Anti-glomerular basement membrane nephritis in a 5-year-old girl

.We report a 5-year-old girl with anti-glomerular basement membrane nephritis. Her outcome was excellent with clearance of antibody and recovery of renal function 5 weeks after the start of immunosuppression and plasmaphaeresis. Received December 11, 1995; received in revised form May 16, 1996; accepted May 20, 1996     

Clinicopathological characteristics and predictors of poor outcome in anti-glomerular basement membrane disease – a fifteen year single center experience

IntroductionAnti-glomerular basement membrane (anti-GBM) disease is a small vessel vasculitis affecting the renal and lung capillary beds. We aim to study the clinicopathological characteristics and predictors of poor outcome of this disease in our population.Materials and methodsThis is a 15 year retrospective, single center observational study of Indian cohort. Patients with biopsy proven anti-GBM disease were studied.ResultsAnti-GBM disease was found in 0.5% of the total cases. The mean age at presentation was 46.7 years. Compared to renal limited disease those with pulmonary-renal syndrome had a higher frequency of hypertension, oliguria, percentage of crescents, interstitial inflammation and glomerulosclerosis. Double positive (anti-GBM and ANCA antibodies) patients showed more of glomerulosclerosis, tubular atrophy/interstitial fibrosis (IFTA) as well as periglomerular granulomas on biopsy. Patient survival at one year was 40.4% and death censored renal survival was 9.7%. Factors affecting the dialysis dependency at presentation were oligoanuria (p = .04), creatinine levels >5.7 mg/dl (p = .003), and high mean anti-GBM titers (p = .008). Atypical cases accounted for 8.3% of these patients. Oligoanuria (HR = 5.0, p = .05), high serum creatinine (HR = 1.55, p = .05), severe glomerulosclerosis (HR = 1.09, p = .03), and IFTA (HR = 2, p = .04) were associated with poor renal outcome. Advanced age (HR = 1.92, p = .03), high serum creatinine (HR = 1.9, p = .04) and high anti-GBM titers (HR = 1.01, p = .03) were associated with poor patient survival.ConclusionsAnti-GBM is a rare disease with poor prognosis and varied presentations. Patients with pulmonary-renal syndrome showed severe disease whereas double positive had more of chronic changes. The predictors of poor prognosis include advanced age, oliguria, serum anti-GBM levels, serum creatinine levels, degree of glomerulosclerosis and IFTA. Atypical anti-GBM cases should be kept in mind while evaluating renal biopsies.     

Incidence and outcome of antiglomerular basement membrane disease in Chinese

Background: Antiglomerular basement membrane (anti‐GBM) disease is an uncommon disease, especially among Asian population. Many reports and studies on this condition in the Caucasian population are available, but little information exists on anti‐GBM disease in Asians. To study the incidence and clinical characteristics of anti‐GBM disease among Chinese patients, we reviewed our experience of anti‐GBM disease in our hospital (Queen Mary Hospital, Hong Kong) from 1992 to 2003. Methods: All patients who were admitted for acute renal impairment, which was caused by crescentic glomerulonephritis associated with linear immunoglobulin G (IgG) staining on immunofluorescence, were included in the analysis. Serum anti‐GBM antibodies were detected by either enzyme‐linked immunofluorescence or indirect immunofluorescence. Ten patients were treated for anti‐GBM disease during this 11‐year period, yielding an incidence of approximately 0.6 cases per million population per year. Results: In this cohort, anti‐GBM disease predominantly affected older patients (mean age: 58.6 ± 21.7 years). Eight patients were aged between 60 and 80 years and there was a female preponderance (M:F = 2:8). The 1‐year renal and patient survival was 15% (95% CI 0–40%) and 70% (95% CI 42–98%), respectively. Most patients presented with non‐specific symptoms as well as impaired renal function. Detection of anti‐GBM antibody provided a good screening test for the disease. Antiglomerular basement membrane antibodies were not detected in two patients. All but two patients received steroid, cyclophosphamide and intensive plasmapheresis therapy. Haemoptysis occurred in four patients (40%), and usually lagged behind the renal presentation and commencement of treatment. Six patients required long‐term dialysis after the acute disease. Three patients died from the disease, two died from pulmonary complications and one died suddenly after a partial recovery of renal function. Conclusion: Antiglomerular basement membrane disease is uncommon among the Chinese population. It predominantly affects older patients, and prognosis is poor. Long‐term preservation of renal function after the initial attack is unusual.     

