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The range of the predictable within-day change in blood pressure, assessed as the circadian blood pressure amplitude, is greater in newborns who have been exposed in utero to betamimetics than in those not exposed. A larger circadian blood pressure amplitude is also found in infants and children with a positive versus those with a negative family history of high blood pressure. In adulthood, an excessive circadian blood pressure amplitude is associated with a 6-fold increase in risk of ischaemic stroke. To determine whether the large circadian blood pressure amplitude associated with intrauterine exposure to betamimetics in newborns persists later in life, the progeny of mothers who had had similar obstetric situations but had been treated either with spasmolytics (not including betamimetics) or with betamimetics to prevent premature labour was assessed. The blood pressure of 43 adolescents aged between 11 and 14 years was measured at 15-minute intervals for 2 days with an ambulatory monitor; an echocardiogram was also taken. A multiple regression analysis accounting for gender- and age-related changes revealed a dose-dependent effect of betamimetic exposure on the circadian blood pressure amplitude of the offspring. Exposed children also tended to have a larger left ventricular mass index. Thus, in utero exposure to betamimetic drugs may have cardiovascular effects lasting into adolescence.

A boy developed recurrent steroid-responsive nephrotic syndrome following renal transplantation for congenital nephrotic syndrome. The first episode was associated with mild tubulointerstitial rejection on kidney biopsy. Subsequent episodes showed normal histology by light microscopy and epithelial foot process fusion on electron microscopy, consistent with minimal change nephrotic syndrome. Serum analysis for soluble immune response suppressor was negative pre-nephrectomy, positive during each bout of nephrotic syndrome, and negative during each remission. This case represents de novo occurrence of steroid-sensitive minimal change nephrotic syndrome following renal transplantation for congenital nephrotic syndrome. We stress the need for histological examination of the renal allograft to diagnose rejection, recurrent disease, or de novo disease.

Chronobiologic cardiovascular screens are provided while reference standards for blood pressure and heart rate in uneventful pregnancies are collected for comparison with the nonpregnant state in health and for the evaluation of elevated risk and/or disease. Starting in the first or second timester, 66 women wore an ambulatory monitor manufactured by Colin Instruments for nearly two days. 92 such Minnesotan profiles during pregnancy are compared with profiles of 85 clinically healthy age-matched nonpregnant women. The overall range of change in a healthy pregnancy averages 58 and 40 mm Hg for systolic and diastolic blood pressure, respectively, and 47 beats per minute for heart rate. During pregnancy, the midline-estimating statistic of rhythm M (MESOR) is statistically significantly higher for heart rate and lower for blood pressure. Compared to the nonpregnant state, the circadian amplitudes of systolic and diastolic blood pressure are higher during pregnancy and are statistically significantly correlated with the questionnaire-assessed risk of developing high blood pressure and/or cardiovascular disease. >

Hemolytic uremic syndrome (HUS) consists of an acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. HUS-associated colitis can be seen in up to 100% of patients and is usually associated with severe abdominal pain and distention. Colonic perforation is a complication of HUS that has a reported incidence of 1%-2%, and although there are several case reports in the literature describing perforation of the colon, it is still very difficult to discern the abdominal symptoms associated with HUS colitis from perforation. Four cases of colonic perforation are reported here from a consecutive series of 57 patients, in which a trend in the length of time from the onset of symptoms of HUS to colonic perforation was determined. A review of the literature for cases of HUS-associated colonic perforation was also performed. The time from the onset of HUS symptoms to colonic perforation in our series was similar to that found in the literature review (11 +/- 5 vs 14 +/- 8 days). Awareness that this complication has a tendency to occur towards the end of the 2nd week during the course of HUS is essential to avoid an unnecessary and untimely surgical intervention.

Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus. Heparan sulfate proteoglycans (HSPG) are negatively charged constituents of the renal extracellular matrix including the glomerular basement membrane (GBM) and mesangial matrix. Biochemical and functional studies of patients with type-1 insulin dependent diabetes mellitus (IDDM) suggest that alterations of HSPG may occur in diabetic nephropathy. We have utilized a specific cy-tochemical method and electron microscopy to quantitate the distribution of HSPG in the GBM of 10 normal people and in 16 IDDM patients with a spectrum of clinical and structural changes. Enzyme incubation studies of normal infant kidney demonstrated that heparitinase removed 94&percnt; of the stainable anionic sites in the lamina rara externa (LRE) and 77&percnt; of the sites in the lamina rara interna (LRI) of the GBM. In contrast, incubation in the enzyme chondroitinase ABC did not reduce the number of sites in the LRE but reduced the number of sites in the LRI by 26&percnt;. The HSPG anionic sites in normal subjects were distributed in the LRE as 20.9 ± 1.3, and in the LRI as 13.1 ± 2.2 per micron GBM length. Anionic sites were slightly reduced ( 19.6 ± 1.3, P< 0.04) in the LRE of IDDM patients with normal urinary albumin excretion rates (UAE), or microalbuminuria, and were reduced in both the LRE and LRI of IDDM patients with clinical proteinuria (13.1 ± 2.3,P< 0.001 and 8.9 ± 2.1, P < 0.001, respectively). The number of anionic sites in the LRE and LRI, respectively, correlated with UAE (r = +0.78, P < 0.001, r = +0.58, P < 0.02), with GBM thickness (LRE, r = +0.81, P < 0.001; LRI, r = +0.67, P < 0.01) and with the volume fraction of mesangium (LRE, r = +0.59, P < 0.02; LRI, r = +0.58, P < 0.03). These data confirm earlier biochemical findings of a reduction of HSPG in the GBM in advanced diabetic nephropathy but do not provide evidence for the loss of HSPG in the GBM as a mechanism for early microalbuminuria.

