Membranoproliferative Glomerulonephritis and Persistent Hypocomplementaemia

The clinical, laboratory, and histological findings of 50 patients with membranoproliferative glomerulonephritis are described. Three-quarters of the patients, who were mostly older children and young adults, presented clinically with a mixture of “nephritic” and “nephrotic” symptoms; the remaining quarter had no symptoms and were diagnosed after the discovery of proteinuria and microscopic haematuria.Though this clinical picture may occur in other forms of glomerulonephritis, the patients described here were unified as a group by their glomerular morphological appearance—namely, a combination of mesangial proliferation and capillary wall thickening, mainly due to subendothelial accumulations of mesangial matrix.In 68% serum C3 (β10-globulin) levels were reduced initially, while a further 16% subsequently showed a fall to abnormally low levels. All patients had substantial proteinuria, usually of moderately impaired selectivity, and all but one had haematuria in addition. Children frequently presented with an illness resembling acute nephritis, whereas adults usually had a nephrotic syndrome from the start.In 31 patients, followed for periods of one to eight and a half years, serial measurements of glomerular filtration rate were made. Sixteen have experienced no deterioration of renal function, though their proteinuria continues unchanged. Fifteen have shown progressive deterioration; six of them are still well, six are on regular dialysis treatment, and three have died. Treatment with corticosteroids, azathioprine, or cyclophosphamide, alone or in combination, did not seem to influence the course of the disease, and another two patients died from complications of steroid therapy. The disease usually runs a chronic course and appears to be progressive.     

Cyclophosphamide Therapy in the Nephrotic Syndrome in Childhood

Forty-six children with the nephrotic syndrome whose renal biopsy specimens showed minimal changes and whose response to corticosteroid therapy was unsatisfactory were treated with cyclophosphamide. Three patients were completely steroid-resistant from the outset and the remainder were steroid-dependent. In several patients steroids controlled the condition less effectively with time. Most patients showed signs of steroid toxicity, and growth retardation was striking.A moderate leucopenia was induced with cyclophosphamide, and treatment was maintained for three to four months in the majority of cases. Thirty-eight children (83%) have remained in complete remission off all treatment for periods of 3 to 23 months, 33 after one course of cyclophosphamide and five after a second course. Two other patients who remitted but relapsed later are still on treatment. In only six patients was full remission not obtained, and three of these were steroid-resistant from the start. Two died from pneumonia and adrenal failure and four continued to have proteinuria, though in one an impressive reduction occurred.The results indicate that cyclophosphamide therapy is an effective alternative for nephrotic children with normal glomeruli on light microscopy who develop steroid dependence or resistance, and who exhibit toxic effects of steroid therapy.     

The Spectrum of Kidney Pathology in B-Cell Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma: A 25-Year Multicenter Experience

Background

Chronic lymphocytic leukemia and small lymphocytic lymphoma are 2 different presentations of the most common B-cell neoplasm in western countries (CLL/SLL). In this disease, kidney involvement is usually silent, and is rarely reported in the literature. This study provides a clinicopathological analysis of all-cause kidney disease in CLL/SLL patients.

Methods

Fifteen CLL/SLL patients with kidney biopsy were identified retrospectively. Demographic, clinical, pathological and laboratory data were assessed at biopsy, and during follow-up.

Results

At biopsy 11 patients presented impaired renal function, 7 patients nephrotic syndrome, 6 patients dysproteinemia, and 3 patients cryoglobulinemia. Kidney pathology revealed CLL/SLL-specific monoclonal infiltrate in 10 biopsies, glomerulopathy in 9 biopsies (5 membranoproliferative glomerulonephritis, 2 minimal change disease, 1 glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits, 1 AHL amyloidosis). Five patients presented interstitial granulomas attributed to CLL/SLL. After treatment of the hematological disease, improvement of renal function was observed in 7/11 patients, and remission of nephrotic syndrome in 5/7 patients. During follow-up, aggravation of the kidney disease systematically occurred in the absence of favorable response to hematological treatment.

Conclusions

A broad spectrum of kidney diseases is associated with CLL/SLL. In this setting, kidney biopsy can provide important information for diagnosis and therapeutic guidance.     

Value of urine microscopy in predicting histological changes in the kidney: double blind comparison.

Fresh, first morning specimens of urine from 22 consecutive patients were examined by quantitative microscopy on the morning of renal biopsy; the renal biopsy samples were evaluated "blindly." Five patients showed no abnormality in the biopsy samples but eight had minimal, one mild, six moderate, and two severe histological changes. Comparison of the results of quantitative microscopy of urine with the presence or absence of histological evidence of disease showed that sensitivity was 88%, specificity 83%, accuracy 86%, positive predictive value 93%, and negative predictive value 71%. When combined with microscopy of a second urine specimen these values were 100%, 50%, 87%, 85%, and 100% respectively. There was a significant relation between number of casts and severity of the histological changes (p less than 0.01). Comparison of renal functional abnormalities with histological findings gave values of 64%, 100%, 73%, 100%, and 50% respectively. It is concluded that quantitative microscopy of the first morning specimen of urine is a sensitive test with high predictive value for the presence or absence of renal disease. If no casts are detected in two early morning specimens the likelihood of finding anything more than minimal changes in a biopsy sample is virtually zero.     

