A study indicates an essential link between a mild deterioration in excretory kidney function and the risk of neutropenia during cancer chemotherapy.

PURPOSE: Neutropenia, defined as a number of neutrophils in patients' blood specimen lower than 1500 cells/µm3, is a common adverse event during myelosuppressive oncological chemotherapy, predisposing to febrile neutropenia (FN). Patients with coexisting moderate-to-severe chronic kidney disease (CKD) have an increased risk of FN, included in the guidelines for the primary prophylaxis of FN. However, this does not include mild kidney function impairment with estimated glomerular filtration rate (eGFR) 60-89 ml/min/1.73 m2. This prospective study analyzed the risk of neutropenia in patients on chemotherapy without indication for the primary prophylaxis of FN. METHODS: The study enrolled 38 patients starting chemotherapy, including 26 (68.4%) patients aged 65 years or more. The median duration of follow-up was 76 days. The methodology of creatinine assessment enabled the use of the recommended CKD-EPI formula for identifying patients with a mild reduction of glomerular filtration. RESULTS: Sixteen (42.1%) patients developed at least G2 neutropenia without episodes of FN. Only five (13.1%) patients had eGFR < 60 ml/min/1.73 m2, while 15 (62.5%) eGFR < 90 ml/min/1.73 m2. The relative risk of neutropenia in patients with impaired eGFR was over six times higher than in patients with eGFR > 90 ml/min/1.73 m2 (RR = 6.08; 95%CI:1.45-27.29; p < 0.01). CONCLUSIONS: Our observation indicates that even a mild reduction in eGFR is a risk factor for the development of neutropenia and a potential risk factor for FN. Authors are advised to check the author instructions for the journal they are submitting to for word limits and if structural elements like subheadings, citations, or equations are permitted.

Polypharmacy in Polish Older Adult Population-A Cross-Sectional Study: Results of the PolSenior Project.

Polypharmacy is a challenging issue in geriatrics. The aim of the study was to characterize correlates of polypharmacy in the PolSenior project. The PolSenior project, was a comprehensive survey in a large and longitudinal representative sample of thePolish older population. The project was conducted by the International Institute of Molecular and Cell Biology in Warsaw between 2008 and 2011. All medications consumed during the week preceding the survey were evaluated for each participant (n = 4793, including 2314 females (48.3%)). Thereafter, the percentage of those with polypharmacy (at least 5 medications) and excessive polypharmacy (at least 10 medications) was calculated, and their correlates were determined. The average number of medications used by participants was 5.1 ± 3.6, and was higher in females than in males (5.5 ± 3.5 vs. 4.8 ± 3.5; p < 0.001). Polypharmacy characterized 2650 participants (55.3%) and excessive polypharmacy-532 of them (11.1%). The independent correlates associated withpolypharmacy were: age over 70 years, female sex, higher than primary education, living in an urban area, comorbidities, any hospitalization during past five years, and visiting general practicioners at least yearly. As for correlates with excessive polypharmacy, they were: age 80-84 years, female sex, living in an urban area, diagnosis of at least four chronic diseases, and at least two hospitalizations in the last five years. This study serves as a starting place to understand patient characteristics associated with polypharmacy, excessive polypharmacy, and identify targeted interventions.

A rare case of fatal poisoning during long-term therapy with lithium carbonate - chronic poisoning, suicide or psychiatric malpractice? / Rzadki przypadek smiertelnego zatrucia w trakcie dlugotrwalej terapii weglanem litu ­ samobójstwo, przewlekle zatrucie czy blad medyczny psychiatry?

