Renal disorders

David Gracey : Renal Unit and Renal Transplant Unit, Statewide Renal Service, Royal Prince Alfred Hospital, Camperdown NSW and Central Clinical School, Faculty of Medicine, University of Sydney, Sydney NSW

Renal disease has emerged as one of the predominant non-infectious comorbidities seen among patients with human immunodeficiency virus (HIV) infection. It has long been recognised that patients with HIV infection are at particular risk of renal disease, although the pattern of disease has changed significantly over time. In the era of modern antiretroviral medication the burden of renal disease has increased, despite a reduction in HIV-specific renal diseases such as HIV-associated nephropathy (HIVAN).[1] With the widespread use of antiretroviral therapy (ART), the burden of renal disease reflects the increasing prevalence of non-infectious comorbidities in this patient group, such as hypertension and diabetes, as well as the ageing of the cohort with HIV and increased exposure to potentially nephrotoxic medications. The patterns of renal disease may be different in countries with limited access to modern ART, with HIVAN still a predominant cause of renal disease in countries with limited resources, particularly sub-Saharan Africa.[2]

Renal disease is important in this patient group, as the presence of renal impairment is associated with increased rates of morbidity and mortality. Increasing numbers of patients with HIV are observed with chronic kidney disease (CKD), as well as patients requiring dialysis or kidney transplantation.[3] Early detection of renal disease and management of renal risk factors may help reduce the current burden of renal disorders.

Risk factors for renal disease

Renal impairment is reported commonly in the population with HIV infection, although estimates of the prevalence of renal disease vary according to study design, location and the definition of renal impairment used. The reported prevalence of CKD, defined as a glomerular filtration rate (GFR) less than 60 mL/min on two separate occasions 6 months apart, ranges from 4.7 - 9.7% in the United States of America (USA) and Europe. Rates of up to 30% are reported in some studies. As well, proteinuria is common in these patients with rates of up to 10% reported in the Australian population.[4][5][6][7][8]

Factors associated with an increased risk of CKD are well recognised. Some of these risks are modifiable, emphasising the importance of their early detection and management. Renal risk factors are specific for patients with HIV (Table 1); other renal risk factors have been described in the general population (Table 2).[9][10][11] It is important to consider an individual patient’s risk of renal disease at diagnosis, and modify his or her therapy and subsequent monitoring accordingly.

Table 1. Risk factors for renal disease in patients with HIV infection
  • Older age
  • Female sex
  • Hypertension
  • Diabetes
  • Injecting drug use
  • Co-infection with hepatitis C
  • Some antiretroviral medications
  • Low CD4+ T cell count
  • High HIV viral load
  • History of acute kidney injury

 

Table 2. Other risk factors for renal disease found in the general population
  • Cigarette smoking
  • Ethnicity (e.g. Indigenous populations)
  • Family history of kidney disease
  • Obesity
  • Cardiovascular disease
  • Nephrotoxic medications

Detection of renal disease

The estimated glomerular filtration rate (eGFR) is the most widely used estimate of renal function. This value is derived from the serum level of creatinine; a breakdown product of muscle metabolism. The serum creatinine level is not an ideal measure of glomerular filtration rate, as creatinine is both filtered by the glomerulus and actively excreted by proximal renal tubular cells. Therefore, medications interfering with the excretion of creatinine may alter the serum creatinine level, without an actual change in GFR. This has implications for some antiretroviral agents, which can interfere with the tubular transport of creatinine. As well, the serum creatinine level is determined by muscle mass and so varies by sex, race, age and body mass index. The serum creatinine level must be interpreted mindful of these individual patient factors.[12][13][14]

The urinalysis, or urine dipstick, is used to detect proteinuria, as well as to provide information regarding other markers of renal damage, such as haematuria and glycosuria. The urinary dipstick predominantly detects albuminuria and may not detect other urinary proteins. This characteristic is important; as other proteins may predominate in certain clinical situations, e.g. tubular proteinuria, which may be seen with the use of tenofovir disoproxil fumurate (TDF). As well, the urinary albumin:creatinine ration (uACR) is designed only to detect albuminuria, one of the hallmarks of glomerular disease. In the general population screening with uACR is recommended for detection of renal disease. It is recommended that a urinary protein:creatinine ratio (uPCR) be monitored in the population with HIV infection, particularly in patients receiving TDF. As well, patients receiving TDF should have their serum phosphate monitored; low serum phosphate may be seen with proximal tubular dysfunction.[15][16]