Nephrotic Syndrome Due to Primary Renal Disease in Adults: II. A Controlled Trial of Prednisolone and Azathioprine

A controlled trial in 20 adult patients with the nephrotic syndrome due to proliferative glomerulonephritis compared the effects of consecutive eight-week courses of treatment with prednisolone in conventional dosage and a low-dose azathioprine–prednisolone combination. Though the azathioprine regimen avoided serious toxicity and produced a statistically significant improvement in creatinine clearance and urine protein excretion, the results were not significantly better than with prednisolone itself and overall were not of great clinical value. Prolongation of the azathioprine–prednisolone treatment to one year was associated with some small improvement in the results.The effectiveness of prednisolone in the nephritic syndrome of adults with minimal renal histological abnormality was confirmed by a complete loss of proteinuria within eight weeks in six out of eight patients and substantial reduction in the other two. These two patients subsequently received azathioprine as well but with equivocal results.     

Renal disease,epidermal necrosis,and epithelial cell antibodies.

OBJECTIVE--To describe the association between epithelial cell IgM, which has previously been associated with an increased incidence of loss of renal graft in children, with a novel cutaneous eruption and unexplained native renal disease. DESIGN--Observational study on children with epithelial cell antibody presenting with unexplained renal or skin disease. SETTING--General paediatric department and regional paediatric nephrology unit. PATIENTS--Six children (five girls, one boy), who presented to the unit in 1989-90. RESULTS--Three children, two of whom had a history of a hyperpigmented rash, presented with hypertension, proteinuria, and impaired renal function. Renal biopsy specimens from two of these children showed severe arteriolar endothelial cell swelling with arteriolar occlusion. These children fully recovered after treatment with antihypertensive drugs. The third child developed end stage renal failure and required dialysis. Three other children presented with an unusual cutaneous eruption but no evidence of renal disease. Histology of the skin lesions showed acute epidermal necrosis and features consistent with a viral infection. CONCLUSIONS--The aetiology and pathogenesis of the epithelial cell antibody are unknown. These cases indicate that it may have a role in native kidney disease and focal epidermal necrosis. Clinical and histological features suggest that the antibody may be associated with a viral infection.     

Nephrotic Syndrome with Heart Disease: A Reappraisal

The evidence that heart failure alone may cause a nephrotic syndrome is inconclusive. Mercurial diuretics, which have also been implicated as a cause of the nephrotic syndrome, had been given in 23 of the 24 well-documented cases.Two cases of heart disease and nephrotic syndrome are described. Glomerular lesions were minimal on light microscopy, but thickening of the glomerular tuft basement membrane and partial fusion of the epithelial cell foot processes were apparent on elecronmicroscopy. The response to prednisone was such as to justify a trial of corticosteroid therapy in such cases despite the presence of cardiac disease.     

Nephrotic Syndrome Due to Primary Renal Disease in Adults: I. Survey of Incidence in South-east England

In a prospective survey of the nephritic syndrome due to primary renal disease in adult patients in the South-east Metropolitan Region of England 50 patients were seen in a two-year period—a minimum annual incidence of 9·0 new cases per million adult population. The frequency distribution of the three main histological groups was “minimal change” 30%, membranous nephropathy 12%, and proliferative glomerulonephritis 58%. The higher proportion of patients with minimal histological change compared with that found in most previously published series may be explained by the avoidance of selection of patients for inclusion. The much lower incidence of membranous nephropathy probably reflects the use of stricter histological criteria for this diagnosis.     

Hypertension,Asymmetric Renal Parenchymal Defect,Sterile Urine,and High E. coli Antibody Titre

During an 11-year period four children were seen with asymmetric renal parenchymal reduction, arterial hypertension, and sterile urine. The history and radio-logical or histological findings, or both, were consistent with “abacterial pyelonephritis” induced by bacterial infection in early childhood. All four had raised antibody titres to Escherichia coli. Three possibilities may explain the high antibody titres and insidious course of the renal damage—the presence of bacterial variants or amorphous bacterial antigen in the kidneys or the fact that because of cross-reactivity between certain E. coli O antigens and renal tissue the “E. coli antibodies” were, in fact, autoantibodies.     

