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Renal Manifestations of Sexually Transmitted Diseases: Sexually Transmitted Diseases and the Kidney

Posted on: Tuesday, 15 February 2005, 03:00 CST

Sexually transmitted diseases (STDs) are traditionally caused by bacterial infections such as gonorrhea or chlamydia [I]. However, in the present era, especially in the adolescent patient population, a diagnosis of STD heralds high-risk behaviors that merit further investigation for the more virulent and persistent viral infections, including hepatitis B (HBV), hepatitis C (HCV), and HIV; these virus infections are associated with intrinsic renal disease [1-3]. With evidence of possible renal disease in the form of either proteinuria or hematuria, the search for viral venereal disease (VVD) is imperative [4].

The mechanisms by which viruses generate intrinsic renal injury, as well as other major organ disease, are not fully understood, although during the last decade HIV has provided a unique prototype for study [5]. These viral pathogens invade the nuclear envelope by DNA and RNA replication and transcription. They are capable of persistent latent infection and may manifest systemic disease through immune reactivity within the host.

The Adolescent Medicine specialist faces the arduous task of addressing and treating three emerging classes of patients: (1) the sexually active "at-risk" adolescent, (2) the HIV-infected pregnant adolescent female and her unborn infant, and (3) the surviving "perinatally infected" adolescent with pervasive medical and psychosocial health care needs [1-3,6].

Fig. 1. Schema for diagnostic evaluation: adolescent with STD and kidney disease. |iAlb, microalbumin; AB, antibody; Ag-Ab, antigen- antibody; ANA, antinuclear antibodies; BKV, Polyoma virus BK; CBC, complete blood count; Ccr, creatinine clearance; CMV, cytomegalovirus; dsDNA, double-stranded DNA; EBV, Epstein Barr virus; FSGS, focal segmental glomerular sclerosis; GFR, glomerular filtration rate; GN, glomerulonephritis; HUS, hemolytic uremie syndrome; IgAN, IgA nephropathy; INR, international normalized ratio; Mag3, radionuclide mercaptoacetyltriglycine; MGN, membrane glomerulopathy; MPGN, membranoproliferativc glomenilonephrilis; PCR, polymerase chain reaction; PT, prothrombin time; PTT, partial thromboplastin time; RhF, rheumatoid factor; RTA, renal tubular acidosis; UP/C, urine protein-to-creatinine.

This article addresses the mechanisms, evaluation, and treatment of intrinsic renal diseases associated with VVD in the adolescent population.

Viral assays of activity and infectivity

The array of viral test technologies has expanded, especially relative to HIV infection, and this may enhance an adolescent's willingness to be tested and learn his or her HIV status. HIV tests can use specimens collected by less invasive methods (eg, saliva, urine, and finger-stick blood) in addition to serum specimens collected by venipuncture. Rapid HIV testing allows results to be reported the same day, which is useful in urgent medical circumstances and settings where clients tend not to return for HIV test results (eg, some STD clinics). HIV testing can also be conducted using commercially available home testing kits. Regularly updated information may be obtained from the Public Health Service Web site (http://www.aidsinfo.nih.gov). The following assays are generally available for all VVD:

* Specific serum immunoglobulin antibody titers:

a. IgM usually indicates recent or active infection.

b. IgG usually indicates previous infection (recent or latent) with some degree of "humoral" immunity.

* ELISA studies with amplification of nuclear proteins by polymerase chain reaction.

* Viral replication: viral load is the most quantitative and reliable assay of viral activity and response to therapies.

Clinical and laboratory assessment for renal disease

Urinalysis

The urinalysis may be the single most cost-efficient and effective method for early detection of renal disease. The American Academy of Pediatrics includes a urinalysis by dipstick in its recommendations for routine adolescent follow-up. Any proteinuria by dipstick is highly predictive of significant proteinuria and should be further quantitated [7]. Leukocyturia, especially in adolescent males, suggests the need for further assessment for STDs. Moreover, in patients with an established diagnosis of STD, leukocyturia with proteinuria may herald the presence of an interstitial nephritis or glomerular lesion (Fig. 1, Table 1).

