perinatal HIV-1 infection
In the pre-HAART era, dialysis was not offered to patients with HIV infection because of poor survival and concerns regarding high infection rates in these children [49]. Following the introduction of HAART, several studies have confirmed short-term survival rates in adults that are similar to non-HIV-infected patients, such as diabetics [5,107]. Predictors of poor outcome of patients on dialysis with HIV-infection include low CD4 counts, high viral load, HIVAN as the cause of end-stage kidney disease, absence of HAART and opportunistic infections.
Given the improved survival of these patients with HAART, renal replacement therapy was shown to be feasible. Currently, there is still no consensus on the modality of dialysis that is best for HIV-infected children and adults. Both peritoneal dialysis (PD) and haemodialysis (HD) are effective modes of renal replacement therapy in these patients, though there are various points of concern with both modalities. In the United States, HD is preferred over PD because of the added burden of PD for family members who are often managing their own disease as well as that of their child [37]. Presently, both PD and HD have been used in HIV-infected patients with end-stage kidney disease, and the mode of dialysis is not a determining factor in the survival of adult HIV-infected patients with end-stage kidney disease [135,136]. While those patients on PD have a 50% increased risk of peritonitis, patients on HD using tunnelled cuffed catheters have a five-fold higher risk of infection with gram negative bacteria and a seven-fold higher risk of infection with fungal species [137]. PD may also aggravate the malnutrition and hypoalbuminaemia in HIV patients with severe wasting syndrome. HD patients, on the other hand, have a higher risk of thrombosis [138,139]. In resource-limited settings, PD may be the modality of choice mainly due to cost implications and distance from centres able to provide HD.
There is little data on the outcome of children with end-stage kidney disease secondary to HIV on maintenance dialysis. In the early stages of the epidemic when HAART was not available, Ortiz et al. reported that once full-blown AIDS develops in an HIV-infected patient on HD, survival was significantly decreased [140]. Following the introduction of HAART, Tourret et al. reported that the survival of HIV-infected adult patients on HD was not statistically different from non-HIV patients on HD. In this study, the factors associated with mortality were a high viral load and a history of opportunistic infections [141]. Gordillo et al. reported on 12 HIV-infected children with end-stage kidney disease on maintenance HD compared to 32 non-HIV-infected children over a five-year period [142]. Their main findings were that body mass index and cardiovascular disease were associated with increased mortality in the HIV-infected children. A negative correlation of mortality in HIV-infected children to CD8 counts was consistent with studies in adult HIV populations [141]. Children who died also had lower CD4 counts and higher viral loads, although this did not show statistical significance given the small sample size. However, this was consistent with studies in adult HIV-infected patients [141]. Given the high mortality from cardiovascular deaths in this group of children, the authors, in a subsequent report, proposed that routine echocardiography be periodically performed in HIV-infected children on renal replacement therapy. This would enable detection of subclinical increased left ventricular mass index, or reduced shortening fraction, both of which may be early predictors of mortality [143]. To date, there are no reports on the outcome of HIV-infected children with end-stage kidney disease on maintenance PD.
Prior to the introduction of HAART, the morbidity and mortality of HIV-infected patients was too high to justify using scarce resources in transplanting HIV-infected patients [98]. There were concerns that immunosuppression may exacerbate HIV replication in an already immunocompromised patient resulting in rapid progression of disease and increased mortality [144]. The ability to suppress HIV replication with HAART, as well as improved prophylaxis and treatment of opportunistic infections, encouraged the transplant community to reconsider this option in HIV-infected individuals.
Further impetus was provided by the serendipitous finding that many of the commonly used immunosuppressive agents were also effective against HIV. Cyclosporine inhibition of interleukin-2-dependent T-cell proliferation may suppress HIV replication [145,146]. Furthermore, by binding to cyclophyllin A, cyclosporin prevents the formation of HIV gag protein/cyclophyllin A complex necessary for nuclear transport of HIV DNA [147,148]. A prospective study showed more rapid immune reconstitution in HIV-infected patients treated with cyclosporine and HAART versus cyclosporine alone [149]. Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase, a rate-limiting enzyme in the synthesis of guanosine nucleotides, markedly decreasing intracellular nucleotides in lymphocytes and monocytes as these cells lack a salvage pathway for generating purines, and thereby preventing replication of these cells [150152]. Hence, MMF can provide synergistic action with nucleotide analogues such as abacavir and didanosine, which are often integral components of HAART therapy [152,153]. Of potential concern is the in vitro antagonism with stavudine and zidovudine that may inhibit the action of MMF. However, this has not been demonstrated in vivo [144]. Sirolimus inhibits the mammalian target of the rapamycin (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1) that down-regulates the CCR5 receptor, which is the T-cell co-receptor for the HIV virion [154].
Transplants performed in HIV-infected patients on HAART show one-year graft and patient survival rates comparable to HIV-uninfected patients, although acute rejections are seen more frequently in the former, at a rate double that seen in those that are uninfected [144]. It has been postulated that this may be the result of immune dysregulation, but could also represent incomplete immunosuppression due to changes in overall drug exposure. Higher acute rejection rates have been observed in patients of African descent [155157].
The “Transplant Study for People with HIV” (www.HIVtransplant.com) has proposed selection criteria that continue to evolve as more experience accumulates in this group of transplant patients [158]. The inclusion criteria for selecting a suitable kidney transplant recipient with HIV-infection include, inter alia:
  • Meeting the standard criteria for kidney transplantation.
  • In children, the percentage of CD4+T-cell is better than an absolute CD4+T-cell count in defining an intact immune system, hence modification of criteria to include a T-cell percentage. For children 1–2 years of age, the T-cell percentage must be >30%, and in children 2–10 years of age it must be >20%.
