Clinical implications of serum anti-PLA2R levels and glomerular PLA2R deposits in primary membranous nephropathy


Introduction. The clinical implications of serum anti-PLA2R with glomerular PLA2R deposits in primary membranous nephropathy (PMN) is scarcely reported. Hence the study was designed to demonstrate the prevalence of serum anti-PLA2R levels and PLA2R staining in glomeruli in PMN and the clinical implications of the two parameters.

  1. Investigate the prevalence of anti PLA2R positivity in PMN.
  2. Ascertain correlation between serum anti-PLA2R levels and glomerular staining for PLA2R with clinical and lab parameters in PMN.

Patients and Methods. Fifty PMN patients during the period from October 2017 to December 2018 were included. Labs were done and eGFR was calculated as per MDRD 6. Anti-PLA2R titres were done in all patients. Titres more than 20 RU/ml were considered positive. Glomerular staining for PLA2R was graded on fresh frozen tissue by immunofluorescence technique.
Results. Anti-PLA2R antibody positivity and glomerular PLA2R deposition was observed in 42% (21/50) and 86% (43/50) patients respectively. 79.3% (23/29) had positive glomerular PLA2R deposition with negative serum anti PLA2R. Positive correlation were observed between serum PLA2R antibody and serum creatinine (p = 0.0001) and urine protein-creatinine ratio levels with tissue PLA2R staining grades (p = 0.04). Negative association was found between serum albumin (p = 0.026) and tissue PLA2R staining grades.
Conclusion. Serum anti-PLA2R wasn’t a sensitive marker of primary membranous nephropathy in our study group emphasising the need to consider a compendium of serological markers for diagnosis of primary membranous nephropathy and to rely more on glomerular deposition of PLA2R as a better clinical indicator for PMN.

Keywords: anti-PLA2R, Membranous Nephropathy, Glomerular PLA2R deposits, Tissue PLA2R staining, Nephrotic Syndrome


Membranous nephropathy (MN) is an important aetiology of adult onset nephrotic syndrome which is subclassified into primary (PMN) and secondary membranous nephropathy. Secondary membranous nephropathy is implicated in clinical scenarios such as cancer, autoimmune diseases and infections [1, 2]. PMN can be diagnosed on the basis of biomarkers like Anti PLA2R levels which can be useful in adjusting the therapeutic initiatives for management of the disease process. These biomarkers may be used to predict clinical consequences like decreased eGFR or proteinuria [3]. The discovery of phospholipase A2 receptor (PLA2R) antibody has contributed to an improvised understanding of the pathophysiology of PMN [4]. The specificity and sensitivity of PLA2R antibody for the PMN has been approximated to be around 100% [5] and 50% to 80% respectively [6]. Previous studies have tried to assess the utility of antibodies to PLA2R in clinical practice. However, there is a definite need for more studies to study the prevalence of glomerular PLA2R deposits, so that it can be applied as a diagnostic and prognostic test in the patients with PMN. 

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Pediatric Minimal Change Disease and AKI following the Pfizer-BioNTech COVID-19 Vaccine: causal or incidental correlation?


The global coronavirus 2019 (COVID-19) pandemic required vaccination even in children to reduce infection.
We report on the development of acute kidney injury (AKI) and minimal change disease (MCD) nephrotic syndrome (NS), shortly after the first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech).
A 12-year-old previously healthy boy was referred to our hospital with complaints of peripheral edema and nephrotic range proteinuria.
Nine days earlier he had received his first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech).
Seven days after injection, he developed leg edema, which rapidly progressed to anasarca with significant weight gain. On admission, serum creatinine was 1.3 mg/dL and 24-hour urinary protein excretion was 4 grams with fluid overload.
As kidney function continued to decline over the next days, empirical steroid treatment and renal replacement therapy with ultrafiltration were started and kidney biopsy was performed.
Seven days after steroid therapy, kidney function began to improve, gradually returning to normal.
The association of MCD, nephrotic syndrome and AKI hasn’t been previously described following the Pfizer-BioNTech COVID-19 vaccine in pediatric population, but this triad has been reported in adults.
We need further similar case reports to establish the real incidence of this possible vaccine side effect.

Keywords: nephrotic syndrome, Acute Kidney Injury (AKI), SARS-CoV-2 vaccines, pediatric population


The global coronavirus 2019 (COVID-19) pandemic has shown an evolution in morbidity and mortality in the last years.
The advent of the vaccine has made it possible to modify the natural history of the disease as well as its transmission globally.
SARS-CoV-2 vaccines has good effectiveness with limited side effects and low rate of adverse event, among adults and pediatric population.
We describe a case on the development of acute kidney injury (AKI) with MCD nephrotic syndrome, shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech).