Proteinuria

Proteinuria is the single most important indicator of pathologic renal disease and its progression, so quantification by specific assays that distinguish glomerular from tubular injury is required. For some time, the most accurate and expedient measure of daily proteinuria in children has been the quantitation of random urine protein-to-creatinine ratio (UP/C) expressed as milligrams/ milligram creatinine (mg/mg) [7,8]. The random specimen correlates most closely with daily proteinuria when assayed on the second morning void fasting [9]. However, the first morning void has frequently been used in adolescents as an indication of the absence of "orthostatic proteinuria," believed to be a benign condition. Any degree of proteinuria in a sexually active adolescent should be considered pathologic. The urinary dipstick measures only large amounts of albumin and thus is not considered sensitive enough to detect early significant disease [6].

Table 1

Clinical manifestations of STD kidney disease

In the clinical laboratory, the assay for urinary total protein measures all protein components, including small amounts of physiologically secreted Tamm-Horsfall proteins and variable concentrations of proteins originating from potential abnormalities of glomerular or renal tubular integrity. Total proteinuria is considered to be abnormal if UP/C is greater than 0.2 (equivalent to > 100 mg/m^sup 2^/d). The "glomerular" proteinuria is the albumin component, which is abnormal in extremely small concentrations designated as less than 30 g per milligram creatinine. Intermediate- range proteinuria is a UP/C greater than 0.2 and less than 2.0 (> 100 and < 1000 mg/m^sup 2^/d), whereas heavy or nephrotic-range proteinuria is a UP/C greater than 2.0 (> 1 g/m^sup 2^/d) [1O].

The traditional components of the nephrotic syndrome, defined as heavy proteinuria (UP/C >2.0), include clinical and metabolic consequences of heavy proteinuria, such as edema, hypoalbuminemia, and hyperlipidemia (Figs. 2 and 3) (Table 2). In patients with severe malnutrition, which is common in HIV-infected patients, the clinical picture may not be precise. The cause of the hypoproteinemia must be confirmed by quantitative UP/C and assessed against measures of malnutrition, such as serum "prealbumin." Likewise, the hyperlipidemia may not be present if the patient is malnourished, despite significant proteinuria [U].

Glomerular filtration rate or creatinine clearance

Accurate measurements of renal function are difficult in ill pediatrie patients. The traditional estimates are based on the Schwartz equations [12], which include the height expressed in centimeters multiplied by a constant (k) and factored by the serum creatinine. The constant (k) was derived from carefully measured inulin and creatinine clearances in a large population of normal children and adolescents. The k equals 0.55 for children and adolescent females and 0.7 for adolescent males. Unfortunately, the great majority of patients with HIV/AIDS are significantly malnourished, with inordinately low serum and urine creatinine concentrations that are due to low muscle mass. This factor renders both measurements inaccurate in assessing renal function. In this scenario, the serum creatinine grossly overestimates glomerular filtration rate (GFR), whereas the creatinine excretion grossly underestimates renal function [8]. Therefore, it is recommended that the serum creatinine be doubled for a gross estimate of GFR.

Fig. 2. Spectrum of renal pathology in viral venereal disease with acute renal failure. ATN, acute tubular necrosis; FSGS, focal segmental glomerular sclerosis; HUS, hemolytic uremie syndrome; SLE, systemic lupus erythematosus; TIN, tubulo-interstitial nephropathy.

Fig. 3. Spectrum of renal pathology in viral venereal disease with chronic kidney disease. FSGS, focal segmental glomerular sclerosis; HUS, hemolytic uremie syndrome; IgAN, IgA nephropathy; MGN, membranous glomerulonephritis; MPGN, membranoproliferative glomerulonephritis.

Table 2

Viral infections and the kidney: viruses and renal manifestations

Practically speaking, clinical therapeutic decisions that require an estimate of GFR to determine dosing of renally excreted medications or therapeutic interventions should lean toward cautious underestimation of GFR. For example, an adolescent male with a creatinine of 1.0 mg/dL who is clinically malnourished should be considered to have a GFR of less than 50% of normal.

