NDT Advance Access published online on July 21, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn407
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Malignant hypertension in HIV-associated glomerulonephritis
1 Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain 2 Department of Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain
Correspondence and offprint requests to: Enrique Morales, Servicio de Nefrología, Hospital 12 de Octubre, Avda, Andalucía s/n, 28041 Madrid, Spain. Tel: +34-91390-8208; Fax: +34-91390-8393; E-mail: emoralesr{at}senefro.org
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Abstract |
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Background. Glomerular diseases other than HIVAN (HIV-associated nephropathy) are common among HIV patients but the information about their clinical characteristics and prognosis is very scarce. We have observed several HIV patients with glomerulonephritis in whom malignant hypertension (MHT) was the first clinical manifestation.
Methods. All HIV-infected individuals with a biopsy-proven glomerulonephritis at our hospital were reviewed. Information about clinical characteristics, histopathologic data and outcome was collected. The incidence of MHT among HIV and non-HIV patients with glomerulonephritis was studied.
Results. Thirty HIV patients with glomerulonephritis were identified. Ten of them (33%) presented with MHT (severe hypertension and grade III hypertensive retinopathy). In comparison with patients without MHT, they showed a significantly higher blood pressure at presentation, a higher finding of IgA nephropathy (50% versus 15%; P < 0.05) and of malignant nephrosclerosis (60% versus 0%; P < 0.05) in renal biopsies, a higher viral load and a lower CD4+ cell count at the end of follow-up and a worse patient and renal survival: six patients (60%) started chronic dialysis and seven (70%) died after a follow-up of 11.8 ± 16.2 and 39 ± 35 months, respectively. Co-infection by HCV (hepatitis C virus) and HBV (hepatitis B virus) was very frequent among patients with malignant hypertension. The incidence of malignant hypertension among non-HIV patients with glomerulonephritis was significantly lower than that among HIV-infected patients.
Conclusions. Malignant hypertension is a common presentation of patients with HIV-associated glomerulonephritis, particularly in those with IgA nephropathy, and is associated with a very poor patient and renal survival.
Keywords: malignant hypertension; HIV-associated glomerulonephritis; IgA nephropathy; HCV infection; glomerular disease
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Introduction |
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A collapsing form of focal glomerulosclerosis (C-FSG), the so-called HIV-associated nephropathy (HIVAN), has been considered the most frequent and most representative glomerular disease in HIV-infected patients [1–4]. Recent reports have suggested a better prognosis for HIVAN after the generalized treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) [5,6]. Most of HIVAN patients are black, and the pathogenic reasons for this racial predisposition have not been resolved. However, several studies have shown that glomerular diseases other than HIVAN are common among HIV patients; in fact, in some European reports predominantly involving white patients, immune-complex glomerulonephritis (GN) was more common than HIVAN [7,8]. The most common immune-complex GN associated with HIV infection are membranoproliferative GN (MPGN), IgA nephropathy (IgA), membranous GN (MGN), non-collapsing forms of FSG (NC-FSG) and the so-called lupus-like GN [9]. The pathogenesis of these types of GN remains largely unknown. However, the role of some viral co-infections very frequent among HIV patients, such as hepatitis C (HCV) and hepatitis B virus (HBV), appears to be decisive, particularly in MPGN and MGN [10,11]. Although the clinical picture of HIVAN has been well characterized, information about clinical characteristics, outcome and therapeutic alternatives for HIV patients suffering GN other than HIVAN is scarce. In the past few years, we have observed several HIV patients without previously known renal diseases that presented with very severe forms of hypertensive crisis, meeting criteria for the diagnosis of malignant hypertension (MHT). Subsequent renal biopsies demonstrated different types of glomerular diseases. These observations prompted us to review our experience with HIV-associated GN, in order to ascertain the incidence, the clinical characteristics and the final outcome of HIV patients developing MHT.
