A 75-year-old man presented with a blistering skin disease and nephrotic syndrome. Bullous pemphigoid was diagnosed by linear immunoglobulin G (IgG) and C3 staining along the basement membrane zone of a skin biopsy specimen and by the presence of circulating IgG recognizing the 180-kDa bullous pemphigoid antigen (BP180; type XVII collagen). A kidney biopsy specimen showed endocapillary inflammation without crescents. Direct immunofluorescence showed strong IgG and C3 staining in a combined granular and linear pattern along the glomerular basement membrane. Electron microscopy showed subepithelial deposits. In serum, no antibodies against the Goodpasture antigen (type IV collagen) or phospholipase A2 receptor were detected. Indirect immunofluorescence studies using the patient's serum showed a strikingly linear but not granular IgG pattern along the epithelial basement membranes of monkey esophagus and kidney. Although type XVII collagen was recently identified in the glomerulus, the patient's serum did not produce a 180-kDa band on immunoblot of kidney tissue and still stained glomeruli of BP180 knockout mice by indirect immunofluorescence. The patient was treated with prednisone and azathioprine, which resulted in complete remission of skin and kidney manifestations. Although bullous pemphigoid has been reported previously in association with anti-glomerular basement membrane disease or membranous nephropathy, this case demonstrates both elements in 1 patient. This concurrence and the linear pattern on indirect immunofluorescence support the possibility of cross-reactive or parallel autoantibodies to basement membranes with a secondary membranous component.

Antisense oligonucleotides have been explored widely in clinical trials and generally are considered to be nontoxic for the kidney, even at high concentrations. We report a case of toxic acute tubular injury in a healthy 56-year-old female volunteer after a pharmacologically active dose of a locked nucleic acid antisense oligonucleotide was administered. The patient received 3 weekly subcutaneous doses of experimental drug SPC5001, an antisense oligonucleotide directed against PCSK9 (proprotein convertase subtilisin/kexin type 9) that is under investigation as an agent to reduce low-density lipoprotein cholesterol levels. Five days after the last dose, the patient's serum creatinine level increased from 0.81 mg/dL at baseline (corresponding to an estimated glomerular filtration rate [eGFR] of 78 mL/min/1.73 m(2)) to 2.67 mg/dL (eGFR, 20 mL/min/1.73 m(2)), and this increase coincided with the presence of white blood cells, granular casts, and minimal hematuria on urine microscopy. The patient's serum creatinine level peaked at 3.81 mg/dL (eGFR, 13 mL/min/1.73 m(2)) 1 week after the last oligonucleotide dose. Kidney biopsy showed multifocal tubular necrosis and signs of oligonucleotide accumulation. Upon conservative treatment, the patient's serum creatinine level gradually decreased and reached her baseline level 44 days after the last oligonucleotide was administered. The patient recovered fully and kidney function was normal at every follow-up visit.

In lupus erythematosus, elevated serum creatinine levels and urinary abnormalities implicate a kidney disorder, which may not always be lupus nephritis as defined by the current classification of the International Society of Nephrology/Renal Pathology Society. The signs of renal dysfunction may be caused by lupus-unrelated renal injury such as drug toxicity or infection or by lupus-associated mechanisms that are not part of the classification, such as minimal change nephrotic syndrome or thrombotic microangiopathy. The latter seems to complicate lupus nephritis more frequently than previously thought. An unbiased assessment of kidney disease in lupus requires a kidney (re-)biopsy to define the appropriate management.

Glomerular injury can be caused by numerous insults including hemodynamics, infections and immunity, hereditary and metabolic diseases, and toxicity. Basic and translational experimental studies in combination with clinical research in patients with renal disease have advanced our understanding of the etiology and pathogenesis of many forms of glomerulonephritis. This new knowledge has facilitated classification and treatment and has contributed to a better outcome of patients with renal disease. Since renal disease almost without exception leads to systemic cardiovascular complications, these advances are also of general health interest. Here, we shall briefly review general principles in the pathology of glomerular injury and discuss recent developments in the study of podocytopathies; membranous glomerulopathy; ANCA-associated vasculitis; C3 glomerulopathies and the role of complement in endothelial injury; and the prognostic value of the renal biopsy in predicting long-term outcome in lupus nephritis, vasculitis and IgA nephropathy.

