Warren K. Bolton

A comparative study of open surgical and percutaneous renal biopsies.

Percutaneous renal biopsy was performed on 171 patients during the same interval as an open surgical biopsy was done on 100 patients in the same hospital. Patients who underwent an open biopsy had more severe renal dysfunction and hypertension than those who had a percutaneous biopsy. Tissue adequate for diagnosis was obtained in 100 per cent of the open biopsies. The kidney was reached in 88 per cent of all percutaneous biopsies with tissue adequate for diagnosis in 82.5 per cent. Of 87 patients biopsied with image-amplification fluoroscopy renal tissue was obtained in 97 per cent with tissue adequate for diagnosis in 92 per cent. No nephrectomies were done and no deaths occurred in either group. Our complications and yield by percutaneous biopsy compared favorably to those of other series. Further, open biopsy in a high risk population was associated with a high yield of tissue adequate for diagnosis with no increase in complications. Procurement of renal tissue need rarely be denied a patient if a biopsy is clinically indicated.

Therapy of the idiopathic nephrotic syndrome with alternate day steroids

Eighty-one adult patients with the idiopathic nephrotic syndrome were treated with prednisone, 60 to 120 mg, on alternate days. Treatment was continued with diminishing drug doses for up to 10 years. Biopsy specimens were categorized as showing lipoid nephrosis 36 per cent, focal sclerosis 12 per cent, diffuse proliferative 22 per cent and membranous nephropathy 30 per cent. Patients with systemic causes of the nephrotic syndrome were excluded. Proteinuria decreased to normal or to less than or equal to 3 g with a greater than or equal to 50 per cent decrease from base line in 83 per cent of the patients with lipoid nephrosis, 30 per cent of the patients with focal sclerosis, 50 per cent of the patients with diffuse proliferative nephritis and 71 per cent of the patients with membranous nephropathy. Improvement occurred in those with focal sclerosis, diffuse proliferative nephritis and membranous nephropathy only after prolonged treatment (14 to 15 months). Stable or improved renal function occurred in 97 per cent of those with lipoid nephrosis, 50 per cent of those with focal sclerosis, 73 per cent of those with diffuse proliferative nephritis and in 83 per cent of those with membranous nephropathy. Death or dialysis occurred in 12 per cent of the patients, and complications coincident with treatment occurred once every 12 patient years. Compared to other series of patients with the idiopathic nephrotic syndrome, therapy of our patients with prolonged alternate day steroids resulted in (1) decreased protein excretion, (2) maintenance of good renal function and (3) decreased number of complications of therapy.

Ventriculojugular shunt nephritis with Corynebacterium bovis: Successful therapy with antibiotics☆

A patient with hydrocephalus and a ventriculojugular shunt presented with acute nephritis, nephrotic syndrome (proteinuria 10 g/24 hours), decreased complement levels, circulating immune complexes and diminished creatinine clearance (41 ml/min). Seven blood cultures grew Corynebacterium bovis. A renal biopsy specimen revealed mesangiocapillary glomerulonephritis by light microscopy, and thickened glomerular basement membranes with areas of increased granular density by electron microscopy. Immunofluorescent examination of the biopsy specimen demonstrated 2+ granular glomerular basement membrane deposits of immunoglobulin M (IgM), with trace third component of complement (C-3), fourth component of complement (C-4) and immunoglobulin G (IgG). Rabbits immunized with C. bovis produced a line of partial identity in agar with patient serum against a sonicate of C. bovis. Indirect fluorescein staining of the biopsy specimen with the rabbit antiserum demonstrated 1+ granular glomerular basement membrane deposits. Potassium thiocyanate microelution of sections prior to examination markedly diminished staining with antihuman antiserum, but did not affect staining with rabbit antiserum. Following initial therapy with intravenous penicillin for six weeks the bacteremia cleared, serum complement levels returned to normal, proteinuria decreased and creatinine clearance increased. A relapse occured four weeks later with decreased complement levels, increased proteinuria and decreased creatinine clearance. Blood cultures were again positive for C. bovis. Following therapy with erythromycin and rifampin, the bacteremia cleared and there was a sustained improvement of all parameters. To our knowledge, this is the first time an association has been noted between C. bovis ventriculojugular shunt infection and glomerulonephritis. These findings support the potential role of C. bovis as an etiologic agent in human renal disease and further define the immune complex nature of shunt nephritis.