Increased urinary catecholamines in a hypertensive child with renal artery stenosis

We report a hypertensive child with renal artery stenosis who exhibited increased urinary excretion of norepinephrine (NE) and normetanephrine (NMN), while vanillylmandelic acid (VMA) excretion was within the normal range. The NMN values prompted us to investigate the patient for pheochromocytoma; for this purpose, NE was determined by plasma catecholamine assays in venous samples obtained by catheterization. The moderately increased NE levels could not be localized to any particular sampling site. Arteriography demonstrated right renal artery abnormalities. Following right nephrectomy with preservation of the right adrenal gland, arterial blood pressure returned to normal. The cause of increased NMN excretion without a concomitant rise in VMA during hypertension is discussed. Received May 23, 1995; received in revised form and accepted February 6, 1996     

Anti-glomerular basement membrane antibody disease: a case report and a review of Japanese patients with and without alveolar hemorrhage

A 73-year-old man was admitted to our hospital because he had developed loss of appetite, abnormal behaviors, and consciousness disturbances that had begun in late February 1998. On admission, a renal biopsy was performed because of progressive deterioration of renal function, as evidenced by a serum urea nitrogen (UN) level of 109 mg/dl and a serum creatinine level of 16.3 mg/dl. Light microscopic examination showed severe cellular crescent formation with fibrin deposition in glomeruli and markedly degenerated Bowman's capsule. Immunofluorescence examination revealed linear deposits of IgG along glomerular basement membranes (GBM), and granular deposits of C3 on the GBM, as well as deposits of fibrinogen in Bowman's capsule. The patient was diagnosed as having anti-GBM antibody disease, based on negative results for myeloperoxidase (MPO)/proteinase-3 (PR-3)-anti-neutrophil cytoplasmic antibody (ANCA), high serum anti-GBM antibody titers, and the absence of pulmonary hemorrhage. He was treated with both combination therapy (cyclophosphamide and prednisolone) and plasmapheresis. In spite of the disappearance of anti-GBM antibody, his renal function did not improve, and he has been treated with regular hemodialysis since March 1998. We reviewed 49 cases of anti-GBM antibody disease in patients with alveolar hemorrhage (group A; Goodpasture's syndrome) and 39 cases in patients without it (group B) reported in Japan from 1975 to 1999, examining the differences between these groups, and we clarified the characteristics of these rare diseases in Japan. There was no difference in age, sex, and ANCA positivity between the two groups. The mortality rate was higher in group A (56.2%) than in group B (18.4%). About half of the patients underwent plasmapheresis, but it did not reduce the mortality rate or improve the renal prognosis. Received: November 20, 2000 / Accepted: November 19, 2001     

Anti-glomerular basement membrane antibody disease in Japan: part of the nationwide rapidly progressive glomerulonephritis survey in Japan

Anti-glomerular basement membrane (anti-GBM) antibody disease is a rare, but well characterized cause of glomerulonephritis. It is defined by the presence of autoantibodies directed at specific antigenic targets within the glomerular basement membrane. This pattern of rapidly progressive glomerulonephritis and alveolar hemorrhage is often referred to as Goodpasture’s syndrome. The prognosis for patients with anti-GBM antibody disease is poor. In Japan, to improve the prognosis of patients with rapidly progressive glomerulonephritis (RPGN), we conducted a nationwide survey of patients with RPGN and investigated the initial symptoms, laboratory findings including renal biopsy findings, treatment methods, and outcomes. Among patients with RPGN, patients with anti-GBM antibody disease were rare: 6.6% (47/715). Alveolar hemorrhage (Goodpasture’s syndrome) was observed in 23.4% of patients with anti-GBM antibody disease. Most patients with anti-GBM antibody disease had renal failure at the time of diagnosis. The mean serum creatinine level of patients with renal-limited anti-GBM antibody disease was 7.07 ± 4.21 mg/dl and that of patients with Goodpasture’s syndrome was 7.99 ± 4.31 mg/dl. The mean level of crescent formation was 78.99 ± 23.54% in patients with anti-GBM antibody disease, and a cellular crescent form was observed in 63.2% of those patients. The prognosis for patients with anti-GBM antibody disease is poor; the renal survival rate at 6 months after onset was 20.9%, and the mortality at 6 months after onset was 23.3%. To improve the prognosis for anti-GBM antibody disease, it may be necessary to detect this disease in the early stages and to treat it without delay. Presented at the 36th Eastern Regional Meeting of the Japanese Society of Nephrology.     