The study aims to present a case of atypical poisoning with lithium carbonate in a 57-year-old woman treated for bipolar affective disorder with lithium carbonate for about 30 years. The patient was admitted to the hospital with significant agitation. An important finding obtained from the family interview was the patient's significant weight loss over the past year. In the hospital, the patient received haloperidol and clonazepam. Laboratory tests showed a very high blood lithium concentration of 3.79 mmol/l [N: 0.6─1.2 mmol/l] and elevated serum concentrations of creatinine (3.6 mg/dl) and urea (110 mg/dl). The patient was transferred to the toxicology department, where hemodialysis was performed and intensive treatment initiated. Despite the rapid decrease in lithium levels, her condition gradually deteriorated. The patient died on the fifth day of hospitalization. The autopsy revealed polycystic kidney disease (PKD). During the preparation of the medico-legal report on the correctness of the medical treatment, it was assumed that the cause of death was lithium carbonate poisoning in the course of advanced chronic kidney disease due to PKD, probably a consequence of long-term lithium therapy. The analysis of medical records revealed that despite her psychiatrist's recommendation, the patient had been refusing the monitoring of lithium levels for the past 18 years. This case demonstrates that both psychiatrists and toxicologists should be aware of possible lithium poisoning upon the deterioration of renal function. Therefore, assessment of renal function should be an integral part of monitoring lithium therapy.

Lithium toxicity and the kidney with special focus on nephrotic syndrome associated with the acute kidney injury: A case-based systematic analysis.

Despite the progress made in treating bipolar and unipolar affective disorders, lithium carbonate is still a common drug in psychiatric practice. Lithium-related renal side effects include nephrogenic diabetes insipidus, chronic tubulointerstitial nephropathy, and acute kidney injury (AKI). Nephrotic syndrome (NS) is an uncommon but severe complication of lithium treatment. We present a 49-year-old female treated with lithium carbonate due to a recurrent depressive disorder who developed NS during this therapy. NS spontaneously remitted after the drug withdrawal. Since her lithium serum levels were within the recommended values, we performed a retrospective analysis of lithium-induced NS cases trying to determine causes predisposing to the NS development, underlying histopathology, and preservation or irreversible loss of kidney function. This analysis revealed that in lithium-induced NS with AKI, lithium serum level was the key determinant of AKI development (the ß coefficient = 0.8499 with a confidence interval ranging from 0.7452 to 0.9546 and p value < 0.0001). In these cases, the underlying pathology was mainly minimal change disease (MCD), which was quickly reversible upon the drug withdrawal. The development of chronic kidney disease (CKD) seemed to be associated with lithium therapy duration. However, the multiple regression analysis for CKD as the dependent variable showed that the decisive factor was focal segmental glomerulosclerosis (FSGS) as the underlying pathology (the ß coefficient = 0.7866 with a confidence interval ranging from 0.600 to 0.9704 and the p value < 0.0001). Thus, we conclude that in lithium-induced NS/AKI, serum lithium levels contribute to these complications, while FSGS lesions are responsible for CKD's disease progression.

The role of the alternative pathway of complement activation in glomerular diseases.

The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

Prevalence of Renal Impairment in Palliative Care Inpatients: A Retrospective Analysis.

BACKGROUND AND OBJECTIVE: Multiple drugs used in palliative care, including most opioids or their active metabolites may accumulate in patients with abnormal renal function, leading to serious adverse effects. The incidence and severity of renal impairment in palliative care inpatients has not been evaluated. The aim of the study was to investigate the incidence and severity of renal impairment in palliative care inpatients. METHODS: A retrospective analysis of medical records of patients admitted to the palliative care ward was performed. Estimated glomerular filtration rate (eGFR) was derived using the Cockcroft-Gault (C-G) and abbreviated Modification of Diet in Renal Disease (aMDRD) equations. RESULTS: Serum creatinine levels (SCr) were determined in 332 subjects aged 66.4±11.80 years (194 women; mean body mass index [BMI] 22.7±5.21 kg/m(2)). Mean SCr was 107.7±112.31 µmol/L. Elevated SCr (>115 µmol/L) was found in 20.2% of patients. Mean eGFR calculated with C-G and aMDRD equations was 66.6±38.52 mL/min and 78.7±43.55 mL/min/1.73 m(2), respectively. Between 35.2% and 51.8% of patients had eGFR <60 mL/min/1.73 m(2) (depending on the equation used). More than 10% of patients had eGFR <30 mL/min/1.73 m(2). In patients with normal SCr, between 18.9% and 39.2% had eGFR <60 mL/min/1.73 m(2). CONCLUSION: Renal impairment is common in palliative care inpatients, including considerable number of subjects with moderately to severely reduced kidney function.