Monoclonal antibodies to human renal basement membranes: Heterogenic and ontogenic changes. Monoclonal antibodies reactive with rensssssal basement membranes have been developed following immunization of mice, subsequent hybridization of spleen cells with the NS1 cell line, and appropriate cloning techniques. The antibody reactivity and specificity of clonal supernatants and ascites fluid were evaluated by indirect epifluorescence-phase contrast microscopy on sections of human kidney and other tissues. This permitted characterization of clones based on the immunohistochemical phenotype of the antibody in binding to anatomically defined basement membranes as well as to site-specific loci or regions within the membrane. Based upon unique immunohistochemical reactivity, nine different antibodies were developed: two reacting with known components of basement membrane by ELISA (MBM4-type IV collagen and MBM20-fibronectin) and seven failing to react with these or other defined antigens (fibronectin, laminin, or types IV and V collagen). Among the latter group, five immunohistochemical phenotypes were identified in mature human kidney: (1) MBM7 and MBM15 reacted with the lamina densa, Bowman's capsule, tubular basement membrane, and vascular walls. (2) MBM10 and MBM14 fixed in a double-linear granular pattern to each side of the tubular basement membrane and Bowman's capsule as well as within the mesangium and in vascular basement membranes but not the glomerular basement membrane (GBM). (3) MBM11 identified sites along the internal aspect of Bowman's capsule and the tubular basement membrane but not within the glomerulus. It also stained type I but not type II skeletal muscle. (4) MBM12 reacted with the full thickness of Bowman's capsule, the mesangium and stalk region, the tubular basement membrane, but not the GBM. (5) MBM21, which had the most restricted binding in tissue, identified an antigen in the tubular basement membrane of the proximal tubules. During nephron formation type IV collagen and fibronectin were redistributed from the undifferentiated mesenchyme to appear with induction within the "S" shaped anlage, in latter stages in the region of the primitive GBM, and in the mature glomerulus in the mesangium and the GBM. This pattern seen in the human kidney is similar to that described in the mouse. Changes in the distribution of antigens identified by other monoclonal antibodies were observed during ontogenesis. Eight monoclonal antibodies recognized antigens in fetal GBM, but only four of these reacted with mature GBM. Certain antibodies (MBM4, MBM10, MBM14, MBM12) had a broad range of reactivity with basement membranes in different tissues, whereas others (MBM7, MBM15, MBM11) demonstrated more limited reactivity; MBM21 was the most restrictive of all reacting only with the proximal tubular basement membrane. Specific basement membranes in different tissues shared the same antigens as evidenced by similar profiles of reactivity with various antibodies. Basement membranes in human kidney are heterogeneous with respect to constituent antigens and undergo changes during ontogenesis. These studies provide the foundation for further studies that will permit mapping and characterization of immunoreactive basement membrane components. Anticorps monoclonaux a les membranes basales renales humains: Modifications des heterogenique et ontogenique. Des anticorps monoclonaux reagissant contre des membranes basales renales ont ete developpes apres immunisation de souris, puis hybridation de cellules speniques avec la lignee cellulaire NS1, et techniques de clonage appropriees. La reactivite et la specificite des anticorps des surnageants de clonage et de liquides d'ascite ont ete evaluees par microscopie a contraste de phase avec epifluorescence indirecte sur des coupes de rein et d'autres tissus humains. Cela a permis la caracterisation de clones fondee sur le phenotype immunohistochimique des anticorps se liant aux membranes definies anatomiquement, et a la specificite de site pour certains lieux ou certaines regions de la membrane. En utilisant uniquement la reactivite immunohistochimique, neuf anticorps differents ont ete developpes: deux reagissant avec des constituants connus de la membrane basale par ELISA (MBM4-collagene de type IV et MBM20-fibronectine) et sept ne reagissant pas avec ces antigenes ou d'autres (fibronectine, laminine, ou collagene de type IV et V). Dans ce dernier groupe, cinq phenotypes immunohistochimiques ont ete identifies dans du rein humain mature: (1) MBM7 et MBM15 reagissaient avec la lamina densa, la capsule de Bowman, la membrane basale tubulaire, et les parois vasculaires. (2) MBMIO et MBM14 se fixaient avec un aspect granulaire en double contour a chaque cote de la membrane basale tubulaire et de la capsule de Bowman, ainsi que dans le mesangium et sur les membranes basales vasculaires, mais non sur la membrane basale glomerulaire (GBM). (3) MBM11a permis l'identification de sites le long de la partie interne de la capsule de Bowman et de la membrane basale tubulaire mais non dans le glomerule. Il colorait egalement le muscle squelettique de type I mais non de type II. (4) MBM12 reagissait avec la totalite de l'epaisseur de la capsule de Bowman, le mesangium et la region des tiges, la membrane basale tubulaire mais non la GBM. (5) MBM21, qui avait la liaison tissulaire la plus reduite permettait la localisation d'un antigene dans la membrane basale tubulaire des tubules proximaux. Pendant la formation nephronique, le collagene de type IV et la fibronectine etaient redistribues a partir du mesenchyme non differencie pour apparaitre lors de l'induction a l'interieur des structures en forme de "S" aux stades plus tardifs dans la region de la GBM primitive, et dans le glomerule mature, dans le mesangium et la GBM. Cet aspect vu dans le rein humain est identique a celui decrit chez la souris. Des modifications dans la distribution d'antigenes identifies par d'autres anticorps monoclonaux ont ete observees pendant l'ontogenese. Huit anticorps monoclonaux ont reconnu des antigenes dans la GBM foetale, mais seulement quatre d'entre eux ont reagi avec des GBM matures. Certains anticorps (MBM4, MBM10, MBM14, MBM12) avaient un large eventail de reactivite avec les membranes basales dans differents tissus, tandis que d'autres (MBM7, MBM15, MBM11) ont demontre une reactivite plus limitee; MBM21 etait le plus restreint de tous, reagissant seulement avec la membrane tubulaire proximale. Des membranes basales specifiques dans differents tissus partageaient les memes antigenes, comme cela ete montre par des profils de reactivites identiques avec des anticorps varies. Les membranes basales du rein humain sont heterogenes en ce qui concerne les antigenes les constituant et subissent des modifications pendant l'ontogenese. Ces etudes constituent la base pour des travaux ulterieurs qui permettront de localiser et de caracteriser definitivement biochimiquement les constituants immuno-reactifs des membranes basales.