The biopsy report for nonneoplastic kidney diseases represents a complex integration of clinical data with light, immunofluorescence, and electron microscopic findings. Practice guidelines for the handling and processing of the renal biopsy have previously been created. However, specific guidelines for essential pathologic parameters that should be included in these pathology reports do not exist. The Renal Pathology Society has coordinated an effort through the formation of an ad hoc committee to enumerate the essential elements and pathologic parameters that should be reported for every biopsy specimen. This endeavor aims to establish a minimum reporting standard and to improve communication between pathologists and other physicians. This document represents the collective effort and consensus opinions of this ad hoc committee of the Renal Pathology Society.

The history of renal pathology can be divided into two eras: one starting with the invention of the microscope and its application to renal tissue; the second with the introduction of the renal biopsy, which coincided with the development of electron microscopy and immunofluorescence microscopy that allowed the analysis of pathological changes in great detail with an eye for pathogenesis and pathophysiology. These two eras started in 1650 and 1950, respectively; an interval of no less than three centuries during which clinicians and pathologists struggled with a lack of clear understanding of the causes and evolution of renal disease. In concordance with the design of this series on the history of pathology, we focus primarily on the history of renal pathology before 1970.

A 38-year-old female patient received her second deceased donor kidney transplant in January 2011. Two weeks after implantation she was re-admitted for a rise in creatinine. A percutaneous biopsy was taken for a suspected rejection, for which treatment (methylprednisolone and antithymocyte globulin) had already been initiated. Two days after the biopsy the patient had a hemoglobin level of 4.3mmol/l (compared with 6.1mmol/l before the biopsy), for which she received a blood transfusion with one unit of blood. An ultrasonography was performed; this demonstrated a hypoechogenic lesion in the lower pole of the kidney (30 × 20mm), a small fluid collection around the lower pole, and adequate vascular signals. Pathological examination of the biopsy showed a type 1 cellular rejection. The anti-rejection treatment failed, the patient was discharged and sent for hemodialysis. Three weeks after the biopsy the patient presented at our emergency department with hemodynamic instability and sudden massive hematuria. Blood testing showed a hemoglobin level of 3.2mmol/l, for which she received three units of blood. Computed tomography–angiography was performed; a hemorrhage was seen in the lower pole of the transplanted kidney (42 × 33mm) with a blush in the arterial phase. As she was progressively hemodynamically unstable and she had unsuccessfully been treated for biopsy-proven rejection, it was decided to perform an emergency transplantectomy. Macroscopic examination of the removed kidney demonstrated a contained hemorrhage directly next to the pyelum and part of the medulla, as well as surrounding necrosis (Figure 1). Pathological examination of the graft showed vascular rejection; C4d staining was negative. Additional slides through the biopsy tract were made for microscopic evaluation. Besides necrosis and hemorrhage, these slides also demonstrated destruction and vanishing of the arterial wall (Figure 2). Development of a (contained) pseudoaneurysm after percutaneous biopsy should be considered a potentially dangerous complication.Figure 2Microscopic image through the biopsy tract demonstrating necrosis, destruction of the arterial wall, and hemorrhage.View Large Image Figure ViewerDownload (PPT)

TGFβ1, -β2, and -β3 are involved in control of wound repair and development of fibrosis. Connective tissue growth factor expression is stimulated by all TGFβ isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGFβ1 or to facilitate interaction of TGFβ1 with its receptor, but its interactions with TGFβ isoforms in nonpathological conditions are unexplored sofar. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGFβ, we compared expression patterns of CTGF and TGFβ isoforms in rat and human glomerulogenesis, and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the commaand S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGFβ1, -β2 and -β3 protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGFβ2 and -β3 protein, and in absence of TGFβ1, CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGFβ1 and CTGF were again coexpressed, often with TGFβ2 and -β3, in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy. Coordinated expression of TGFβ isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGFβ1 and CTGF is associated with development of severe glomerulonephritis and

