Jan J. Weening

The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults

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.

Acute Kidney Injury During Therapy With an Antisense Oligonucleotide Directed Against PCSK9

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 patients 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 patients 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 patients 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.

Historical milestones in renal pathology

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.

Acute nephritic syndrome after anti-VEGF therapy for renal cell carcinoma

Sir, In a recent issue of Nephrol Dial Transplant, Poggio and Rule discuss the many inherent problems associated with estimating GFR (eGFR) by evaluating the fluctuation of serum creatinine [1]. Unfortunately, all renal biomarkers to date are influenced by a wide range of non-renal factors that can vary across different patient populations, disease states, diet and drug intake—both prescribed and over the counter. A great deal of effort has been devoted towards the development of correction formulas to improve the diagnostic value of biomarker-based estimates, MDRD being one example. Given the large number of variables—both known and unknown—eGFR tests are not likely to achieve the high level of accuracy, reproducibility and reliability associated with a measurement-based test. An accurate GFR test relies on measuring the renal clearance of a filtration probe under controlled conditions. Correctly administrated, a measured GFR test will provide the correct value. The general method to accurately measure GFR is simple and straightforward. The test requires a series of timed blood or timed blood and urine collections postadministration of the filtration probe and the test is completed in 4 h on average. Some nephrologists, many of whom have never performed this procedure, view the length of the test as a major clinical barrier. However, in terms of time, a measured GFR test is no longer than many other clinical diagnostic procedures used in other fields of medicine. At present, there are several different analytical methods available to measure the concentration of a filtration probe in collected samples. Most recently, an ELISA method that is both inexpensive and readily adaptable in most clinical laboratory settings has been reported [2]. Many recent papers suggest that there are urgent clinical settings where a measured GFR test is preferred, particularly in patient populations where kidney function is expected to be >60 ml/min/1.72 m2, such as healthy kidney donors, patients on nephrotoxic drugs, applications in clinical trials and risk stratification for interventional cardiovascular procedures. Moreover, a GFR measurement can compliment eGFR screening by providing a confirmatory test for early stages of CKD. Most papers discussing eGFR, including Poggio and Rule, state that an accurate GFR is important and eGFR values are unreliable in many clinical settings and that a measured GFR test is unfortunately ‘expensive and inconvenient.’ We believe that the technical impediments to obtaining an accurate GFR measurement have been removed and the field of nephrology can now advance to fulfilling its clinical needs with a measured GFR test using the diagnostic tools currently available.

BK virus nephropathy in an immunodeficient patient with chronic lymphocytic leukemia

BACKGROUNDnBK virus, genus polyomavirus, is known as an important cause of nephropathy (BKVN) in renal transplant patients. Cases of BKVN in native kidneys are rare.nnnOBJECTIVESnTo report a case of BKVN in a patient with chronic lymphocytic leukemia (CLL) and to examine viral and immune parameters.nnnSTUDY DESIGNnQuantitative BK virus DNA in plasma and relevant immune parameters were recorded in one CLL patient with BKVN and ten consecutive CLL patients without BKVN.nnnRESULTSnBKVN in the native kidneys of a CLL patient was histologically confirmed. The presence of BKVN correlated with immunologic parameters as well as factors known to cause renal tissue injury. BK viral load levels in the patient steadily increased and exceeded those of the control CLL patients.nnnCONCLUSIONSnThe results document a pathogenic role for BK virus in native kidneys of immuno-compromised CLL patients and indicate a role for quantitative BK virus DNA detection for early management of BKVN in native kidneys.

A position paper on standardizing the nonneoplastic kidney biopsy report.

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.

Diagnosis and treatment of HIV-associated nephropathy

Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological syndrome that occurs almost exclusively in black patients with an AIDS defining diagnosis. It is characterized by rapidly progressive renal failure with a severe nephrotic syndrome. The renal biopsy typically shows a collapsing glomerular sclerosis and variable tubulo-interstitial nephritis. The pathogenesis most likely involves infection of renal tubular and epithelial cells with HIV. The use of ACE-inhibitors and steroids may slow down the progression to end-stage renal failure. With the introduction of highly active anti-retroviral therapy, HIVAN may now be treated effectively although clinical data are so far limited to case-reports.

Bullous Pemphigoid With a Dual Pattern of Glomerular Immune Complex Disease

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 patients 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 patients 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.