Radiologie studies

The primaiy radiologie finding considered characteristic of HIVAN is that of "hyperechoic enlarged kidneys" by renal ultrasound [13]. Diuretic technetium-99 mercaptoacetyltriglycine (MAG3) scintirenography shows nonspecific diffuse parenchymal dysfunction in pediatrie patients with HIVAN and may provide important estimates of GFR that are not distinguishable clinically [14]. Such dysfunction may provide corroborative evidence of HIVAN and should be recognized when the test is performed for standard indications. The test may be usefu\l to follow the progression of disease and the effect of treatment.

Biochemical parameters

Metabolic acidosis may be divided according to the plasma anion gap. This designation attempts to differentiate a metabolic acidosis (defined as a total plasma bicarbonate [T^sub co2^] <18 mM/L (millimoles per liter)) as renal in origin (normal anion gap) from an extraneously imposed acid load (positive anion gap). The renal acidosis is related to a defect in the renal tubules to excrete endogenous acid (ie, renal tubular acidosis). Most often, this defect is related to the toxic effects of medications such as trimethoprim-sulfamethoxazole (Bactrim) or protein-calorie malnutrition with inadequate generation of net acid (ammonium). The metabolic acidosis due to increased acid load and a positive anion gap is most frequently related to endogenous acid production, such as lactic acid from acute anaerobic metabolism [11,15,16].

Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking nucleoside analogue reverse transcriptase inhibitors. Decompensated, life-threatening lactic acidosis and hepatic steatosis are rare and appear to be more prominent in those patients treated with stavudine. It is probable that some patients are genetically predisposed to such an adverse reaction because of host mitochondrial dysfunction, insulin resistance, or obesity. The timing of this complication and previous reports suggest that surgery may be an increased risk factor for nonischemic (type B) lactic acidosis [17].

Immunologie evaluation

Any viral infection that invades the nuclear integrity of an organism is capable of stimulating the immune system by the mechanisms of (1) complement cascade and (2) stimulation of B-cell lymphocyte populations in the genesis of immunologie disease.

Mechanisms of local tissue injury by systemic viral invasion

With HIV-I infection as the prototype, research directed toward better understanding and combating the immunologie manifestations of viral diseases has blossomed. This article focuses on VVD and their renal manifestations through mechanisms of immune invasion that are pervasive and may be attributable to nonvenereal viral infections. Although the renal manifestations are divided primarily between immune-mediated and non-immune-mediated renal disease, the final mechanisms may be quite similar. The possible cascade of biologic events is outlined below [4,5,18,19]:

* Viral invasion with infection of bursal (B)-lymphocytes leading to activation of immunoglobulins and possible production of circulating immune complexes if complement is activated.

* Viral invasion of CD4 T-lymphocytes with activation of latent infection through intracellular signaling pathways dependent on mediators of nuclear transcription: nuclear factor kappa-B (NF- κ B) and nuclear factor of activated T cells (NF-AT).

* Circulating immune complexes may involve

(a) Viral antigens and host antiviral antibodies.

(b) Endogenous antigens modified by viral injury and host autoantibodies, including "cryoglobulins" with or without rheumatoid factor activity.

* In situ viral or local mediators lead to activation of NF- κ B within proximal tubular cells; this appears to be an important intracellular signal that leads to transcriptional activation of chemokine genes.

* Expression of viral or noxious host proteins in tissue may induce

(a) Cell death through necrosis or apoptosis

(b) Increased matrix synthesis or decreased matrix degradation

(c) Release of cytokines, chemokines, adhesion molecules, and growth factors

* Proteinuria resulting from local injury to the glomerular and tubular basement membranes may also perpetuate and contribute to ongoing local tissue injury, leading to ultimate glomerular sclerosis and collapse.

