Glomerular lesions in HIV-positive patients: a 20-year biopsy experience from Northern Italy.

AIM: Glomerular involvement in HIV-positive patients is quite heterogeneous. In the present paper we reviewed 73 renal biopsies performed during a period of more than 20 years in a single Nephrology Unit, Milan, Northern Italy, in order to evaluate the aspects of single types of glomerular lesions (including HIV associated nephropathy-HIVAN), grouped according to histological patterns and clinical presentation. Moreover, in the group of non-HIVAN patients, the possible differences in histological characteristics from non-HIV lesions were investigated. MATERIALS AND METHODS: Renal tissues were obtained by percutaneous biopsies and were studied by light microscopy, immunofluorescence and electron microscopy. For the histological description three histological groups were identified: HIVAN, immune complex glomerulonephritis (GN) and glomerulopathies not related to immune-mediated mechanisms (so-called "various" glomerulopathies). RESULTS: HIVAN was observed in 9 cases, immune complex GNs in 40 cases (10 mesangial proliferative GN, 8 membranoproliferative GN, 5 lupus-like GN, 4 "acute" GN, 2 crescentic GN, 4 IgA nephropathy, 4 membranous GN and 3 immunotactoid GN) and "various" glomerulopathies in 24 cases (13 non-collapsing focal segmental glomerulosclerosis, 3 minimal changes, 3 end-stage renal disease, 4 diabetic nephropathy and one amyloidosis). CONCLUSIONS: Our 20-year biopsy series of HIV-related glomerular involvement confirmed the heterogeneity of lesions. In our series, the vast majority of HIV-related GN are the so-called immune complex GNs, with some peculiar aspects, as multiple site location of deposits and a frequent tendency towards sclerosis, in agreement with experimental data regarding HIV and fibrosis.

HIV infection in dialysis centers in Italy: a nationwide multicenter study.

The prevalence of HIV infection in dialysis populations varies according to different countries and geographic areas. We performed a nationwide epidemiological study by means of a questionnaire in the period from January 1990 to December 1995. Questions were about whether and which HIV tests were performed and which preventive measures were adopted. A separate survey evaluated the data the HIV-positive patients. Only 62% of the centers responded to the questionnaire, corresponding to 21,500 dialysis patients in 1990 and 27,000 in 1995. The prevalence of HIV-positive subjects was 0,13% for 1995. A total of 48 patients with HIV infection were identified: risk factors were drug abuse in 16 cases, homosexuality in 9, heterosexual contact in 8, transfusion in 7, renal transplant in 3 and unknown cause in 5. Forty-five patients were on hemodialysis, and 3 were receiving peritoneal dialysis. At follow-up, 19 patients died: infection and malnutrition were the most frequent causes of death. The death rate of patients who were already HIV positive when dialysis was started (group 1, 29 cases) was 19.36 deaths/1,000 patient/month. The correlations, performed only for group 1, showed a significantly worse prognosis for patients with CD4 < 200/mm3 and for those with AIDS. In conclusion, in Italy the prevalence of HIV infection in the dialysis population is low, and the outcome of HIV-positive patients in dialysis was found to be better than earlier literature reports. The use of chronic dialysis for HIV patients with uremia should not be discouraged.

Clearances and solutes extraction in biofiltration and hemodialysis with the AN 69 S.

Clearances and solutes extraction were assessed in biofiltration (BF) and in hemodialysis (HD) with the new polyacrylonitrile AN 69 S membrane. Three patients treated for three months by acetate dialysis (4 hours X 3) and subsequently by BF (3 hours X 3) were studied after achievement of steady state. Total intradepurative clearances (diffusive and convective) and solutes extraction of urea, creatinine, uric acid and phosphate were determined. Clearance of small molecular weight solutes was better in BF than in HD especially for uric acid and phosphate. This confirms the high depurative efficiency of the AN 69 S. BF gave better total clearances than HD, but the extraction of lower molecular weight solutes (due to the one-hour reduction of dialysis time) suggests that adequate treatment time is needed with this technique.

Changes in peritoneal membrane after continuous ambulatory peritoneal dialysis--a histopathological study.