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Methods |
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All HIV-infected individuals who underwent renal biopsy at our hospital between 1992 and 2007 were retrospectively studied. We identified 30 patients in whom a biopsy-proven diagnosis of glomerular disease had been established. For each patient, the following data were extracted from the patients’ medical chart: demographic characteristics, clinical data (blood pressure, abnormal findings on physical examination including funduscopic examination, presence of oedema or macroscopic urinary abnormalities, time elapsed since the diagnosis of HIV infection and onset of glomerular disease, medications) comorbid conditions (HCV and HBV infection, other previous or concurrent infections) and laboratory data (complete blood count, coagulation tests, routine serum biochemistry profile, serum electrophroresis, urine sediment examination, 24-h proteinuria, HIV viral load, CD4 cell count, C3 and C4 serum complement factors, antinuclear and anti-DNA antibodies, cryoglobulins, rheumathoid factor and anticardiolipin antibodies). Estimated glomerular filtration rate (eGFR) was calculated by the MDRD-4 formula in every patient. Evolution of all these clinical and laboratory data until last patient's visit, death or onset of chronic dialysis was also recorded from patient's medical charts.
Renal biopsy specimens were revised for the present study by the same renal pathologist (MAM). The different types of glomerular diseases were classified according to the current definitions. Lesions of malignant nephrosclerosis (fibrinoid necrosis in glomerular capillaries, intimal thickening, luminal narrowing and fibrinoid necrosis in arterioles) and the presence of intravascular thrombi or cortical necrosis were recorded and graded in every renal biopsy, as well as the severity of tubulointerstitial fibrosis.
MHT was defined by the presence of severe diastolic hypertension (usually >110 mmHg) accompanied by grade III retinopathy (flame-shaped haemorrhages and soft exudates). Thrombotic microangiopathy (TMA) was defined by the presence of thrombocytopenia and microangiopathic haemolytic anaemia (anaemia accompanied by increased LDH, low haptoglobin levels and schistocytes in peripheral blood smear). Dates and causes of death as well as date of chronic dialysis onset were recorded. Chronic renal insufficiency was defined as an eGFR <60 ml/min/1.73 m2 without the need of chronic dialysis, whereas the preserved renal function was defined as an eGFR >60 ml/min/1.73 m2. Renal survival was defined as the maintenance of a renal function sufficient to avoid dialysis.
In order to compare the incidence of MHT among HIV-associated glomerulonephritis and non-HIV glomerulonephritis, we reviewed patient's medical charts of all the cases of biopsy-proven MPGN, IgAN, NC-FSG, C-FSG and MGN in patients without HIV infection between 1992 and 2007. Patients infected by VHC, VHB or other agents (excluding HIV) were also included in this analysis. Similarly, in order to evaluate the proportion of patients infected by HIV, we reviewed all the cases of MHT (defined by clinical criteria, see above), diagnosed in our department in the period 1992–2007 regardless of their aetiology.
Statistical analyses
Descriptive statistics using means ± standard deviation and proportions were performed on all variables when appropriate. For statistical analysis, we used the paired and unpaired t-test and the non-parametric Mann–Whitney test when appropriate. Qualitative variables were analysed by Fisher's test and the chi-square test. The cumulative probability of renal survival in patients with or without MHT was estimated by survival analysis according to the Kaplan–Meier method, and the log-rank test was used for comparison of different groups. P < 0.05 was considered statistically significant. Statistics were calculated using SPSS for Windows, version 11 (SPSS Inc., Chicago, IL, USA).
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Results |
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We identified 30 HIV-infected patients with biopsy-proven GN between 1992 and 2007 (9 MPGN, 8 IgAN, 7 NC-FSG, 4 C-FSG, and 2 MGN). Ten patients presented with MHT, according to the criteria stated in the Methods section.
Baseline characteristics of patients with MHT
The demographic, clinical and laboratory characteristics of the 10 HIV patients presenting with MHT are shown in Table 1. There was a male preponderance (80%) and all of them were white. Symptoms and signs of MHT (severe headache, impaired vision and marked increase in blood pressure) were the cause of hospital admission in every case. No patient referred previous symptoms of renal disease (oedema and macroscopic haematuria) although all of them had noticed progressive asthenia and anorexia in the last months.