IgA nephropathy and thin basement membrane disease in association with Crohn disease

  There have been a wide variety of reported renal parenchymal diseases associated with inflammatory bowel disease, ranging from interstitial nephritis to amyloidosis to immune complex glomerulonephritis. Two pediatric cases of renal parenchymal pathology in association with Crohn disease are presented. The first is an 11-year-old child who presented with recurrent bouts of gross hematuria, biopsy-proven IgA nephropathy, and later developed Crohn disease 4 years after the initial presentation. Her renal function is normal with persistent isolated microscopic hematuria. The second case is that of a 9-year-old male who presented with the classic gastrointestinal manifestations of Crohn disease, later developed hematuria and proteinuria, and was found on a renal biopsy to have thin basement membrane disease. There have been several reported cases of IgA nephropathy associated with inflammatory bowel disease; but to our knowledge, this is the first case of thin basement membrane disease occurring in conjunction with Crohn disease. Discussion focuses on the relationship of IgA nephropathy with inflammatory bowel disease with additional comments on thin basement membrane disease. Received December 4, 1996; received in revised form and accepted March 11, 1997     

Absence of α6(IV) collagen in kidney and skin of X-linked Alport syndrome patients

Ab stract. To identify the abnormalities of the type IV collagen α6 chain, α6(IV), in Alport syndrome, we examined renal and skin tissue using rat monoclonal antibodies against non-consensus amino acid sequences of α6(IV). Immunofluorescence of normal human kidney and skin tissue revealed linear α6(IV) staining in the basement membrane (BM) of Bowman’s capsule, in some tubules, and also in the epidermal BM. Renal specimens from five male patients of four families with X-linked Alport syndrome showed no reactivity for α6(IV) in Bowman’s capsules and tubules. In these patients, α1(IV) and α2(IV) were normal, whereas α3(IV), α4(IV), and α5(IV) were absent from the BMs of the kidney. In skin tissue of male patients, neither α5(IV) nor α6(IV) were detected. The epidermal BM of female heterozygotes with X-linked Alport syndrome showed a mosaic staining for α5(IV) and α6(IV). These findings indicate that, in addition to a disturbed α3(IV)-α4(IV)-α5(IV) network, patients with X-linked Alport syndrome have abnormalities in α6(IV) of the renal and epidermal BMs at the protein level. Received October 6, 1995; received in revised form April 25, 1996; accepted April 29, 1996     

Glycosaminoglycans,proteins, and stone formation: adult themes and child’s play

The relative infrequency of renal stones in children is probably the main reason for the paucity of literature devoted to the study of urolithiasis in pediatric patients. Nonetheless, when pediatricians do address the issue, the contents of their papers reflect those prevalent in the adult literature; with one notable exception. Papers dealing with the potential role of urinary macromolecules in pediatric stone disease are very scarce indeed; to my knowledge, only four have been published in the English literature in the last 15 years. One of these is to be found in this issue and, like the remaining three, it compares the urinary excretion of glycosaminoglycans in healthy children and those with stones. This article briefly reviews the history of the association of urinary macromolecules, particularly glycosaminoglycans and proteins, with calcium oxalate urolithiasis, and discusses in more detail the published experimental evidence for their fulfilling a determinant role in stone formation. Received May 16, 1996; accepted May 28, 1996     

Morphometric study of glomerular basement membrane and proximal tubular basement membrane in adult thin basement membrane disease