Peritoneal membrane changes in continuous ambulatory peritoneal dialysis (CAPD) patients have been widely described but poorly classified. Our aim was to identify the morphological changes occurring after CAPD treatment. To this end, 17 biopsies of parietal peritoneum (1 cm in diameter) were withdrawn at least 5 cm from the catheter entry hole and stained with Van Gieson, hematoxylin-eosin, trichrome, and some immunohistochemical stains: keratin, vimentin, CD34, CD20, CD4, CD8, desmin, and collagen IV. The morphology of mesothelium, vessels, and basement membrane (BM) of mesothelium and vessels, the presence of inflammatory cells, fibrin, and calcifications, and the distribution and thickness of submesothelial tissue were evaluated. Patients were divided into three groups according to the thickness of the sclerotic band replacing mesothelium: group 1, band up to 40 microns; group 2, band less than 40 microns; group 3, no sclerotic band. The main histopathological alterations noted were: loss of mesothelium; sclerotic alteration of vessels or duplication of BM; presence of myofibroblasts; and presence of inflammatory cells (sparse, focal, or perivascular), mainly represented by macrophages and CD4+ lymphocytes. No significant qualitative differences were observed between the three groups. In conclusion, the variable histological changes in peritoneal membrane suggest a routine peritoneal biopsy in any surgical procedure to better understand pathological changes in the course of CAPD treatment.

[Borderline indications for renal biopsy]. / Indicazioni "borderline" della biopsia renale.

The Authors report 3 cases with clinical renal manifestations where the indication to perform a renal biopsy was defined as borderline. The uncertain indication was related to the clinical presentation, with a pattern of urinary abnormalities, such as isolated microscopic hematuria, microscopic hematuria associated with mild proteinuria, and isolated proteinuria. In addition, similar questions on biopsy are raised for chronic renal failure and elderly patients. In the literature, microscopic hematuria without significant proteinuria shows that 25% of adult patients have no histological abnormalities. A higher percentage is found among children. The other cases exhibit a pattern of IgA nephropathy, Alport's syndrome, thin BM nephropathy and arteriolar C3 deposition. The percentage of an abnormal histological picture increases if the patients have a family history of hematuria, and if there are concomitant episodes of macroscopic hematuria, because of an increase in IgA nephropathy and Alport's syndrome, respectively. In the last cases, therefore the indication to perform a renal biopsy increases. For those patients without these characteristics, a renal biopsy can be delayed whereas in cases of microscopic hematuria with proteinuria or isolated proteinuria the indication for a renal biopsy is stronger, because the spectrum of glomerulopathies is wider, and the possible evolution to renal failure after 10 years is higher (10-14% of cases). In patients with chronic renal failure the biopsy is contraindicated for cases where the thickness of the cortical section of the kidney is lower than 8-10 mm, because of possible technical difficulties, lower diagnostic information due to sclerosis and higher risk of complications. The prolonged bleeding time and the consequent risk of bleeding can be avoided by i.v. infusion of vasopressin 2 hours prior to biopsy. The higher indications are for those patients who may be susceptible to a medical treatment, capable to slowing down the progression of nephropathy. Finally, in elderly patients the biopsy is indicated in almost all cases because of the recently confirmed high incidence of glomerulopathies. In the aged there is a higher frequency of membranous GN, crescentic-ANCA associated GN, amyloidosis and, according to some Authors, post-infectious GN. In all cases a precise histological diagnosis can correct an erroneous diagnosis made according to clinical data alone. In the elderly the indication for biopsy aims at making an exact diagnosis of nephropathy, especially for acute renal failure: for this purpose age itself should not become an obstacle.

[Post-infectious glomerulonephritis]. / Glomerulonefriti post-infettive.

Post-infectious glomerulonephrites (GNs) include a wide spectrum of nephropathies, with known etiological agent, bacterial, parasitic, viral. Among GNs secondary to bacterial infections, post-streptococcal GN is the most frequent; nevertheless, its incidence in developed countries has decreased during the last 20 years, while some of the characteristics such as types of infection, exposed subjects, clinical and evolutionary patterns have changed. Prognosis has worsened and is correlated with some clinical and histological parameters. The viral infection-related GNs include those associated with HBV, HCV, HIV plus other rarer forms. Membranous GN (MGN), membranoproliferative GN (MPGN) and IgA nephropathy may occur in the course of HBV infection, while different GNs can be detected in relation to HCV, the most frequent being mixed cryoglobulinemic GN, a MPGN with peculiar morphological features. Multiple glomerular involvements are seen from HIV infection, the more characteristic form being the so-called HIV associated nephropathy (HIVAN), a focal segmental glomerulosclerosis with tuft collapse affecting African subjects, which starts with a nephrotic syndrome and rapidly develops into uraemia. Other GNs derive from HIV-related immunecomplexes, some with diffuse proliferative characteristics, or lupus like, with less severe clinical manifestations compared with HIVAN. Among the rare viral infections, we ultimately, mention the association between Parvovirus B19 and "collapsing" focal segmental glomerulosclerosis.

Pattern of double glomerulopathies. A clinicopathologic study in nine nondiabetic patients.

Nine new cases of double glomerulopathies (GP) were found among 1,715 renal biopsies. Immunofluorescence and electron microscopy were needed to achieve a correct diagnosis and the prevailing relevance of these techniques in single cases was stressed. IgA nephropathy was the most commonly found GP, being associated with membranous glomerulonephritis (GN) (2 patients), minimal change disease (3 patients), and focal segmental glomerulosclerosis (1 patient). In addition, single cases of membranous GN plus crescentic GN and acute GN plus cryoglobulinemic GN were recorded. Possible factors involved in the pathogenesis and clinical significance of double glomerulopathies are discussed.

Glomerulonephritis with dense deposits: a variant of membranoproliferative glomerulonephritis or a separate morphological entity? Light, electron microscopic and immunohistochemical study of eleven cases.

Eleven cases of glomerulonephritis with dense deposits were selected on the basis of electron microscopic examination performed either on material treated according to conventional techniques (9 cases) or on previously paraffin-embedded material (2 cases). While uniform immunohistochemical patterns were observed, different features were shown by light microscopy: in only 3 cases were membranoproliferative or lobular patterns present, while in the others a varying degree of mesangial cell proliferation (moderate, mild or even very scanty with focal and segmental distribution) was detected. The generally accepted statement that glomerulonephritis with dense deposits represents a subgroup of membranoproliferative glomerulonephritis therefore seems questionable. In addition to several clinical and serological data, these morphological features give further support to the hypothesis that glomerulonephritis with dense deposits in all respects a peculiar and distinct form of glomerulonephritis.

Absence of HIV antigens in renal tissue from patients with HIV-associated nephropathy.

HIV-associated nephropathy (HIV-N) is considered a distinctive disease, the pathogenesis of which is still undefined. Direct virus-induced renal cell damage has been postulated. The numerous cytolytic ultrastructural changes and a few studies by immunoperoxidase support this hypothesis, but there has been no demonstration of virus by electron-microscopy (EM) or by tissue culture. In seven out of 12 cases with histological characteristics of HIV nephropathy, with proteinuria (five cases) or with nephrotic syndrome (two cases), we tested renal tissue for HIV antigens: core p18 and p25; envelope gp45 and gp110, by means of immunoperoxidase avidin-biotin complex monoclonal antibodies (MoAbs). Light-microscopy (LM) showed in five patients a focal and segmental glomerular sclerosis, and in two a mesangial hyperplasia with vacuolisation of visceral epithelium and protein inclusions. Electron-microscopy, performed in five of seven patients, showed several protein inclusions in podocyte cytoplasm, tubuloreticular inclusions in endothelial cell cytoplasm in all cases, nuclear degranulation of tubular cells in four cases and nuclear bodies in two. HIV antigens by MoAbs on renal tissue were negative in all cases, in both glomeruli and tubules. These results do not confirm the presence of HIV proteins in renal tissue of patients with HIV nephropathy. A possible explanation, apart from no direct HIV in the disease, may be the low viral load in tissues, because of the early phases of renal damage in most cases.

Steroid-sensitive nephrotic syndrome with mesangial IgA deposits: a separate entity? Observation of two cases.

