Infectious Diseases

Renal Disease in the HIV Patient

OVERVIEW: What every practitioner needs to know

Are you sure your patient has renal disease? What should you expect to find?

Regardless of cause, kidney disease is manifested by changes in one or more laboratory parameters to include a/an:

  • increase in creatinine

  • increase in either urine albumin or urine total protein excretion

  • decrease in serum bicarbonate due to increased urinary loss or decreased renal production

  • decrease in serum phosphate due to increased urinary loss or increase in serum phosphate due to decreased ability to excrete excess

How did the patient develop renal disease? What was the primary source from which the infection spread?

At present, our understanding of the pathobiology of kidney disease suggests it develops based on the presence of a genetic predisposition, complications of metabolic or infectious diseases, or toxicities of medications. The precise risk factors for kidney disease differ based on the type of kidney disease.

  • Independent of the cause of kidney disease among persons with human immunodeficiency virus (HIV), risk factors for the presence of chronic kidney disease (CKD) include hepatitis C coinfection, lower cluster of differentiation (CD)4 lymphocyte count, and higher HIV ribonucleic acid (RNA) level.

  • Among people with kidney disease related to diabetes mellitus (DM) or hypertension (HTN), risk factors for end organ damage among persons with DM include time since diagnosis of DM (generally 3-5 years in type 2 DM) and less rigorous control of blood sugar. Risk factors for kidney disease related to both DM and hypertensive nephropathy also include higher blood pressures and African-American race.

Among persons with kidney disease, a family history of kidney disease should be sought. Although the importance of identifying diseases with direct genetic transmission, such as polycystic kidney disease and Alport syndrome, are clear, identifying families with a genetic predisposition to kidney disease may become increasingly important over the next decade. Current research suggests a role for alleles at the MYH9 and apolipoprotein L1 genes in the development of kidney disease and end-stage renal disease, particularly among African-Americans. Therefore, the finding of a relative with kidney disease or on dialysis may prompt increased surveillance.

Which individuals are of greater risk of developing renal disease?

Risk factors for kidney disease need to be considered in light of the different etiologies of kidney disease. The etiologies of kidney disease can be categorized into three large groups:

  • 1. kidney diseases NOT directly related to HIV

  • 2. kidney diseases related to HIV

  • 3. medication toxicities

For kidney diseases NOT directly related to HIV, the list of potential causes of kidney disease is quite extensive (Table I). The most frequently seen causes include diabetic nephropathy and hypertensive nephrosclerosis.

Table I.

Common kidney diseases NOT related to human immunodeficiency virus that should be considered.

Kidney diseases related to human immunodeficiency virus

  • HIV-associated nephropathy (HIVAN): Among African-Americans with HIV and kidney disease, the etiology of approximately 50% of kidney disease is likely HIVAN. This has been linked to alleles for apolipoprotein L1 seen in approximately 40% of African-Americans (0% of European-Americans or people of Asian descent). Other risk factors for HIVAN include lower CD4 lymphocyte count and higher HIV RNA. Reports of HIVAN among Caucasians are rare.

  • Glomerular lesions other than HIVAN: Although 50% of glomerular disease in African-Americans is HIVAN, it must be underscored that 50% of glomerular disease in African-Americans falls within the category of a “glomerular lesion other than HIVAN.” In Caucasians, all glomerular disease is in this category.

    • Glomerular lesions include membranous nephropathy, immune-complex glomerulonephritis, immunoglobulin (Ig)A nephropathy, and membranoproliferative glomerulonephritis.

    • It is not entirely clear if they are related to HIV infection in the same way that HIVAN is, but, given their relative infrequence in the general population, a relationship likely exists.

    • These glomerular diseases may also be slightly more frequent in persons with HIV coinfected with either hepatitis B or C, than in HIV-monoinfected patients.

  • Although the presence of a glomerular disease has a typical clinical appearance (i.e., substantial proteinuria often accompanied by low serum albumin, peripheral edema, and hypercholesterolemia - the so-called nephrotic syndrome), the diagnosis of the specific glomerular disease is not possible at present without a kidney biopsy.

  • Practically, failure of kidney disease to respond to antiretroviral therapy or appearance of a glomerular disease while an individual has a nondetectable viral load suggests a kidney disease other than HIVAN and should prompt consideration of a biopsy.

Medication toxicities

  • While HIVAN and glomerular lesions other than HIVAN affect the glomeruli and result in substantial proteinuria, toxicities related to medications usually affect the tubules. The histology of these toxicities can include acute tubular necrosis (ATN), allergic interstitial nephritis (AIN), as well as changes in renal hemodynamics and blood flow. A full review of all medications taken should be performed as multiple medications that could potentially affect the kidneys need to be considered (Table III).