Primary Ficolin-3 deficiency--Is it associated with increased susceptibility to infections?

Ficolin-3 (also called H-ficolin or Hakata antigen) is the most potent activator of the lectin pathway of complement in vitro. Its genetically determined deficiency in Caucasians is associated with a frame-shift mutation +1637delC (rs28357092) of the FCN3 gene. When it was described for the first time, it was postulated to be strictly associated with enhanced susceptibility to infections. At present, with our knowledge extended by several other patients that issue seems to be more complicated and less clear-cut. Two new cases of primary Ficolin-3 deficiency are reported here: a 50-year old male, suffering from membranous nephropathy and an 11-month old male infant who was operated on to repair congenital heart disease. Based on those cases and a literature review, we conclude that the clinical consequences of congenital Ficolin-3 deficiency are still unclear and such questions as whether it may be life-threatening or acts as a disease modifier remain to be elucidated.

Do circulating antibodies against C1q reflect the activity of lupus nephritis?

INTRODUCTION: The results of recent studies suggest that there is a link between the presence of antibodies against C1q (anti-C1q Abs) and kidney involvement in systemic lupus erythematosus (SLE). However, it remains unclear whether the clinical symptoms of lupus nephritis (LN) may be associated with the presence of anti-C1q Abs in serum. OBJECTIVES: The aim of the study was to compare the prevalence and levels of anti-C1q Abs and antibodies against double-stranded DNA (anti-dsDNA Abs), circulating immune complexes binding C1q (CIC-C1q), as well as complement components C3 and C4 in the sera of patients with LN in relation to the clinical activity of SLE and symptoms of LN. PATIENTS AND METHODS: The study involved 48 patients with LN and 66 healthy controls. Anti-dsDNA Abs, anti-C1q Abs, and CIC-C1q levels were determined by immunoenzymatic methods, while C3 and C4 by immunoturbidimetry. SLE activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: Anti-dsDNA Abs, anti-C1q Abs, and CIC-C1q were detected in 77%, 60%, and 43.7% of the patients with LN, respectively. The prevalence and mean levels of anti-dsDNA and anti-C1q Abs were significantly higher in patients with active LN than in those with inactive LN or controls. The levels of C3 and C4 were significantly lower in active LN than in inactive LN or controls. In active LN, a positive correlation between anti-C1q and anti-dsDNA Abs was observed. In patients with detected anti-C1q Abs, microhematuria (59% vs. 16%, P = 0.003), urinary casts (28% vs. 8%, P = 0.02), and low levels of serum C3 (P = 0.03) and C4 (P = 0.01) were observed statistically significantly more often. CONCLUSIONS: Simultaneous presence of hematuria and anti-C1q Abs may indicate an ongoing inflammatory process in the glomeruli in patients with SLE.

[Pathomorphological assessment of renal biopsy specimens: principles and directions for clinicians]. / Patomorfologiczna ocena biopunktatów nerek: podstawy i wytyczne dla klinicystów.

The renal biopsy is a principal diagnostic method to provide information on type, activity and the intensity of the disease. The aim of the article is to describe the handling, fixation and processing of the renal tissue in pathomorphological laboratories, as well as to provide any information about histopathological glomerular lesions observed in glomerulopathies. The assessment of the renal biopsies includes light microscopy, immunofluorescence microscopy and electron microscopy. In each case clinicians should provide information on the patient's clinical history and recent laboratory values. Immunomorphological evaluation of the renal biopsy specimen should be done in all cases. In view of the high cost of the electron microscopy it seems that the best solution is to preserve the renal tissue in epon and provide ultrastructural evaluation according to the clinical data and light microscopy and immunofluorescence findings. The diagnosis of glomerulopathies requires a close cooperation between clinicians and pathologists. Pathologists should have access to clinical data, and clinicians should understand the limitations of the pathomorphological techniques.