Extramembranous glomerulonephritis is an uncommon but distinct pathologic lesion in children. The diagnosis is established by the characteristic light, immunofluorescent, and ultrastructural abnormalities in renal biopsy specimens. This report describes seven of the ten children with this lesion studied in the past 11 years. Emphasis is given to the comparison of four children with idiopathic membranous glomerulonephritis with three others who presented with a nephrotic syndrome but subsequently developed evidence of systemic lupus erythematosus. Two of the latter three children, and three others with SLE and MGN not described in detail, demonstrated deposition of IgA by immunofluorescence along glomerular capillaries. Five of six children with SLE and MGN had microtubular structures in glomerular endothelial cells demonstrable by electron microscopy. These observations suggest that children with MGN require careful and continuing study for evidence of SLE.

We analyzed the clinical course, pathologic findings, and results of aggressive medical management and renal transplantation in 41 infants with onset of nephrotic syndrome in the first 3 months of life. All but one infant with congenital onset failed to thrive and had progressive renal insufficiency; 17 were given steroids or cytotoxic drugs or both, without benefit. Severe bacterial infections occurred in 85% of the infants, pyloric stenosis in 12%, gastroesophageal reflux in 8%, and thrombotic events in 10%. All children prior to the era of renal transplantation died before 4 years of age. The last 24 infants received aggressive medical management, which allowed renal transplantation in 17. Two-year patient and graft survival rates were 82% and 71%, respectively. There was no recurrence of the nephrotic syndrome in the children who underwent transplantation. All but one surviving infants has had normal or accelerated growth, although mean height for the group is 3.1 SD below the mean. School and social performance has been normal in 80%. Thus intensive medical therapy combined with renal transplantation offers a very good opportunity for survival with an acceptable quality of life for infants with congenital nephrotic syndrome.

We examined renal-transplant tissue from 12 diabetic and 28 nondiabetic patients who had had a renal graft for at least two years. In 10 diabetic patients arteriolar hyalinosis lesions developed in the graft. In six these lesions involved both afferent and efferent limbs of glomerular arterioles - a pathological finding virtually diagnostic of diabetes mellitus. In all cases these lesions were present within five years of transplantation. Only three of the 28 nondiabetic patients had hyaline vascular changes (P less than 0.001), which occurred only in rare vessels, did not appear within the first five years after transplantation and did not involve both afferent and efferent arterioles, One diabetic patient had nodular glomerulosclerosis. Thus, the first clearly distinguishable lesion of diabetes to occur with frequency in normal kidneys transplanted into diabetic patients is arteriolar hyalinosis.

A 9-year-old body with sialidosis had nephrotic-range proteinuria. Histological studies demonstrated massive distension of renal cells, particularly glomerular visceral epithelial cells, by cytoplasmic vesicles which contained material reactive with concanavalin A and wheat-germ agglutinin. In addition, some glomeruli exhibited segmental mesangial thickening or glomerulosclerosis. Ultrastructurally, focal detachment of visceral epithelial cells from the underlying glomerular basement membrane was observed. We postulate that glomerular visceral epithelial cell dysfunction may underlie the proteinuria and focal glomerulosclerosis exhibited by this patient. Hyperfiltration, as suggested by the child's elevated creatinine clearances, may be a contributing factor.

The clinical syndrome of recurrent macroscopic hematuria, unassociated with hypertension, edema or anatomical urinary tract abnormalities, is relatively common in children and young adults. Baehr [1] in 1926 described 14 young adults with a “benign and curable form of hemorrhagic nephritis”, who appeared to be examples of this syndrome. The syndrome is characterized by recurrent episodes of hematuria which often begin at the height of an upper respiratory infection; one of the most striking clinical features of these patients. Typically, dark urine, red blood cell casts and hematuria appear the day of, or within two to three days of, the onset of the infection. Macroscopic hematuria rarely lasts longer than two to five days and is often accompanied by transient low grade ( < 1.0 g/24 hr) proteinuria. Microscopic hematuria without proteinuria usually persists between the attacks of macroscopic hematuria. Renal function is usually normal during the attacks, although an occasional patient has been described who has exhibited a transient reduction of renal function during the episode of gross hematuria. In addition to respiratory infection, a clear relationship between the onset of hematuria and strenuous exercise has been emphasized by several reports [2–3]. In spite of multiple attacks of hematuria, renal failure has been rarely observed in the reported series followed three to five years; hence, the terms “benign” and “asymptomatic” have often been applied to these patients.Because of the association of the presenting sign, hematuria, with upper respiratory infection, numerous reports have focused upon the bacterial flora of the upper respiratory tract in these patients during the attacks. Although throat cultures and/or serologic evidence for recent infection with beta-hemolytic streptococci have been found in 30 to 40% of hospitalized children in some studies [3], this incidence of presumed streptococcal infection closely approximates the average experience in hospitalized children, and no clear evidence of a regular relationship between streptococcal or other infectious agent(s) has been documented. It seems likely that the syndrome is the result of a variety of etiologic factors operating through a common pathogenetic mechanism [4].An additional important characteristic of patients with recurrent hematuria is the rather consistently normal value of serum complement [4–6]. Since complement concentrations are low in the majority of patients with acute poststreptococcal glomerulonephritis, normal sequential complement concentrations are of great value in reducing the likelihood of that diagnosis, especially in the patient with a positive throat culture for beta-hemolytic streptococci and the recurrent hematuria syndrome.Several reports describe an incidence of recurrent macroscopic hematuria in other family members and relatives of patients with this syndrome [3, 7, 8]. Although familial nephritis, such as Alport's syndrome, is usually recognizable by virtue of a history of overt nephritic manifestations and/or deafness in relatives, this important differential diagnostic problem must always be considered in patients with symptomless hematuria.