Case report

A 12-year-old previously healthy boy was referred to our hospital with complaints of peripheral edema and nephrotic range proteinuria.
He received his first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) nine days before.
The first side effect was pain in the injection area.
He developed headache resistant to paracetamol seven days after injection, legs edema, which progressed to anasarca with significant weight gain from 65 kg to 76 kg.
On admission, blood pressure was 140/70 mmHg, and heart rate 80 beats/min.
Physical examination showed facial, upper and lower limbs and extremities edema, and evidence of ascites on POC ultrasound.
Previous laboratory test (13 months earlier) showed creatinine 0.78 mg/dL and negative protein urine test.
The patient and his family denied the use of non-steroidal anti-inflammatories and any other drugs-induced nephrotoxicity, before or after the vaccination.
Laboratory tests performed showed AKI with serum creatinine 1.3 mg/dL, serum urea nitrogen 85 mg/dL, albumin 2.2 g/dl, normal c3 and c4, negative ANA and ANCA testing. Molecular PCR test swab for SARS -CoV-2 was negative. Serology testing for HBV, HIV, HCV and SARS-CoV-2 was negative, but serology qualitative testing for SARS-CoV-2 for spike protein subunits S1 and S2 was positive for IgG. Urinalysis revealed proteins 185 mg/dL, β2 microglobulin 45 μg/L, and urinary sediment showed 10-15 red blood cells dysmorphic. Chest X-Ray was negative. The patient was admitted and intravenous infusion of human albumin (0,5 g/kg) was immediately administered; 24-hour urinary collection revealed proteinuria of 86 mg/m2/h.
In four days after the admission kidney function continued to decline: serum creatinine increased to 4 mg/dL and the patient developed fluid overload with dyspnea and oliguria resisted to furosemide, spironolakton and thiazide-diuretic. On day six renal replacement therapy (RRT) with ultrafiltration was started and kidney biopsy was performed. Light microscopy examination showed 11 glomeruli characterized exclusively by mild mesangial hypercellularity, tubular obstruction with cytoplasmic degeneration, and the presence of flaking elements in the lumen. Immunofluorescence was negative. Electron microscopy showed GBM with aspects of rehash, stretches of capillary wall with tortuous course, and aspects of collapse, swelling and extensive fusion of the pedicels and no electron-dense deposits. High-dose pulse intravenous steroids with 1 g of methylprednisolone (MEP) was given daily for three days, followed by oral PDN 60 mg daily. Seven days after the beginning of steroid therapy, kidney function began to improve with creatinine 1.82 mg/dL, albumin 3.2 g/dL, 24-hour urine collection for protein of 58 mg/m2/h, urine output increased, and renal replacement therapy was stopped after 5 sessions.
The patient was discharged in 15 days with a 10 kg weight loss, serum creatine 0.8 mg/dL, plasma albumin 3.1 g/dL, urinalysis showed no further proteinuria and protein-creatine ratio was 0.5. His blood pressure was well controlled. The patient continued oral PDN 60 mg daily for 4 weeks, and then taped down to 40 mg for 4 weeks. After 4 and 8 weeks of outpatient steroid therapy and on discontinuation at 12 weeks complete remission of nephrotic syndrome was maintained. Parents did not consent to the second vaccine dose.