[The structure and role of CR1 complement receptor in physiology]. / Budowa i rola receptora CR1 ukladu dopelniacza w fizjologii.

CR1 (Complement Receptor type 1, C3bR, CD35) is a polymorphic glycoprotein expressed on erythrocytes, leukocytes and glomerular podocytes. It consists of extracellular, transmembrane and cytoplasmic domains. Soluble form of CR1 (sCR1), lacking the transmembrane and cytoplasmic domains, is present in serum. CR1 belongs to the Regulator of Complement Activation (RCA) family, which is characterized by the appearance of small consensus repeats (SCR). Gene for CR1 is localized on chromosome 1q32. Polymorphism of erythrocyte CR1 is connected with the difference in length of molecule (molecular weight), level of the expression of CR1 (number of receptors) on red blood cells and the Knops blood group antigens. CR1 is a receptor for C3b and C4b and plays an important role in the removal of immune complexes coated with C3b and C4b. It also regulates the complement cascade activation by preventing formation of classical and alternative pathway convertases and by acting as a cofactor for factor I mediated cleavage of C3b to iC3b, C3c i C3dg. CR1 takes part in pathogenesis and development of various autoimmune and infection diseases.

[The role of CR1 complement receptor in pathology]. / Rola receptora CR1 ukladu dopelniacza w patologii.

CR1 (Complement Receptor 1, CD35) is a membrane receptor for C3b and C4b expressed on erythrocytes, leukocytes and podocytes. It plays an important role in removal of immune complexes and pathogens coated with C3b and C4b. It also regulates the complement cascade activation by preventing formation of classical and alternative pathway convertases and by acting as a cofactor for factor 1 mediated cleavage of C3b to iC3b, C3c and C3dg. CR1 is a polymorphic molecule differing in molecular weight and the level of the CR1 expression on erythrocytes. It takes part in pathogenesis and development of various autoimmune and infectious diseases. The difference in expression of CR1 seems to correlate directly with the development of systemic lupus erythematosus (SLE) and severe form of malaria. The therapeutical potential of soluble CR1 (sCR1) is at present the subject of many investigations.

[Renal involvement in systemic lupus erythematosus]. / Zmiany w nerkach w toczniu rumieniowatym ukladowym.

Lupus nephropathy belongs to the most severe clinical manifestations of systemic lupus erythematosus (SLE). In 40-60% of patients impairment in renal function is stated on diagnosis and in 10-25% of them the disease progresses to the end-stage renal failure. There is an ample of evidence that the kidney is involved very early in the course of SLE and the occurrence of low-level proteinuria and haematuria may be associated with a significant renal disease. Glomerular lesions are the main prognostic factor. Two classifications of these lesions exist at present, i.e.: the World Health Organization classification from 1982 and the new one developed by the International Society of Nephrology/Renal Pathology Society in 2003. Since new morphological presentations with glomerular necrosis and crescent formation, associated with the presence of anti-neutrophil cytoplasmic antibodies have been reported, some difficulties in the interpretation of glomerular lesions further exist. Despite this complexity, the assessment of the kidney biopsy specimen remains the "gold standard" in handling with patients with lupus nephropathy.

[The involvement of neprilysin in the pathogenesis of glomerulopathies]. / Udzial neprylizyny w patogenezie klebuszkowych chorób nerek.

Neprilysin (NEP, CD10, CALLA-common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is the first podocytic antigen, which has been shown to induce human membranous glomerulonephritis (GN). Debiec et al. in a case of antenatal membranous GN identified NEP as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. However, NEP is expressed on normal podocytes and renal proximal tubular epithelial cells. Moreover, decreased podocyte expression of NEP has been found in a variety of glomerular diseases. Recent studies show that in patients with GN the podocyte expression of NEP correlates with that of other podocyte proteins, i.e.: synaptopodin and CR1 and reflects the severity of glomerular damage.