Forty-nine patients with systemic lupus erythematosus (SLE) during childhood and adolescence presenting over a period of 17 years were followed during treatment with prednisone and azathioprine. The average period of follow-up was 5.7 years. Detailed analyses of clinical parameters of renal function and sequential changes in glomerular abnormalities by percutaneous renal biopsy are reported. Therapy was directed towards normalizing the results of urinalysis and renal function, eliminating proteinuria and maintaining normal serology (normal serum complement and negative antiDNA titers). The 10 year survival of the entire group was 86 per cent. A survival of 73 per cent and 87 per cent over this interval in patients with diffuse and focal proliferative lupus nephritis, respectively, was achieved. The major cause of mortality in this series was infection. It appears that intensive observation and monitoring of serologic parameters in SLE, along with aggressive steroid and immunosuppressive therapy, lead to a prognosis in SLE more favorable than previously reported.

We describe two patients with a unique granulomatous syndrome who presented with renal failure secondary to diffuse eosinophilic interstitial nephritis. Both had bilateral anterior uveltis, bone marrow granulomas, hypergammaglobulinemia and an increased sedimentation rate. One patient had lymph node granulomas and an immunoglobulin G (IgG) rheumatoid factor. An extensive investigation for an etiologic agent was unrewarding, and neither patient could be placed into any existing diagnostic category. Over a period of 2 years both patients have experienced improved renal function and dissolution of their bone marrow granulomas

This article reviews the development of the normal kidney, the cystic kidney diseases, and recent experimental observations that may provide improved understanding of the clinical problem.

Herein we report a new familial form of hepatic disease. Each of the four patients had splenomegaly, hypersplenism, a small liver, biochemical evidence of hepatic excretory dysfunction and hepatocellular damage, kidneys without demonstrable cysts, and normal blood pressure. An evaluation of serum immunoproteins, autoantibodies, histocompatibility antigens, and mixed lymphocyte reactivity further defined the immunologic features of this syndrome. Extrahepatic manifestations included a papulosquamous dermatitis with deposition of immunoglobulins and complement in both normal and abnormal skin, a membranoproliferative glomerulonephritis with subendothelial deposits, arthritis, and pericardial, pleural, and synovial effusions.

Six children with glucocorticoid induced pancreatitis are described and compared with the previously reported 19 adults and 15 children with this syndrome. The typical clinical symptomatology is emphasized and prompt diagnosis and early therapy are shown to be lifesaving.

In five children a nephrotic syndrome developed within one month (three cases), 11 months, and 10 years of the onset of diabetes mellitus. The syndrome, which responded to steroid therapy, was morphologically typical of the idiopathic nephrotic syndrome of childhood. In all patients light, fluorescence and electron microscopy performed on the initial kidney-biopsy specimens demonstrated normal glomerular basement-membrane thickness and early mesangial and arteriolar changes compatible with diabetes mellitus. Although this may represent a chance association, a metabolic defect in the basement membrane common to both diabetes mellitus and the nephrotic syndrome remains a possibility.

Despite many reports regarding the apparent benign prognosis of acute poststreptococcal glomerulonephritis in children,1-4there remains some question about the relationship of this disease to chronic nephritis.5-9While many observers have concluded that the two diseases represent distinct and often unrelated entities, recent evidence, primarily from renal biopsies in adults, indicates that certain cases of chronic glomerulonephritis are the results of acute poststreptococcal disease which has failed to heal.9-11Many previous studies have been deficient because of inadequate follow-up, poor sampling, and the inclusion of diseases that were not clearly acute poststreptococcal glomerulonephritis. Because of these inadequacies, particularly with regard to precise definition of etiology of the acute disease, we observed a large group of children who had been clearly afflicted with acute poststreptococcal glomerulonephritis in 1953. One-hundred percent (61) of the surviving persons involved in a well-defined epidemic of streptococcal infection with a nephritogenic strain (Redlake

In the belief that sequential studies of the pathology of the kidney might improve our understanding of the pathogenesis of a variety of forms of renal disease in childhood, we began to perform percutaneous renal biopsies in children in 1955. Our studies were stimulated by the pioneering investigations of Iversen and Brun1 in Europe, and Muehrcke, Kark, and Pirani2 in the United States. Our experience3 now includes more than 500 kidney biopsy specimens obtained from approximately 400 children of all ages. The incidence of complications has been low, and the method has proved to be safe enough to justify the small risk entailed. Bleeding into the perirenal tissues, sufficient to cause pain, or a measurable fall in hemoglobin, or the appearance of a mass, has occurred in eight children. Gross hematuria of more than transient nature has occurred in six additional children. There has been no recognized permanent renal functional impairment or other chronic sequelae of these accidents. Surgical exploration of the biopsied kidney has never been necessary and no deaths have occurred as a consequence of the procedure. The confusion which exists regarding classification and diagnosis of many renal diseases arises because of inadequate knowledge of their etiology, and is further compounded by conflicting use of terminology by clinicians and pathologists. The terms nephritis, nephrosis, mixed nephritis-nephrosis, and the modifying terms acute, subacute, and chronic, are, for example, applied by these two groups of physicians in circumstances which differ widely depending upon the experience of the user. Widespread use of the renal biopsy technique over the past 7 years has not eliminated the difficulties in use of terminology, but some progress has been made.

