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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2002  |  Volume : 13  |  Issue : 3  |  Page : 344-352
Chronic Renal Disease Associated with HIV Infection


Patrick Clements Clinic, Department of GUM/HIV, Central Middlesex Hospital, London, United Kingdom

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   Abstract 

To describe current knowledge on the etiology, pathology, diagnosis and treatment of HIV-associated nephropathy (HIVAN), a Medline search was performed from 1989 to March 2002 using the key words, "HIV", "nephropathy", "renal" and "kidney". A further search was performed for each of the currently licensed anti-retroviral agents linked to key words "renal" or "kidney" and also using the MeSH heading "pharmacokinetics". Following the introduction of highly active anti-retroviral therapy with subsequent immune reconstitution different patterns of renal disease have occurred. In patients suffering from HIV-infection, the most common cause of renal failure is HIVAN. This rapidly progressing renal failure is the commonest complication of HIV in black African and Afro-Caribbean patients. Fortunately, if patients are diagnosed and treated soon enough with highly active anti-retroviral therapy, the evidence suggests that full recovery of renal function is possible. In conclusion, since HIVAN is a treatable condition, it should be actively sought in HIV­infected patients if they are to receive the benefits of therapy.

Keywords: HIV, Nephropathy.

How to cite this article:
Holden BM, Brook M G. Chronic Renal Disease Associated with HIV Infection. Saudi J Kidney Dis Transpl 2002;13:344-52

How to cite this URL:
Holden BM, Brook M G. Chronic Renal Disease Associated with HIV Infection. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2020 Sep 22];13:344-52. Available from: http://www.sjkdt.org/text.asp?2002/13/3/344/33117

   Introduction Top


Renal disease is a common complication of HIV infection. Both acute and chronic renal failure can occur for all of the usual reasons, but some forms of renal disease occur more frequently than others [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12] [Table - 1].

Immunosuppression leading to infection and septicaemiae increases the incidence of pre-renal failure. Infections such as Myco­bacterium tuberculosis are more common and can affect the kidney. [6] Drugs used to treat both the HIV and associated oppor­tunistic infections can cause renal damage. Thrombotic micro-angiopathies and immune complex deposition are linked to HIV infection and the disruption of the immune system which the virus causes. Finally, direct infection of renal epithelial cells by the HIV virus is linked to the most common cause of chronic renal failure in HIV positive patients so called HIV associated nephropathy (HIVAN). [13]

The spectrum of renal disease seen in HIV infection has changed over time. [14] With the advent of highly active antiretroviral therapy (HAART) the incidence of opportunistic infections has declined with preservation and restoration of immune function. It has now been recognised that HIVAN is the most common form of chronic renal disease in HIV-1 infected people. HIVAN however does not affect all population groups equally. It seems to be a disease predominantly afflicting those of Caribbean or African descent. [2],[15],[16],[17],[18],[19],[20],[21],[22] As the advent of HAART with immune reconstitution has had a major impact on the decline of opportunistic infections, so HAART has had a similar effect on HIVAN. HAART has been shown to delay the progression to end-stage renal disease (ESRD) and improve the long-term survival of patients on renal replacement therapy. [23]

This paper will concentrate on HIVAN as this is the most common cause of HIV related renal failure worldwide. Although there have been improvements in both treatment and outcome, important questions still remain unanswered, perhaps the most important being related to the suitability of HIV infected patients to have renal transplants now that HAART can keep the virus under control.


   HIV Associated Renal Disease Top


Although HIVAN is the most common cause of chronic renal failure worldwide other HIV glomerular lesions are seen frequently especially in centers with fewer Afro Caribbean patients. Thrombotic microangio­pathies are associated with HIV infection and will progress to ESRD if not treated. [14],[15]

Disruption of the normal vascular endo­thelial cells is thought to be responsible for the abnormal activation of components of the clotting cascade. A range of presen­tations varying from haemolytic uremic syndrome to thrombotic thrombocytopenic purpura can be seen.