[Neprilysin--structure of the gene and protein product and the localization of expression]. / Neprylizyna--budowa genu i produktu bialkowego oraz lokalizacja ekspresji.

Neprilysin (NEP, CD10, CALLA - common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is involved in the metabolism of a number of regulatory peptides and plays an important role in turning off peptide signalling at the cell surface. NEP gene is located on chromosome 3q 25.1-q25.2 and is composed of 24 exons. Four types of NEP cDNAs have been identified resulting from alternative splicing of exons 1, 1bis, 2a or 2b to the common exon 3. Neprilysin is expressed in normal and malignant hematopoietic cells and in epithelial cells of many organs. In kidneys, it is expressed in podocytes, renal proximal tubular epithelium and in smooth muscles of the vessels.

[The relevance of neprilysin for systemic homeostasis and its involvement in the pathological processes]. / Znaczenie neprylizyny w utrzymywaniu homeostazy ustroju oraz jej udzial w procesach patologicznych.

Neprilysin (NEP, CD10, CALLA-common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is involved in the metabolism of a number of regulatory peptides and plays an important role in turning off peptide signalling at the cell surface. Neprilysin is involved in many physiological and pathological processes in organism. It regulates blood pressure and inflammatory response, takes part in the pathogenesis of Alzheimer disease, influences cellular proliferation and differentiation, as well as neoplastic progression.

[Structure and function of complement protein C1q and its role in the development of autoimmune diseases]. / Budowa i funkcja C1q skladowej dopelniacza oraz jej znaczenie w rozwoju chorób o podlozu autoimmunologicznym.

Complement plays an important role in the immune system. Three different pathways of complement activation are known: the classical, alternative, and lectin dependent. They involve more than 30 serum peptides. C1q is the fi rst subcomponent of the classical pathway of complement activation.It is composed of three types of chains, A, B, and C, which form a molecule containing 18 peptides. Each of the chains has a short amino-terminal region followed by a collagen-like region(playing a role in the activation of C1r2C1s2) and a carboxy-terminal head, which binds to immune complexes. Recent studies have shown a great number of ligands for C1q, including aggregated IgG, IgM, human T-cell lymphotropic virus-I (HTLV-I), gp21 peptide, human immunodeficiency virus-1 (HIV-1) gp21 peptide, beta-amyloid, fragments of bacterial walls, apoptotic cells, and many others. However, the role of C1q is not only associated with complement activation.It also helps in the removal of immune complexes and necrotic cells, stimulates the production of some cytokines, and modulates the function of lymphocytes. Complete C1q deficiency is a rare genetic disorder. The C1q gene is located on the short arm of chromosome 1. So far, only a few mutations in C1q gene have been reported. The presence of these mutations is strongly associated with recurrent bacterial infections and the development of systemic lupus erythematosus(SLE). Recent clinical studies point to the significance of anti-C1q antibodies in the diagnosis and assessment of lupus nephritis activity.

The Comparison of the Podocyte Expression of Synaptopodin, CR1 and Neprilysin in Human Glomerulonephritis: Could the Expression of CR1 be Clinically Relevant?

Podocytes are considered as the most important cells that determine loss of structure and function of the glomerular filter. We compared the expression of three podocyte markers, i.e.: synaptopodin (SYN), CR1 and neprilysin (NEP) in 107 patients with different forms of glomerulonephritis (GN) and 5 normal kidneys (NK). A quantitative immunohistochemistry was applied to evaluate the expression of podocyte proteins. The results were related with serum creatinine (Scr), estimated glomerular filtration rate (eGFR) and urinary protein. We observed the reduction in the podocyte expression of NEP, SYN and CR1 in proliferative and non-proliferative forms of GN. Interestingly, in mesangial proliferative GN (MesPGN), the expression of SYN and CR1 was lower in IgA-MesPGN than in non-IgA-MesPGN (p<0.005 and p<0.02, respectively). In all the patients, the expression of NEP and SYN was positively related (r=0.53, p=0.02) as that of NEP and CR1 (r=0.39, p=0.04). Yet, clinical correlations with Scr (r=-0.33, p=0.03) and eGFR (r=0.26, p=0.05) were obtained only with respect to CR1. In conclusion, SYN, CR1 and NEP may be used as markers of podocyte loss in patients with GN. However, in agreement with previous studies, the clinical relevance draws a special attention to the expression of CR1.

