Key words : Hemodialysis, Literature search, Nephrology, Peritoneal dialysis

Introduction

Nephrology is a medical specialty that has under-gone important scientific developments in the past 50 years. These developments have formally revolutionized clinical practice, namely, by renal biopsy, renal replacement therapy, and renal transplantation.^1,2

In addition to improved understanding of the pathogenesis and the clinical course of renal disease, there has been a renewal of definitions, classifications, and therapeutics in nephrology.^3,4 In this context, publications with nephrological content are also expanding.

The aim of our study was to determine the number of publications related to nephrology-specific key words as they appear in the PubMed database in order to analyze the time course of research in the field.^5,6 Furthermore, our aim was to confirm the reliability of such a bibliometric analysis and investigate its usefulness for future research planning. In this context, we applied a more specific search and analysis in a clear-cut nephrology field, namely, the pathophysiology of membranous nephropathy.

Materials and Methods

PubMed is a database of citations and abstracts for biomedical literature from MEDLINE and additional life science journals.⁷ Links are provided when full-text versions of the articles are available in PubMed Central or other websites (ie, publisher websites). PubMed Central is a digital archive of full-text biomedical and life sciences journal articles, including articles in clinical medicine and public health.

We used nephrology-related key words as search terms in the PubMed database: “nephrology,” “acute renal failure,” “renal biopsy,” “hemodialysis,” “peritoneal dialysis,” and “renal transplantation.” Additional terms of interest were chronic kidney disease and acute kidney injury. We also used the term “kidney” as an alternative to “renal.”

For reliability and usefulness of our analysis, we searched more specific terms, namely, “pathogenesis of membranous nephropathy” and “pathogenesis of Heymann nephritis.”

The search in the PubMed database (https://pubmed.ncbi.nlm.nih.gov) was conducted in May 2022. Based on the number of hits, we conducted a descriptive analysis of publication numbers and an exploration of the publication number time course.

Results

“Nephrology” as a term appeared 185 545 times in the database; its presence has rapidly expanding, especially in the past 3 decades since 1948. The yearly number of publications that included the term nephrology was 21.3 times higher when we compared 1991 versus 2021. During the same period, the number of publications in oncology increased 4.5 times (total number of publications was 4 014 539, with first oncology publication in 1890), and the number of publications that included the term cardiology increased 17.1 times (total number of publications was 456 644, first publication in 1914).

Renal biopsy appeared from 1943 in a total number of 18 048 publications. One publication on renal transplant appeared in 1946, and the total number of publications related to renal transplant was 106 075. We found the term “acute renal failure” for the time in 1932 in 1 publication and in a total number 92 278 of publications. Hemodialysis appeared in 182 730 citations. Peritoneal dialysis appeared in 32 266 citations.

With regard to the specific search on the research field of pathogenesis of membranous nephropathy, the search terms “pathogenesis of membranous nephropathy” and “pathogenesis of Heymann nephritis” both resulted in a similar number of hits (about 4800 hits). Furthermore, the graphs of the time course of the publication numbers were strikingly similar for both searches (Figure 1).

Such a similarity is obviously not incidental. Certain important publications on the pathogenesis of membranous nephropathy during this 70-year period had seminating effects on the subsequent number of publications and influenced the spikes (corresponding to increased numbers of publication during the period of time) in the PubMed graph of publication number.

Discussion

We used the PubMed database for all our searches because it is the largest electronic database that provides free access to biomedical and life science literature. Entries in PubMed are updated daily. PubMed offers a free and flexible search and has therefore become synonymous with medical literature searches. In contrast, Scopus, Web of Science, and Google Scholar cover most scientific areas. PubMed includes old MEDLINE, with Web of Science covering the oldest publications. Scopus includes publications from the year 1966 and Google Scholar later.

The PubMed system is developed and main-tained by the National Center for Biotechnology Information (NCBI) at the US National Library of Medicine, located at the National Institutes of Health. It is linked to several other databases, such as the National Library of Medicine, MEDLINE, and PubMed Central. Moreover, PubMed provides users access to abstracts of articles, reviews of articles, or options to access full text of publications.

Although PubMed provides a list of all indexed journals, it does not appropriately categorize them according to their professional content and nature. For this reason, we searched nephrology and the various nephrological diseases merely as word terms as we also did for cardiology and oncology. This kind of search is by no means complete; however, it is representative and gives a clear picture of publications in the field of nephrology. Furthermore, because the above PubMed searches include the same degree of methodological error, they are also suitable for comparisons.