Indications for biopsy

The primary indication for renal biopsy of patients with suspected intrinsic renal disease is significant proteinuria, whether or not this is associated with renal insufficiency. In the adolescent with clinical evidence of immune-mediated disease and significant proteinuria, a biopsy with special attention to in situ viral studies and immunofluorescent assays is indicated.

Spectrum of renal biopsy morphologies

The spectrum of renal biopsy morphologies is broadly categorized into immune-mediated and non-immune-mediated diseases [20,21]. Although each of the morphologies may be attributable to any of the VVD discussed in this review, some are particularly attributable to a recognized association or coinfection to be detailed below. Moreover, it is important to distinguish between acute and chronic clinical presentations, because timely therapeutic interventions improve management and prognosis.

Non-immune-mediated renal lesions

Focal segmental glomerular sclerosis

The predominant lesion of HIV-!-associated nephropathy (HIVAN) in both children and adults is characterized morphologically by focal glomerular sclerosis, tubular microcysts, interstitial fibrosis, and inflammation. At the level of electron microscopy, tubular reticular inclusions in renal endothelial cells are a typical, but not pathognomonic, feature of HIVAN [11,19-21]. An increasingly described lesion is the "collapsing glomerulopathy," which has emerged as a particularly aggressive pathologic variant of focal segmental glomerular sclerosis (FSGS). This lesion, in addition to the glomerulosclerosis, demonstrates segmental collapse of the glomerular tufts with marked hyperplasia of the overlying podocytes. Although the pathogenic mechanisms remain poorly understood, transgenic mice models suggest a direct effect of the virus within the renal tissue. One report from New York indicates that, with highly effective antiretroviral therapy (HAART), the collapsing lesions may be reversible if treated early. Moreover, they offer evidence that the renal epithelial cells may be a persistent reservoir of the HIV-I RNA transcription [21].

Recent advances in molecular histology link the pathogenesis of HIVAN to factors associated with the viral life-cycle. Cytopathic effects of HIV gene products include the elaboration of chemokines and cytokines as a result of virally induced host protein synthesis. Patients of African lineage appear to have a genetic susceptibility to this type of nephropathy with or without viral infection (Table 3) [20,21].

The clinical presentation may be insidious, with early recognition provided by assays for microalbumin. Progression to end- stage renal disease in the authors' pediatrie population has been exclusively in the African American population and has always been associated with proteinuria. In the early HIV era of the 198Os, pediatrie HIVAN showed a broad spectrum of renal pathology, from "minimal-change" disease through mesangial proliferation [11,20- 22]. Currently, long-term survivors of perinatally acquired infection are reaching their adolescence, and more are being maintained off dialysis with early recognition and conservative management of their renal disease [23]. Unfortunately, HIVAN has risen to the third most common diagnosis in the African American population for entry into the end-stage renal disease program [24,25].

Table 3

Pathologie renal manifestations of sexually transmitted disease with racial-ethnic predominance

Hemolytic uremie syndrome

The hemolytic uremie syndrome (HUS) remains an enigma in the constellation of renal disease manifestations associated with HIV and related viral infections. The diagnostic criteria include microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The constellation of signs and symptoms can be extensive, and it is often difficult to confirm the microangiopathy. A degree of renal dysfunction is common, with "tubular" proteinuria usually predominant. Patients with hemoglobinopathies, including sickle cell disease and sicklethalessemia disease, as well as those patients with positive antiphospholipid antibodies, may be more prone to renal failure secondary to microangiopathy [26]. In a large series of 90 patients with HIV infection and acute renal failure reported from France, over half had HUS associated with active coinfection with the cytomegalovirus (CMV) [27]. Unlike those with non-HIV- associated HUS, these patients had elevated plasma tissue-type plasminogen activator activity.

Tubulo-interstitial nephropathy

Among the major VVD (HIV, HBV, HCV), coinfection with other viruses, such as the Epstein Barr virus, CMV, or Polyoma virus, predisposes to the development of tubulo-interstitial nephritis. It is recommended that laboratory assays be obtained for these copathogens so that treatment may be instituted.