[Nephrotic syndrome in the elderly. The most frequent causes of the nephrotic syndrome in the elderly (part I)]. / Zespól nerczycowy u osób starszych. Najczestsze przyczyny zespolu nerczycowego w wieku podeszlym (czesc I).

Nephrotic syndrome (NS) is an essential clinical problem in the elderly. It may be difficult to recognize NS in the elderly because its symptoms are frequently missed with congestive heart failure or venous insufficiency. Glomerular diseases are not most common in elderly population but they play important role in renal pathology in this group of patients. Many structural and functional changes occur in the kidney with an increasing age. These changes may make, at least in part, the interpretation of renal lesions difficult. Glomerular pathology in this group of patients may be secondary to neoplastic diseases, and, therefore before the kidney biopsy screening for malignancies should be performed. The occurrence of particular forms of glomerular diseases differs between the older and young population. The most common forms of primary glomerular diseases in elderly are membranous nephropathy and focal-segmental glomerulosclerosis, whereas diabetic nephropathy and amyloidosis are common causes of secondary nephropathies. Kidney biopsy in the elderly gives valuable information, just as it is in the other age groups. It is a reasonably safe procedure, although associated with an increased risk of bleedings, when compared to younger population.

[Nephrotic syndrome in the elderly. Treatment of the nephrotic syndrome in the elderly (part II)]. / Zespól nerczycowy u osób starszych. Leczenie zespolu nerczycowego u chorych w wieku podeszlym (czesc II).

Nephrotic syndrome (NS) in elderly may increase mortality. The severity of NS determines its management. In the milder forms, with serum albumin concentrations greater than 2.5 mg/dl, significant sodium retention, volume expansion and hypertension patients should be treated with diuretics and hypertensive agents alone. Hypercholesterolemia needs to be treated in patients with NS because this is an important contributor to progressive loss of renal function and increased morbidity and mortality from cardiovascular disease in patients with renal insufficiency Statins decrease proteinuria and have antinflammatory action. Patients with severe NS will likely require immunosuppressive agents to significantly reduce heavy proteinuria. Elderly individuals should receive an appropriate immunosuppressive therapy to induce remission of NS and reduce the risk of progressive loss of renal function. However, since side effects of the used drugs and infectious complications occur more frequently in elderly, careful monitoring of therapy should be carried out.

[The role of podocytes in normal glomerular function and in the pathogenesis of glomerulonephritis. Part II. Phenotypic and functional changes of podocytes in glomerulonephritis]. / Znaczenie podocytów w prawidlowym funkcjonowaniu klebuszka nerkowego oraz w patogenezie klebuszkowych zapalen nerek. Czesc II. Zmiany fenotypowe i funkcjonalne podocytów w przebiegu klebuszkowych zapalen nerek.

Recent results indicate that intrinsic glomerular cells (podocytes, mesangial and endothelial cells) are active participants in the inflammatory process in the glomerulus. Particular attention is drawn to podocyte injury in glomerulonephritis. Podocytes are end-differentiated cells which have lost their proliferation abilities and can only compensate by hypertrophy. The inability to proliferate is the cost which a podocyte must pay for the development of highly specialized structures and ability to adhere to the glomerular basement membrane. Collapsing focal-segmental glomerulosclerosis is a condition in which podocytes proliferate, but this process is associated with loss of their maturity markers as well as with abnormalities in the expressions of cell cycle proteins. Dysfunction of slit diaphragms is an important element in the pathogenesis of glomerulopathies with marked proteinuria. Recent studies also underline the importance of neprilysin in the pathogenesis of glomerulonephritis. This is the first podocytic antigen which has been shown to induce human membranous glomerulonephritis.