Screening for renal disease

In 2014 the Infectious Disease Society of America recommended that all patients with HIV infection be screened clinically for renal disease during the baseline assessment. It stated, additionally, that these patients should be evaluated with a serum creatinine and eGFR, urinalysis, uPCR, as well markers of proximal tubular function. A minimum of 6-monthly eGFR testing was recommended, with more frequent testing in patients at risk. Urinalysis was recommended at baseline, when ART changed, or at least annually in all patients.[17] Other guidelines have similar recommendations, with a variety of suggested frequencies of screening (3-12 monthly).[18] As well, it is suggested that the serum phosphate level be monitored in patients treated with TDF. A suggested approach to screening for renal disease in patients with HIV is shown in Figure 1.

An Australian consensus statement regarding the monitoring of patients treated with TDF suggests that patients be tested at baseline for serum creatinine, eGFR, serum phosphate level, urinalysis and assessment of the uPCR. Repeat screening is suggested at 3-monthly intervals for a year and then at least annually in all patients; more frequently if any abnormalities are detected.[19]

Figure 1. Screening for renal risk in patients with HIV infection (adapted from Gracey et al.,[20] Lucas et al.[21] and European AIDS Clinical Society [EACS] guidelines[22]).

renal fig1

Management of abnormal screening tests

If a patient’s baseline screening tests or clinical assessment demonstrate an abnormality, underlying reasons for renal disease should be sought. Further investigation of the aetiology of renal impairment may be required, and referral to a renal specialist is recommended if there is CKD, significant proteinuria (uPCR > 100 mg/mmol).), haematuria or difficult-to-control hypertension. Referral to a renal specialist should also be considered for patients after the commencement of ART with the development of any of these features, as well as those patients with progressively declining renal function, or features of ART toxicity, particularly sustained hypophosphataemia or renal glycosuria, if on a tenofovir-containing regimen.[23][24][25][26]

A patient’s individual risk for the development of kidney disease should also be evaluated and modifiable risk factors addressed. The close association between renal and cardiovascular disease mandates that the patient’s risk of cardiovascular disease should also be addressed in those at high risk, or in those with abnormal baseline screening tests. Management approaches include lifestyle modification such as weight loss and smoking cessation.[27][28] As well, pharmacological control of hypertension with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) should be commenced, especially if there is proteinuria at baseline.[29] Other modifiable risk factors which should be addressed include dyslipidaemia and hyperglycaemia. Some improvement in renal function and proteinuria has been described after commencing ART.[30][31] Other specific therapy may be required, depending on the aetiology of the patient’s renal disease. These therapies are usually commenced by a renal specialist.

Consideration should also be given to the identification of any reversible factors, such as the cessation of nephrotoxic medications and attention should be paid to dose adjustment of medications excreted through the kidneys.[32] An important consideration is also the renal profile of ART and the renal risk factors of an individual patient. In some circumstances, potentially nephrotoxic ART may be avoided if a patient is at very high risk of renal disease, or has established renal disease at baseline.[33]

Specific renal disorders in patients with HIV infection

HIV-related renal disease

HIVAN and HIV immune complex kidney (HIVICK) disease are the predominant forms of renal disease related to HIV. HIVAN is seen almost always in patients with advanced HIV infection, and occurs predominantly in patients of African descent, explained by a genetic predisposition. Increased susceptibility to HIVAN among this group of patients is associated with polymorphisms in the apolipoprotein L1 gene.[34] HIVAN typically manifests clinically with heavy proteinuria, without haematuria.[35] There is usually a rapid decline in renal function and increased echogenicity of the kidneys on renal ultrasound. Histologically, the lesion is a collapsing focal segmental glomerulosclerosis. Treatment for the underlying renal lesion is ART.[36] Prednisone and antiproteinuric agents (ACE inhibitors, ARBs) may also be used.[37] Supportive treatments such as dialysis and renal transplantation may be required. The prognosis for patients with HIVAN remains poor, but has improved following the widespread introduction of antiretroviral agents. Because of modern ART, HIVAN is now uncommon among the population with HIV infection.[38] HIVICK disease is composed of a variety of histological conditions, including immunoglobulin A (IgA) disease, and a lupus-like syndrome. It is characterised by the deposition of immune complexes within the kidneys, associated with cellular proliferation, inflammation and damage.[39] Tubulointerstital inflammation may also be prominent (Figure 2). Although associated with advanced HIV-infection, HIVICK disease may be seen in other settings. The clinical picture of HIVICK disease is more variable than HIVAN. Other HIV-related renal diseases, such as thrombotic thrombocytopenic purpura and amyloid have been reported, but are less common.[40]