An often overlooked but significant cause of acute renal insufficiency in patients undergoing treatment for VVD is the occurrence of allergic interstitial nephritis due to antiviral or other therapies. Some of the antiviral drugs, most notably indinavir, adiavir, foscavir, and gangiclovir, cause nephrolithiasis and microtubular precipitation that can lead to acute and chronic renal insufficiency [27]. Although the list of drugs potentially associated with interstitial nephritis is extensive, a reference guide is provided in Table 4.

Table 4

Nephrotoxic drags in the viral venereal disease-infected host

Immunologically mediated renal lesions

Systemic lupus erythematosus-like variant

In the initial description of HIVAN in children, the spectrum of renal disease morphology ranged from minimal-change disease to full- blown FSGS [11,22]. Unique among that small group of patients was a rare manifestation that has been termed the "lupus-like" nephritis. It is characterized by clinical and serologic evidence of systemic lupus erythematosus (SLE). Laboratory assays show positive antibody to double-stranded DNA, positive antinuclear antibody, and activation of the complement cascade, with decreased C3 and C4 complement. Other autoantibodies may include the antiphospholipid antibodies, which \predispose to vascular thromboses [26]. The clinical picture is often one of rapidly progressive renal failure with nephrotic-range proteinuria. In the authors' experience and that of other reporters, aggressive treatment with corticosteroids and HAART may reverse or modify the clinical deterioration in renal function.

Systemic symptoms, including arthritis, headaches, rash, and hemolytic anemia, may respond to corticosteroids, intravenous gamma globulin, and hydroxychloroquine (Plaquenil). The renal biopsy has shown diffuse proliferative glomerulonephritis resembling diffuse proliferative (World Health Organization class IV) lupus nephritis [28]. Considering previously reported cases, it appears that lupus- like nephritis is a rare but well-defined pattern of immune-complex- induced renal injury seen in HIV-infected patients. As a caveat, however, the authors note that their practice is currently treating a 14-year-old female with perinatally acquired HIV infection who presented with a "lupus-like" picture at 12 years of age and has a biopsy showing collapsing FSGS. She requires systemic treatment for debilitating arthritis and has stable renal function and moderate proteinuria on HAART and angiotensin antagonists.

Membranous nephropathy

HBV is the causative agent associated with the lesion of membranous nephropathy, with its antigen identified by immunofluorescent staining within the immune-complexes and distributed in a regular pattern on the epithelial surface of the glomerular basement membrane. It is often a silent infection transmitted by intimate contact or vertically at birth. Although this immune-mediated renal disease is comparatively rare, it was the first virally associated glomerulopathy to be described and studied. The clinical presentation is usually the nephrotic syndrome with heavy proteinuria followed by progressive decline in renal function, although subclinical cases occur with presentation at "end stage." Thromboembolic phenomena are also more common in association with this lesion. Although the disease is immune-mediated, serum complements are usually normal unless associated with a "lupus- like" vasculitis [28].

Coinfection with HBV and HIV is considered extremely significant, because each imparts a negative prognosis for the ultimate outcome of both liver and renal disease. In recent years, treatment with lamivudine has greatly improved the prospective outcomes of transplanted patients. The accepted protocol is 6 months' treatment with lamivudine before transplantation, followed by continuous treatment posttransplant.

Membranoproliferative glomerulonephritis

HCV has emerged as an ominous VVD in the last decade, with a strong propensity to progress to liver failure and hepatic cancer [29]. The predominant renal lesion is an immune-mediated membranoproliferative glomerulonephritis, which is characterized by mesangial cell proliferation and sporadic deposits of large immune complexes along the endothelial surface of the glomerular basement membrane and within the mesangium. The clinical picture may be one of systemic vasculitis with circulating immune complexes and hypocomplementemia. Up to 65% of these patients will have an associated cryoglobulinemia, very often accompanied by a palpable or ulcerating rash [4,29,3O]. Early treatment with solumedrol and intravenous cytoxan has successfully reversed the renal and systemic vasculitis. Interest also exists in the potential therapeutic benefits of an anti-CD20 monoclonal antibody, rituximab. Treatment with interferon-alpha has been less successful and does not prevent recurrence of the disease activity [31]. Interferon has actually caused exacerbation of renal disease. Also, the use of ribavarin is contraindicated in patients with decreased renal function [4,29,3O].