Severe hypertension of at least 7 years' duration, due to coarctation of the right renal artery, was treated by reconstruction of the abnormal artery and restoration of blood flow to the coarcted kidney. Renal biopsies revealed normal microscopic architecture in the right kidney and advanced hypertensive pathology in the opposite kidney. After 8 months' observation of persistent, moderate hypertension, the left kidney was removed with prompt return of blood pressure to normal levels during the subsequent 2½ years. These observations demonstrate the precise correlation of hypertension due to renal artery stenosis in the human with the experimental model in rats.

Summary1) Intravenous injection of small amounts of nephrotoxic serum produced a syndrome in rats whose characteristics include proteinuria and proliferation of glomerular endothelial cells. This dosage of nephrotoxic serum was well tolerated by the rats. 2) Rats were shown to tolerate E. coli lipopolysaccharide endotoxin over a wide range of dosages. 3) Simultaneous injection of nephrotoxic serum and minute amounts of Gram-negative bacterial endotoxin resulted in acute death in a high percentage of rats and renal lesions resembling those of the generalized Shwartzman reaction. 4) The possible implications of these observations on susceptibility to necrotizing effects of endotoxin-like substances and on the pathogenesis of renal disease are discussed.

It is clear that congenital abnormalities of the urinary system must be recognized early for optimal management and correction, which at best is relatively ineffective; the ultimate solution of these problems is prevention, which will require improved understanding of the normal development of the urinary system.

Renal disease in nail-patella syndrome: Clinical and morphological studies. Clinical and morphological features of seven patients with the nail-patella syndrome are described. Progression to renal failure after a prolonged period of asymptomatic proteinuria is reported. Kidney tissue from these seven patients studied by light, immunofluorescent and electron microscopy demonstrated abnormalities characteristic of this disease. Focal glomerular basement membrane thickening was observed by light microscopy. Immunofluorescent microscopy showed focal glomerular basement membrane and arteriolar staining with serum proteins, predominantly IgM and β1C. Electron microscopy revealed markedly abnormal glomerular basement membranes containing bundles of cross-striated fibrils. These fibrils were more readily demonstrated in phosphotungstic acid-stained sections. The data presented suggest that the inborn error of connective tissue metabolism of the nail-patella syndrome is associated with renal disease as the result of deposition of collagen moieties in glomerular basement membranes with subsequent alterations of glomerular structure and function.

The renal clearances of sodium iothalamate I131 after a single intravenous dose of 10 µCi were compared with inulin clearances and endogenous creatinine clearances. In a total of 40 comparative studies made between the isotope and inulin clearances, correlation was excellent (r = .995) with a very small standard error (±5.9), suggesting that sodium iothalamate I131 clearance accurately measures glomerular filtration rate. In 43 comparative studies between endogenous creatinine and inulin clearances, correlation was good (r = .935) only when determined simultaneously, and even then the standard error was so great (± 18.7) that any individual creatinine clearance was of limited value. In performing the isotope clearance, adequate hydration is maintained orally. Ten microcuries of sodium iothalamate I131 are injected intravenously. After a 30 to 60 minute equilibration period, the bladder is emptied by voiding and a blood specimen obtained. A timed, voided urine is then collected and again a blood specimen obtained at the time of voiding. Both blood specimens and the urine are counted in a well-type scintillation counter with gamma spectrometer. The mean of the beginning and end-point plasma radioactivity is used in the clearance formula. This isotope method is recommended as the test of choice in measuring glomerular filtration rate.

Two patients with congenital heart disease who developed the nephrotic syndrome are discussed. Neither had evidence of heart failure or increased venous pressure. The possible pathophysiologic mechanisms leading to the nephrotic syndrome are discussed. The interesting possibility is raised that the associated occurrence of congenital heart disease and the nephrotic syndrome in such patients may represent different expressions of an inherited or developmental abnormality.

Three patients with steroid-resistant idiopathic nephrotic syndrome were studied at onset and during recurrent nephrotic syndrome after renal transplantation. Renal biopsies at the onset of the nephrotic syndrome showed typical features of the idiopathic nephrotic syndrome; no or minimal focal glomerular abnormalities were present by light microscopy and glomerular-basement-oriented deposits were not demonstrated by immunofluorescent or electron microscopy. Progression to renal failure occurred in 2, 2, and 6 years. Recurrence of nephrotic syndrome was noted 1, 11/2, and 5 months after transplantation. Renal biopsies done 11/2, 5, and 7 months after transplantation when proteinuria was 12·8, 7·6, and 8·5 g. per 24 hours, respectively, showed minimal or no glomerular abnormalities by light microscopy. Immunofluorescent and electron microscopic studies revealed no evidence suggesting immunological injury. Subsequent kidney specimens after transplantation obtained from two of these patients with recurrent nephrotic syndrome showed focal segmental glomerulosclerosis limited primarily to the juxtamedullary glomeruli—a feature further suggesting recurrence of the original disease in the transplanted kidney. These observations suggest that the pathogenesis of the steroid-resistant idiopathic nephrotic syndrome may involve systemic circulating factors; this hypothesis would account for development of a recurrent nephrotic syndrome in the transplanted kidney.

A typical case of cystic disease of the renal medulla in a seven year old girl is presented. Investigation of the patient's family revealed a five year old sibling with early cystic disease. Thus an opportunity was presented to confirm the familial nature of this disease and to study medullary cystic disease in its earliest stages. The similarities between cystic disease of the renal medulla and juvenile familial nephronophthisis are discussed and a hypothesis relating to the pathogenesis of cystic disease is formulated.

Three adolescents with unilateral renal vein thrombosis and the nephrotic syndrome are presented. Light, fluorescent, and electron microscopic examination of bilateral renal biopsy specimens in each patient demonstrated membranous glomerulonephritis in both kidneys. In the first case there was no evidence of preexisting renal disease and the initial biopsy at the time of thrombosis revealed near normal glomeruli on light microscopy. Fluorescent staining and the electron microscope demonstrated immune complex deposition along the glomerular basement membrane. Follow-up biopsy of the same case seven months later showed advanced membranous glomerubonephritis on light and electron microscopy. These cases as well as data from recent animal experiments raise the interesting suggestion that renal vein thrombosis and the nephrotic syndrome might be an immunologic disease. Unilateral obstruction of the renal vein may result in renal antigen release and antigen-antibody complex formation with subsequent glomerular deposition, bilateral glomerular disease, and the nephrotic syndrome.