    • Examples include nonsteroidal anti-inflammatory drugs (NSAIDS), antibiotics (causing AIN, such as trimethoprim-sulfamethoxazole), and antiretroviral medications (to include tenofovir and protease inhibitors). Risk factors for medication toxicities vary based on the medication.

    • In general, AIN is idiosyncratic and, therefore, should always be considered or ruled out.

    • In general, an increased risk of ATN can be linked to elevated drug levels. These in turn may be due to dosing in excess for the patient's renal function, or concurrent use of another medication that boosts levels of the nephrotoxic drug.

Table III.

Medication toxicities.

It should be remembered that it is always possible for a patient to have kidney function affected by more than one of the above categories of etiologies at a time. For example, an individual with HIV and diabetes may have diabetic nephropathy, HIVAN, or both, and a person with a glomerular disease may subsequently develop medication toxicity. It is, therefore, imperative in the evaluation of risk factors for any kidney abnormality that the totality of the medical history and medications be considered.

A special case: Tenofovir (tenofovir disoproxil fumarate- TDF)

Tenofovir is probably the most-used anti-retroviral drug, because it is part of the vast majority of combination treatments. In particular, three of the four available 1-pill-a-day combinations contain tenofovir (Atripla™, Complera™, and Stribild™), as does the commonly used combination of tenofovir and emtricitabine (Truvada™).

Tenofovir may cause tubular dysfunction with Fanconi syndrome, i.e. glucosuria and phosphaturia, and renal failure. Phosphate loss in urine may lead to hypophosphatemia, an increase in parathormone concentrations, and a decrease in bone mineral density.

Tenofovir accumulates in persons with renal failure; there is potential for a vicious cycle, with nephrotoxicity leading to drug accumulation which in turn worsens nephrotoxicity. The usual dose of 300 mg (equivalent to 245 mg of tenofovir disoproxil) daily in patients with a creatinine clearance of more than 50 ml/min should be given every 48 hours if the creatinine clearance is between 20 and 49 ml/min, and every 72 to 96 hours if it is between 10 and 29 ml/min. Serum creatinine should be measured before starting tenofovir, and every three to six months during treatment - more frequently if non-steroidal anti-inflammatory agents are co-administered, or if serum creatinine is abnormally high.

A derivative of tenofovir, tenofovir alafenamide or TAF, accumulates intracellularly and retains its anti-HIV activity at much lower doses and plasma concentrations than the present formulation (TDF). TAF has shown no evidence of nephrotoxicity and is expected to largely replace TDF by 2016.

Beware: there are other diseases that can mimic renal disease:

It is important to know that, without a kidney biopsy, it is not possible to precisely identify the exact cause of an individual’s kidney disease (i.e., any attempt to identify the specific histology of kidney disease is, therefore, conjecture). Rather it is only possible to determine whether the site of the disease is localized to the glomerulus or the tubule within the nephron. Categorizing location can be used to identify empiric therapies.

With respect to HIV-related kidney disease, particularly in an African-American, a misconception exists that all kidney disease that is primarily glomerular is HIVAN. Biopsy series suggest that, among persons with kidney disease related to HIV, only approximately one-half of African-Americans have HIVAN, whereas virtually no Caucasians with similar findings in their urine have HIVAN.

Many renal diseases, with divergent histologic lesions, present with increased serum creatinine, proteinuria, or proteinuria with hematuria. These include:

  • HIVAN

  • immune-complex glomerulonephritis

  • membranous nephropathy

  • IgA nephropathy

  • membranoproliferative glomerulonephritis

The type of kidney disease can only be defined by kidney biopsy. Biopsy is a relatively low risk procedure that, however, should only be performed where a change in therapy is likely.

Patients may be selected for biopsy based on their response to empiric therapy. If proteinuria declines while on empiric therapy, and serum creatinine plateaus, or falls, it may not be necessary to perform a biopsy. However, when the activity of the disease (as manifested by an elevated urine protein excretion that doesn't suppress or a continued rise in serum creatinine) is unaffected by empiric therapy, a biopsy to define the kidney lesion is indicated.

Of note, when the urine analysis indicates the presence of tubulointerstitial disease, biopsy may not be very informative. The two most common histologies for tubulointerstial diseases include ATN and AIN. Each can have multiple etiologies, including hemodynamics, as well as medications. Therefore, biopsies are not commonly performed in clinical settings that suggest one of these processes, and empiric treatment, including discontinuation of all potentially inciting agents, is employed.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

The two tools to detect kidney disease are the urine analysis and serum creatinine.