IgA nephropathy

This nephropathy is an immune-mediated disease characterized by gross, painless hematuria, moderate to severe proteinuria, and renal biopsy morphology that can range from minimal mesangial hypercellularity to an aggressive crescentic glomerulonephritis [32]. The diagnosis is contingent on the positive staining by immunofluorescence of all glomeruli with the immunoglobulin IgA. This unique lesion, whether or not associated with HlV infection, has a predominance in Asian populations and is rarely observed in patients of African descent [32,33].

Treatment interventions

Highly active antiretroviral therapy

Currently, 15 licensed antiretroviral drugs compose the HAART armamentarium. These fall into the two general categories of nonnucleoside reverse-transcriptase inhibitors and protease inhibitors (Table 5). Prognostic indicators of poor response to a HAART regimen (≥ two antiviral drugs) in a small prospective study of HIV-infected children were higher HIV-I RNA load and lower CD4+ cell count after 30 or more consecutive days of therapy. These criteria were significantly correlated with increased risk for HIV clinical disease progression and viral resistance through mutations [34]. Principal toxicities include mitochondrial toxicity, hypersensitivity, and lipodystrophy, as well as more drug-specific adverse effects such as gastrointestinal intolerance. In acute and chronic HIVAN, the HAART regimens have been consistently shown to benefit and alter the progression of the renal lesion [34,35].

Angiotensin antagonists

As in other forms of progressive proteinuric renal disease in both children and adults, significant renal protection and slowing of progression have been demonstrated with the use of angiotensin- converting enzyme inhibitors or angiotensin-receptor blockers. The benefits and mechanisms of renoprotection are multifaceted. A decrease in proteinuria effected by angiotensin antagonists allows monitoring of the response to therapy and interrupts the noxious effects perpetuated by heavy proteinuria. Modification of intraglomerular and systemic hypertension may help to avert secondary adverse cardiac events. Local and systemic modulation of noxious cytokine release, as well as promotion of diuresis despite hypoproteinemia, offers significant clinical relief when the patient is edematous [34-36].

Table 5

Components of therapy in adolescent patients with viral venereal renal disease

Immune modulation

The use of immune-modulating therapies in the setting of virulent viral disease must be approached cautiously. Growing experience has shown that short courses of intravenous pulse solumedrol, as well as low-dose oral corticosteroids, have been well tolerated but are of limited long-term benefit [19,35,36]. Similarly, immune-mediated disease with circulating immune complexes and systemic manifestations of vasculitis may benefit from intravenous gamma globulin in doses ranging up to 2 g/kg body weight given in five doses divided over 5 to 10 days [37]. In a small group of patients with systemic vasculitis and glomerulonephritis associated with HCV, a short course of intravenous cyclophosphamide (500 mg/m^sup 2^/ dose) in two to six monthly doses proved to be well tolerated and resulted in reversal of the glomerulonephritis [3O]. More recently, the use of an anti-CD20 (CD, immunophenotyping of lymphocyte subsets; CD might mean "cell or clonal designation". B cells are CD 19-20; T-lymphocytes are CD4 and CDS) monoclonal antibody, rituximab, has resulted in excellent clearing of viremia and reversal of proteinuria in early nephritides. The dose is 375 mg/ m^sup 2^/dose in two to five weekly doses administered intravenously with monitoring of CD20 counts [31]. In children and adolescents, the authors have begun with half the recommended dose (188 mg/m^sup 2^) administered over 4 to 6 hours.