Figure 2. HIV immune complex kidney (HIVICK) disease, with prominent interstitial inflammation and glomerular hypercellularity (Figure 2a); glomerulosclerosis (Figure 2b); and deposits of IgA on electron microscopy (arrow) (Figure 2c) (Reproduced with permission of Dr Lyndal Anderson and Associate Professor Paul McKenzie, Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney NSW).

renal fig2

Other forms of renal disease

As in the population without HIV, the commonest causes of renal disease in the population with HIV infection are related to non-infectious comorbidities, in particular, hypertension and diabetes.[41] The clinical and histological features of these conditions are similar to the general population, although some studies suggest an additive role for HIV infection in the progression of renal disease in this setting.[42] Both conditions may be associated with proteinuria and CKD, although haematuria is less commonly seen. Their progression is usually insidious without stringent attention to the patient’s vascular risk profile. Diabetic nephropathy is characterised by nodular expansion of the glomerulus, with associated scarring and fibrosis, as shown in Figure 3. Hepatitis C co-infection may also increase the risk of CKD in HIV infection, particularly with a higher HCV viral load.[43]

Figure 3. Diabetic nephropathy in a patient with HIV-infection. The glomerulus is expanded and exhibits nodular change (arrow) and patchy inflammation (Reproduced with permission of Dr Lyndal Anderson and Associate Professor Paul McKenzie, Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney NSW).

renal fig3

Antiretroviral medications and renal disease

In addition to those conditions mentioned above, data suggest a role for specific antiretroviral medications in adding to the risk of CKD in this patient population.[44][45] The risk of CKD relates not only to the use of potentially nephrotoxic medications, but also to the patient’s comorbid conditions, polypharmacy and advancing age (as well as to HIV-specific factors).[46] Current ART (tenofovir disoproxil fumurate, atazanavir and ritonavir-boosted lopinavir) may place a patient at particular risk of CKD. In addition some ART may increase the serum creatinine because of their effect on the excretion of creatinine by the proximal renal tubule (Table 3), causing an apparent change in glomerular function.

Antiretroviral agent Tenofovir disoproxil fumarate Ritonavir/lopinavir Ritonavir/darunavir Ritonavir/atazanavir Cobicistat (with elvitegravir, tenofovir disoproxil fumarate, emtricitabine) Cobicistat/atazanavir (with elvitegravir, tenofovir disoproxil fumarate, emtricitabine) Dolutegravir Rilpivirine

Table 3. Renal effects of current antiretroviral therapy (adapted from Yombi et al.[47]).
Antiretroviral agent Possible renal effects
Tenofovir disoproxil fumarate

Renal dysfunction (acute or chronic)

Proximal tubular dysfunction

Fanconi syndrome (rare)

Ritonavir/lopinavir Chronic kidney disease
Ritonavir/darunavir Crystalluria
Ritonavir/atazanavir

Inhibition of tubular creatinine excretion

Renal dysfunction (acute or chronic)

Crystalluria

Cobicistat (with elvitegravir, tenofovir disoproxil fumarate, emtricitabine) Inhibition of tubular creatinine excretion
Cobicistat/atazanavir (with elvitegravir, tenofovir disoproxil fumarate, emtricitabine) Inhibition of tubular creatinine excretion
Dolutegravir Inhibition of tubular creatinine excretion
Rilpivirine Inhibition of tubular creatinine excretion

TDF is the most widely prescribed antiretroviral agent in Australia, and is a first line agent in guidelines for the treatment of HIV infection. Case reports have suggested that TDF may cause acute renal impairment, CKD and proximal renal tubular dysfunction.[48] TDF is found at high concentrations in the proximal renal tubular cells, and may cause mitochondrial toxicity. In some cases the tubular dysfunction may be subclinical, but in a minority of patients it may be associated with Fanconi syndrome triad consisting of proteinuria, hypophosphataemia and renal glycosuria. If Fanconi syndrome is observed in patients on TDF the agent should be ceased, as these effects may be significant, and in some cases life threatening.[49] Subclinical proximal tubular dysfunction may be clinically important for long-term renal function as well as bone health.[50] In this situation there are limited data to suggest a uniform clinical approach and dose reduction, increased vigilance with monitoring or cessation of TDF may be appropriate. Overall, serious adverse renal effects are uncommon with TDF (0.5% of patients); however, because of the potential clinical importance of these effects increased vigilance with screening for nephrotoxicity is suggested (Figure 4).[51][52][53]