Nephrology as a medical specialty began with kidney biopsy. Compared with peritoneal dialysis, transplantation, and certain kidney diseases, hemo-dialysis remains the most frequently used term in nephrology-related publications.

Our search showed a clear rise in nephrological publications, reflecting a real expansion of the field in the past decades. This expansion was comparable for cardiology and oncology. However, these 2 disciplines appeared much earlier, namely, at about the beginning of the 20th century, and with a much higher number of publications.

Furthermore, the time course of the numbers of publications on membranous nephropathy and its pathogenesis (Figure 1) is clear cut and self-explanatory. A more detailed explanation of this time course, namely, how certain important publications in the field had seminating effects leading to a visible rise of the subsequent number of publications, is described here.

In the 1950s, membranous nephropathy was first described by Jones.⁸ At the same time, Heymann nephritis was introduced as an experimental animal model with histological homologous findings by Heymann and colleagues.⁹ For both searches, the first publications in PubMed were in 1955. Heymann nephritis, induced by infusion of antibodies against antigens of the tubular brush border (ie, anti-Fx1a), was an important step in clarifying the existence and pathogenesis of passive Heymann nephritis.¹⁰ This clarification, in the 1970s, obviously led to a subsequent surge of the number of membranous pathogenesis-related publications in the PubMed database.

Nevertheless, the exact primary site of the autoantigen and of the immune-complex formation in Heymann nephritis remained unclear. It was unclear whether the antigen part of the renal podocytes was planted subepithelially or whether the immune complexes were primarily in the blood of the rats and subsequently the subepithelial deposits. These questions also remained unanswered for membranous glomerulopathy.

In 1978, the location of the antigen, at least for Heymann nephritis, in the kidney was clearly solved by 2 almost simultaneous publications.^11,12 Specifically, passive Heymann nephritis and subepithelial deposits were induced by anti-Fx1a BB antibody infusion in the model of the isolated perfused rat kidney. This finding excluded formation of the immune complexes primarily in blood or external subepithelial implantation of the autoantigen as the pathogenic mechanism for Heymann nephritis. Finding the certain epithelial target autoantigen remained open. These research efforts are shown in (Figure 1).

Finally, the autoantigen involved in Heymann nephritis was identified as a 300-kDa glycoprotein called megalin.¹³ Megalin (LDL receptor-related protein 2) is the autoantigen in Heymann nephritis. It acts in protein pinocytosis by ubiquitin mechanisms. In rats, megalin is found in tubular cells, podocytes, and placenta.

However, megalin has not been found either in human podocytes or in hypoepithelial deposits in human membranous nephropathy.¹⁴ The absence of megalin in the human kidney led to research disappointments and to an obvious flattening of the number of research publications on the pathogenesis of membranous glomerulopathy (Figure 1).

The next seminating research event was a case report of transient neonatal membranous nephro-pathy 2002.¹⁵ The patient’s mother was genetically deficient by a mutation of the gene for the glomerular protein neutral endopeptidase, and the fetus inherited the normal gene from the father. Antibodies against placenta endopeptidase, produced by the mother, were transferred to the fetus (allo-alloantibodies) to induce membranous nephropathy. Subepithelial deposits resulted from the immune complexes after the reaction of the alloantibodies with neutral endopeptidase on the fetal podocytes. Six months after birth, nephrotic syndrome subsided. This case report was followed by an increase in research activity in the field.

In 2009, the first autoantigen involved in the pathogenesis of idiopathic membranous nephropathy was eventually determined to phospholipase A2 receptor.¹⁶ This achievement was facilitated by technical developments in methodology and by holding the disulfide bonds intact for reaction with the putative membranous autoantibodies. This was accomplished by a reaction environment with an alkaline pH.

In addition to the phospholipase A2 receptor, thrombospondin, a second epithelial autoantigen shown to be involved in the pathogenesis of membranous nephropathy was described.¹⁷ The usefulness of these findings in clinical practice was further extensively explored.

In conclusion, our search on membranous nephropathy in the PubMed database (Figure 1) showed that analyzing publications on certain research topics can be useful to understanding the research and publication trends in these fields and in nephrology in general. The bibliometric analysis of specific research areas and fields is an important tool for future planning, especially as we are in the era of ever-expanding knowledge and expanded informa-tion sources and as we approach the new era of precision medicine.¹⁸

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