Urine analysis

Urine analysis has tremendous value in identifying early kidney disease, as well as potential etiologies.

  • Early kidney disease: The creatinine doesn’t have to be elevated for kidney disease to exist. An abnormal urine analysis in the setting of a normal creatinine clearance or estimated glomerular filtration rate (eGFR) may be the first sign of kidney disease and should be given the same priority as an abnormal urine in the setting of an elevated creatinine.

  • Diagnosis of the etiology of kidney disease: The differential diagnosis for intrinsic kidney disease (i.e., kidney dysfunction NOT related to either prerenal or obstructive causes) can be divided into two categories using the urine analysis: likely glomerular or likely tubulointerstitial. The parameters particularly useful in making this distinction are the results for proteinuria, hematuria, specific gravity, glycosuria, and pH on the urine analysis.s

    • Proteinuria frequently indicates a glomerular disease. The dipstick provides values of trace, +1, +2, and +3, but these values are qualitative and susceptible to fluctuations related to the concentration of the urine.

      • If proteinuria is seen on the dipstick, the next appropriate step in the evaluation is to obtain a spot urine protein and spot urine creatinine. The ratio of these two values approximates the number of grams of protein excreted in 24 hours. For example a spot urine protein measure of 140 mg/dL and a spot urine creatinine measure of 70 mg/dL provide a ratio of 140/70 or 2 and suggests the individual excretes approximately 2 g of protein in their urine per 24 hours.

      • 1g or less of proteinuria (a ratio of 1) can sometimes suggest tubular disease as one of the functions of the proximal convoluted tubule is to resorb the normal filtered load of protein.

      • As the amount of proteinuria (ratio of urine protein to creatinine) increases, the more likely and the more active is glomerular disease.

      • In patients with glomerular disease, the spot urine protein to creatinine ratio can also be used as a marker of disease activity within the glomeruli. Interventions that decrease proteinuria generally affect the disease process in a positive way.

    • Hematuria

      • Possible sources of blood in the urine are kidney, ureter, bladder, urethra, and contamination, such as in a menstruating women.

      • The concurrent presence of protein with blood strongly glomerulonephritis while absence of protein in urine containing blood suggests the source of the bleeding is not glomerular.

    • Specific gravity

      • A specific gravity of 1.030 indicates a state in which the kidneys perceive the individual to be volume deplete.

      • A specific gravity of 1.010 may indicate inability to concentrate or dilute the urine in the presence of abnormal tubular function or damage.

    • Glycosuria

      • Serum glucose is freely filtered in the urine and resorbed by the proximal convoluted tubule.

      • In the setting of elevated blood glucose, the ability of the tubule to resorb a larger than normal filtered load may be exceeded and glucose may appear in the urine.

      • In the setting of normal blood glucose levels, the presence of glucose in the urine suggests abnormal tubular function or damage.

    • pH

      • Most people, except those with a vegetarian diet, need to excrete a highly acid urine because of their production of volatile acids.

      • In the setting of a lower than normal serum bicarbonate, a urine pH that is anything except maximally acidic (either 5 or 6, depending on the dipstick) could suggest abnormal tubular function or damage.

Operationally, the urine analysis is particularly important in identifying whether the elevation in creatinine is related to a glomerular or tubular pathology. The presence of proteinuria can be a clue as to the location of the abnormality. Glomerular diseases present with substantial proteinuria with or without hematuria. A spot urine protein to creatinine ratio of 3 or greater strongly suggests a glomerular disease. Lower levels of proteinuria, such as a ratio of 1 or less, are more supportive of a tubular lesion.

Taken together, findings on a urine analysis consistent with a glomerular lesion would include significant proteinuria (>1g using the urine protein to creatinine ratio approximately +2 on dipstick) with or without hematuria.

Findings on the urine analysis consistent with a tubular lesion would include a lack of or limited amount of proteinuria, a specific gravity of 1.010, glucose in the urine in the setting of normal serum glucose, or a pH not maximally acidic with lower than normal serum bicarbonate.

Serum creatinine

Serum creatinine should not be interpreted in isolation. Two people with different body habitus (i.e., different amounts of lean muscle mass) can have the same kidney function but different serum creatinine levels. Therefore, the use of formulas to estimate creatinine clearance or eGFR is essential. Although each formula has its limitations, they all serve to assist the provider in not overlooking early kidney disease (i.e., a creatinine that is only slightly elevated in someone with lesser muscle mass, such as a creatinine of 1.2 in a 60-year-old white female).