Nephrotic syndrome is the most frequent glomerular disease in childhood. It is characterized by leakage of a large amount of proteins through the glomerular filter, leading to hypoalbuminemia, hyperlipidemia, decreased oncotic pressure, and edema. In overt forms, proteinuria exceeds 50 mg/kg/day or 40 mg/m2/h, and the urine protein/creatinine ratio is > 2 mg/mg [1].
Histological examination renal biopsy shows minimal change on light microscopy with negative immunofluorescence and unspecific electronic response. Whether MCD and focal segmental glomerulosclerosis are different entities or two extremes of the same disease is currently debated [2]. Anyway, data collected in past decades on the pathogenesis of NS show an immunologic dysfunction of both T and B cells, and also suggest podocyte’s direct role in activating cell pathways that cause proteinuria. Trigger events, such as viral infection, vaccination or allergens stimulate antigen-presenting cells (APCs) and activate T cells to induce cytokine release and B-cells to produce immunoglobulins. Several T-cell alterations have been described in NS: first of all, an imbalance between Th2 and Th1 Cell with an increase in production of Th2-specific interleukin 13 (IL-13), the reduction in frequency and function of T cells (T-regs) and the increase of Th17 cell activities. B cell pathway alterations have also been described, such as an increase in soluble form of CD23 (immunoglobulin-E receptor), a correlation between memory B cell repopulation and relapse after anti-CD20 therapy and circulating anti-CD40 autoantibodies. Moreover, the existence of other circulating permeability mediators (i.e. hemopexin, the soluble form of the urokinase-type plasminogen activator receptor, the cardiotrophin-like cytokine factor 1, and a hyposialylated form of the angiopoietin-like-4 glycoprotein) produced by abnormal T cell can directly affect podocytes and glomerular permeability barrier. In addition, podocytes can recognize microbial antigens by toll-like receptor (TLRs) and produce proteins leading to T-cells activation [3].
Throughout the literature, there are a lot of case reports that suggest a link between glomerular and autoimmune disease to immunization. MCD has been described after vaccinations against diseases such as meningitis C conjugate, influenza, hepatitis B, pneumococcus, diphtheria, tetanus, whooping cough, and measles. Moreover, some studies refer an increasing risk of relapsing subsequently vaccinations [410].
Additionally, evidence of temporal association between SARS-CoV-2 vaccinations and glomerular disease, including MCD with AKI and IgA nephropathy, is emerging in adults and in pediatric population [1113].
Nakawaza E. et al report the first case of nephrotic syndrome subsequent to BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A previously healthy 15-year-old Japanese boy presented proteinuria, hypertension, eyelid, and lower extremities edema 4 days after the first injection of vaccine. Evaluation for secondary glomerular disease was negative. Twenty-one days after vaccination, 60 mg of oral daily prednisolone was started. He achieved complete remission in 12 days without complications such as hypertension or acute kidney injury. Biopsy was not performed [14].
Pondtip J. et al describe in a healthy 14-year-old boy a nephrotic syndrome 5 days after the first injection of the SARS-CoV-2 BNT162b2 evolving in AKI (anuria and creatinine of 9 mg/dL) at day ten from vaccination. Secondary causes of glomerular disease were excluded. The patient received three daily doses of pulse methylprednisolone followed by oral prednisolone, 60 mg daily. He also received hemodialysis for 3 weeks. Light microscopy showed eighteen unremarkable glomeruli and diffuse tubular injury and interstitial inflammatory cell infiltration were noted. Immunofluorescence staining was negative. Electron microscopy showed diffuse foot process effacement, consistent with MCD [15].
Pella E. et al reported a case of an 18-year-old male adolescent who developed nephrotic syndrome eleven days after the first Pfizer-BioNTech injection. Diagnostic kidney biopsy showed no significant glomerular or tubular abnormalities in light microscopy with negative immunofluorescence and electronic picture referred to MCD. Treatment with methylprednisolone 48 mg daily was initiated and then tapered and leading to a complete remission six weeks later [16].
Our patient represents the second pediatric case reported of MCD subsequent to Pfizer-BioNTech vaccination. Differently we performed renal biopsy, despite not being recommended, because of the rapid decline of renal function and the need of hemodiafiltration. In addition to electronic picture of foot process effacement, on light microscopy we also found tubular obstruction and the presence of flaking element in lumen. We speculate that tubular involvement could be the cause of AKI.
All those cases showed typical clinical presentation characterized by vaccination, nephrotic syndrome, and AKI. In this report we described the first pediatric patient who experienced the same triad presented in adults; tubular edema with luminal obstruction and absence of significant glomerular change explained AKI evolution.
After vaccination, the vaccine’s antigen is presented to T-cells by dendritic cells resulting in activation of antigen-specific effector T cells, that peak between 7 and 14 days after vaccination.
It is not currently possible to establish whether the occurrence of AKI and MCD with nephrotic- syndrome is triggered by vaccination or completely random.
Vaccine-disease correlation is an exclusive diagnosis. Diagnosis is based on timing (7-14 days after vaccination) and exclusion of other triggers in the absence of conclusive means demonstrating a causal link.
We suggest that all patients who develop AKI and nephrotic syndrome following COVID-19 vaccine administration undergo renal biopsy in the immediately next days.
We suggest the use of steroids intravenously and subsequently per os with subsequent tapering down.
This therapeutic approach has proved to be useful as well as decisive in the case of our patient.
We await any other reports of similar cases to establish the true incidence of this possible important side effect of the vaccine.



  1. Eddy AA, Symons JM (2003) Nephrotic syndrome in childhood. Lancet 362(9384):629–639,
  2. Vivarelli M, Massella L, Ruggiero B, Emma F (2016) Minimal change disease. Clin J Am Soc Nephrol.
  3. Colucci, M., Corpetti, G., Emma, F., & Vivarelli, M. (2018). Immunology of idiopathic nephrotic syndrome. