Glomerulopathy associated with schistosomiasis mansoni

Schistosomiasis is a parasitic disease directly related to poor sanitation. In Brazil, 42 million people live in areas where the disease is endemic, and it is still considered a serious public health problem. The kidney is one of the organs typically affected by this worm, with descriptions of renal tubular alterations, acute kidney injury and glomerular diseases. Among patients with active schistosomiasis, the incidence of glomerulopathy is 5-6% overall and 15% in those with the hepatosplenic form with the most commonly described histological patterns being membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis. Although the pathogenesis of glomerular disease associated with schistosomiasis is uncertain, it is thought to involve immune complexes, especially in membranoproliferative glomerulonephritis, formed against a schistosome antigen and deposited in the glomeruli. The uncertain pathogenesis makes schistosomiasis treatment a challenge, as eradicating the parasite through the use of an anti-parasitic agent does not stop the progression to chronic kidney disease, raising questions about the need for immunosuppressive therapy. Thus, the aim of this review was to describe the so-called classic information on glomerular disease associated with schistosomiasis and to explore its probable pathogenic mechanisms in order to promote future discussion on the development of better treatment options.

Introduction The prevalence of kidney diseases, glomerular and tubulointerstitial, varies with the geographical area, socioeconomic conditions of the people, population demographics, race and ethnicity, access to health care, and also the threshold for doing a renal biopsy. Objective The primary objective was to study the prevalence of biopsy-proven kidney diseases presenting to a tertiary care hospital in Mysore, South India. Patients and methods We have retrospectively analyzed the renal biopsy data from 2005 to 2013. The clinical and laboratory data of patients were collected from biopsy request forms, and histopathology data were recorded. Biopsy specimens were examined by light and immunofluorescence microscopy. As a hospital policy, all biopsies were based on definite indications. A total of 1113 biopsies were considered. Transplant biopsies and those with inadequate specimen were excluded. Results A total of 914 patients had some kind of glomerulopathy. Minimal change disease (n=182/1113) was the commonest histological type among glomerular diseases, followed in order by postinfectious glomerulonephritis, focal segmental glomerular sclerosis, membranous glomerulopathy, and immunoglobulin A nephropathy. Among the secondary glomerular diseases, the commonest was diabetic nephropathy (n=72) followed by lupus nephritis (n= 58) and crescentic glomerulonephritis. Most common indication for renal biopsy was nephrotic syndrome (n=274/1113), chronic kidney disease (n=141), acute glomerulonephritis (n=107), acute kidney injury with unclear etiology or delayed recovery, and rapidly progressive glomerulonephritis. Conclusion Nephrotic syndrome was the commonest indication for renal biopsy, and minimal change nephrotic syndrome (MCNS) was the most common glomerular disease followed by focal segmental glomerular sclerosis. Membranoproliferative glomerulonephritis, the incidence of which has decreased in the developed world, still accounts for a significant number in our population. There is a need for electronic data monitoring in India with nationwide integration for a proper analysis of the changing trends of diseases occurring over an extended time frame.

Recovery of Kidney Function Among Patients With Glomerular Disease Starting Maintenance Dialysis

Given the reported efficacy of mycophenolate mofetil (MMF) in the treatment of glomerular diseases, we question whether MMF can reduce the rate of renal allograft loss due to glomerular disease recurrence compared to azathioprine (AZA) as adjunctive therapy to cyclosporine (CSA)-based immunosuppression. This is a retrospective study based on the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database designed to compare the Kaplan-Meier rates of graft loss due to disease recurrence stratified by primary renal diagnoses between recipients receiving CSA+AZA versus CSA+MMF. Recipients of primary kidney transplants (both deceased donor and living, related and unrelated) renal transplants performed between 1 January 1988 and 31 December 2007 with the primary renal diagnosis of IgA nephropathy (IgAN), membranous glomerulonephropathy (MGN), membranoproliferative glomerulonephropathy (MPGN), lupus nephritis (LN) or focal segmental glomerulosclerosis (FSGS) with a functioning allograft at discharge were included. Seven thousand eight hundred and twenty-six recipients of primary deceased donor kidney transplants (DDKT) [CSA + AZA: IgAN (890), MGN (380), MPGN (193), LN (1324), FSGS (1314) and CSA+MMF: IgAN (855), MGN (614), MPGN (116), LN (715), FSGS (1425)] and 5498 recipients of living donor kidney transplants (LDKT) [CSA+AZA: IgAN (694), MGN (229), MPGN (100), LN (592), FSGS (654) and CSA+MMF: IgAN (1066), MGN (435), MPGN (89), LN (530), FSGS (1109)] were included in the analysis. At 10-year follow-up (mean duration was 5.6 to 6.7±1.8 years in DDKT and 6.2 to 7.4±1.7 years in LDKT), mean times of transplantation (era of transplantation) were: 1992±1.6 years and 2002±1.9 years for the CSA+AZA and CSA+MMF groups, respectively. There was no statistically significant difference in the Kaplan-Meier rates of graft loss due to disease recurrence of any glomerular disease studied between the CSA+AZA and CSA+MMF groups in either DDKT or LDKT recipients. Chi-square analysis revealed no statistically significant difference between the two immunosuppressive regimen groups in terms of age, gender and ethnic background. The OPTN/UNOS database revealed no difference in the rates of renal allograft loss due to disease recurrence of IgAN, MGN, MPGN, LN and FSGS among recipients receiving either CSA+AZA or CSA+MMF maintenance immunosuppressive therapy at 10-year follow-up.

Expression of DNA topoisomerases in chronic proliferative kidney disease

The occupants of our globe, on average, are steadily growing older consequent to lower birth rates and longer life expectancy. While the actual tempo of this global aging process varies from region to region, due to the impact of epidemics of disease (e.g. AIDS), reduced infant mortality, hygiene, malnutrition and violence, there is little doubt that the aging of society as a whole will have profound effects on healthcare systems and clinical practice. The discipline of nephrology is not exempt from these events, indeed it has already been and is continuing to be impacted by the aging of society, particularly in income-rich countries. The prevalence of acute and chronic kidney diseases is expected to increase significantly in the next few decades, largely in the older adult population. The specific causes or nature of these diseases are quite heterogeneous and often difficult to categorize on clinical grounds alone. Renal biopsy has been and continues to be a powerful tool to add precision to diagnosis. Many surveys of renal pathology, as it exists in a given population and how it changes over time, have been published, mostly collected in regional renal biopsy registries, but relatively few have focused mainly on the older and elder adult, conventionally defined as having attained the age of 65 years or more [1–3]. The survey by Jin et al. [4] from Jinling Hospital and the Nanjing University School of Medicine in Nanjing, China, published in this issue of Nephrology Dialysis Transplantation is a good example of this kind of morphological/epidemiological investigation. Remarkably, over 29 000 renal biopsies were performed in adults (age 18–81 years) at a single center over a 10-year period, of which ∼850 (2.9%) were performed in older or elder adults. These older subjects had a variety of clinical presentations and indications for performance of renal biopsy, but the actual rate of renal biopsy performance is not precisely known, but a rate of ∼2900 renal biopsies per year would be high by any standard. Undoubtedly, selection pressures such as the referral nature of and the cachement areas sub-served by the center play large roles in the epidemiological observations reported. Not surprisingly, proteinuria (including nephrotic syndrome; NS) with or without hematuria or acute kidney injury (AKI) was commonly the reason for performance of renal biopsy—observed in almost two-thirds of the subjects. Glomerular or vasculitic diseases predominated— slightly over 70% of all biopsies showed lesion of membranous nephropathy (MN), IgA nephropathy (IgA N), minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), small vessel vasculitis (SVV), diabetic nephropathy (DN) or amyloidosis (AM). DN is likely under-represented (at 9.75%) in this series, compared with its actual prevalence in the population as a whole—even though in this series renal biopsies were performed in diabetic subjects with renal involvement and without biopsy ‘contraindications’. It is not clear if the extent of ‘atypical’ characteristics at presentation influenced the decision to perform renal biopsy in diabetic subjects. Among elderly subjects presenting with NS, four lesions (MN, AM, MCD and IgA N) accounted for 80% of those observed. The distribution of these lesions in the elderly is strikingly different from that observed in the ‘control’ younger population. It is also noteworthy that the most common lesion in the very old (>75 years) was MN. Of great interest is the low prevalence of lesions of FSGS in both the young and old subjects alike (5.8 and 4.7%, respectively). Among older patients presenting with NS (with or without AKI) on only 28/851 (3.3%) demonstrated FSGS on renal biopsy. The frequency of FSGS in this and other studies in Asians is much different that seen in non-Asian populations, especially in subjects of African ancestry [5]. This difference is likely explained on a genetic basis (lack of APOL1 risk alleles in Asians), but environmental influences cannot be excluded [6]. The relative rarity of ‘primary’ or ‘idiopathic’membrano-proliferative glomerulonephritis (MPGN) in the elderly is notable (only 7 in 851 cases; 0.82%). These data support the contemporary view that IN F O C U S

Interferon therapy: a double-edged sword?

Hepatitis C virus (HCV) infection is a global public health problem. Chronic HCV infection is an important cause of chronic liver disease. Since the first reported association between HCV and membranoproliferative glomerulonephritis (MPGN) in 1993, HCV has been described with other types of glomerular diseases, although less frequently. Focal segmental glomerulosclerosis (FSGS) is one such glomerular disease that has been rarely reported in association with HCV. Antiviral therapy with interferon and ribavirin has been shown to be beneficial in HCV-associated MPGN. The optimal therapy of HCV-associated FSGS is not currently known. To our knowledge, long-term response to pegylated interferon monotherapy in treatment of HCV-associated FSGS has not been reported. We report an adult patient with HCV-associated FSGS who presented with nephrotic syndrome and renal failure. Treatment with pegylated interferon alfa-2a monotherapy resulted in sustained virological response with a clinical remission of nephrotic syndrome and stabilization of renal function. Patient continued to remain in clinical remission of nephrotic syndrome with stable renal function, 5 years after treatment. We also briefly review the literature on HCV-associated glomerular diseases, particularly HCV-associated FSGS.

The changing face of schistosomal glomerulopathy

Considerations in Retransplantation of the Failed Renal Allograft Recipient

Efficacy of Eculizumab in Coexisting Complement C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome

There is evidence that HIV-associated nephropathy (HIVAN) can be prevented and its progression slowed by HAART. More than 20 antiretroviral drugs and drug combinations are available, and life expectancy of HIV-infected individuals is now measured in decades. However, it is likely that more indolent forms of HIVAN remain common in the HAART era, predisposing patients to nephrotoxicity from HAART and related therapies. Indeed, the prevalence of acute renal failure and chronic kidney disease appears to be increasing among HIV-infected patients in the United States [1,2], and kidney disease has emerged as an important predictor of mortality [2,3]. Adverse effects of antiviral treatments should be considered, including their long-term renal toxicity and their role in renal scarring after acute adverse events. In addition, the burden of comorbid chronic kidney disease is likely to increase with ageing of the HIV-infected cohort, continued growth of the epidemic among susceptible minorities and increasing prevalence of HAART-related metabolic abnormalities. In this population of patients, evaluation of renal disorders and prevention of evolution toward chronic renal failure are a crucial challenge. Epidemiology of HIV-associated nephropathy and HIV-related diseases Most epidemiological data on HIVAN generated in the pre-HAART era are based on the US Renal Data System (USRDS). Initial clinical studies indicated that 10% of HIV-1-infected patients appeared to develop renal disease, of which 90% showed clinical and/or pathological features consistent with HIVAN [4,5]. Past postmortem studies also yielded a prevalence of HIVAN ranging between 1% and 15%, depending on the population [6,7]. The prevalence and distribution of HIVAN was associated strongly with African-American ancestry [8,9] as indicated by an USRDS-based report of 3653 patients with end-stage renal disease (ESRD) secondary to HIVAN during 1992 to 1997 [10]. Since the introduction of HAART, national epidemiological data show a reduction of incidence of ESRD associated with HIV-associated renal disease in the United States [11,12] contrasting with the steady increase in HIV/AIDS in the general population [13]. From a mathematical model using available epidemiological data on HIV-infected patients in the USRDS database and the Centers for Disease Control and Prevention data for HIV-seropositive patients, Blower et al.[14] suggested that HAART decreases the incidence of ESRD in patients with HIVAN and the mortality from HIV, with an overall efficacy of 23%. This trend has been attributed, in part, to beneficial effects of HAART, which was commenced in 1996. Preliminary retrospective series or case reports support the efficacy of HAART in improving outcome in HIVAN [15–19]. In a retrospective cohort study, Szczech et al.[20] reported that treatment with protease inhibitors (and prednisone) was associated with a slower decline in renal function in patients with HIVAN or other HIV-1-related renal diseases. Cosgrove et al.[18] reported another retrospective series of 23 patients with HIV-1-related nephropathies, including patients with HIVAN. Patients with HIVAN were treated with HAART and none doubled their serum creatinine. In the non-HAART group, all patients showed a doubling of serum creatinine, two patients died and eight required dialysis. One study [21], retrospectively comparing two cohorts of 102 and 33 patients with biopsy-proven-HIVAN in the pre-HAART and in the HAART eras, respectively, also argues for improvement of renal survival by HAART. However, a recent postmortem-based survey reported that 12% of African-American patients dying of HIV-1 infection have histologically confirmed HIVAN [22]. Even if HAART decreases the incidence of HIVAN in African-Americans, the prevalence of HIVAN may not change because of the improvement in the survival of these patients. The onset of HIVAN could, therefore, just be delayed. Indeed, we have recently reported a patient with biopsy-proven HIVAN despite the lack of any past or present AIDS-defining condition and HAART-controlled HIV-1 infection for at least 2 years [23] Schwartz et al.[1] developed a mathematical model of the dynamics of HIV infection in the ESRD population in order to assess the impact of HAART on the progression of patients with AIDS to the development of ESRD and to predict the prevalence of HIV-related ESRD through to 2020. The authors concluded that, despite the potential benefit of HAART, the prevalence of HIV-related ESRD in the United States would be expected to rise in the future as a result of the expansion of the number with AIDS among black individuals. Nonetheless, while prospective controlled trials evaluating HAART on HIVAN or other HIV-1-related nephropathies are not ethically acceptable, consensus guidelines recommend consideration of HAART in HIV-infected patients with chronic renal insufficiency [24]. Changes in clinicopathological presentation HIV-associated nephropathy HIVAN is an unusual form of poorly responsive glomerular disease characterized by nephrotic syndrome, focal segmental glomerulosclerosis and a rapid fulminant progression to ESRD. Proteinuria occurs in up to 30% of HIV-infected patients, but not all of these patients have HIVAN [25–27]. The true prevalence of HIVAN is not known. The geographic distribution of HIVAN is not uniform, and it depends on specific risk factors for HIV disease, including race, gender and drug use. There is a striking predilection for HIVAN among African-Americans, as is also true for focal segmental glomerulosclerosis associated with intravenous drug use [4]. HIVAN is 7–10 times more common in men than in women, and 30–60% of people with HIVAN have a history of intravenous drug use [7]. In the pre-HAART era, patients with HIVAN typically presented with a nephrotic syndrome consisting of nephrotic-range proteinuria classically without oedema despite severe hypoalbuminaemia. Urinalysis reveals microhaematuria. Patients with HIVAN are typically not hypertensive, even in the face of renal insufficiency, and their kidneys are usually normal to large in size and highly echogenic by ultrasonography. The most common histological light microscopy finding is a collapsing form of focal segmental glomerulosclerosis. Tubulo-interstitial scarring, atrophy and marked dilatation of the tubules (microcystic dilatations) are usually present. Immunofluorescent microscopy is usually negative. Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation and focal foot process effacement. Tubulo-reticular structures in the glomerular endothelial cells consisting of ribonucleoprotein and membrane, the synthesis of which is stimulated by alpha-interferon, is highly predictive of HIVAN. Risk factors for progressive renal disease include CD4 cell count < 200 cells/μl, detectable plasma HIV RNA, hypertension, low plasma albumin and elevated serum creatinine [28]. In our experience during the HAART era, where most patients have well-controlled HIV, a nephropathy typically presents as stable or slowly progressive renal failure, hypertension, glomerular proteinuria, not necessarily of nephrotic range, and a preserved rather than increased kidney size. Pathologically, simple tuft ischaemia tends to replace florid (?) glomerular collapse while mild interstitial infiltration and cystic tubular dilatation are seen. Paradoxically, we noted more frequent atherosclerotic vascular changes even in younger affected patients. Until recently, the clinical course of HIVAN was one of inexorable progression to ESRD in 6–12 months, with limited treatment options. More options are now available to patients; these include antiretroviral therapy, steroid treatment and angiotensin-converting enzyme inhibitors. Evidence exists that antiretroviral therapy can reverse or improve the progression of HIVAN [15,16,19]; however despite the widespread use of HAART, no prospective studies have demonstrated benefit in slowing the progression of HIVAN. The survival benefit from antiretroviral therapy is indisputable. HAART may also prevent the development of HIVAN in at-risk groups. Lucas et al.[29] evaluated a cohort of 3976 at-risk patients in the Johns Hopkins HIV clinic database from 1989 to 2001. They identified 135 cases of HIVAN based on either clinical or pathological criteria. There was a 50% decline in HIVAN incidence in 1998–2001 compared with 1995–1997, and HAART was associated with a 60% reduction in risk for developing HIVAN. Patients with AIDS developed HIVAN at a rate of 12.5/1000 person-years, compared with 3.1/1000 person-years in patients without AIDS (relative risk, 4.1). However, it is notable that in over 1071 person-years of follow-up, no patient developed HIVAN when HAART was initiated prior to the onset of AIDS. The rationale for treating HIVAN with corticosteroids is that steroids are the mainstay of treatment for idiopathic focal segmental glomerulosclerosis [30]. The first report of steroid treatment in four patients with HIVAN found a significant reduction in serum creatinine after a course of corticosteroids lasting 2–4 weeks [31]. The initial case report study has now been extended to include 20 patients, and these results confirm that prednisone at a dose of 60 mg daily for 2–11 weeks leads to a significant reduction in serum creatinine and in 24-hour urinary protein excretion [30]. The encouraging short-term results must be balanced by the findings during the follow-up period. During a median follow-up of 44 weeks, 8 of 20 patients required maintenance dialysis, 11 of 20 died of HIV disease after completing prednisone treatment, and 6 of 20 developed serious infections while receiving prednisone. Only 7 of 20 patients were alive and free from ESRD after a median of 25 weeks following initiation of prednisone. A more recent retrospective study reported the course of HIVAN in 13 patients treated with prednisone and a further eight patients not treated with prednisone. Even after controlling for baseline creatinine, proteinuria, and CD4 cell count, among other variables, the prednisone group had an 80% reduction in risk of progressive azotaemia after 3 months [32]. Prednisone may work by reducing the amount of interstitial inflammation [33]. In 1995, The AIDS Clinical Trials Group (ACTG) designed a phase II randomized, double-blind, placebo-controlled multicentre trial to determine the efficacy of prednisone therapy in HIVAN, but this trial was cancelled because of poor patient recruitment. The angiotensin-converting enzyme inhibitors captopril and fosinopril have also been studied as possible therapy for HIVAN [34]. In one study in which 18 patients were enrolled, nine were treated with captopril, 6.5–25 mg three times daily, and nine controls did not receive captopril. All patients had biopsy-proven HIVAN, and renal survival was defined as the time from initiation of captopril treatment to initiation of dialysis (ESRD). The initial mean serum creatinine concentration was 34 mg/l (±7.0) in the captopril group and 37 mg/l (±0.5) in the controls. A small renal survival advantage of approximately 8 weeks (median 83 versus 30 days), was seen in the captopril group [35]. Two non-randomized studies have investigated the effect of fosinopril on the progression of HIVAN. Both studies showed a significantly lower risk of reaching ESRD in the fosinopril group compared with non-treated controls [35,36]. Despite the limitations of these studies, they suggest that therapy with an angiotensin-converting enzyme inhibitor initiated early may offer renal survival benefits in HIVAN. The ACTG is currently developing a clinical trial (protocol A5179) to compare treatment with an angiotensin receptor blocker (valsartan) plus HAART with HAART alone in patients with HIVAN. Indications for kidney biopsy The decision to obtain a renal biopsy sample is somewhat controversial in the general medical community. Even if a patient presents with the classic clinical features of HIVAN, clinical presentation is predictive of the biopsy diagnosis in only 50–60% of patients. Furthermore, non-invasive tests or clinical markers to identify the precise renal lesion do not exist. Renal biopsy should be offered to patients because a variety of renal lesions occur in HIV-infected patients, and the treatment implications and prognosis vary according to the biopsy results. We, therefore, believe that to distinguish HIVAN from other forms of renal disease, and to redefine HIVAN pathological findings in the HAART era, HIV-positive patients who have unexplained renal abnormalities (i.e., kidney failure and/or daily protein excretion greater than 1 g and/or microscopic haematuria) should have a renal biopsy. HAART-related kidney disorders Electrolyte and acid-base profiles It is noteworthy that the biological profile in HIV-infected patients has dramatically changed in the HAART era. Previous studies stated that hyponatraemia, hyperkalaemia or hypokalaemia and acidosis were the main biological abnormalities in HIV-positive patients [37,38]. A prospective cross-sectional descriptive study (1219 HIV-infected patients over 3 months) undertaken to assess the prevalence of fluid electrolyte and acid–base disturbances showed hyperuricaemia and hypophosphataemia to be the most prevalent abnormalities [39]. Hyperuricaemia was detected in 140 (41.3%) out of the 339 patients tested. Among hyperuricaemic patients, only 47% were treated with didanosine. Multivariate analysis showed that patients not taking non-nucleoside transcriptase inhibitors (NNRTI) had a 1.8-fold risk [95%confidenceinterval(CI),1.1–2.9] of hyperuricaemia. With protease inhibitor treatment and male gender, the risk of hyperuricaemia rose to 4.4 (95% CI, 2.1–9.6). A plasma phosphate level below the normal range was observed in 63 (17.2%) of the patients tested for plasma phosphate. Multivariate analysis showed that patients taking an NNRTI regimen had a 1.9-fold increase in risk of hypophosphataemia (95% CI, 1.1–3.3), male patients had a 2.6-fold increase in risk (95% CI, 1.1–6.3). Bicarbonate plasma level below the normal range was observed in 112 patients (13.6%) out of the 824 patients tested. Multivariate analysis showed that patients taking HAART had a 4.4-fold increase in risk having a low plasma bicarbonate level (95% CI, 2.2–8.9), women had a 2.4-fold increased risk (95% CI, 1.5–3.8) and patients with CD4 cell count < 200 cells/μl had a 1.8-fold increased risk (95% CI, 1.2–2.9). Only 13 patients (3.1%) out of the 419 patients tested exhibited low calcium levels (n = 13). Factors significantly associated with low plasma calcium concentrations were NNRTI regimen and CD4 cell count. An absolute CD4 count < 200 cells/μl was associated with an increased risk of hypocalcaemia when compared with a cont of > 200 cells/μl. Lactic acidosis Approximately 20–30% of patients who are treated with nucleoside reverse transcriptase inhibitors (NRTI) can be found to have asymptomatic hyperlactataemia; this typically develops after several months of therapy and may be transient [40–42]. Severe lactic acidosis is much rarer, occurring in 1.5–2.5% of patients, is usually preceded by fatigue, nausea, vomiting, anorexia, abdominal pain and other systemic symptoms, and is associated with a mortality rate of approximately 80%. Lipoatrophy, myopathy, peripheral neuropathy and pancreatitis are more often observed in patients with symptomatic hyperlactataemia rather than in patients who have frank lactic acidosis. Risk factors include NRTI use, longer duration of treatment, older age, female gender, pregnancy, hypertriglyceridaemia, obesity, concomitant hepatitis C infection, use of ribavirin, impaired kidney function and alcohol ingestion [41–44]. Acute renal failure Before the HAART era, mild acute renal failure, defined as a peak serum creatinine ≥ 20 mg/l, was been reported to occur in up to 20% of hospitalized HIV-infected patients [45]. This is in comparison with an incidence rate of 1% in hospitalized non-HIV-infected patients [46]. The two major acute renal complications in HIV disease that resulted in potentially reversible failure were acute tubular necrosis and HIVAN. Sepsis contributed to the development of severe acute tubular necrosis, defined as a peak creatinine ≥ 60 mg/l, in up to 75% of cases [47]. A study of kidney biopsy specimens in HIV-infected patients with severe acute renal failure not thought to be from prerenal causes or acute tubular necrosis reported the following distribution of renal lesions: 53% haemolytic uraemic syndrome; 40% acute tubular necrosis, either of ischaemic–toxic origin or rhabdomyolysis; 26% obstructive renal failure, extrinsic, drug induced or secondary to paraprotein precipitation; 23% HIVAN; 3% acute interstitial nephritis; and 6% various glomerulonephritides [48]. In a recent cohort study of ambulatory HIV-infected patients, acute renal failure occurred in nearly 10% of patients, with an incidence rate of 5.9 episodes/100 person-years [49] Antiretroviral agents have been shown to have a range of nephrotoxic effects, including crystal-induced obstruction, tubular toxicity, interstitial nephritis and electrolyte abnormalities. Drugs are responsible for one-third of all acute renal failure events. Although only responsible for a few events, antiretroviral drugs cause two-thirds of all obstructive acute renal failure. Indinavir, tenofovir, and nevirapine were the antiretroviral drugs associated with acute renal failure in this cohort [49–52]. Iatrogenic acute renal failure can be dose dependent, manifesting as acute tubular necrosis, acute glomerulopathy, vascular disease or interstitial immunoallergic reactions. Table 1 summarizes the nephrotoxicities induced by antiretroviral drugs [53–77]. According to the renal syndrome, the clinician will attempt to distinguish between possible causes from each of the four aetiopathogenic groups of nephropathies defined above. Depending on the situation, renal biopsy may be indicated. Table 2 proposes a diagnostic flowchart applicable for a HAART- treated patient with renal abnormalities.Table 1: Antiretroviral drug-induced renal abnormalities.Table 2: HIV-infected patients with renal abnormalities: a diagnosis proposition.Chronic renal failure Chronic renal abnormalities are frequently observed in HIV-infected individuals. Despite drug adjustment, some HIV-infected patients experience progressive renal disease. Usually, the diagnosis of renal toxicity of antiretroviral treatment is considered when patients experience acute renal abnormalities. However, the potential insidious long-term renal toxicity of antiviral treatment may be underappreciated in the pathogenesis of nephropathies of chronic progression in HIV infected patients. In prospective studies evaluating the safety and efficacy of the protease inhibitor indinavir, or some reverse transcriptase inhibitors, a of patients with acute renal failure did not their baseline renal function and data the of renal after acute renal related to antiretroviral the large range of kidney diseases that may occur in HIV-positive patients taking HAART, each case should be and the benefits and of drug The main for the clinician is to determine the of the nephropathy in order to specific in to symptomatic complications With the of HIV the complications associated with HIV infection have to include changes in HIV protease inhibitors and the to peripheral and impaired distribution elevated plasma and and elevated plasma have been reported in clinical trials and in changes in may be related to HIV disease or may be a of treatment with antiretroviral agents through in to long-term antiretroviral therapy the development of chronic kidney disease, through metabolic complications Indeed, black and have been associated with the development of Both protease inhibitors and NNRTI have been associated with and studies have shown plasma concentrations to be associated with increased mortality in in and/or older patients Evidence of hyperuricaemia in HIV-positive patients should to change in the of patients, as of The impact of and antiretroviral metabolic disorders on the of kidney or disease in patients with HIV therefore, an important Risk factors for nephrotoxicity renal adverse are not it is possible to identify patients who may be at increased risk factors for kidney disease, including older age, African-American comorbid and kidney disease, to be associated with renal failure in patients In addition, disease and hepatitis have been associated with increased risk for acute or chronic kidney disease in HIV-infected patients kidney function is one of the most of risk for acute or chronic kidney disease in patients The recently consensus guidelines for chronic kidney disease in all HIV-infected patients at the time of with frequent in the of kidney function or other evidence of kidney disease [24]. Initial should include and serum creatinine with of the glomerular rate by either the or of in Renal Disease has been in patients with HIV, are more than serum creatinine of patients with a glomerular rate < 60 will for dose of by the and should more frequent of kidney toxicity and The according to the glomerular rate and the of dose for each are in Table The of proteinuria by or also chronic kidney disease, and may identify patients at increased risk for nephrotoxicity [24]. In to chronic kidney disease, other factors as and concomitant of other nephrotoxic agents may also patients to the nephrotoxic effects of HAART or related HAART can also to Indeed, studies over the past 20 in patient have demonstrated a between in disease and et found a increase in the risk of developing elevated among patients receiving compared with receiving In addition, the results suggested that the increased risk associated with was at least in part, through an increase in Antiretroviral dose based on creatinine with HIV and hepatitis or C The effect of with hepatitis in and C on disease progression and survival among patients infected with HIV has an increasing this has from the effects of while this function and decreases the incidence of infections in HIV-infected patients, it also the of chronic disease to the overall and mortality of these individuals. use of alcohol is an in this Approximately of HIV-infected patients are Among intravenous drug with HIV, this rate is at least 50% and can be up to 90% in with and HIV is with of HIV-infected individuals having evidence of past or infection The prevalence of chronic of among HIV-infected individuals is Among intravenous drug 90% of HIV-infected individuals have evidence of to and 60% also have evidence of past infection with the of of renal disorders has not been reported in However, proteinuria and have been reported frequently in or patients without HIV proteinuria to and in infected patients; proteinuria to 30% and 30% in patients. has been in and patients and is characterized by and peripheral neuropathy The renal presentation of in patients may include renal insufficiency, proteinuria, and The course of renal disease is much more in the with some to ESRD in a of months However, while reports had shown between HIV and with et did not an between HIV infection and In patients not with HIV, the of nephropathy with and has also been and the reports of nephropathy in HIV-infected patients may be by the incidence of infection, and in this population The life expectancy of HIV-positive patients treated with HAART now that of the general The has to the and renal that can increase with more in patients hypertensive, 2 and risk factors to renal disorders from HIV infection and HAART. it more important to develop for treating these patients from the renal Renal to be in patients with HIV/AIDS and potentially reversible factors to be identified and the we suggest the antiretroviral drug use and kidney disease in HIV-infected patients. All patients at the time of HIV diagnosis should be for kidney disease with a for proteinuria and a of renal is no evidence of proteinuria at initial patients at risk for the development of renal disease (i.e., African-Americans, with CD4 cell < 200 cells/μl or plasma HIV > and with hypertension, or should Renal function should be on a to assess for changes over proteinuria, renal renal biopsy. Patients with glomerular rate 60 or with proteinuria > by or on should be to a for further evaluation and In HIV-infected patients with evidence of should be controlled to a level no than enzyme inhibitors or angiotensin receptor are the drugs of first for patients with proteinuria, and these drugs should also be considered in HIV-infected patients with renal disease. should be in patients receiving protease inhibitors. Patients with HIVAN should be treated with HAART at HAART should not be from patients because of the of their renal The antiretroviral regimen is a between the benefits of and the risk of adverse events, including The of renal insufficiency should the and dose of the antiretroviral of prednisone should be considered in patients with HIVAN if HAART alone not result in improvement of renal function or in patients with HIVAN renal failure is A that the of short-term the benefit of slowing the progression to ESRD and the should the decision reduction of for antiretroviral drugs that are the kidneys is With dose and renal insufficiency or ESRD is not an absolute to the use of any antiretroviral nucleoside should not be in patients with renal function for of the development of lactic acidosis. Drugs that are by dialysis should be after to of In HIV-positive renal are important between the inhibitors and protease inhibitors, and the NNRTI drug may increase levels of and tenofovir, their In the of protease inhibitors, a major reduction in the of inhibitors may be Although most antiretroviral agents are free of renal toxicity, renal can occur and may to be from progression of HIVAN or other HIV-related kidney kidney diseases by other infections or or kidney diseases to HIV infection and its and diseases have emerged as important complications in patients, infections as causes of among HIV-infected patients. patients with risk or a history of a consideration should be to or to protease antiretroviral with the use of NRTI or NRTI and and between disease and will diagnosis and treatment of chronic kidney and vascular diseases with the of progression to ESRD. The authors and for their The authors in the had to all the data in the study and had for the decision to to

Changing incidence of glomerular diseases in adults

We report the spectrum of biopsy-proven glomerular disease (GD) in a single center in Eastern India. Medical records of 666 patients with biopsy-proven GD over a period of 2 years from July 2010 to July 2012 were retrospectively analyzed. The clinical, laboratory, and histological data were recorded. All biopsy specimens were examined by the same pathologist with light and immunofluorescence microscopy. Electron microscopic analysis was performed only in selected cases. Histologic spectrum of various GDs was studied along with its correlation with the clinical and laboratory parameters. The clinical diagnosis was nephrotic syndrome (NS) in 410 (61.56%), rapidly progressive renal failure/glomerulonephritis in 130 (19.52%), subnephrotic proteinuria/asymtomatic urinary abnormalities in 52 (7.81%), acute kidney injury/acute nephritic syndrome in 40 (6.01%), and macroscopic hematuria in 4 (0.6%) patients. Male: Female ratio was 1.05; 27.92% (n = 186) were < 18 years, 68.47% (n = 456) were 18–59 years, and 3.6% (n = 24) were ≥ 60 years of age. The most common GD was minimal change disease (MCD) (20.12%, n = 134); others were focal segmental glomerulosclerosis (FSGS) (18.02%, n = 15.32%), lupus nephritis (LN) (15.32%, n = 102), membranous nephropathy (MN) (12.01%, n = 80), and IgA nephropathy (IgAN) (8.11%, n = 54). Primary GD was present in 79.13% (n = 527) and common histologies were MCD (25.42%), FSGS (22.58%), MN (14.42%), and IgAN (10.25%). Secondary GD was present in 20.87% (n = 139), with the most common being LN (73.38%, n = 102). Among the NS (n = 410), the most common GD was MCD (31.46%), followed by FSGS (25.6%), MN (15.58%), LN (7.8%), IgAN (6.09%), and membranoproliferative glomerulonephritis (4.88%). FSGS was the most common primary GD in adults, MCD in children, and MN in the elderly patients. The spectrum of GD varies according to the area of study and changes over time. A biopsy registry is needed for documenting this variation.

Background and Aims Glomerular diseases are a prevalent cause of end-stage renal disease; however, there is a scarcity of population-based epidemiological data concerning glomerulonephritis. This study aims to analyze the epidemiological patterns and clinical presentations of biopsy-proven primary and secondary glomerular diseases sourced from a tertiary nephrology unit, which serves as a reference center for the diagnosis and treatment of glomerular diseases in the Republic of North Macedonia, a country with a population of 1.8 million. Method This investigation is a single-center, retrospective study encompassing 228 adult patients (aged over 14 years) diagnosed with biopsy-proven primary or secondary glomerular disease. The study was conducted at the University Hospital of Nephrology in Skopje, North Macedonia, over a five-year period (2020–2024). Excluded from the analysis were the biopsies of kidney transplant patients and those with incomplete data. Results A total of 228 native renal biopsies were evaluated via light microscopy, with 62 patients (27.2%) undergoing immunofluorescence analysis and 127 patients (55.7%) undergoing electron microscopy. The majority of the patients were male (143 patients; 62.72%), with a mean age at the time of renal biopsy of 47.45 ± 15.92 years; 37 patients (16.23%) were aged over 65 years. The average serum creatinine level at the time of biopsy was 182 ± 150.66 µmol/l, the mean glomerular filtration rate was 58.9 ± 36.77 ml/min/1.73 m², and the mean proteinuria was 3.04 ± 3.0 g/l. Geographically, 92 patients (40.35%) resided in the Skopje Region, followed by the Eastern Region (11.84%), and the Pelagonia and Southwestern Regions (each with 10.08%) within North Macedonia. The most frequently diagnosed glomerulonephritis in our cohort was membranous nephropathy, identified in 33 patients (14.47%), followed by focal segmental glomerulosclerosis in 27 patients (11.84%), and IgA nephropathy in 25 patients (10.96%). Other diagnoses included amyloidosis and various fibrillary glomerulopathies in 23 patients (10.08%), minimal change disease in 22 patients (9.65%), membranoproliferative glomerulonephritis in 20 patients (8.77%), extracapillary glomerulonephritis in 19 patients (8.33%), diabetic nephropathy and/or nephroangiosclerosis in 15 patients (6.57%), mesangial glomerulonephritis without IgA in 15 patients (6.57%), lupus nephritis in 12 patients (5.26%), global glomerulosclerosis in 7 patients (3.07%), acute kidney injury in 3 patients (1.31%), and other diagnoses in 7 patients (3.07%). Re-biopsy procedures were performed in only a small minority of the patients. Conclusion The data presented herein provide valuable insights into the incidence of glomerular diseases in North Macedonia and could serve as a foundational resource for the establishment of a National Registry for Glomerular Diseases. Such a registry would facilitate the assessment of the burden that these diseases impose on the healthcare system and budget, as well as enable comparisons with data from registries in other countries across Europe and globally.