In some patients presenting with renal disease specific HIV directed IgG or IgM immunoglobulins could be isolated, with associated membranous glomerulonephritis. More common in those of Caucasian or Hispanic descent, IgA HIV related immunoglo­bulins have given rise to IgA nephropathy. [24]


   HIV Associated Nephropathy Top


This has to be recognized as being by far the most common renal disease afflicting patients with the HIV infection, particularly those of Afro-Caribbean extraction [16],[17],[19],[21] but is seen in Hispanics too. [22] In the United States of America the number of patients receiving dialysis following HIVAN has increased by 20% per year. [20] By 1999 HIV related renal disease had become the third leading cause of ESRD amongst black men aged between 20-64. [17],[18],[19] This may even be an underestimate since it does not take into account patients in the early stages of disease or those who are still undiagnosed. The pathology seen in HIVAN is not specific to this entity. Indeed, many similarities are noted with Heroin nephropathy, Hepatitis C, HTLV-1, acute monoblastic leukaemia and multiple myeloma. [25]


   Pathology Top


The most common and characteristic histological finding on renal biopsy or necropsy is focal and segmental glomerulosclerosis (FSGS). [1],[2],[5],[8],[15],[16],[17],[18] There may also be glomerular collapse and microcystic tubulo-interstitial disease. [8],[15] However, this histology is not unique and may be seen in HIV-negative patients. Other features suggestive of HIVAN include podocyte swelling, intracytoplasmic protein resorption droplets and less hyalinosis than is seen in FSGS of other causes, such as that associated with intravenous heroin misuse or the idiopathic non-HIV form. [8],[13] Electron microscopy changes are also distinctive and include wrinkling, retraction pleating and thickening of the glomerular basement membrane and foot process effacement. [8] Particularly distinctive is the presence of numerous tubulo-reticular inclusions within the cytoplasm of the glomerular endothelial cells, interstitial capillary and arterial endo­thelial cells and interstitial leucocytes. [8] It has been documented that patients on HAART have fewer, if any, tubulo-reticular inclusions. [26]

The exact cause of HIVAN is not fully understood although proliferation of renal epithelial cells with concurrent apoptosis is a feature. [19],[27] There are some in-vitro data suggesting that HIV-1 can infect renal tubular epithelial cells [13] causing failure of growth and regeneration. HIV-1 infected monocytes, under the influence of locally secreted interleukin-6 and tissue necrosis factor alpha, may also be an important factor. [28] Cytokines such as transforming growth factor beta and macrophage chemoattractant protein are also thought to have a role in the pathogenesis, perhaps stimulated by HIV-1 proteins such as gp­ 120. [29],[30],[31] Podocyte damage with resulting loss of function seems to have a significant role in the loss of renal function. [32]


   Clinical Features Top


Adults

Most patients have late-stage HIV infection with a high viral load and low (<250/mm 3) CD4+ lymphocyte count. [15],[16],[17],[33],[34] There are reports of HIVAN also occurring at HIV seroconversion. [35] In the majority of reported case series HIVAN has been diagnosed as a result of routine investigations of HIV infected patients and presents as acute or chronic renal failure. Symptoms are non­specific but may include fatigue, malaise, anorexia, and pruritus. Although 40-75% of patients have nephrotic-range proteinuria (>3 g/24hrs) at presentation and many have full-blown nephrotic syndrome with hypo­albuminemia (<30 g/dl), peripheral edema is surprisingly uncommon. [15],[16],[20] Hyper­ tension is also uncommon. [15]

Black African or Afro-Caribbean patients predominate, forming 85-97% of patients with this diagnosis. [16],[17],[19],[21] Conversely, HIVAN is uncommon in other races except when associated with intravenous heroin abuse [5],[6],[22] although between five and fifty percent of black adult patients with HIVAN have also been reported to be intravenous drug users. [15],[16]

Part of the explanation for the prevalence in the Afro-Caribbean population indicates a genetic predisposition to renal disease, as shown by the familial clustering of end­stage renal disease in black patients with HIVAN. [21] There is no difference in incidence between the sexes. [22]

Data on long-term follow-up of adults comes mainly from the pre-HAART era and suggests a median time to death of approximately one year although there is a wide range. Death is usually due to other HIV-related problems. [2],[16] The progression of disease can also vary from a slow deterioration over years to rapid onset of end-stage renal disease within weeks. Prognosis worsens the higher the proteinuria or serum creatinine, or the lower the CD4+ lymphocyte count or the hemoglobin. [16]

Children

Black children are as prone to HIVAN as adults and the natural history in this group has been well-documented. [18] Early features include proteinuria, urinary casts, fluid/ electrolyte disorders and enlarged echogenic kidneys on ultrasound. The mean time to development of renal failure or frank nephrotic nephrotic syndrome after diagnosis of early disease is about twenty months. All thirty children in this cohort had other features of symptomatic HIV disease, which included cardiomyopathy in 65%. [18] Hypertension was uncommon and hematuria (microscopic or macroscopic) was rare, and so when present would suggest an alternative cause for the renal dysfunction.