BACKGROUND/AIMS:Connective tissue growth factor (CTGF; CCN2) has been implicated as a marker and mediator of fibrosis in human and experimental renal disease.METHODS:We performed a comparative analysis of CTGF expression in hypertensive patients with and without nephrosclerosis, and in uninephrectomized and sham-operated spontaneously hypertensive rats (UNX-SHR and 2K-SHR).RESULTS:Urinary and plasma CTGF were elevated in patients with hypertensive nephrosclerosis, and increased renal CTGF expression was mainly localized in podocytes. Accordingly, elevation of urinary, plasma, and tissue CTGF in UNX-SHR coincided and correlated with proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis. Thirty-two weeks after uninephrectomy, mean glomerular CTGF mRNA expression was increased 1.3-fold over baseline, mainly due to 1.7-fold higher expression in glomeruli undergoing sclerosis. In parallel, tubulointerstitial CTGF and α-smooth muscle actin were upregulated in UNX-SHR. CTGF was increased in the media of arcuate and interlobar arteries, while arterioles remained negative.CONCLUSIONS:Glomerulosclerosis, tubulointerstitial fibrosis, and arterial media hypertrophy lesions of hypertensive nephrosclerosis are all characterized by increased CTGF tissue expression, which is associated with a concomitant increase in CTGF in blood and urine. These findings identify CTGF as a promising biomarker for progression of hypertensive nephrosclerosis, and as a likely key factor in the pathogenesis of this disease.

Transforming growth factor (TGF)-beta(1), -beta(2), and -beta(3) are involved in control of wound repair and development of fibrosis. Connective tissue growth factor (CTGF) expression is stimulated by all TGF-beta isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGF-beta(1) or to facilitate interaction of TGF-beta(1) with its receptor, but its interactions with TGF-beta isoforms in nonpathological conditions are unexplored so far. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGF-beta, we compared expression patterns of CTGF and TGF-beta isoforms in rat and human glomerulogenesis and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the comma- and S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGF-beta(1), -beta(2), and -beta(3) protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGF-beta(2) and -beta(3) protein, and in the absence of TGF-beta(1), CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGF-beta(1) and CTGF were again coexpressed, often with TGF-beta(2) and -beta(3), in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy (IgA NP). Coordinated expression of TGF-beta isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGF-beta(1) and CTGF is associated with development of severe glomerulonephritis and glomerulosclerosis.

BACKGROUND:Renal ischemia leads to apoptosis of tubular epithelial cells and results in decreased renal function. Tissue repair involves re-epithelialization of the tubular basement membrane. Survival of the tubular epithelium following ischemia is therefore important in the successful regeneration of renal tissue. The cytokine stem cell factor (SCF) has been shown to protect the tubular epithelium against apoptosis.METHODOLOGY/PRINCIPAL FINDINGS:In a mouse model for renal ischemia/reperfusion injury, we studied how expression of c-KIT on tubular epithelium and its ligand SCF protect cells against apoptosis. Administration of SCF specific antisense oligonucleotides significantly decreased specific staining of SCF following ischemia. Reduced SCF expression resulted in impaired renal function, increased tubular damage and increased tubular epithelial apoptosis, independent of inflammation. In an in vitro hypoxia model, stimulation of tubular epithelial cells with SCF activated survival signaling and decreased apoptosis.CONCLUSIONS/SIGNIFICANCE:Our data indicate an important role for c-KIT and SCF in mediating tubular epithelial cell survival via an autocrine pathway.

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.