In minimal-change steroid-sensitive nephrotic syndrome with selective proteinuria, mesangial IgA deposition at immunofluorescence is a very rare finding which has been previously considered a pure coincidence. Two patients, aged 6 and 14 years, respectively, with a steroid-sensitive but frequently relapsing nephrotic syndrome and highly selective proteinuria, exhibited minor glomerular alterations at light microscopy and an immunofluorescence deposition of predominant and diffuse mesangial IgA, confirmed by electron microscopy as dense deposits. The observed syndrome, that is surprisingly identical to sporadic literature reports, can be considered a separate entity or subgroup belonging either to IgA nephropathy or to lipoid nephrosis. In the latter case mesangial IgA could be the marker of an easy relapsing course.

[Necrotizing angiitis with glomerular and arterial deposits of IgA ]. / Angéite nécrosante et dépôts glomérulaires et artériels d'IgA.

A 68 year old woman presented a rapidly progressive renal failure associated with manifestation of a systemic disease and showed, at renal biopsy, a picture of severe necrotizing angiitis with a proliferative glomerulonephritis with 80% crescents. Renal function improved after a treatment with high doses of steroids, heparin and immunosuppressive drugs. Immunofluorescence study showed diffuse predominant deposits of IgA and C3 both along capillary walls and in the majority of vessels. Skin and muscle biopsies failed to show lesions of vasculitis. The nosological definition of this condition is discussed, the patient presenting with some aspects suggestive of a Schönlein-Henoch syndrome, and others of polyarteritis nodosa.

HIV-associated nephropathy: a new entity. A study of 12 cases.

The existence of an HIV-related nephropathy as a distinct disease entity is controversial. Twelve patients affected by HIV infection (eight drug-abusers, three homosexuals and one black heterosexual) who showed nephrotic syndrome (five patients) or urinary abnormalities (seven patients), four with renal insufficiency, were submitted to renal biopsy. Six patients were in pre-AIDS, six had AIDS. Light microscopy, performed in all cases, showed focal segmental glomerular sclerosis in nine patients, a moderate hypercellularity in six, vacuolisation of visceral epithelium in ten, focal collapsed tuft in seven, and tubular microcystic dilatation with large dense protein casts in lumina in seven. Immunofluorescence, available in 11 patients, showed small deposits in mesangium or mesangial and subendothelial spaces. IgG, IgM, and C3 were more frequently found, while three cases were negative. Electron-microscopy (five patients), besides confirming light-microscopy changes, showed several tubuloreticular inclusions (four patients), nuclear bodies (mainly complex) in nuclei of tubular cells (three patients), and nuclear granulofibrillary transformation of tubular cells. Various histological aspects and clinical data confirm the hypothesis that HIV nephropathy can be considered as a separate entity, different from heroin nephropathy and idiopathic focal glomerulosclerosis.

Glomerular disease and pregnancy. A study of 123 pregnancies in patients with primary and secondary glomerular diseases.

The clinical course of 123 pregnancies in 86 patients with biopsy-proven glomerular diseases have been studied. In 35 women the onset of nephropathy occurred during pregnancy. No complications were observed in more than half of the pregnancies. In the others, one third of the complications were obstetrical or fetal accidents, one third were renal manifestations (hypertension or deterioration of renal function) and one third were both causes. The lowest incidence of complications was observed in patients with membranous nephropathy and the highest in membranoproliferative glomerulonephritis patients. There were 6 spontaneous late abortion, 6 stillbirths and 5 neonatal deaths. 17 deliveries were preterm and 7 fetuses were small for gestational age. Hypertension appeared in 24 pregnancies, in 13 of which it was reversible and related to superimposed preeclampsia and in 11 it persisted after delivery (5 of these 11 pregnancies were in patients with IgA nephropathy). Renal function deteriorated in 10 cases during pregnancy. The deterioration was reversible in 6 and progressive in 4 (2 of whom had membranoproliferative glomerulonephritis). It is suggested that in most patients pregnancy does not change the natural history of glomerular disease.

Pattern of glomerular involvement in human immunodeficiency virus-infected patients: an Italian study.