  • Undetectable viral load (<50 copies/mL) for more than 6 months.
  • No change in the HAART regimen for at least 3 months prior to kidney transplantation.
  • There must be compliance to treatment for at least 6 months and caregivers and/or recipients must demonstrate willingness and an ability to comply with the immunosuppression protocol, ARV therapy and prophylaxis for opportunistic infections.
  • In the case of pulmonary coccidiodomycosis, the recipient must be disease-free for at least 5 years prior to kidney transplantation and in the case of neoplasms, for at least 2 years.
  • Female candidates of child-bearing potential must have a negative serum human chorionic gonadotropin pregnancy test 14 days prior to transplantation. All candidates must practice barrier contraception.
  • The ability to provide informed consent and, for children between 7 and 12 years, signed assent. In the case of minors between the ages of 13 and 18 years, the minor and parent(s) must both provide informed consent. These ages may vary according to the laws and Institutional Review Boards of various regions.
Exclusion criteria include, inter alia, the following:
  • Advanced-cardio-pulmonary disease.
  • Active uncontrolled malignancy with reduced life span;
  • Significant infection which may flare or reactivate with immunosuppression, such as tuberculosis, aspergillosis and other fungal infections, severe bacterial infections and active human papilloma virus infection.
  • Documented progressive multifocal leukoencephalopathy.
  • Epstein-Barr virus and human herpes virus 8 associated lymphoproliferative disease.
  • Documented poor compliance.
  • Failure to obtain informed consent or where required, assent.
Pharmacokinetic interactions between immunosuppresants and HAART agents can be profound with the most notable drug interactions occurring between ARV agents and immunosuppressive agents that induce or inhibit the P-glycoprotein 1 flux transporters and the cytochrome P450 3A (CYP3A4)-metabolizing enzymes found in the gut and liver [98]. Interactions can lead to unexpected increases or decreases in drug plasma levels and result in organ rejection, toxic adverse reactions of drugs and possible exacerbation of HIV replication. Patients on PIs and cyclosporine require only about 20% of the immunosuppressant dose of the latter drug normally administered to renal transplant recipients without HIV [98]. Patients on a ritonavir-boosted PI regimen require even lower doses of calcineurin inhibitors than patients on other HAART regimens [159]. In patients on tacrolimus or sirolimus using PIs as part of HAART, not only is the dose of these immunosuppresive drugs markedly decreased, but the interval of dosing needs to be increased more than five-fold [98]. Azole antifungal and macrolide antibiotics also inhibit the CYP3A4 system, increasing immunosuppressant levels of calcineurin inhibitors and sirolimus [160]. Patients taking steroids usually need proton-pump inhibitors for gastric ulcer prophylaxis. Since proton pump inhibitors can reduce intestinal absorption of Atazanavir, this PI must always be used in conjunction with a boosting dose of ritonavir. Zidovudine as a component of HAART used in combination with MMF could lead to additive myelosuppressive effects [161].
Post-transplant prophylaxis used in HIV-infected kidney transplant recipients is the same as that in HIV-uninfected recipients [98]. These regimens include prophylaxis for CMV and fungal infections (including Pneumocystis jiroveci) in the early postoperative period. For those patients with acute rejection treated with lymphocyte-depleting agents, prophylaxis regimen should be resumed for 3–6 months after discontinuation of the anti-rejection treatment.
Although HIV-infected adults are at increased risk for cancers such as Kaposi's sarcoma and non-Hodgkin's lymphoma, the rates of these cancers have declined with the introduction of HAART [162,163]. In adults, however, hepatocellular carcinoma rates have increased and this is probably related to increased longevity of patients with HIV co-infected with hepatitis B or C [164]. There are no similar reports in children.
In summary, kidney transplantation in HIV-infected patients treated with HAART has shown excellent graft and patient survival rates at 3–5 years [156,157,165]. Most issues revolve around interactions between ARV agents and the immunosuppressive agents used to prevent rejection. Opportunistic infections in these patients do not seem to have considerably increased although these patients have higher rates of acute rejection. Hepatitis B and C co-infection in adults remain a major concern, both in terms of treatment options and long-term effects on progression of liver disease [98].
Based on the current evidence, exclusion of children with HIV-infection from receiving a kidney transplant can no longer be justified.
The life expectancy of HIV-infected patients with kidney disease has greatly improved following the introduction of HAART [105]. Progression to end-stage kidney disease with its attendant complications still remains a significant co-morbidity. Thus, early detection of kidney disease would enable clinicians to intervene in a timely manner.
Routine screening for kidney disease is therefore recommended, where resources permit. The guidelines implemented by the New York State Department of Health AIDS Institute include measuring estimated glomerular filtration rate, blood urea nitrogen and urinalysis at baseline and every six months in HIV-infected patients. For those on a tenofovir-containing regimen, this needs to be performed at baseline, one month and thereafter at least every four months (www.hivguidelines.org) [166]. It is important that this be tailored to the resources and facilities available in different parts of the world and is consistent with local guidelines. Additional screening evaluations, urine microalbumin/creatinine ratios for example, may be indicated with additional risk factors such as concomitant diabetes mellitus. All HIV-infected patients, even if asymptomatic for kidney disease, should be educated on the importance of ARV therapy in preventing HIVAN and monitoring for other causes of kidney disease, including medication-related nephrotoxicity, hypertension and diabetes [54,167].