On March 11, 2010, nephrologists and patients all over the world participated in the yearly World Kidney Day—an initiative to raise awareness of the importance of our kidneys for overall health. On March 13–17, the 2010 spring clinical meetings of the National Kidney Foundation took place in Orlando, FL, USA, which presented a unique opportunity to learn about new aspects of nephrology. Protect the kidney, protect the heartMany doctors may view nephrology as a remarkable kind of intensive care. A patient presents in an acute crisis, close to death. The creatinine is over a thousand. Immediate transfer to the renal team follows, then the magical effects of dialysis, and finally recovery. Nephrology is not for normal doctors. The kidney is for exceptionally skilled specialist physicians. Full-Text PDF Giuseppe Remuzzi—a pioneer in nephrologyA career in medicine looked unlikely for Giuseppe Remuzzi. Born in 1949, in Bergamo, Italy, he was raised in a family whose business was in marble, sculpture, and art. But an urge to help others switched his focus first to psychology and then to a medical degree at Milan University. Remuzzi's specialism in kidney medicine was pure chance—he needed a full-time job, and Bergamo Hospital had a vacancy in nephrology. Here he applied his knowledge of platelet function and coagulation to haemolytic-uraemic syndrome, which can lead to chronic kidney disease and renal replacement therapy. Full-Text PDF Genetic kidney diseasesKnowledge of the primary cause of a disease is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Recently, the causes of many kidney diseases have been shown to be single-gene defects—eg, steroid-resistant nephrotic syndrome, which is caused by podocin mutations in about 25% of children and nearly 15% of adults with the disease. Knowledge of a disease-causing mutation in a single-gene disorder represents one of the most robust diagnostic examples of personalised medicine because the mutation conveys an almost 100% risk of developing the disease by a defined age. Full-Text PDF Early recognition and prevention of chronic kidney diseaseChronic kidney disease is a common disorder and its prevalence is increasing worldwide. Early diagnosis on the basis of presence of proteinuria or reduced estimated glomerular filtration rate could permit early intervention to reduce the risks of cardiovascular events, kidney failure, and death that are associated with chronic kidney disease. In developed countries, screening for the disorder is most efficient when targeted at high-risk groups including elderly people and those with concomitant illness (such as diabetes, hypertension, or cardiovascular disease) or a family history of chronic kidney disease, although the role of screening in developing countries is not yet clear. Full-Text PDF Kidney regenerationNeonephrogenesis, the capacity to regenerate renal tissue, is a distinctive feature of fish but not usually of mammals. However, evidence exists for kidney repair in response to insulting agents for animals and human beings. Studies have therefore been designed in the past few years to clarify the cellular and molecular basis of renal repair, with the aim to investigate the potential regenerative capacity of animal and human kidneys. Three main questions are being addressed by this research: whether terminally differentiated cells in adult animal kidneys have regenerative capacity; whether multipotent progenitor cells exist in kidneys; and whether renal repair can be favoured or accelerated by cells of extrarenal origin migrating to the kidney in response to injury. Full-Text PDF

Acute pyelonephritis, frequently caused by Escherichia coli, is a substantial health problem. Plasminogen activator inhibitor type-1 (PAI-1) not only inhibits plasminogen activation but is also involved in cell migration. To determine if it has a role in host defense, we induced pyelonephritis in PAI-1 gene knockout and wild-type mice by intravesical inoculation with uropathogenic E. coli 1677. Bacterial growth was determined on blood agar plates in portions of the kidneys homogenized in sterile saline. Kidney levels of PAI-1 were increased in infected compared to control mice, suggesting a physiological role for PAI-1 during pyelonephritis. The knockout mice had significantly more bacterial outgrowth in kidney homogenates compared to the wild-type mice. Strikingly, higher colony-forming units were accompanied by increased levels of the cytokines TNF-alpha, IL-1 beta, and IL-6 in the kidneys of knockout mice, but levels of the chemokines KC and MIP-2 were not different. Remarkably, plasma levels of KC were higher, but renal neutrophil influx was significantly lower, in the knockout than in the wild-type mice. Our study shows that PAI-1 is critically involved in host defense against E. coli-induced acute pyelonephritis, in part, by modulating neutrophil influx.