A study of fibrin ultrastrtucture utilizing ferritin-conjugated antihuman fibrinogen antibody is reported. The structure of fibrin strands in thin section, and the periodic banding of the fibrin by ferritin conjugated antibody permits conclusions regarding the structural formation of the clot. The observations are in accord with the model of fibrin strand formation suggested by Hall and Slayter. Further areas of investigation utilizing this technic are suggested.

Summary Specimens of kidney from 20 humanfetuses, ages 1 1/2 to 5 months' gestation, have been studied by light and electron microscopy. Glomeruli of all stages of maturity from the most primitive glomerular anlage to the mature, adult type of glomerulus were found in the renal cortex of fetuses of all ages. Glomerular maturation was noted to proceed progressively from about 1 1/2 month (origin of metanephros) to about 35 weeks of gestation. Of the total glomerular population, about 30 per cent were mature at 5 months of age. It was shown that the glomerular capillaries form in situ in the endothelial cell mass, rather than from ingrowth of capillaries of the primitive afferent arteriole. Branches of the afferent arteriole connect with the previously formed capillaries of the glomerulus, and continuity of circulation is thus established. No evidence was obtained of in situ formation of blood cells within the glomerulus. The primitive capillaries are surrounded by a very thin basement membrane which consists only of the opposed plasma membranes of the epithelial and endothelial cells, separated by an essentially empty space of 500 Angstrom units. As the development of the glomerulus progresses, the width of the basement membrane increases to about 1,100 A and a dense fibrillar layer (the lamina densa, about 700 A) appears in the middle of the space separating the limiting membranes of the epithelial and endothelial cells. Evidence is presented that the source of the lamina densa is primarily the epithelial cells. Foot processes form by infoldings of the plasma membranes of the epithelial cell, and a normal complement of the adult-type foot processes are present in 30 per cent of the glomeruli in fetuses of 5 months of age. Thinning of the luminal endothelium results in the formation of endothelial fenestra, which reesmble the adult structure, but are fewer in number. An additional endothelial cell type, the intercapillary cell, is readily identified in fetal glomeruli. The structure of this cell and its relationship to other cells in the glomerulus are described. Thus, many glomeruli from fetuses of 5 months' gestation, near the period of viability of premature infants, appear structurally fully capable of function. The implications of the findings to thestructure and formation of glomeruli in the infant and children in health and disease, are discussed.

Experimental renal disease was produced in young rats by daily subcutaneous injections of 6-dimethylamino purine, 3-amino-d-ribose (aminonucleoside). The physiologic, biochemical, and light microscopic changes were similar to those observed in human nephrosis. Electron microscopy of the glomeruli from animals which received seven or more daily injections of aminonucleoside revealed characteristic abnormalities of the epithelial cells of the glomerular capillaries. These changes consisted of swelling, coalescence, and eventual obliteration of the epithelial cell foot processes and an increase in the number and the size of epithelial cytoplasmic vacuoles. The serial development of the ultramicroscopic pathologic changes in the epithelial cells, as observed by study of animals through the course of the disease, indicated that the smudging of the foot processes occurred at the time of onset of severe proteinuria. Further changes, consisting of hypercellularity due primarily to an increase in the number of endothelial cells and an increase in the amount of basement membrane-like material, were regularly observed by the 12th day after injections were begun. These abnormalities were correlated with the development of uremia in the later stages of the disease process. The distal and proximal renal tubules were abnormal by the 7th day after injections were begun, and showed localized swelling between the cristae of the mitochondria and a decrease in over-all cytoplasmic density, described as hydropic change. Electron microscopy of glomeruli from animals which had partially recovered from aminonucleoside nephrosis revealed areas of normal epithelial cell morphology. This observation was interpreted as evidence of partial reversal of the ultramicroscopic changes in the recovery phase of the disease. These observations of the fine structure of pathologically altered glomeruli and tubules in aminonucleoside nephrosis are similar to our findings in human nephrosis as revealed by electron microscopy of serial renal biopsies.

Studies with the light microscope (Am. J. Path., 34: 631, '58) indicated that an injection of endotoxin into the carotid artery of a rabbit alters the blood-brain barrier allowing the distribution of subsequently injected colloidal iron throughout the cerebral cortex. The present investigation by electron microscopy determined the distribution of the colloidal iron oxide in the normal and endotoxin altered cerebral capillaries of rabbits. Four hours prior to the intracarotid injection of saccharated iron oxide the animal received an injection via the same artery of either 50 μg gram-negative endotoxin or a control dose of normal saline. The animals were sacrificed at times from 15 minutes to two hours after the injection of iron oxide and samples of the cerebral cortex were processed for electron microscopy by routine methods. In those animals that did not receive endotoxin, the colloidal iron was limited to the lumen of the cerebral capillaries and occasional large endothelial vacuoles. None of the iron was found in the endothelial pinocytotic vesicles. In the endotoxin animals the iron oxide particles were found in quantity in the capillary endothelium phagosomes, the basement membrane, and in astrocytes and their processes. The fine structure of the cerebral capillary is reviewed and evidence is presented in support of the hypothesis that the barrier mechanism for colloidal tracers lies in a unique property of the brain's endothelial pinocytotic vesicles.