The differential diagnosis of the kidney diseases that are associated with HIV has expanded well beyond HIVAN. It includes toxicity from ARV and other therapeutic agents, immune complex-mediated kidney disease, and other comorbid unrelated kidney diseases. Given the broad differential diagnosis and inadequate sensitivity and specificity of non-invasive diagnostic testing, kidney biopsy is the gold standard for the diagnosis of HIVAN. There is increasing evidence that HAART improves kidney function in HIVAN although a clear benefit in non-HIVAN kidney disease has not been demonstrated. Kidney transplantation is now a viable alternative to dialysis in HIV-infected patients with end-stage kidney disease. Expanding access to HAART and further insights into the pathogenesis of HIVAN will help curb the devastating projected epidemic of kidney diseases, especially in the developing world. However, the most lasting impact on the epidemiology of this disease remains the prevention of new HIV infections.
Competing interests
The authors have no competing interests to declare.
Authors' contributions
All authors have contributed equally to the work.
1. WHO. Treatment of children living with HIV. Global Health Sector Strategy in HIV/AIDS. 2011–2015 2013 September 2012 [cited 2013 Feb 19]. Available from: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/JC2434_WorldAIDSday_results_en.pdf.
2. UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2010. 2010. [cited 2013 Feb 5]. Available from: http://www.unaids.org/globalreport/Global_report.htm.
3. Rao TK, Filippone EJ, Nicastri AD, Landesman SH, Frank E, Chen CK, et al. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med. 1984;310(11):669–73. [PubMed]
4. Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol. 2002;13(12):2997–3004. [PubMed]
5. Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int. 2004;66(3):1145–52. [PubMed]
6. Selik RM, Jr, Byers RH, Dworkin MS. Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987–1999. J Acquir Immune Defic Syndr. 2002;29(4):378–87. [PubMed]
7. Trullas JC, Barril G, Cofan F, Moreno A, Cases A, Fernandez-Lucas M, et al. Prevalence and clinical characteristics of HIV type 1-infected patients receiving dialysis in Spain: results of a Spanish survey in 2006: GESIDA 48/05 study. AIDS Res Hum Retroviruses. 2008;24(10):1229–35. [PubMed]
8. Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853–60. [PubMed]
9. Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30(Suppl 1):S5–14. [PubMed]
10. Naicker S, Fabian J. Risk factors for the development of chronic kidney disease with HIV/AIDS. Clin Nephrol. 2010;74(Suppl 1):S51–6. [PubMed]
11. Shahinian V, Rajaraman S, Borucki M, Grady J, Hollander WM, Ahuja TS. Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis. 2000;35(5):884–8. [PubMed]
12. Daugas E, Rougier JP, Hill G. HAART-related nephropathies in HIV-infected patients. Kidney Int. 2005;67(2):393–403. [PubMed]
13. Ramsuran D, Bhimma R, Ramdial PK, Naicker E, Adhikari M, Deonarain J, et al. The spectrum of HIV-related nephropathy in children. Pediatr Nephrol. 2012;27(5):821–7. [PubMed]
14. Pardo V, Meneses R, Ossa L, Jaffe DJ, Strauss J, Roth D, et al. AIDS-related glomerulopathy: occurrence in specific risk groups. Kidney Int. 1987;31(5):1167–73. [PubMed]
15. Strauss J, Abitbol C, Zilleruelo G, Scott G, Paredes A, Malaga S, et al. Renal disease in children with the acquired immunodeficiency syndrome. N Engl J Med. 1989;321(10):625–30. [PubMed]
16. Fauci AS. The AIDS epidemic–considerations for the 21st century. N Engl J Med. 1999;341(14):1046–50. [PubMed]
17. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, et al. 3’-Azido-3’-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA. 1985;82(20):7096–100. [PubMed]
18. Purswani MU, Chernoff MC, Mitchell CD, Seage GR, 3rd, Zilleruelo G, Abitbol C, et al. Chronic kidney disease associated with perinatal HIV infection in children and adolescents. Pediatr Nephrol. 2012;27(6):981–9. [PubMed]
19. Estrella M, Fine DM, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, et al. HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients. Clin Infect Dis. 2006;43(3):377–80. [PubMed]
20. Winston JA. HIV and CKD epidemiology. Adv Chronic Kidney Dis. 2010;17(1):19–25. [PubMed]
21. Kalayjian RC, Lau B, Mechekano RN, Crane HM, Rodriguez B, Salata RA, et al. Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AIDS. 2012;26(15):1907–15. [PMC free article] [PubMed]
22. Wyatt CM, Meliambro K, Klotman PE. Recent progress in HIV-associated nephropathy. Annu Rev Med. 2012;63:147–59. [PubMed]
23. Ray PE. Taking a hard look at the pathogenesis of childhood HIV-associated nephropathy. Pediatr Nephrol. 2009;24(11):2109–19. [PMC free article] [PubMed]
24. Conaldi PG, Bottelli A, Wade-Evans A, Biancone L, Baj A, Cantaluppi V, et al. HIV-persistent infection and cytokine induction in mesangial cells: a potential mechanism for HIV-associated glomerulosclerosis. AIDS. 2000;14(13):2045–7. [PubMed]
25. Green DF, Resnick L, Bourgoignie JJ. HIV infects glomerular endothelial and mesangial but not epithelial cells in vitro. Kidney Int. 1992;41(4):956–60. [PubMed]
26. Tokizawa S, Shimizu N, Hui-Yu L, Deyu F, Haraguchi Y, Oite T, et al. Infection of mesangial cells with HIV and SIV: identification of GPR1 as a coreceptor. Kidney Int. 2000;58(2):607–17. [PubMed]