Background. Thin basement membrane disease (TBMD) is a benign hereditary glomerulopathy with a diffuse attenuation of glomerular basement membrane (GBM). Whether the development of renal basement membranes other than GBM is normal in TBMD has not yet been resolved. Methods. We performed a morphometric study to measure the thickness of GBM and proximal tubular basement membrane (P-TBM) in 44 adult patients with TBMD and in 10 adult diseased controls confirmed to have minor glomerular abnormalities. Results. There was a significant difference between the patients with TBMD and the diseased controls in the thickness of the GBM; however, there was no significant difference between the two groups in the thickness of the P-TBM. In the patients with TBMD, the thickness of the GBM was unchanged with age, but the thickness of the P-TBM increased with age, as did that in the diseased controls. Conclusion. Our morphometric study clarified that the development of P-TBM was normal in the patients with TBMD. Received: October 7, 1998 / Accepted: May 27, 1999     

Anti-glomerular basement membrane disease mediated by IgG and IgA: a case report

BackgroundAnti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune condition responsible for rapidly progressive glomerulonephritis. This disease is usually mediated by IgG autoantibodies against the noncollagenous domain of the α3(IV) collagen chain. In rare cases, IgA or IgM anti-GBM antibodies are involved. This raises the question of whether there are different types of antibody-mediated anti-GBM disease at the same time.Case reportA 37-year-old woman with anti-GBM disease mediated by IgG and IgA. The patient developed rapidly progressive glomerulonephritis with nephrotic syndrome. Indirect immunofluorescence analysis indicated the presence of IgG and IgA antibodies reactive with a basement membrane component, identified by enzyme-linked immunoadsorbent assay and Western blotting as the α3(IV) collagen chain. After plasmapheresis and immunotherapy (steroids and cyclophosphamide), much improved the massive proteinuria and renal function. Follow up to date, she had normal renal function without proteinuria.ConclusionsThis is the first case report of anti-GBM disease mediated by IgG and IgA. If the clinical presentation and histopathological findings are suggestive of atypical anti-GBM disease, alternative laboratory tests such as Western blotting analysis can be used to confirm the diagnosis.     

Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays.

BACKGROUND: The role of anti-glomerular basement membrane (GBM) antibodies in the pathogenesis of Goodpasture syndrome (GPS) is firmly established. Untreated, the disease may follow a fulminating course. Early identification of patients has important implications in terms of management and prognosis. Therefore, a diagnostic test for the determination of circulating anti-GBM antibodies, of very high sensitivity and specificity, is necessary. A number of assays, using different antigenic substrates, are available, but studies comparing the 'performances' of the different tests are scarce. METHODS: The aim of our work was to evaluate the sensitivity and specificity of four immunoassay-based anti-GBM antibodies kits. Thirty-four serum samples from 19 GPS patients, 41 pathological and 28 normal controls were studied retrospectively (the follow-up samples were not included in the analysis of performance data). Cut-off limits were derived from receiver operating characteristics curve analysis. RESULTS: All the assays showed a comparable good sensitivity (between 94.7 and 100.0%), whereas specificity varied considerably (from 90.9 to 100.0%). The better performance in terms of sensitivity/specificity was achieved by a fluorescence immunoassay which utilizes a recombinant antigen. CONCLUSION: All the assays have a good performance, with high sensitivity; however, the specificity may vary considerably.     

Prolonged local infusion of streptokinase in pulmonary artery thrombosis with nephrotic syndrome

A child with nephrotic syndrome presenting with right heart failure and severe pulmonary hypertension due to pulmonary artery thrombus was treated with locally administered streptokinase infusion. Streptokinase infusion was continued for 8 days, eventually leading to complete dissolution of thrombus. Received September 19, 1995; received in revised form and accepted July 10, 1996     