An Evaluation of Diabetic and Pseudodiabetic Glomerulosclerosis

Diabetic glomerulosclerosis must be either a primary manifestation or a secondary consequence of the metabolic abnormalities of diabetes. Several earlier reports have attempted to support the former hypothesis by describing cases of pathognomonic renal lesions in nondiabetic subjects; however, the clinical and pathologic data in these reports are inconclusive. We have reviewed our experience at the University of Virginia Hospital with 447 percutaneous renal biopsies performed over a period of four years from July 1973 through July 1977. Of these cases, only two appeared to represent diabetic glomerulosclerosis occurring in nondiabetic subjects. Upon further investigation, one case provided to be light chain disease demonstrated by immunofluorescence staining. The other case, on repeat renal biopsy, proved to be membranoproliferative glomerulonephritis. We conclude that a diagnosis of diabetic glomerulosclerosis must be viewed with suspicion in nondiabetic subjects. Suspected cases should be labeled pseudodiabetic glomerulosclerosis and investigated further.

T cells and dendritic cells in glomerular disease: the new glomerulotubular feedback loop

A newly described glomerulotubular feedback loop may explain the relationship between glomerular damage, epitope spreading, tubulointerstitial nephritis, proteinuria as a progression factor, and the importance of the local milieu in kidney damage. It also opens the horizons for exciting innovative approaches to therapy of both acute and chronic kidney diseases.

Analyzing pulsatile endocrine data in patients with chronic renal failure : a brief review of deconvolution techniques

Deconvolution analysis provides an important new technique to evaluate underlying hormone secretory rates quantitatively based upon serially measured plasma hormone concentrations with or without prior knowledge of the half-time of hormone disappearance from the blood. Information about endocrine glandsecretion is particularly important in chronic renal failure, wherein the decreased metabolic clearance rates of various hormones would otherwise confound the interpretation of plasma hormone concentrations. Here we review two particularly useful techniques of deconvolution, one of which is a waveformdefined algorithm and the other waveform independent. The first method can be used to estimate both hormone half-life and secretory rates in vivo. The second methodology allows calculation of in vivo hormone secretion rates without assuming any special form for the secretion event, but requires a priori knowledge of hormone half-life. We illustrate examples of these two deconvolution approaches, and discuss why the interpretations of hormone concentration measurements in earlier studies (where deconvolution methods were not employed) must be viewed with caution. Based on such considerations, additional investigations of in vivo hormone secretory pathophysiology will be required in children and adults with chronic renal failure.

Referral and Comanagement of the Patient With CKD

CKD is a common condition with well-documented associated morbidity and mortality. Given the substantial disease burden of CKD and the cost of ESRD, interventions to delay progression and decrease comorbidity remain an important part of CKD care. Early referral to nephrologists has been shown to delay progression of CKD. Conversely, late referral has been associated with increased hospitalizations, higher mortality, and worsened secondary outcomes. Late referral to nephrology has been consequent to numerous factors, including the health care system, provider issues, and patient related factors. In addition to timely referral to nephrologists, the optimal modality to provide care for CKD patients has also been evaluated. Multidisciplinary clinics have shown significant improvements in other disease states. Data for the use of these clinics have shown benefit in mortality, progression, and laboratory markers of disease severity. However, studies supporting the use of multidisciplinary clinics in CKD have been mixed. Evidence-based guidelines from groups, including Renal Physicians Association and NKF, provide tools for management of CKD patients by both generalists and nephrologists. Through the use of guidelines, timely referral, and a multidisciplinary approach to care, the ability to provide effective and efficient care for CKD patients can be improved. We present a model to guide a multidisciplinary comanagement approach to providing care to patients with CKD.

Association of Plasma Des-acyl Ghrelin Levels with CKD

BACKGROUND AND OBJECTIVES There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty-one CKD and 15 hemodialysis patients were enrolled. Acyl ghrelin (AG) and des-acyl ghrelin (DG) were determined using separate two-site-specific assays. Leptin, insulin, growth hormone, insulin-link growth factor-1, C-reactive protein, TNF-α, and IL-6 were also measured. RESULTS Univariate correlation analyses showed that CKD stage was highly, positively correlated with the levels of preprandial and postprandial DG and positively correlated with TNF-α, IL-6, leptin, and age. Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG, whereas TNF-α, IL-6, leptin, insulin, and age were not independently associated with either. Geometric mean (GM) preprandial and postprandial AG were comparable between CKD stages ≤2 and >2, whereas GM preprandial DG and postprandial DG were 1.95-fold and 2.17-fold greater, respectively, for CKD stage >2 versus stage ≤2. DG was the dominant form of ghrelin preprandially and postprandially for both CKD stages ≤2 and >2. Dialysis had no effect on AG, but reduced DG by 73% to levels even lower (GM 48.7 pg/ml) than those seen postprandially in CKD stage ≤2 patients (GM 77.0 pg/ml). CONCLUSIONS This study shows a strong and independent correlation of DG with CKD stage. Postprandial suppression of ghrelin is impaired with reduced renal function. Hemodialysis selectively removes DG but not AG.