27. Barbiano di Belgiojoso G, Genderini A, Vago L, Parravicini C, Bertoli S, Landriani N. Absence of HIV antigens in renal tissue from patients with HIV-associated nephropathy. Nephrol Dial Transplant. 1990;5(7):489–92. [PubMed]
28. Eitner F, Cui Y, Hudkins KL, Stokes MB, Segerer S, Mack M, et al. Chemokine receptor CCR5 and CXCR4 expression in HIV-associated kidney disease. J Am Soc Nephrol. 2000;11(5):856–67. [PubMed]
29. Husain M, Gusella GL, Klotman ME, Gelman IH, Ross MD, Schwartz EJ, et al. HIV-1 Nef induces proliferation and anchorage-independent growth in podocytes. J Am Soc Nephrol. 2002;3(7):1806–15. [PubMed]
30. Husain M, D'Agati VD, He JC, Klotman ME, Klotman PE. HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN. AIDS. 2005;19(17):1975–80. [PubMed]
31. Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, et al. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol. 2006;17(10):2832–43. [PubMed]
32. Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int. 2005;68(3):1048–60. [PubMed]
33. Rosenstiel PE, Chan J, Snyder A, Planelles V, D'Agati VD, Klotman PE, et al. HIV-1 Vpr activates the DNA damage response in renal tubule epithelial cells. AIDS. 2009;23(15):2054–6. [PubMed]
34. Snyder A, Alsauskas ZC, Leventhal JS, Rosenstiel PE, Gong P, Chan JJ, et al. HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells. AIDS. 2010;24(8):1107–19. [PMC free article] [PubMed]
35. Rosenstiel PE, Gruosso T, Letourneau AM, Chan JJ, LeBlanc A, Husain M, et al. HIV-1 Vpr inhibits cytokinesis in human proximal tubule cells. Kidney Int. 2008;74(8):1049–58. [PubMed]
36. Doublier S, Zennaro C, Spatola T, Lupia E, Bottelli A, Deregibus MC, et al. HIV-1 Tat reduces nephrin in human podocytes: a potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy. AIDS. 2007;21(4):423–32. [PubMed]
37. Ray PE, Xu L, Rakusan T, Liu XH. A 20-year history of childhood HIV-associated nephropathy. Pediatr Nephrol. 2004;19(10):1075–92. [PubMed]
38. Connor E, Gupta S, Joshi V, DiCarlo F, Offenberger J, Minnefor A, et al. Acquired immunodeficiency syndrome-associated renal disease in children. J Pediatr. 1988;113(1 Pt 1):39–44. [PubMed]
39. Albaqumi M, Barisoni L. Current views on collapsing glomerulopathy. J Am Soc Nephrol. 2008;19(7):1276–81. [PubMed]
40. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129–37. [PubMed]
41. Bostrom MA, Freedman BI. The spectrum of MYH9-associated nephropathy. Clin J Am Soc Nephrol. 2010;5(6):1107–13. [PubMed]
42. Nelson GW, Freedman BI, Bowden DW, Langefeld CD, An P, Hicks PJ, et al. Dense mapping of MYH9 localizes the strongest kidney disease associations to the region of introns 13 to 15. Hum Mol Genet. 2010;19(9):1805–15. [PMC free article] [PubMed]
43. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841–5. [PMC free article] [PubMed]
44. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet. 2010;128(3):345–50. [PMC free article] [PubMed]
45. Purswani M, Patel K, Kopp J, Winkler C, Specter S, Hazra H, et al. Philadelphia: Pediatric HIV/AIDS Cohort Study; 2013. Frequency of APOL1 risk alleles among a US cohort of children with perinatal HIV-1 infection and associations with renal phenotypes. In ESPR meeting.
46. Kimmel PL, Phillips TM, Ferreira-Centeno A, Farkas-Szallasi T, Abraham AA, Garrett CT. HIV-associated immune-mediated renal disease. Kidney Int. 1993;44(6):1327–40. [PubMed]
47. Haas M, Kaul S, Eustace JA. HIV-associated immune complex glomerulonephritis with “lupus-like” features: a clinicopathologic study of 14 cases. Kidney Int. 2005;67(4):1381–90. [PubMed]
48. Bruggeman LA, Nelson PJ. Controversies in the pathogenesis of HIV-associated renal diseases. Nat Rev Nephrol. 2009;5(10):574–81. [PMC free article] [PubMed]
49. McCulloch MI, Ray PE. Kidney disease in HIV-positive children. Semin Nephrol. 2008;28(6):585–94. [PMC free article] [PubMed]
50. Balow JE. Nephropathy in the context of HIV infection. Kidney Int. 2005;67(4):1632–3. [PubMed]
51. Anochie IC, Eke FU, Okpere AN. Human immunodeficiency virus-associated nephropathy (HIVAN) in Nigerian children. Pediatr Nephrol. 2008;23(1):117–22. [PubMed]
52. Gerntholtz TE, Goetsch SJ, Katz I. HIV-related nephropathy: a South African perspective. Kidney Int. 2006;69(10):1885–91. [PubMed]
53. Kala U, Petersen K, Faller G, Goetsch S. Spectrum of severe renal disease in children with HIV/Aids at Chris Hani Baragwanath Hospital, Johannesburg. Pediatr Nephrol. 2007;22:301. [PubMed]
54. Wearne N, Swanepoel CR, Boulle A, Duffield MS, Rayner BL. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant. 2012;27(11):4109–18. [PubMed]
55. Okpechi I, Swanepoel C, Duffield M, Mahala B, Wearne N, Alagbe S, et al. Patterns of renal disease in Cape Town South Africa: a 10-year review of a single-centre renal biopsy database. Nephrol Dial Transplant. 2011;26(6):1853–61. [PubMed]
56. Ray PE, Rakusan T, Loechelt BJ, Selby DM, Liu XH, Chandra RS. Human immunodeficiency virus (HIV)-associated nephropathy in children from the Washington, D.C. area: 12 years’ experience. Semin Nephrol. 1998;18(4):396–405. [PubMed]
57. Steel-Duncan J, Miller M, Pierre RB, Dunkley-Thompson J, Palmer P, Evans-Gilbert T, et al. Renal manifestations in HIV-infected Jamaican children. West Indian Med J. 2008;57(3):246–52. [PubMed]
58. Nourse P, Bates W, Gajjar P, Sinclair P, Sinclair-Smith , McCulloch M. Paediatric HIV renal disease in Cape Town, South Africa. Pediatr Nephrol. 2007;22:1597.