Because serum creatinine reflects both the muscle mass as well as the kidney function of the individual in essence, it needs “adjusted for” muscle mass using one of three equations:

  • The Cockcroft-Gault equation is most useful in medication dosing given its use in the product labeling of most pharmaceutical products.

  • The modification of diet in renal disease (MDRD) equation estimates the kidney function more accurately than the Cockcroft-Gault equation for those individuals with an eGFR less than 60mL/min.

  • The CKD-epidemiology collaboration (EPI) equation estimates the kidney function more accurately than the Cockcroft-Gault equation for all individuals along the spectrum of eGFR.

Irrespective of which equation is used the following should be noted:

  • The standard error of measurement of serum creatinine is 0.1mg/dL. For any given level of kidney function, such as a serum creatinine of 0.9, serum creatinine could, therefore, fluctuate between 0.8 and 1.0mg/dL based on this standard error alone.

  • Given changes expressed in mg/dL early in the onset of kidney disease represent far more kidney function than identical changes in later stages. For example, a change of 0.5mg/dL from 1.0 to 1.5 represents a far greater loss than from 3.0 to 3.5.

  • Therefore, vigilance to early onset of kidney disease needs to be balanced against the error in measurement and expected fluctuation of the creatinine.

Results that confirm the diagnosis

Among persons with substantial proteinuria (and the potential for glomerular disease), the following laboratory tests play a role in evaluating etiology:

  • hemoglobin A1c or fasting blood glucose

  • hepatitis B and C serologies

  • screening tests for lupus erythematosus, such as antinuclear antibodies

  • anti-neutrophil cytoplasmic antibody (ANCA)

  • anti-glomerular basement membrane antibody (anti-GBM)

  • complement levels (C3 and C4)

Although it is reasonable to rule out diabetes and coinfection with hepatitis for most if not all patients, the additional serologies may be ordered in subsets of patients as supported by symptoms and physical findings.

Persons without substantial proteinuria more likely have tubulointerstitial disease. The following laboratory or imaging tests may play a role in evaluation of etiology:

  • renal ultrasound

  • urine for eosinophils

  • fractional excretion of sodium

  • fractional excretion of phosphorus

What imaging studies will be helpful in making or excluding the diagnosis of renal disease?

Ultrasound of the kidneys is useful to rule out obstruction to the urinary tract, as well as to evaluate kidney size. Bilaterally small kidneys (e.g., <9cm) can indicate a chronic process with potentially irreversible loss of kidney function. Bilaterally large kidneys (i.e., >11cm) can indicate an infiltrative or proliferative process, such as diabetes mellitus, amyloid, or HIVAN. Kidneys that have greater than 1cm difference in size could indicate the presence of renal artery stenosis.

Infrequently, tracer uptake and excretion may be required to further evaluate kidney artery function and obstruction of the urinary tract.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has renal disease, what therapies should you initiate immediately?

The general approach to the treatment of kidney disease includes the following steps. A nephrologist can be helpful at any point in this approach and is particularly helpful when a biopsy is required.

  • Attempt to identify the cause of the disease noninvasively.

  • Identify what therapies can be initiated empirically.

  • Observe the impact of these empiric therapies on urine protein excretion and serum creatinine.

  • If empiric therapies fail to achieve the desired result (i.e., a decrement in urine protein excretion or a plateau or fall in serum creatinine), kidney biopsy should be considered to identify the histology of the kidney disease for more specific therapy.

For a person with glomerular disease, the amount of protein in their urine (quantified using the spot urine protein to creatinine ratio) should be used as an intermediate outcome. Instituting therapies with a goal of reducing proteinuria is a key concept in the therapy of glomerular disease. Following the institution of such therapies (as detailed in Table II), a reduction in the quantitative level (i.e., the ratio) indicates therapeutic success. Therapies should be titrated up to suppress the proteinuria to the lowest degree possible. It is generally felt that suppression of an elevated urine protein excretion to 1g or less (i.e., a ratio of 1) is associated with better kidney survival.

Table II.

Table II. Key principles of therapy.

Controversial or evolving therapies

Case reports suggest a potential role for immunosuppressive therapies for glomerular diseases (other than HIVAN). Immunosuppressives, such as cyclosporine, tacrolimus, prednisone, mycophenolate mofetil, and rituximab, have been utilized in persons with HIV for indications, such as prophylaxis against transplant rejection and the treatment of lymphomas. Given their potential utility in the treatment of glomerular disease in persons without HIV infection, their use in persons with HIV infection could be considered on a case by case basis.

What complications could arise as a consequence of renal disease?