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At admission, the marked increase in blood pressure and grade III hypertensive retinopathy was detected in every patient. All of them showed an acute deterioration of the renal function (Scr ranging from 1.5 to 9 mg/dl) accompanied by microhaematuria in 8/10 patients and proteinuria ranging from 1.2 to 10.9 g/24 h. Baseline eGFR was <60 ml/min/1.73 m2 in all the patients. Renal echographies and echo-Doppler studies showed normal kidneys in every patient, without size differences or signs indicative of renal artery stenoses.
All the patients but three were receiving antiretroviral treatment before admission. HIV viral load and CD4 cell count are shown in Table 1. Nine patients (90%) were co-infected by HCV and five (50%) by HBV.
In addition to the acute renal failure, three patients (30%) met the criteria for TMA (thrombocytopenia and microangiopathic haemolytic anaemia). Four patients (two of them with TMA) showed abnormal prolongation of aPTT (activated partial thromboplastin time) at admission. Anticardiolipin antibodies were tested in two patients (without TMA criteria), being positive in one.
Histologic findings in patients with MHT
A percutaneous renal biopsy was obtained in every patient once blood pressure was controlled. As shown in Table 1, IgAN was demonstrated in five cases (50%), MPGN in two (20%) and C-FSG, NC-FSG and MGN in one patient each. Malignant nephrosclerosis (arteriolar fibrinoid necrosis with intimal thickening and luminal narrowing; see Figure 1) was detected in six cases (three of them with IgAN, one with C-FSG, one with NC-FSG and one with MGN). Tubulointerstitial fibrosis was absent or mild.
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Evolution and outcome
All the patients received parenteral antihypertensive agents (sodium nitroprusside mostly) and renin–angiotensin blockade (ACEI or ARB) since the first days of admission. Other antihypertensive agents (calcium-channel blockers, beta-blockers, diuretics and alpha-blockers) were added if necessary in order to obtain an adequate control of blood pressure. A satisfactory control of blood pressure was achieved in every patient; however, renal and patient survival was very poor, as shown in Table 1. Only three patients showed an improvement of the renal function (patients 1, 3 and 10, Table 1).
Patients 1 and 10 died because of the liver failure after a follow-up of 40 and 72 months, respectively. Patient 3 was the only survivor that had not started chronic dialysis at the end of the follow-up (72 months, serum creatinine 1.5 mg/dl). Patient 9 died because of liver failure after a follow-up of 16 months, in a situation of advanced renal insufficiency. The remaining six patients (patients 2, 4, 5, 6, 7 and 8) started chronic dialysis after a mean follow-up of 11.8 ± 16.2 (1–36) months. Four of them died because of septic shock (patients 6 and 7), liver failure (patient 2) and cerebral haemorrhage (patient 5), 1–24 months after the onset of dialysis.
Comparison between HIV-associated glomerulonephritis with or without MHT
The baseline characteristics as well as the evolution and final outcome of patients with HIV-associated GN separated by the presence or absence of MHT are shown in Tables 2 and 3. As shown in 2, both systolic and diastolic blood pressures were significantly higher in MHT patients. Co-infection by HBV (50% versus 25%) and HCV (90% versus 65%) tended to be more common among patients presenting with MHT, but without statistical significance. Similarly, a non-significant tendency towards worse renal function and higher HIV viral load was detected among MHT patients.
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Patient and renal survival was significantly worse in MHT patients, as shown in Table 3. Final serum creatinine and GFR were significantly worse and the percentage of patients with preserved renal function significantly lower (10% versus 60%) among patients presenting with MHT. The percentage of patients that started chronic dialysis was significantly higher among MHT patients (60% versus 15%). The probability of renal survival (absence of chronic dialysis) in HIV patients with or without MHT is shown in Figure 2.