59. Atta MG. Diagnosis and natural history of HIV-associated nephropathy. Adv Chronic Kidney Dis. 2010;17(1):52–8. [PubMed]
60. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS. 2004;18(3):541–6. [PubMed]
61. Tarshish P. Guidelines for the care of children and adolescents with HIV infection. Approach to the diagnosis and management of HIV-associated nephropathy. J Pediatr. 1991;119(1 Pt 2):S50–2. [PubMed]
62. Ingulli E, Tejani A, Fikrig S, Nicastri A, Chen CK, Pomrantz A. Nephrotic syndrome associated with acquired immunodeficiency syndrome in children. J Pediatr. 1991;119(5):710–6. [PubMed]
63. Turner ME, Kher K, Rakusan T, D'Angelo L, Kapur S, Selby D, et al. A typical hemolytic uremic syndrome in human immunodeficiency virus-1-infected children. Pediatr Nephrol. 1997;11(2):161–3. [PubMed]
64. Chaparro AI, Mitchell CD, Abitbol CL, Wilkinson JD, Baldarrago G, Lopez E, et al. Proteinuria in children infected with the human immunodeficiency virus. J Pediatr. 2008;152(6):844–9. [PubMed]
65. Eke FU, Anochie IC, Okpere AN, Eneh AU, Ugwu RO, Ejilemele AA, et al. Microalbuminuria in children with human immunodeficiency virus (HIV) infection in Port Harcourt, Nigeria. Niger J Med. 2010;19(3):298–301. [PubMed]
66. Han TM, Naicker S, Ramdial PK, Assounga AG. A cross-sectional study of HIV-seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int. 2006;69(12):2243–50. [PubMed]
67. Nourse PJ, Cotton MF, Bates WD. Renal manifestations in children co-infected with HIV and disseminated tuberculosis. Pediatr Nephrol. 2010;25(9):1759–63. [PubMed]
68. Esezobor CI, Iroha E, Onifade E, Akinsulie AO, Temiye EO, Ezeaka C. Prevalence of proteinuria among HIV-infected children attending a tertiary hospital in Lagos, Nigeria. J Trop Pediatr. 2010;56(3):187–90. [PubMed]
69. Mistry BJ, Kala UK. Relevance of microalbuminuria in screening for HIV-associated nephropathy. Pediatr Nephrol. 2010;25:1870.
70. Joshi VV. Pathology of childhood AIDS. Pediatr Clin North Am. 1991;38(1):97–120. [PubMed]
71. Tabatabai S, Sperati CJ, Atta MG, Janjua K, Roxbury C, Lucas GM, et al. Predictors of complication after percutaneous ultrasound-guided kidney biopsy in HIV-infected individuals: possible role of hepatitis C and HIV co-infection. Clin J Am Soc Nephrol. 2009;4(11):1766–73. [PubMed]
72. Parkhie SM, Fine DM, Lucas GM, Atta MG. Characteristics of patients with HIV and biopsy-proven acute interstitial nephritis. Clin J Am Soc Nephrol. 2010;5(5):798–804. [PubMed]
73. Berns JS, Cohen RM, Stumacher RJ, Rudnick MR. Renal aspects of therapy for human immunodeficiency virus and associated opportunistic infections. J Am Soc Nephrol. 1991;1(9):1061–80. [PubMed]
74. Bourgoignie JJ. Renal complications of human immunodeficiency virus type 1. Kidney Int. 1990;37(6):1571–84. [PubMed]
75. Olyaei AJ, deMattos AM, Bennett WM. Renal toxicity of protease inhibitors. Curr Opin Nephrol Hypertens. 2000;9(5):473–6. [PubMed]
76. Chugh S, Bird R, Alexander EA. Ritonavir and renal failure. N Engl J Med. 1997;336(2):138. [PubMed]
77. Kopp JB, Miller KD, Mican JA, Feuerstein IM, Vaughan E, Baker C, et al. Crystalluria and urinary tract abnormalities associated with indinavir. Ann Intern Med. 1997;127(2):119–25. [PubMed]
78. Carbone LG, Bendixen B, Appel GB. Sulfadiazine-associated obstructive nephropathy occurring in a patient with the acquired immunodeficiency syndrome. Am J Kidney Dis. 1988;12(1):72–5. [PubMed]
79. Dong BJ, Rodriguez RA, Goldschmidt RH. Sulfadiazine-induced crystalluria and renal failure in a patient with AIDS. J Am Board Fam Pract. 1999;12(3):243–8. [PubMed]
80. Simon DI, Brosius FC, 3rd, Rothstein DM. Sulfadiazine crystalluria revisited. The treatment of Toxoplasma encephalitis in patients with acquired immunodeficiency syndrome. Arch Intern Med. 1990;150(11):2379–84. [PubMed]
81. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204–12. [PMC free article] [PubMed]
82. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. [PMC free article] [PubMed]
83. Praga M, Gonzalez E. Acute interstitial nephritis. Kidney Int. 2010;77(11):956–61. [PubMed]
84. Agarwal A, Soni A, Ciechanowsky M, Chander P, Treser G. Hyponatremia in patients with the acquired immunodeficiency syndrome. Nephron. 1989;53(4):317–21. [PubMed]
85. Glassock RJ, Cohen AH, Danovitch G, Parsa KP. Human immunodeficiency virus (HIV) infection and the kidney. Ann Intern Med. 1990;112(1):35–49. [PubMed]
86. Tang WW, Kaptein EM, Feinstein EI, Massry SG. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. Am J Med. 1993;94(2):169–74. [PubMed]
87. Marks JB. Endocrine manifestations of human immunodeficiency virus (HIV) infection. Am J Med Sci. 1991;302(2):110–17. [PubMed]