THE INTRODUCTION of cortisone and adrenocorticotropin (ACTH) into clinical medicine by Hench et al. has profoundly influenced both medical practice and medical science. Voluminous literature which has collected during the 5 years since their introduction establishes securely the effectiveness of these hormonal agents in diseases previously refractory to medical management. In the laboratory these drugs have also opened whole fields to investigation with a new experimental approach. Data already available suggest that ultimate discovery of the basis of the action of cortisone and ACTH will carry broad inmplications concerning physiologic function and mechanisms of disease. A natural consequence of the introduction of such potent and versatile weapons into clinical medicine is that they should be widely used. In almost every human disease, ranging from the common cold to disseminated malignancy, the steroid hormones and ACTH have been tried. For example, it can be factually stated that few truly ill patients reach the diagnostic medical center without having had at least small amounts of cortisone or ACTH, and it is the extremely unusual patient who reaches the necropsy table without the "benefit" of ACTH, cortisone or one of its analogues. As these drugs have been studied, it has become ever more apparent that they are extraordinarily potent pharmacologic agents which effect or control mammalian physiology in multitudinous areas, perhaps in several different ways. More gradually it has been realized that their effects are not all beneficial. Because of enthusiasm engendered by the availability of potent new pharmacologic agents, reporting from most clinics to date has emphasized the dramatic beneficial effects and tended to minimize the untoward side effects, toxic reactions and potential hazards of hormone therapy. It is the purpose of this report to review some of the hazards of treatment with cortisone and ACTH in pediatric practice.

An ultrastructural study of clots formed in recalcified platelet-rich, human plasma has revealed an intimate platelet-fibrin association. A number of the dense platelet granules, the alpha granules, formed an osmophilic mass in the center of platelets undergoing viscous metamorphosis. Fibrin strands appeared to be connected to the altered alpha granulomere of these platelets. The observed association between fibrin strands and platelets in the clot was supported by experiments with an electron dense stain for fibrinogen. Clots formed from platelet-rich plasma preincubated with fer-A.F. antibody contained altered platelets with an intracellular distribution of the ferritin conjugated antibody. Connections between intracellular fer-A.F. antibody and fibrin strands periodically banded by the ferritin stain were observed. These observations indicate that the altered platelet granulomere attached to fibrin strands may play a role in clot retraction.

CMPGN with hypocomplementemia appears to be one identifiable form of progressive and destructive glomerulonephritis, but whether this is a specific pathogenetic entity has not been proven. The clinical features of the "disease" include presentation with either asymptomatic proteinuria and hematuria, nephrotic syndrome, or gross hematuria and an acute nephritic syndrome. Morphologic studies reveal extensive mesangial cell proliferation and increased matrix with thickening of the glomerular capillary. Deposits of C3 and properdin uniformly are found predominantly in a peripheral lobular distribution by immunofluorescent microscopy; immunoglobulins are seen less consistently. These deposits are different from those seen in other glomerular diseases. Serum complement abnormalities have also been demonstrated: depression of C3t (and ß1C/ß1A) with relatively normal earlier components, evidence for in vivo breakdown of C3 by labeled isotope studies and elevated α2D, presence of a serum inhibitor that inactivates guinea pig C3t and a pseudoglobulin lytic factor that in combination with a normal serum cofactor enzymatically cleaves C3 to α2D and ß1A. The terminal complement inactivation and the uniform presence of properdin in these deposits suggesting an alternate pathway of immune injury must be balanced against immunopathologic observations which demonstrate glomerular deposits of immunoglobulins and earlier complement components. It is possible that both mechanisms may be operative in CMPGN.

Forty-five children with anaphylactoid (Henoch-Schönlein's) purpura were studied. Evidence of recent streptococcal infection, as determined by positive ASO titers, was found in 13 of 39 patients (33%), an incidence of positive ASO titers only slightly higher than that expected in children with nonstreptococcal illness. This observation suggests that streptococcal infection is not the major cause of anaphylactoid purpura. Microscopic study of skin biopsy specimens from 12 children showed perivascular cellular infiltration of the dermis. Numerous leukocyte-platelet thrombi were observed in small dermal vessels. Muscle biopsy specimens were usually normal. Kidney biopsy specimens from 11 children with anaphylactoid purpura-nephritis of variable severity and duration were studied. The principal microscopic abnormality consisted of focal lesions of fibrinoid deposition and endothelial proliferation within scattered glomeruli. Renal biopsy specimens obtained during clinical recovery from anaphylactoid purpura-nephritis showed focal glomerular scars. The differences between the glomerular pathology of anaphylactoid purpura-nephritis and other forms of glomerulonephritis are discussed. Clinical, experimental and pathologic data are reviewed which support the concept that anaphylactoid purpura is a form of diffuse vascular disease, probably caused by hypersensitivity to a variety of agents.

Renal biopsies from 16 patients with nephrosis, 7 patients with glomerulonephritis, and 3 patients with disseminated lupus erythematosus were studied with the electron microscope. The observations presented indicate that early in the course of each of these diseases alterations occur in the fine structure of the glomeruli which serve to distinguish one disease process from another. In nephrosis, some distortion of the organization of the epithelial foot processes was seen in all patients. These epithelial changes constituted the early, consistent lesion of the disease. There was frequently also a swelling of the endothelium. In glomerulonephritis, pronounced proliferative changes involving the endothelium and to a lesser extent the epithelium, together with the laying down of a basement membrane-like material, represented the predominate pathologic processes. There was also a swelling of both endothelial and epithelial cytoplasm. The epithelial foot processes generally appeared normal. In patients with a clinically "mixed" picture of nephrosis and nephritis, the glomerular changes were likewise "mixed," for various combinations of epithelial, endothelial, and basement membrane abnormalities were present. In disseminated lupus erythematosus, a more or less generalized thickening of the basement membrane proper associated with a variable degree of endothelial proliferation was seen. It is suggested that an accentuation of the process of basement membrane thickening results in the "wire loop" appearance sometimes seen by light microscopy. Although the earliest alterations in glomerular fine structure were characteristic for each of the disease processes, at later stages the changes were not always distinctive. The resulting scarred or "hyalinized" glomeruli, composed of relatively homogeneous, basement membrane-like material, and a few atrophic cells, appeared quite similar. Although the functional implications of the structural changes observed remain obscure at this time, it is believed that insight into mechanisms may stem from such observations.