Protective effects of mesenchymal stromal cells on adriamycin-induced minimal change nephrotic syndrome in rats and possible mechanisms

Background aimsMinimal change nephrotic syndrome is the most frequent cause of nephrotic syndrome in childhood. Current treatment regimes, which include glucocorticoid hormones and immunosuppressive therapy, are effective and have fast response. However, because of the side effects, long treatment course, poor patient compliance and relapse, novel approaches for the disease are highly desired.MethodsThe adriamycin-induced nephrotic rat model was established. Rats were allocated to a model group, a prednisone group or mesenchymal stromal cell (MSC) group. Clinical parameters in each treatment group were determined at 2 weeks, 4 weeks and 8 weeks. The messenger RNA (mRNA) levels of synaptopodin, p21 and monocyte chemoattractant protein-1 were determined through the use of quantitative real-time–polymerase chain reaction. Protein levels were determined by means of Western blot or enzyme-linked immunosorbent assay. Podocytes were isolated and apoptotic rate after adriamycin with or without MSC treatment was analyzed by means of flow cytometry.ResultsMSC intervention improved renal function as assessed by urinary protein, blood creatinine and triglyceride levels. MSC intervention reduced adriamycin-induced renal tissue damage visualized by immunohistochemistry and light and electron microscopic analysis and reduced adriamycin-induced podocyte apoptosis. After MSC intervention, mRNA and protein levels of synaptopodin and p21 in renal cortex were significantly increased. MSCs also restored synaptopodin mRNA and protein expression in isolated podocytes. In addition, monocyte chemoattractant protein-1 mRNA in renal cortex and protein level in serum of the MSC treatment group were significantly decreased compared with that in the adriamycin-induced nephropathy model group.ConclusionsOur data indicate that MSCs could protect rats from adriamycin-induced minimal change nephrotic syndrome, and the protective effects of MSCs are mediated through multiple actions.     

Profound urinary protein loss and acute renal failure caused by cyclooxygenase-2 inhibitor

Cumulative evidence has shown that nonsteroidal anti-inflammatory drugs (NSAIDs) can induce acute renal failure and nephrotic-range proteinuria. Cyclooxygenase-2 (COX-2) inhibitors have less nephrotoxicity; however, recent data indicate that they may cause the same renal problems as NSAIDs do. Herein, we present a case of celecoxib-associated minimal change disease (MCD) with profound urinary protein loss and acute renal failure. Renal function and nephrotic syndrome in this patient resolved completely after discontinuation of celecoxib and treatment with methylprednisolone. Clinicians should keep high index of suspicions in patients developing nephrotic syndrome and acute renal failure after taking COX-2 inhibitors since secondary MCD responds well to timely cessation of COX-2 inhibitors and administration of steroid therapy.     

Histological Reassessment of Three Kidneys Originally Described by Richard Bright in 1827-36

Portions of kidney from three patients with renal disease that were originally described by Richard Bright between 1827 and 1836 have been preserved in the Gordon Museum at Guy''s Hospital. Histological study has shown that two cases fall into the current diagnostic category of mesangiocapillary (membranoproliferative) glomerulonephritis. One of these patients had a five-year clinical history and died with chronic renal failure and uraemia. The other patient died after three to four months with a severe nephrotic syndrome. The third patient was a young woman with chronic “phthisis pulmonalis” and renal amyloidosis.     

Manifestations of adaptive processes in the epithelium of the renal glomerular filter

Fifteen kidney biopsy samples+, obtained from children suffering from the primary nephrotic syndrome, characterized with a high selective proteinuria and non-inflammatory character of changes in the renal corpuscles have been investigated after hormonotherapy (11 cases before and 4 cases 2-3 weeks after it). In podocytes certain disturbances in the lysosomal-vascular apparatus develop with a successive appearance of degeneration, desquamation and even necrosis of these cells. After prednisolone++ treatment edema of cytoplasm of the cells and their processes disappears, amount and size of the filtration slits are partly restored.     

Modification of Plasma Corticosteroid Concentrations during and after Surgery by Epidural Blockade

The adrenocortical response to major surgery was assessed by the measurement of plasma corticosteroid concentrations in patients receiving either a general anaesthetic alone or in combination with an epidural block. The expected increase in plasma corticosteroid concentration seen in the general anaesthesia group was significantly inhibited by epidural block. The inhibition was related to the duration of the epidural block. The lack of the normal adrenocortical response to surgery was not associated with cardiovascular collapse and indeed did not seem detrimental in any way. These findings question the need for corticosteroid “cover” for the stress of surgery in patients who have been taking corticosteroid drugs.     

Secondary amyloidosis due to Schistosoma mansoni infection.

Four children with Schistosoma mansoni infection and the nephrotic syndrome with varying degrees of renal dysfunction were found on histological examination to have amyloidosis. In one boy who had no evidence of renal failure complete clinical regression of his nephrotic syndrome and almost complete disappearance of renal amyloid deposits followed adequate treatment of his schistosomal infection. Conditions known to cause secondary amyloidosis were excluded in all four patients. Amyloidosis in association with mansoni infection is probably more common than is currently recognised. Early treatment of the infection, before renal function becomes impaired, may result in regression of the amyloidosis.     