88. Kalin MF, Poretsky L, Seres DS, Zumoff B. Hyporeninemic hypoaldosteronism associated with acquired immune deficiency syndrome. Am J Med. 1987;82(5):1035–8. [PubMed]
89. De Beaudrap P, Diallo MB, Landman R, Gueye NF, Ndiaye I, Diouf A, et al. Changes in the renal function after tenofovir-containing antiretroviral therapy initiation in a Senegalese cohort (ANRS 1215) AIDS Res Hum Retroviruses. 2010;26(11):1221–7. [PubMed]
90. Deti EK, Thiebaut R, Bonnet F, Lawson-Ayayi S, Dupon M, Neau D, et al. Prevalence and factors associated with renal impairment in HIV-infected patients, ANRS C03 Aquitaine Cohort, France. HIV Med. 2010;11(5):308–17. [PubMed]
91. Wever K, van Agtmael MA, Carr A. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr. 2010;55(1):78–81. [PubMed]
92. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51(5):496–505. [PubMed]
93. Choi AI, Rodriguez RA, Bacchetti P, Volberding PA, Havlir D, Bertenthal D, et al. Low rates of antiretroviral therapy among HIV-infected patients with chronic kidney disease. Clin Infect Dis. 2007;45(12):1633–9. [PubMed]
94. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2005;40(11):1559–85. [PubMed]
95. Asharam K, Bhimma R, Adhikari M. Human immunodeficiency virus and urinary tract infections in children. Ann Trop Paediatr. 2003;23(4):273–7. [PubMed]
96. Lanjewar DN, Ansari MA, Shetty CR, Maheshwari MB, Jain P. Renal lesions associated with AIDS–an autopsy study. Indian J Pathol Microbiol. 1999;42(1):63–8. [PubMed]
97. Nadasdy T, Miller KW, Johnson LD, Hanson-Painton O, DeBault LE, Burns DK, et al. Is cytomegalovirus associated with renal disease in AIDS patients? Mod Pathol. 1992;5(3):277–82. [PubMed]
98. Frassetto LA, Tan-Tam C, Stock PG. Renal transplantation in patients with HIV. Nat Rev Nephrol. 2009;5(10):582–9. [PMC free article] [PubMed]
99. Rashid A, Abboud O, Al-Kaabi S, Taha M, Ashour A, El-Sayed M. The impact of hepatitis C infection and antiviral therapy on clinical outcome in renal transplantation recipients. Saudi J Kidney Dis Transpl. 1999;10(1):31–5. [PubMed]
100. WHO. Antiretroviral therapy of HIV infection in infants and children: towards univesal access. 2006. pp. 1–152. [cited 2013 Apr 10]. Available from: http://www.who.int/hiv/pub/guidelines/art/en/print.html.
101. Wyatt CM, Klotman PE. HIV-associated nephropathy in the era of antiretroviral therapy. Am J Med. 2007;120(6):488–92. [PubMed]
102. Smith MC, Austen JL, Carey JT, Emancipator SN, Herbener T, Gripshover B, et al. Prednisone improves renal function and proteinuria in human immunodeficiency virus-associated nephropathy. Am J Med. 1996;101(1):41–8. [PubMed]
103. Weiner NJ, Goodman JW, Kimmel PL. The HIV-associated renal diseases: current insight into pathogenesis and treatment. Kidney Int. 2003;63(5):1618–31. [PubMed]
104. Rao TK. Human immunodeficiency virus infection in end-stage renal disease patients. Semin Dial. 2003;16(3):233–44. [PubMed]
105. Novak JE, Szczech LA. Management of HIV-infected patients with ESRD. Adv Chronic Kidney Dis. 2010;17(1):102–10. [PubMed]
106. Jao J, Wyatt CM. Antiretroviral medications: adverse effects on the kidney. Adv Chronic Kidney Dis. 2010;17(1):72–82. [PubMed]
107. Kimmel PL, Barisoni L, Kopp JB. Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations. Ann Intern Med. 2003;139(3):214–26. [PubMed]
108. Fine DM, Perazella MA, Lucas GM, Atta MG. Renal disease in patients with HIV infection: epidemiology, pathogenesis and management. Drugs. 2008;68(7):963–80. [PubMed]
109. Hammer SM, Eron JJ, Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300(5):555–70. [PubMed]
110. Cohen SD, Chawla LS, Kimmel PL. Acute kidney injury in patients with human immunodeficiency virus infection. Curr Opin Crit Care. 2008;14(6):647–53. [PubMed]
111. Kalayjian RC, Franceschini N, Gupta SK, Szczech LA, Mupere E, Bosch RJ, et al. Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease. AIDS. 2008;22(4):481–7. [PMC free article] [PubMed]
112. Fine DM, Perazella MA, Lucas GM, Atta MG. Kidney biopsy in HIV: beyond HIV-associated nephropathy. Am J Kidney Dis. 2008;51(3):504–14. [PubMed]
113. Kimmel PL, Mishkin GJ, Umana WO. Captopril and renal survival in patients with human immunodeficiency virus nephropathy. Am J Kidney Dis. 1996;28(2):202–8. [PubMed]
114. Yahaya I, Uthman AO, Uthman MM. Interventions for HIV-associated nephropathy. Cochrane Database Syst Rev. 2009;(4):CD007183. [PubMed]
115. Kiser JJ, Rutstein RM, Samson P, Graham B, Aldrovandi G, Mofenson LM, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25(12):1489–96. [PMC free article] [PubMed]