Renal biopsy specimens from 26 adult human immunodeficiency virus (HIV)-infected patients with glomerular involvement were reviewed from the files of three hospital pathology services in Northern Italy. All the patients were Italian and most (19 of 26 patients) were intravenous drug addicts. The types of glomerular lesions were as follows: minimal-change glomerulopathy (two cases), mesangial proliferative glomerulonephritis (GN) with scanty immunoglobulin deposits (four cases), and various patterns of immune complex-mediated glomerulonephritis, including postinfectious GN (six cases), membranoproliferative GN (one case), membranous GN (three cases), immunoglobulin (Ig) A nephropathy (four cases), a mixed membranous and proliferative (three cases) and diffuse proliferative lupus-like pattern with subendothelial deposits, and intraluminal thrombi (two cases) or subepithelial and subendothelial deposits (one case). None of the patients had evidence of HIV-associated nephropathy. Our study confirms previous observations on the low incidence of HIV-associated nephropathy among white HIV-infected patients in Europe, where immune complex-mediated GN seems to predominate. Apart from the frequent electron microscopic observation of endothelial tubuloreticular structures, none of the reported lesions could be distinguished on morphologic grounds from those occurring in uninfected patients. The high variability of the glomerular lesions upholds the need for accurate diagnosis for the clinician confronted with an HIV-positive patient with suspected glomerular involvement.

Morphological, immunohistological and clinical findings in renal amyloidosis: correlations with prognosis in 16 patients.

Sixteen patients affected by renal amyloidosis (A.) and submitted to renal biopsy have been studied by light microscopy and immunofluorescence. Clinical manifestations at observation and follow up have been reviewed. Survival was 32% at ten years, lower than all other nephropathies except rapidly-progressive glomerulonephritis. Primary A. had a significantly worse survival rate than secondary A. An observation up to 6 years after biopsy allowed us to isolate a group of patients with a steady good renal function: this group is characterized by: a longer mean duration of nephropathy before observation, a lower incidence of nephrotic syndrome (NS), absence of renal failure at time of biopsy, a higher incidence of increased mesangial areas at light microscopy, a lower percentage of glomerular capillary walls thickening, a higher incidence of amyloid deposits on vessels but not on glomerular capillaries, a definite more elevated presence of Ig and C3 over mesangium and glomerular capillary walls. The possible role of the last findings is discussed.

Ultrastructural glomerular findings in cryoglobulinemic glomerulonephritis.

Thirty-three renal biopsies of patients affected by cryoglobulinemic glomerulonephritis (CRYGN) were investigated by electron microscopy, paying particular attention to the nature of cells responsible of glomerular hypercellularity, the presence and site of electron-dense deposits and their ultrastructural characteristics. Personal as well as literature data suggest (a) diffuse glomerular hypercellularity found in most cases of CRYGN is mainly due to polymorphonuclear leukocytes and even more to monocyte exudation; (b) the interposition of the latter cell type in the glomerular capillary wall is the main responsible cause of the frequent occurrence of the membranoproliferative pattern in CRYGN, and (c) peculiar structures found in the electron dense deposits are characteristic of CRYGN and related to cryoglobulin composition. Electron microscopy therefore seems to be a valuable diagnostic procedure for this type of glomerulonephritis.

Diabetic nephropathy: clinical and histological study in 22 patients.

Twenty-two patients with insulin-dependent diabetes mellitus and renal involvement were submitted to renal biopsy. Mean age was 42 years; 10 were males, 12 females. The mean interval between clinical manifestation of nephropathy and biopsy was about 2 years. At the time of biopsy, 4 groups were distinguished according to clinical conditions, depending on the presence or absence of nephrotic syndrome and renal failure. Renal lesions were semiquantitatively evaluated, a separate score being considered for glomerular and vascular lesions. Immunofluorescence most frequently showed a pattern of faint linear IgG deposits along glomerular basement membranes. Severity of histological lesions and pattern of urinary abnormalities were not correlated with the duration of diabetes or the patients' age. Both glomerular and vascular lesions were correlated with the presence of renal failure, while no relationship with the pattern of urinary abnormalities was found. Fourteen patients were followed for more than one year after biopsy: 5 had normal renal function, 4 were in chronic renal insufficiency and 5 in end-stage renal failure (3 were in dialysis, 2 died). There was no correlation between the 3 above-mentioned types of evolution and glomerular histological findings. Nevertheless a higher score of vascular impairment at biopsy was observed among patients who subsequently were found to have a more unfavorable prognosis. Therefore renal biopsy, by providing information on the degree of renal vascular damage, may have some value in predicting the clinical course of diabetic nephropathy.