On establishing its infection within the host, the virus must coordinate its replication by tapping into the host's CD4 T-cell signaling pathways and their associated transcription factors. T- cell activation and transcription factor NF-κ B have been extensively studied as an initiator of local tissue cytokine release and tissue injury and are the focus of generic immune modulation. In recent years, another transcription factor family involved in T- cell activation, the nuclear factor of activated T cells (NF-AT), has been recognized as having an important and independent role in the regulation of HIV-1 infection. Control of this feedback loop between the viras and host transcription factors may potentially prevent the establishment of early HIV-I infection and the transition from latency to virulence. The immunosuppressive drag cyclosporin A (CsA) inhibits NF-AT activity and thus represents a potential treatment for HIV-I infection. Recent small-scale clinical trials have yielded optimistic results, suggesting roles for CsA after organ transplantation in HIV-1-positive individuals and as adjunct treatment in stable early HlV-I infection [38].

Finally, the drug mycophenolate mofetil (MMF) has been advocated for treatment of refractory FSGS and lupus nephritis; in early experiences with solid organ transplantation in HIV-infected individuals, it has been well tolerated [39-41]. MMF also inhibits the production of the nucleoside guanosine, which is essential for HIV replication, and recent clinical and laboratory studies suggest that it may increase the efficacy of the HAART therapy both pre- and posttransplant [42].

Metabolic abnormalities

Renal tubular acidosis

Renal tubular acidosis is most often a consequence of drug toxicity or malnutrition. Once it has been recognized by serum electrolyte monitoring, therapy with oral buffers, including sodium/ potassium citrate or bicarbonate salts at doses of 2 to 4 mEq/kg/d, should be instituted.

Lactic acidosis

Surveillance for chronic and acute nonischemic lactic acidosis is crucial in the management of patients undergoing treatment with HAART [17]. Predisposed patients include those who develop insulin resistance or who have a large fat mass. Decompensation has occurred with prolonged or invasive surger\y. Because the metabolic defect is linked to mitochondrial dysfunction and intermediary metabolism of fatty acids, treatment with camitine has been advocated. The dose is 100 to 300 mg/kg/d administered orally, intravenously postdialysis, or in parenteral alimentation fluids [43]. Capsules are dispensed as 330 mg per capsule. The intravenous preparation is 1 g/10 mL. The drug is water-soluble and therefore should be given postdialysis. In acute, severe lactic acidosis, hemodiafiltration offers the most likely mechanism for reversal, although the condition is almost universally fatal.

Dialytic therapy

During the past 2 decades since the first recognition of HIVAN as a cause of end-stage renal disease (ESRD), dialysis centers in the United States report a fourfold increase in the number of patients with HIV infection being treated. Currently, in African Americans, it is the third leading cause of entry into the ESRD program. In the same period, the authors' pdiatrie dialysis center at the University of Miami/ Holtz Children's Hospital has dialyzed 21 children (11 males) with HIV infection, for a cumulative experience of 545 patient treatment months. They have ranged in age from 1.5 to 18 years (average 10 6 years). All were of African lineage. Peritoneal dialysis was the initial treatment modality in six patients. Fungal peritonitis necessitated switching modalities to hemodialysis in all patients. Median overall survival by Kaplan Meier estimates is 11 months following initiation of dialysis. When divided between the first and second decades, median survival on chronic dialysis (n = 11) was 5 months versus 14 months, respectively (P = 0.02) (Fig. 4). Mean survival on chronic maintenance dialysis is 34 43 months (range 6-120 months): a stark contrast to the shorter survival of adult HIV-positive patients on maintenance dialysis (median survival: 3 months) [15].

Fig. 4. Kaplan-Mcier graphs of pdiatrie patient survival on chronic dialysis therapy during the pre-and post-HAART eras.

Important considerations in management of these patients include prompt management of intercurrent infections and monitoring of ongoing antiretroviral therapy. Nutritional and hormonal replacement therapy is essential in maintaining positive nitrogen balance and growth [44]. Supplementation with nutraceuticals, vitamins, and minerals is standard. Moreover, recombinant human growth hormone at doses of 0.05 to 0.1 mg/kg/day (maximum 5 mg) has been effective in promoting growth and maintaining muscle mass. Appetite stimulants such as megesterol have been less effective. Aggressive treatment of intercurrent illness, previously perceived as futile, has proved rewarding in most instances. Absence of coinfection, especially by HCV, adequate CD4 counts (> 200 cells/mL), and maintenance of low viral loads appear to be positive prognostic factors for survival and potential transplantation.