116. Couzigou C, Daudon M, Meynard JL, Borsa-Lebas F, Higueret D, Escaut L, et al. Urolithiasis in HIV-positive patients treated with atazanavir. Clin Infect Dis. 2007;45(8):e105–8. [PubMed]
117. Brewster UC, Perazella MA. Acute interstitial nephritis associated with atazanavir, a new protease inhibitor. Am J Kidney Dis. 2004;44(5):e81–4. [PubMed]
118. Nelson M, Azwa A, Sokwala A, Harania RS, Stebbing J. Fanconi syndrome and lactic acidosis associated with stavudine and lamivudine therapy. AIDS. 2008;22(11):1374–6. [PubMed]
119. Ahmad M. Abacavir-induced reversible Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome. J Postgrad Med. 2006;52(4):296–7. [PubMed]
120. Krishnan M, Nair R, Haas M, Atta MG. Acute renal failure in an HIV-positive 50-year-old man. Am J Kidney Dis. 2000;36(5):1075–8. [PubMed]
121. Crowther MA, Callaghan W, Hodsman AB, Mackie ID. Dideoxyinosine-associated nephrotoxicity. AIDS. 1993;7(1):131–2. [PubMed]
122. Izzedine H, Launay-Vacher V, Deray G. Fanconi syndrome associated with didanosine therapy. AIDS. 2005;19(8):844–5. [PubMed]
123. Perazella MA. Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy. Kidney Int. 2010;78(11):1060–3. [PubMed]
124. Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int. 2010;78(11):1171–7. [PubMed]
125. Fernandez-Fernandez B, Montoya-Ferrer A, Sanz AB, Sanchez-Nino MD, Izquierdo MC, Poveda J, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Res Treat. 2011;2011:354908. [PMC free article] [PubMed]
126. Szczech LA. Tenofovir nephrotoxicity: focusing research questions and putting them into clinical context. J Infect Dis. 2008;197(1):7–9. [PubMed]
127. Vigano A, Zuccotti GV, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. Clin Drug Investig. 2007;27(8):573–81. [PubMed]
128. Andiman WA, Chernoff MC, Mitchell C, Purswani M, Oleske J, Williams PL, et al. Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J. 2009;28(7):619–25. [PMC free article] [PubMed]
129. Judd A, Boyd KL, Stohr W, Dunn D, Butler K, Lyall H, et al. Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study. AIDS. 2010;24(4):525–34. [PubMed]
130. Soler-Palacin P, Melendo S, Noguera-Julian A, Fortuny C, Navarro ML, Mellado MJ, et al. Prospective study of renal function in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens. AIDS. 2011;25(2):171–6. [PubMed]
131. Vigano A, Bedogni G, Manfredini V, Giacomet V, Cerini C, di Nello F, et al. Long-term renal safety of tenofovir disoproxil fumarate in vertically HIV-infected children, adolescents and young adults: a 60-month follow-up study. Clin Drug Investig. 2011;31(6):407–15. [PubMed]
132. Della Negra M, de Carvalho AP, de Aquino MZ, da Silva MT, Pinto J, White K, et al. A randomized study of tenofovir disoproxil fumarate in treatment-experienced HIV-1 infected adolescents. Pediatr Infect Dis J. 2012;31(5):469–73. [PubMed]
133. Pontrelli G, Cotugno N, Amodio D, Zangari P, Tchidjou HK, Baldassari S, et al. Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors. BMC Infect Dis. 2012;12(1):18. [PMC free article] [PubMed]
134. Purswani M, Patel K, Kopp JB, Seage GR, 3rd, Chernoff MC, Hazra R, et al. Tenofovir treatment duration predicts proteinuria in a multi-ethnic United States cohort of children and adolescents with perinatal HIV-1 infection. Pediatr Infect Dis J. 2012;32(5):495–500. [PubMed]
135. Mandayam S, Ahuja TS. Dialyzing a patient with human immunodeficiency virus infection: what a nephrologist needs to know. Am J Nephrol. 2004;24(5):511–21. [PubMed]
136. Panel de expertos del Grupo de Estudio de Sida y del Plan Nacional sobre el Sida (PNS) Diagnosis, treatment and prevention of renal diseases in HIV infected patients. Recommendations of the Spanish AIDS Study Group/National AIDS Plan. Enferm Infecc Microbiol Clin. 2010;28(8):520. e1–22. [PubMed]
137. Mokrzycki MH, Schroppel B, von Gersdorff G, Rush H, Zdunek MP, Feingold R, et al. Tunneled-cuffed catheter associated infections in hemodialysis patients who are seropositive for the human immunodeficiency virus. J Am Soc Nephrol. 2000;11(11):2122–7. [PubMed]
138. Brock JS, Sussman M, Wamsley M, Mintzer R, Baumann FG, Riles TS, et al. The influence of human immunodeficiency virus infection and intravenous drug abuse on complications of hemodialysis access surgery. J Vasc Surg. 1992;16(6):904–10. discussion 911–2. [PubMed]
139. Mitchell D, Krishnasami Z, Young CJ, Allon M. Arteriovenous access outcomes in haemodialysis patients with HIV infection. Nephrol Dial Transplant. 2007;22(2):465–70. [PubMed]
140. Ortiz C, Meneses R, Jaffe D, Fernandez JA, Perez G, Bourgoignie JJ. Outcome of patients with human immunodeficiency virus on maintenance hemodialysis. Kidney Int. 1988;34(2):248–53. [PubMed]