Juxtaglomerular body abnormalities in youth-onset diabetic subjects. Abnormal microalbuminuria in insulin-dependent diabetic subjects (IDDS) is significantly associated with pre-clinical nephropathy. In youth-onset IDDS declining plasma renin activity is significantly associated with improved albumin excretion, while persistently elevated renin activity is associated with continued abnormal microalbuminuria. To determine if these changes are reflected in changes in cell count in the juxtaglomerular body and if biopsy findings correlate with abnormal microalbuminuria, renal tissue of 20 IDDS (Study IDDS) ages 16 to 31 years, evaluated concurrently for plasma renin activity and microalbuminuria, were examined by light microscopy. Biopsy or autopsy specimens from 21 normal subjects and 32 IDDS (Non-Study IDDS), ages 2 to 25, were also examined. Specimens from the majority of prepubertal and all pubertal and postpubertal Non-Study IDDS and all Study IDDS independently of status of microalbuminuria had morphologic abnormalities. Normal or mesangially expanded glomeruli were found in association with expanded juxtagomerular bodies and increased cell number, or with sclerotic bodies and decreased cell number. Sclerosis of juxtaglomerular bodies occurred independently of glomerular sclerosis. The highest percentage of glomeruli with expanded juxtaglomerular bodies and high cell count was present in specimens of Study IDDS with the most abnormal levels of microalbuminuria. T lymphocytes, noted within juxtaglomerular bodies, were present in specimens of 62% of the 52 Study and Non-Study IDDS. Abnormalities of the juxtaglomerular body are distinctive features of renal pathology in IDDS. T lymphocytes in the endocrine juxtaglomerular body suggest the presence of an autoimmune process. Confirmatory studies are necessary.

The glomerular mesangium: Uptake and transport of intravenously injected colloidal carbon in rats. Colloidal carbon, 70 mg/100 g, was injected into rats which were sacrificed for histologic study of the kidneys at intervals of five minutes to seven weeks. Transient thrombocytopenia and albuminuria were observed. Uptake of carbon by the mesangium of glomeruli was maximal at 32hr and gradually decreased thereafter. Semiquantitative analysis of the distribution of carbon particles within glomeruli revealed a predominately peripheral localization during early time periods, and increased relative concentrations of particles within more central zones and in the lacis area at the vascular pole of the glomerulus at two to seven weeks, indicating that one of the mechanisms for clearance of materials from the mesangium was movement of particles in the direction of the lacis area. Sequential electron microscopic studies showed that carbon particles moved through fenestrae in the endothelium covering the mesangium into channels between mesangial cells. Observations at later intervals suggested that carbon eventually reached the vascular pole by being passed on from one mesangial cell to the next. Vasoactive amines or other substances derived from platelets may play an important role in initiating the process of mesangial uptake. Mesangium glomerulaire: Captation et transport du carbone colloidal injecte par voie intra-veineuse chez le rat. Du carbone colloidal, 70mg par 100 g, a ete injecte a des rats qui ont ete sacrifies, pour l'etude histologique des reins, apres des delais allant de cinq minutes a sept semaines. Une albuminurie et une thrombocytopenie transitoires ont ete observees. La captation de carbone colloidal est maximale a 32 heures et diminue progressivement au dela. L'analyse semi-quantitative de la distribution des particules de charbon a l'interieur des glomerules revele une localisation peripherique predominante dans les temps precoces et, de deux a sept semaines, une augmentation de la concentration relative des particules dans des zones plus centrales et dans la region du lacis au pole vasculaire du glomerule. Cela indique que l'un des mecanismes d'epuration du mesangium est un mouvement de particules vers la region du lacis. Des etudes sequentielles en microscopie electronique montrent que les particules de carbone vont, a travers des fenetres de l'endothelium qui recouvrent le mesangium, dans des canaux situes entre les cellules mesangiales. Des observations plus tardives suggerent que le carbone atteint finalement le pole vasculaire apres avoir ete transfere d'une cellule mesangiale a la cellule adjacente. Les amines vaso-actives ou d'autres substances derivees des plaquettes pourraient jouer un role important en initiant le processus de captation mesangiale.

One of monoamniotic, monochorionic twins was born with absence of kidneys but had none of the extrarenal manifestations of Potter's syndrome other than low-set ears. His twin had a single kidney with anomalies but was capable of producing a normal amount of urine, and a normal quantity of amniotic fluid was present. These unique observations support the hypothesis that the facial, limb, pulmonary, and skin abnormalities of Potter's syndrome are due to oligohydramnios secondary to absence of intrauterine urine production.

Recent work suggests that the normal barrier to penetration of the renal glomerular basement membrane by anionic plasma proteins may depend in part on the existence of negatively charged sites within the membrane. We describe an in vitro cytochemical method for the quantitative demonstration of anionic sites in the normal human glomerular basement membrane. In five normal subjects, ranging in age from 10 days to 57 years, the sites were distributed at regular intervals in the lamina rara externa, with a frequency of 23.8 +/- 6.8 sites per 1000-nm length of membrane. A similar distribution was observed in the basement membranes from three normal human fetuses. Ex vivo perfusion of one cadaver kidney revealed a similar distribution of anionic sites. The number of anionic sites in the glomerular basement membranes of five patients with the congenital nephrotic syndrome was reduced to 8.9 +/- 3.7 (P less than 0.001). Prior incubation of sections of normal kidney in purified heparinase resulted in a marked reduction in the number of anionic sites. We conclude that congenital nephrosis results from failure of heparan sulfate--rich anionic sites to develop in the lamina rara externa of the glomerular basement membrane.