Standardised approach to gluten challenge in diagnosing childhood coeliac disease.

Thirty-five children, in whom coeliac disease had been diagnosed on inadequate grounds and who had been on a gluten-free diet for one to 10 years, were challenged with gluten in accordance with a standardised procedure. All children were admitted to hospital for 48 hours for general assessment, two one-hour blood xylose tests, and the introduction of gluten. Thirty children underwent a pre-challenge peroral jejunal mucosal biopsy; the specimens were either normal or showed slight non-specific abnormalities. Gluten powder 20 g/day was given in addition to an otherwise gluten-free diet. The children were reassessed as outpatients every two weeks, when a one-hour blood xylose test was performed. Repeat biopsy was performed when xylose absorption fell or after three months. Seventeen children had abnormal post-challenge biopsy appearances compatible with coeliac disease in relapse; 14 of these children completed their challenge within eight weeks. Seventeen children had completely normal biopsy appearances at the end of three months and were returned to a normal diet. One to two years later eight underwent repeat biopsies, which showed nothing abnormal. In only one child, the oldest in the series, were the histological findings equivocal. In the 17 children in whom coeliac disease was confirmed the duration of gluten challenge was not related to age, duration of gluten-free diet, histological findings on the pre-challenge biopsy, or HLA status.     

Nephrotic Syndrome in Adult Africans in Nairobi

The adult nephrotic syndrome as met with in Nairobi is predominantly encountered in young sophisticated African women, most of whom began to use skin-lightening creams containing mercury before the symptomatic onset of their illness. The particular form of mercury involved is well known to cause the nephrotic syndrome in other circumstances—for example, when applied to the skin in the treatment of psoriasis. In these circumstances the pathogenetic mechanism is thought to be of an idiosyncratic type. The use of mercury-containing skin-lightening creams in the patients studied seemed to be particularly associated with a “minimal-change” (“light-negative”) renal glomerular lesion, this lesion being present in half of the patients. The prognosis in this group of patients seems remarkably good, with 50% entering remission, 77% of these doing so spontaneously on discontinuing the use of the creams.     

Urinary fibrin-fibrinogen degradation products in nephrotic syndrome.

The urinary concentration of fibrin-fibrinogen degradation products (F.D.P.) was measured in 90 patients with proteinuria above 2 g/1 and correlated with proteinuria, differential protein clearances, serum urea and creatinine, and renal biopsy findings. There was a linear correlation (r equals 0-7; P less than 0-001) between the urinary F.D.P. excretion and the selectivity of the proteinuria such that patients with highly selective proteinuria excreted only small amounts of F.D.P. whereas those with non-selective proteinuria excreted much higher levels. There was a significant correlation between the urinary F.D.P. excretion and the urine:serum (U:S) ratio of IgG excretion but not with the U:S ratio or urinary excretion of albumin or transferrin. Sephadex G200 column chromatography of the concentrated urine in 26 cases showed that patients with highly selective proteinuria excreted predominantly F.D.P. of low molecular weight in the urine whereas those with non-selective proteinuria excreted mainly fibrinogen and products of high molecular weight. Hence the type and quantity of F.D.P. in the urine are determined primarily by the differential filtration of fibrinogen and the various degradation products from the plasma through the glomerular basement membrane, which in turn is determined by the "pore size" of the basement membrane. In clinical nephrology measurement of the urinary F.D.P. level provides a rapid and convenient means of estimating the differential protein clearance.     

Kidney Disease and Pregnancy

The course of 41 pregnancies was studied in 25 patients with renal disease. Histological classification of the disease in each patient was made by renal biopsy. The analysis suggests that the course of pregnancy in women with coexistent renal disease correlates with the underlying renal lesion and probably with the glomerular filtration rate and blood pressure. In patients with heavy proteinuria there is increased oedema formation, making the nephrotic syndrome a frequent complication.     

The central and renal hemodynamic effects of amino acid infusion in the study of renal reserve in the baboon

Normal human renal function is characterized by a large renal reserve. Recruitment of this reserve is a compensatory and pathological response to renal injury. This study was designed to assess the renal reserve and central hemodynamics of young female baboons and, in doing so, the appropriateness of the use of these animals in a model of human renal disease. Eight female baboons completed the protocol. PAH and inulin clearances were measured before and after an amino acid infusion. Central hemodynamics were measured with arterial and pulmonary artery catheters. Effective renal plasma flow and glomerular filtration rate increased by 42% after amino acid infusion (P = .025). Expansion of renal function was not consistent among individual baboons; two of the eight animals did not demonstrate renal reserve. Central hemodynamics were unaffected by the protocol.