Editorial: Are men rats? Dendritic cells in autoimmune glomerulonephritis

Glomerulonephritis is an inflammatory process in the kidney involving glomerular cell damage, hypercellularity associated with cellular proliferation and leukocyte infiltration, and matrix and extracellular material deposition. Although glomerulonephritis may be self-resolving, as occurs in many postinfectious types of nephritis, many other types progress with scarring and development of tubulo-interstitial disease and progressive loss of renal function and increasingly severe proteinuria. Indeed, acute glomerulonephritis progressing to chronic glomerulonephritis is a major cause of chronic kidney disease and end-stage renal disease worldwide. In the United States, glomerulonephritis is the fourth leading cause of end-stage renal disease, resulting in the need for dialysis and transplantation at enormous societal costs. A better understanding of the pathogenic processes that result in the initiation of the inflammatory process in the glomerulus and its progression is essential to impacting the disease. For many years, glomerulonephritis was presumed to be caused by antibodies against kidney components or as antigen-antibody complexes depositing in the kidney with consequent activation of the inflammatory system. However, evidence of a role for cell-mediated immunity was present even four decades ago. Indeed, it has been shown that T cells in the absence of antibody can induce a robust inflammatory process including glomerulonephritis, pure T cell epitopes can induce glomerulonephritis, and consequent epitope spreading can lead to an augmented phenotype in animals with EAG [1–4]. In recent years, rapid progress toward a broader perspective and deeper understanding of the pathogenesis of glomerulonephritis has been achieved with the aid of major technical advances and the availability of reagents and transgenic and knockout mice. Studies about T cell functions have concretely defined the roles of multiple T cell subsets that are involved in the induction or amelioration of glomerulonephritis [4]. T cell functions are orchestrated by DCs, the professional APC type that is capable of not only internalizing, processing, and presenting foreign and self antigens to antigen-specific T cells but also undergoing maturation processes and transporting antigens from peripheral and mucosal organs to secondary lymphoid organs [4, 5]. They are distinguishable from other APC types by their ability to prime naı̈ve T cells, crosspresent extracellular antigens to cytotoxic T cells, and induce Treg development. Besides antigen presentation, DCs also function in innate immunity by the production of cytokines, chemokines, ROS, NO, arachidonic acid metabolites, and regulatory enzymes (e.g., arginase and indoleamine 2,3-dioxygenase) in response to TLR, carbohydrate, and lipoprotein ligands present on pathogens and to mediators and ligands secreted or expressed by other cell types (Table 1; mouse DC mRNA expression data in NCBI Gene Expression Omnibus Accession Numbers GSE17322 and GSE6259). Such a variety of cellular functions is achieved by the development of DC subsets that exhibit complementary functional specializations. Three broad phenotypically and functionally diverse DC subsets have now been identified in human, mouse, and rat (Table 1). In the mouse, DCs comprise two conventional DC types, the CD8 DEC205 DC (CD8 DC) and the CD11b DCIR2 DC, plus the mPDCA-1 SiglecH B220 Ly6c plasmacytoid DC [5]. CD8 DCs are the migrating DC types that are most efficient in presenting and cross-presenting antigens to CD8 T cells, internalizing apoptotic cells, and inducing Treg cell development. CD11b DCIR2 DCs, on the other hand, are more efficient in presenting soluble antigens to CD4 T cells and are proficient in producing chemokines and other mediators. CD103 DCs in mucosal and peripheral organs, including the kidney and dermal CD207 CD103 DCs, are phenotypically and functionally equivalent to the

Ultrastructure of the Aging Kidney

Man’s aging organs play essential roles in dictating longevity, or lack thereof, of his physical and mental processes. Not the least of these organs are the kidneys, which receive much attention in pathologic states in young and middle life, but little notice in senescence. Gross studies indicate that overall kidney size, weight, amount of cortex, and number of glomeruli decrease with age, although this is variable, while light microscopic examinations reveal numerous alterations including nephron obsolescence, vascular sclerosis, interstitial fibrosis, basement membrane thickening, and various types of histologic degeneration (Dunnill and Halley, 1973; Darmady et al., 1973; McLachlan, 1978; Mclachlan et al., 1977). These changes of aging are associated with a decline of glomerular filtration rate and various types of tubular dysfunction (Friedman et al., 1972; Korenchevsky, 1961; Epstein, 1979; Papper, 1973). Although gross, anatomic, light microscopic, and functional studies in the aging kidney may be few, they are plentiful in relationship to ultrastructural studies of the kidney in aging man.