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The dismal prognosis of patients with MHT (70% deaths after 39 ± 35 months of follow-up) was not shared by patients without MHT (15% deaths, P < 0.01). Although a majority of patients (90% and 85%) received HAART treatment throughout follow-up, HIV viral load was significantly higher and CD4 cell count significantly lower among patients with MHT at the end of the follow-up (Table 3).
The distribution of the different types of GN among patients with or without MHT is shown in Table 4. There were no significant differences regarding MPGN (20% versus 35%), NC-FSG (10% versus 30%), C-FSG (10% versus 15%) and MGN (10% versus 5%). The percentage of IgAN among patients with MHT was significantly higher than among patients without MHT (50% versus 15%, P < 0.05). No histologic findings of malignant nephrosclerosis were observed in renal biopsies of patients without MHT.
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Incidence of MHT among non-HIV patients with glomerulonephritis
As shown in Table 5, the incidence of MHT among non-HIV patients with MPGN (including cases of HCV-associated MPGN) was 1/45 (2.2%), significantly lower than that observed among HIV patients (2/9, 22%; P < 0.05). Similar striking differences were observed in patients with collapsing and non-collapsing forms of FSG and MGN, with a significantly higher incidence of MHT among HIV patients. The incidence of MHT among non-HIV patients with IgAN was 11/130 (9.1%), remarkably higher than that in other types of GN. However, a significant difference was observed again with HIV patients with IgAN in whom the incidence of MHT was 5/8 (62%).
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HIV infection among patients with MHT
As stated in the Methods section, we reviewed all the cases (167 patients) of MHT diagnosed in our department between 1992 and 2007, whatever their aetiology. Ten of them (5.98%) were infected by HIV.
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Discussion |
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The clinical picture of HIVAN, as well as its prognosis, outcome and therapeutic alternatives, has been the subject of several published studies [1–4]. In contrast, available information about HIV-associated glomerular diseases other than HIVAN is rather scarce.
In our experience [8], clinical presentation of HIV-associated GN is frequently explosive and aggressive due to the common presence of macroscopic haematuria, massive proteinuria and acute worsening of renal function at presentation. In this study, we report on a frequent and a not previously described manifestation of these patients: MHT. Ten out of our series of 30 patients with HIV-associated GN (33%) developed MHT, and it was the first clinical manifestation of renal disease in all these patients.
The typical symptoms of MHT (markedly increased BP, blurred vision due to retinal haemorrhages and severe headache) were the initial presentation in all the 10 patients. In addition, acute renal function worsening, a characteristic of MHT whatever its origin, was observed in all. Proteinuria (within the nephrotic range in 4/10 patients) and microhaematuria in 8/10 patients were accompanying manifestations. As shown in Table 2, there were no significant differences between patients with or without MHT with the exception of blood pressure values. Although the percentage of patients co-infected by HCV (90%) and HBV (50%) was remarkable, these co-infections were also common among patients without MHT (65% and 25%, respectively, see Table 2). Not surprisingly, renal function at presentation tended to be worse among patients with MHT.
Contrary to these rather subtle differences at presentation, the final outcome of MHT patients was significantly worse than that in those patients without this complication. As shown in Table 3 and Figure 2, patient and renal survival among patients developing MHT was very poor. After a mean follow-up of 39 ± 35 (2–120) months, seven patients (70%) have died (four of them on chronic dialysis after irreversible loss of renal function) and two out of the three surviving patients were undergoing chronic dialysis. In contrast, the number of deaths (15%) and the number of patients undergoing chronic dialysis (15%) at the end of the follow-up among patients without MHT were significantly lower, and 60% of them had a preserved renal function at the end of the follow-up (see Table 3). To interpret this catastrophic prognosis in HIV patients with GN and MHT, we speculate that the development of MHT has an irreversible detrimental influence on glomerular diseases already having a rather poor prognosis by themselves. On the other hand, the development of chronic renal failure could likely exacerbate the appearance of infectious and cardiovascular complications in these HIV-infected patients because both patients with chronic renal failure and HIV infection are particularly prone to the appearance of such complications [12–14]. The causes of death among our patients with MHT were liver failure in four patients (all of them co-infected by HCV), septic shock in two and cerebral haemorrhage in one.