What should you tell the family about the patient's prognosis?

There are three potential complications of kidney disease that should be considered in a person with decreased kidney function:

  • 1. Anemia: As kidney function declines, a lower than expected serum erythropoeitin response will be associated with anemia. Evaluation for iron deficiency, as well as other potential contributors, should be performed prior to the initiation of therapy.

  • 2. Secondary hyperparathyroidism: As kidney function declines, the kidney’s ability to excrete a daily phosphorus load also declines. Elevated serum phosphorus combines with serum calcium resulting in a transient hypocalcemia corrected by an increase in serum parathyroid hormone ultimately resulting in secondary hyperparathyroidism. At most stages of kidney function, serum phosphorus and calcium will be maintained within normal levels due to this compensatory hyperparathyroidism. Therefore, serum PTH (intact PTH) needs measured to rule this out.

  • 3. Accelerated atherosclerosis: It is well described among persons with HIV and without HIV that kidney disease is associated with a greater risk of cardiovascular events. Kidney disease should, therefore, be considered a cardiovascular risk factor with evaluation and therapy for cardiovascular disease considered on a case by case basis. Among persons with kidney disease, the risk of dying from cardiovascular causes is generally greater than the risk of progressing to dialysis; therefore, a careful consideration of all cardiovascular risk factor reduction is imperative in the person with HIV and kidney disease.

How do you contract renal disease and how frequent is this disease?

Chronic kidney disease varies in terms of its rate of progression to include groups in which serum creatinine or urine protein excretion are abnormal but relatively stable to those in which either measures are worsening at a more alarming rate. Regardless of the rate of progression for each individual, the importance of the association between decreased kidney function and cardiovascular disease is present.

Taken together, approximately 20% of persons with HIV have abnormal urine protein excretion with an additional 10% demonstrating an abnormal albumin excretion. Although these numbers vary based on the risk factors for kidney disease, the prevalence of kidney disease is strikingly common.

The most important risk factors for CKD in persons with HIV include:

  • African-American descent

  • low CD4 lymphocyte count

  • high HIV RNA level

  • coinfection with hepatitis C

  • history of DM or hypertension

  • family history of kidney disease (or a relative on dialysis), particularly among African-Americans

  • kidney stones

  • NSAIDS

  • age

  • lupus

  • sickle cell anemia

  • heart disease (e.g., congestive heart failure)

What other clinical manifestations may help me to diagnose and manage renal disease?

Unfortunately, few symptoms are specific for the onset or progression of kidney disease. Symptoms can be constitutional and include fatigue, general dysesthesia, malaise, change in appetite, or edema. Symptoms related specifically to the kidneys can include frequent urination, urination at night, changes in the appearance of the urine, and pain in the flanks. It should be recognized that these symptoms are also present in pathologies of the urinary collecting system. Importantly, early kidney disease is more often than not subclinical, so waiting for symptoms to trigger screening tests will miss kidney diseases in their earliest and potentially most treatable time.

Physical findings related to kidney disease can be grouped into two categories: those related to the nonspecific decline in kidney function and those related to the cause of kidney disease itself.

Physical findings related to the nonspecific decline in kidney function include:

  • edema

  • hypertension

Physical findings related to the cause of the kidney disease can be approached by either organ system or pathophysiologic mechanism. The latter will be considered here:

  • immunologic: skin rash, joint changes

  • thrombotic or embolic: purpura or other evidence of thrombosis or emboli

  • autoimmune: rash, neuritis, joint changes

  • end-organ damage related to comorbidities such as diabetes mellitus: retinopathy, neuropathy, enlarged left ventricle

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Cockcroft, DW, Gault, MH. "Prediction of creatinine clearance from serum creatinine". Nephron. vol. 16. 1976. pp. 31-41.

Maggi, P, Bartolozzi, D, Bonfanti, P. "Renal complications in HIV disease: between present and future". AIDS Rev. vol. 14. 2012. pp. 37-53.

(An exhaustive, recent review of all aspects of renal disease in the context of HIV.)

Inker, LA, Schmid, CH, Tighiouart, H. "Estimating glomerular filtration rate from serum creatinine and cystatin C.". N Engl J med. vol. 367. 2012. pp. 20-9.

(Limits and reliability of noninvasive measures of kidney function.)

Mocroft, A, Lundgren, JD, Ross, M. "D: A: D study group; Royal Free Hospital Clinic Cohort; INSIGHT study group; SMART study group; ESPRIT study group. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study". PLoS Med. vol. 12. 2015.

(From a large database, a risk score to predict the probability of chronic kidney disease is derived.)
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