Transplantation

Solid organ transplantation in patients infected with virulent viruses, including HIV-I, is no longer considered experimental. Experiences of major centers include recommendations regarding immunosuppression and monitoring of immune status. Those patients with HCV and HBV infections require chronic maintenance therapy with antivirals, including lamivudine [39-42].

An initial experience reported from the San Francisco Trial in 14 patients is extremely encouraging, especially for renal allografts [4O]. All patients met standard transplant criteria. They had undetectable plasma HIV-I RNA levels (viral load) for 3 months, a CD4+ T-cell count of more than 200 cells/mL for 6 months, and no history of opportunistic infections or neoplasm. Younger recipients may be more likely to have a positive outcome with regard to recurrence of disease, morbidity, and mortality. Standard immunosuppression includes prednisone, MMF, and the calcineurin inhibitor cyclosporine [39-42]. After an average of almost 3 years post-transplant, the majority of patients remain stable. Patients receiving protease inhibitors require 25% of the dose of cyclosporine compared with patients receiving nonnucleoside reverse transcriptase inhibitors. Preliminary data are encouraging and indicate that transplantation should be a treatment option for individuals with well-controlled HlV disease [4O].

Future perspectives: adolescent surveillance

With the tremendous health burden imposed by STDs, targeted screening of high risk adolescent populations is recommended, including the following [45]:

Universal annual screening of all women under 25 years of age [2,45].

STDs impose a tremendous health burden on women, and adolescent females are the group at highest risk. Universal annual screening of all women younger than 25 years has been a best practice recommendation since 1997. When implemented, such screening leads to a decrease in disease prevalence and serious sequelae [2,45].

Screening of young incarcerated men during transition and reintegration into the community [46].

Screening of those with concurrent sexual partners [2,3,45,46].

The prevalence of concurrent sexual partners may reach 87% and is associated with high-risk characteristics, including youth, male gender, crack cocaine, and history of incarceration.

Summary

The adolescent population is particularly vulnerable to STDs. Those that cause significant kidney disease are of viral origin. The primary VVD are HIV-I, HBV, and HCV. Screening of high-risk populations should include quantitation of proteinuria, including total protein and microalbumin, to assess severity of renal damage and potential for progression. Renal biopsy is indicated for diagnosis and for planning important treatment interventions if there is significant proteinuria or decreased renal function. Causes of acute renal failure are frequently reversible and should be treated aggressively. These include HUS, vaso-motor or ischemie acute tubular necrosis, and drug toxicities. The spectrum of chronic kidney disease associated with VVD is broad and may include systemic manifestations of vasculitis. HIV-associated nephropathy is the prototype, with the most prevalent lesion remaining FSGS. Progression occurs in up to 15% of the patients, who are overwhelmingly of African lineage. Significant advances in management include ongoing development of HAART, angiotensin antagonists to control proteinuria, and novel immune-modulating drugs such as MMF, CsA, and rituximab. Dialysis therapies have offered improved survival, especially in pediatrie patients. Moreover, transplantation is no longer considered experimental and should be offered to select patients.

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Carolyn L. Abitbol, MD*, Lawrence B. Friedman, MD, Gastn Zilleruelo, MD

Department oj Pediatrics, Divisions of Pdiatrie Nephrology and Adolescent Medicine, University of Miami/ Holtz Children's Hospital, Miami, FL 33101, USA

* Corresponding author. Pediatrie Nephrology, P.O. Box 016960 (M714), Miami, FL 33101.

E-mail address: cabitbol@med.miami.edu (C.L. Abitbol).

Copyright Hanley & Belfus, Inc. Feb 2005

Source: Adolescent Medicine

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