141. Tourret J, Tostivint I, du Montcel ST, Bragg-Gresham J, Karie S, Vigneau C, et al. Outcome and prognosis factors in HIV-infected hemodialysis patients. Clin J Am Soc Nephrol. 2006;1(6):1241–7. [PubMed]
142. Gordillo R, Kumar J, Del Rio M, Flynn JT, Woroniecki RP. Outcome of dialysis in children with human immunodeficiency virus infection. Pediatr Nephrol. 2009;24(1):171–5. [PubMed]
143. Gordillo R, Del Rio M, Woroniecki RP. Dialysis-associated morbidity, ultrafiltration, and cardiovascular variables in children with HIV infection. Clin Nephrol. 2011;75(5):434–9. [PubMed]
144. Stock PG, Roland ME. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation. 2007;84(5):563–71. [PubMed]
145. Andrieu JM, Even P, Venet A, Tourani JM, Stern M, Lowenstein W, et al. Effects of cyclosporin on T-cell subsets in human immunodeficiency virus disease. Clin Immunol Immunopathol. 1988;47(2):181–98. [PubMed]
146. Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992;175(2):331–40. [PMC free article] [PubMed]
147. Schwarz A, Offermann G, Keller F, Bennhold I, L'Age-Stehr J, Krause PH, et al. The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation–data on four cases and review of the literature. Transplantation. 1993;55(1):95–103. [PubMed]
148. Streblow DN, Kitabwalla M, Malkovsky M, Pauza CD. Cyclophilin a modulates processing of human immunodeficiency virus type 1 p55Gag: mechanism for antiviral effects of cyclosporin A. Virology. 1998;245(2):197–202. [PubMed]
149. Rizzardi GP, Harari A, Capiluppi B, Tambussi G, Ellefsen K, Ciuffreda D, et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest. 2002;109(5):681–8. [PMC free article] [PubMed]
150. Samaniego M, Becker BN, Djamali A. Drug insight: maintenance immunosuppression in kidney transplant recipients. Nat Clin Pract Nephrol. 2006;2(12):688–99. [PubMed]
151. Ciuffreda D, Pantaleo G, Pascual M. Effects of immunosuppressive drugs on HIV infection: implications for solid-organ transplantation. Transpl Int. 2007;20(8):649–58. [PubMed]
152. Heredia A, Margolis D, Oldach D, Hazen R, Le N, Redfield R. Abacavir in combination with the inosine monophosphate dehydrogenase (IMPDH)-inhibitor mycophenolic acid is active against multidrug-resistant HIV-1. J Acquir Immune Defic Syndr. 1999;22(4):406–7. [PubMed]
153. Margolis D, Heredia A, Gaywee J, Oldach D, Drusano G, Redfield R. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr. 1999;21(5):362–70. [PubMed]
154. Heredia A, Latinovic O, Gallo RC, Melikyan G, Reitz M, Le N, et al. Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1. Proc Natl Acad Sci U S A. 2008;105(51):20476–81. [PubMed]
155. Roland ME, Barin B, Carlson L, Frassetto LA, Terrault NA, Hirose R, et al. HIV-infected liver and kidney transplant recipients: 1– and 3-year outcomes. Am J Transplant. 2008;8(2):355–65. [PubMed]
156. Kumar MS, Sierka DR, Damask AM, Fyfe B, McAlack RF, Heifets M, et al. Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients. Kidney Int. 2005;67(4):1622–9. [PubMed]
157. Gruber SA, Doshi MD, Cincotta E, Brown KL, Singh A, Morawski K, et al. Preliminary experience with renal transplantation in HIV+ recipients: low acute rejection and infection rates. Transplantation. 2008;86(2):269–74. [PubMed]
158. Peter Stock MR. Solid organ transplantation in HIV: multi-site study. San Franscisco: EMMES Corporation; 2009. pp. 1–82.
159. Frassetto LA, Browne M, Cheng A, Wolfe AR, Roland ME, Stock PG, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant. 2007;7(12):2816–20. [PubMed]
160. Niwa T, Murayama N, Emoto C, Yamazaki H. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr Drug Metab. 2008;9(1):20–33. [PubMed]
161. Jain AK, Venkataramanan R, Shapiro R, Scantlebury VP, Potdar S, Bonham CA, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl. 2002;8(9):841–5. [PubMed]
162. Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123(1):187–94. [PubMed]
163. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA. 2006;296(23):2823–31. [PubMed]
164. MacDonald DC, Nelson M, Bower M, Powles T. Hepatocellular carcinoma, human immunodeficiency virus and viral hepatitis in the HAART era. World J Gastroenterol. 2008;14(11):1657–63. [PMC free article] [PubMed]
165. Roland ME, Stock PG. Review of solid-organ transplantation in HIV-infected patients. Transplantation. 2003;75(4):425–9. [PubMed]
166. Anonymous. New York: State Department of Health AIDS Institute; 2013. Kidney disease in HIV-infected patients.
167. Lescure FX, Flateau C, Pacanowski J, Brocheriou I, Rondeau E, Girard PM, et al. HIV-associated kidney glomerular diseases: changes with time and HAART. Nephrol Dial Transplant. 2012;27(6):2349–55. [PubMed]
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