Bartter syndrome in Costa Rica: a description of 20 cases

Bartter syndrome involves an overlapping set of closely related renal tubular disorders which can be subdivided into at least three clinical phenotypes: (1) classic Bartter syndrome (2) Gitelman syndrome, and (3) a neonatal variant of Bartter syndrome. In contrast to classic Bartter syndrome and Gitelman syndrome, the neonatal variant of Bartter syndrome has both the features of renal tubular hypokalemic alkalosis as well as profound systemic manifestations. Specifically, neonatal Bartter syndrome is characterized by intrauterine polyhydramnios, premature delivery, and life-threatening episodes of fever and dehydration. Most of these infants also have severe hypercalciuria with associated nephrocalcinosis and osteopenia. Over a 22-year period, 20 Costa Rican patients with a congenital syndrome that resembles neonatal Bartter syndrome have been identified and characterized. While these patients exhibit some of the clinical characteristics previously described for neonatal Bartter syndrome, this cohort also has a set of distinct features. They are predominantly female, have a later age of diagnosis, manifest a relatively unique set of physical traits, and appear to have milder clinical disease. Given these differences, it will be important to apply the emerging molecular tools to determine whether the phenotypic variability indicates genetic heterogeneity in neonatal-onset Bartter syndrome. Received July 1, 1996; received in revised form and accepted October 17, 1996     

The uretero-vesical jet as a functional diagnostic tool in childhood hydronephrosis

 Childhood hydronephrosis (HN) is accurately detected by ultrasound (US), but its functional work-up remains a domain of scintigraphy, the Whitaker-test, and clinical follow-up. We utilized color doppler US (CD-Jet) of uretero-vesical jets (UVJ) to visualize the postobstructive ureteral flow in childhood HN. A total of 177 standardized CD-Jet were performed in 132 children aged 1 day to 14.9 years. Sixty-nine investigations in 43 patients with unilateral HN were compared with a standardized technetium 99m-mercaptotriacetylglycine nephrogram; in 10 infants both procedures were performed consecutively on the same day. UVJ were visible in 96% of all investigations. Ureteral obstruction resulted in absence of UVJ in 85% of examinations; in the remaining 15% the jet frequency was less than 10% observed in the contralateral control. Results are highly significant in both uretero-pelvic (P<0.00007) and uretero-vesical lesions (P<0.00005, Wilcoxon test) and are reproducible in sequential investigations. In nonobstructive distal HN the jet frequency averaged 70% of the unaffected side (P<0.05). In proximal lesions it is equal. Jet evaluation in reflux nephropathy did not differ from controls. Compared with scintigraphy, CD-US identifies obstruction with a specificity of 94.2% and sensitivity of 94.8%. CD-US of UVJ therefore may serve as a reliable screening parameter in unilateral childhood HN. Received June 10, 1996; received in revised form October 8, 1996; accepted October 18, 1996     

Abnormal expression of glomerular basement membrane laminins in membranous glomerulonephritis.

BACKGROUND: Proteinuria associated with glomerular diseases is secondary to alterations of the charge-selective and/or size-selective properties of the glomerular basement membrane (GBM), but molecular alterations that are responsible for these functional changes are still poorly understood. Analysis of mice harbouring a null mutation in the gene encoding the beta 2 chain of laminin has suggested that the presence of abnormal laminin chains within the GBM can be responsible for proteinuria. METHODS: We have investigated whether abnormal laminin ss chains could be detected by immunohistochemistry within the GBM of patients with proteinuria and minimal change disease (five patients), focal and segmental glomerulosclerosis (five patients), or primary membranous glomerulonephritis (10 patients). Three patients with mesangiocapillary glomerulonephritis and three patients with IgA nephropathy were also studied as controls. RESULTS: We showed that the GBM of all 10 patients with membranous glomerulonephritis, but not of patients with other glomerulopathies, contained laminin beta 1, which is normally expressed only during metanephros development. The re-expression of the beta 1 chain of laminin was not associated with that of the embryonic alpha 1 chain of type IV collagen, or with the loss of expression of vimentin and synaptopodin, two markers of differentiated podocytes. CONCLUSIONS: The presence of new laminin isoforms within the GBM of patients with membranous glomerulonephritis could play a role in the occurrence of proteinuria, by modifying either the sieving properties of the GBM or the interactions between podocytes and the GBM.     