It is hoped that a newer formulation of tenofovir (TFV), tenofovir alafenamide (TAF), may reduce the incidence of renal adverse effects associated with TDF. TAF is metabolised differently to TDF and demonstrates increased intracellular levels of TFV in lymphocytes, but lower levels in the plasma and proximal renal tubule. Studies suggest less renal toxicity with this new formulation.[54]

Figure 4. A suggested approach for renal monitoring in patients treated with potentially nephrotoxic antiretroviral agents, and agents which may artefactually affect the serum creatinine (Reproduced with permission, from Holt et al.)[55]

renal fig4

Some antiretroviral agents are recognised to inhibit the excretion of serum creatinine by the proximal tubular cell by the blockade of specific transporters.[56][57] These agents (cobicistat (COBI), dolutegravir (DTG) and rilpiverine (RPV)) act on different transporters in the tubular cell, but are not directly toxic to the cell itself. These antiretroviral agents may all increase the serum creatinine level, without altering glomerular function. The actual GFR is unchanged; however, the serum creatinine level and eGFR are artificially increased. This effect is seen because serum creatinine is not an ideal measure of glomerular function; it is both filtered by the glomerulus (80-90%), as well as excreted by the proximal tubular cell (10-20%). The increase in serum creatinine level seen after starting these agents occurs early, usually within 2-4 weeks, and is not progressive.[58] The increase in eGFR should not exceed 25% in patients with normal renal function, but may be higher in those patients with CKD.[59] The evaluation of renal impairment and the calculation of drug doses may become challenging in some patients treated with these agents, particularly those with pre-existing CKD. The detection of TDF-related nephrotoxicity may also be an issue in some patients, and tubular function should be closely monitored (see Figure 4).

Treatment of renal disease

CKD has important implications for clinical outcomes with a higher burden of morbidity and mortality. It is associated particularly with end-stage renal disease (ESRD) and a high burden of cardiovascular disease. Patients with HIV with renal impairment and albuminuria are at particular risk of increased morbidity and mortality.[60][61] These patients should be closely assessed for reversible factors placing them at risk of progression of renal disease; these risk factors should be addressed early. Attention to blood pressure control, treatment of hyperglycaemia, hyperlipidaemia and lifestyle factors such as weight loss and smoking cessation are important considerations. Other reversible causes for renal impairment should be sought, such as the use of nephrotoxic medications, and underlying renal conditions such as HIVAN should be excluded.[62] Patients with HIVAN should be placed on antiretroviral agents, if not already receiving anti-retroviral therapy.[63] Patients with CKD or ESRD should also be placed on antiretroviral agents as they are associated with better outcomes in this patient group.[64][65] Dose adjustment of medications excreted by the kidneys should also be undertaken, and the use of potentially nephrotoxic agents may be avoided in some clinical situations. The management of patients with HIV infection with established renal impairment is usually undertaken in conjunction with the assistance of a renal physician.[66]

Dialysis and renal transplantation

The number of patients with HIV infection with end-stage renal failure (ESRF) is increasing. These patients may be treated with dialysis or renal transplantation, usually in centres with expertise in this area. The one-year survival rate of patients with HIV on dialysis has improved recently, although the rate is still inferior to that of the population without HIV.[67] These improvements may reflect the changing aetiology of renal disease in the population with HIV. Renal transplantation is safe and effective in patients with HIV infection.[68] Assessment for renal transplantation is recommended for Australian patients with HIV infection and ESRF.[69] Patient selection for transplantation should be performed in centres with experience in the management of HIV infection and renal transplantation. Results of renal transplantation in the group with HIV are favourable, particularly if patients have undetectable HIV viral loads and no history of opportunistic infections or cancer, although reported outcomes are inferior to the patient group without HIV infection. Acute renal allograft rejection is reported more commonly in patients with HIV undergoing renal transplantation. Medication interactions and polypharmacy are also important considerations in this setting.[70][71][72]

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