It should be emphasized that such dismal prognosis of our patients with MHT occurred in spite of antiretroviral treatment. Seventy percent of the patients had started HAART treatment before the appearance of MHT and this percentage increased to 90% throughout the follow-up. Similarly, all the 10 patients received renin–angiotensin system blockade (ACEI or ARB) from the first days of admission, and blood pressure was satisfactorily controlled in every case. It is possible, however, that a more precocious detection of hypertension among HIV patients with glomerular diseases could avoid the catastrophic consequences of MHT development that our study shows. On the other hand, it should be considered that we reviewed only biopsy-proven HIV-associated GN. It is likely that some renal biopsies were not performed in HIV patients with glomerular diseases having a less severe clinical presentation, and this bias could overestimate the real incidence of MHT among HIV-associated GN.
Some of our data could suggest a direct pathogenic implication of HIV infection in the appearance of MHT. As shown in Table 2, HIV viral load at presentation was more than three-fold higher among patients with MHT. In spite of HAART treatment administered to the majority of patients with or without MHT (90% and 85%, respectively), the difference in HIV viral load was still more evident at the end of the follow-up (see Table 3): viral load in patients with MHT was 160-fold higher than in patients without MHT. Similarly, although CD4 cell counts were not different at presentation, at the end of the follow-up they were significantly lower among patients with MHT.
Other possible pathogenic pathways to explain this particular propensity of HIV patients with glomerular diseases to MHT could rely on the already known higher incidence of thrombotic microangiopathy (TMA) among HIV patients [15]. Both TMA and MHT could be interpreted as clinical manifestations of a systemic endothelial injury, due to a direct toxic effect of HIV, other infectious agents (particularly HCV and HBV) or other factors (such as drug addictions) linked to the environment of HIV infection. On the other hand, the presence of antiphospholipid antibodies is also more common among HIV patients, and these autoantibodies could play a role in endothelial vascular damage [15,16].
The type of glomerular diseases found among our patients with MHT (membranoproliferative, IgA nephropathy, collapsing and non-collapsing forms of FSG and membranous nephropathy) is representative of the spectrum of GN most commonly observed in HIV patients [8], and their distribution did not differ significantly from that observed among our patients without MHT (Table 4). The only exception was IgA nephropathy, over-represented among patients with MHT (50% of the cases versus 15% among patients without MHT). This finding is particularly interesting because IgA nephropathy also has a special predisposition to MHT among non-HIV patients. As shown in Table 5, the incidence of MHT among our non-HIV patients with different types of GN was remarkably low. The only exception was IgA nephropathy, with an incidence of 9.1%. This particular predisposition of IgA nephropathy to MHT has been previously described [17,18] although the pathogenic mechanisms of such association remain unknown.
It is important to remark that we reviewed all our HIV-negative patients who underwent a renal biopsy in the same period, 1992–2007, and showed a histologic pattern of membranoproliferative GN, IgA nephropathy, FSG and membranous GN, independently of their cause. Patients with systemic disease were also included in this revision, as well as patients with glomerular disorders associated with HCV and HBV infections. In these latter cases, the appearance of MHT was also exceptional, thus suggesting that co-infection by HCV and HBV among our HIV patients did not play a fundamental role in the pathogenesis of MHT.
In summary, in this study we report for the first time a new complication of HIV patients suffering glomerular diseases: MHT. This complication is particularly common among patients with IgA nephropathy, in whom MHT developed in 5/8 (62%). Patient and renal survival was very poor, with 7/10 (70%) of patients dying after a mean follow-up of 39 ± 35 months. More studies are necessary to identify the pathogenic mechanisms of this complication. In addition, considering the dismal prognosis of our patients in spite of HAART treatment and a satisfactory control of blood pressure, early detection and treatment of hypertension in HIV patients with glomerular diseases are mandatory.
Conflict of interest statement. None declared.
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Accepted in revised form: 26. 6.08
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