Distribution of α-integrin subunits in fetal polycystic kidney diseases

An alteration in cell/matrix interactions is one of the suggested mechanisms leading to cyst formation in polycystic kidney diseases. Most of these interactions are mediated by β1-integrins, a subfamily of integrin receptors, formed by the association of the β1-chain with different α-subunits. To date, no study on α-integrin subunit distribution during the early stages of cyst development has been reported. Using immunofluorescence, we analyzed the distribution of α-integrin subunits (α1, α2, α3, α5, and α6) and basement membrane proteins in kidneys of fetuses with autosomal dominant (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The distribution was compared with that observed in normal fetal and post-natal kidneys, and in fetal cystic dysplasia and Meckel syndrome. Marked increase in α1-integrin staining was observed in normal and cystic collecting duct cells of both polycystic diseases (PKD), compared with normal and cystic controls. The distribution of integrin subunits α2, α3, and α6 was irregular in cyst epithelial cells of PKD and cystic controls. The increased expression of the α1-subunit specifically observed in PKD collecting duct cells may be an early consequence of the genetic defect in ARPKD. In ADPKD it parallels the reported expression of polycystin, the protein product of PKD1. The irregular expression of α2, α3, and α6 integrin subunits observed in all types of cysts suggests that cell/matrix interactions are altered early and may participate in the development of cysts, perhaps by contributing to the deregulation of cell survival in cystic diseases. Received May 28, 1996; received in revised form October 2, 1996; accepted October 25, 1996     

Excess prevalence of non diabetic renal disease in native American children in Manitoba

We undertook a 1-year prospective point prevalence study to test the hypothesis that there is an excess of non-diabetic renal disease in native American children; 29.6% (73/247) of the population attending the only regional pediatric nephrology clinic in 1993 were native compared with 8.2% of the Manitoba population in this age group (odds ratio = 4.4, P<0.001). Patients were classified as low risk (normal renal function, no deterioration expected), high risk (normal renal function, deterioration probable), or established chronic renal failure (creatinine clearance chronically low or post renal transplant). Patients were further classified as suffering from congenital renal anomalies, genetic or metabolic disease, or acquired renal disease. Odds ratios were calculated based on data from the Aboriginal Peoples’ Population Survey and Statistics Canada census data. The odds ratios for low-risk renal disease, high-risk renal disease, and chronic renal failure were 3.8, 5.6, and 6.3, respectively (P<0.001 in all categories). The odds ratios for congenital, genetic, or acquired disease were 4.5 (P<0.001), 0.9 (P = ns), and 6.1 (P<0.001), respectively. Native American children in Manitoba demonstrate increased prevalence of serious congenital and acquired renal disease. These children are also more likely to live in medically underserviced communities, long distances from tertiary care centers. This study emphasizes the importance of considering factors other than diabetes mellitus when considering the problem of renal disease in native Americans. Received November 17, 1995; received in revised form and accepted March 19, 1996     

Chronic anemia as a complication of parvovirus B19 infection in a pediatric kidney transplant patient

. This is a report of unexplained anemia that persisted for 4 months in an adolescent renal transplant patient receiving immunosuppression that included prednisone, tacrolimus, and mycophenolate mofetil. This patient required monthly blood transfusions for fatigue, palpitations, and hematocrit levels between 15% and 17%. In addition, his posttransplant course was notable for the development of insulin-dependent diabetes mellitus. While receiving low-dose prednisone, he was switched from tacrolimus to cyclosporin and tapered off insulin injections over the next 2 months. At 4.5 months post-transplantation, further diagnostic evaluation was suggestive of parvovirus B19 infection as the cause for our patient’s chronic anemia. After testing negative for serum-specific parvovirus B19 IgM and IgG antibodies, parvovirus B19 infection was detected in blood by the polymerase chain reaction. Treatment with intravenous immunoglobulin (1 g/kg per day × 2 days) resulted in normalization of both his reticulocyte count and hematocrit within 6 weeks. At 4 months after receiving the immunoglobulin infusion, he has maintained a normal hematocrit level and stable renal function without requiring further blood transfusions. Received August 23, 1996; received in revised form and accepted November 20, 1996