   Diagnosis Top


HIVAN is a disease that may be diagnosed without the need for renal biopsy in many patients with reasonable confidence, [18] especially now that response to anti­retroviral therapy can be added as further supporting evidence (see below). The characteristic findings are of a black patient with relatively late stage HIV disease presenting with proteinuria (>1 g/24hrs), rising serum creatinine and enlarged echogenic kidneys on ultrasound. [36] Other causes of renal failure, [Table - 1] should be excluded [37] and a renal biopsy will be necessary in cases not typical of HIVAN, [Table - 2] or in patients failing to respond to therapy, which should include HAART.


   Management Top


Specific Therapy

The prognosis of HIVAN has improved dramatically in the last three years. [39],[40]

Before HAART the prognosis of patients with HIVAN was poor [15],[16],[17],[18],[19],[20] although therapy with steroids, angiotensin converting enzyme (ACE) inhibitors and zidovudine mono ­therapy were met with limited success in terms of modest improvement in renal function and prolonged survival. [40],[41],[42],[43],[44] There are also a few case reports of cyclosporin use with little success. [0],[45] However, many patients eventually needed hemodialysis [21],[47],[52] if they had not died of other HIV-related problems. Fortunately, in recent years it has become apparent that disease progression in patients with HIVAN can be reversed and renal function improved following the use of HAART. [39],[40] The effectiveness of HAART at treating HIVAN can be seen by the reduced incidence of HIVAN in the United States following the introduction of HAART in the mid 1990s. URSDS figures show a decline in incidence of HIVAN from 1999 onwards. [51] One reported patient [39] was dialysis-dependent with biopsy-proven HIVAN, but following HAART the need for dialysis ceased. A second renal biopsy subsequently showed a dramatic improvement in histology and the serum creatinine fell almost to normal. Needless to say, a high degree of HAART treatment adherence is required. Dosage adjustments according to serum creatinine/creatinine clearance are required for many of the nucleoside analogues but not usually for protease inhibitors or non-nucleoside reverse transcriptase inhibitors, Table 3.52-59 It should be remembered that frequent dosage changes may be required as the renal function improves. Although there have been no formal case controlled trials to prove the effectiveness of HAART in controlling HIV associated nephropathy, the circumstantial evidence supports the need to initiate therapy early in any suspected case of HIVAN.

Other Treatment Considerations

Care of patients with HIVAN, as with any patient with renal impairment, should include monitoring the patient's blood pressure and the use of an ACE inhibitor to keep the systolic and diastolic pressures below 150-90 mm Hg respectively. [40],[41],[44]

Even without elevated blood pressure ACE inhibitors have been shown to be affective at delaying progression to ESRD. However blood pressure in black patients may not respond well to ACE inhibitors and therefore diuretics or calcium channel antagonists may also be required. Anemia is also commonly associated with renal failure and, provided that causes other than renal failure have been excluded, may require treatment with blood transfusion or erythro­poietin. Similarly, serum electrolytes levels, including calcium, should be measured regularly. The use of corticosteroids has been tried in those with progressive disease despite treatment with ACE inhibitors but is associated with side-effects and relapse of disease with a reduced dose. [60],[61],[62]

Renal support with hemodialysis or continuous ambulatory peritoneal dialysis may still be required, [21],[20],[21] particularly in patients presenting with severe renal failure or who do not respond to HAART for whatever reason. Both dialysis methods are considered to be reasonable alternatives and there have been no specific studies to be able to recommend one above the other. There has been a reluctance to offer organ transplantation to HIV-positive patients because of the uncertain prognosis. However given the mounting data from individuals infected at the time of transplant and the continued improvements in outlook due HIV therapy,[63] renal transplantation should be given consideration and may well become a reasonable option for ESRD in such patients.

 
   References Top

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Correspondence Address:
M Gary Brook
Department of GUM/HIV, Central Middlesex Hospital, London NW 10 7NS
United Kingdom
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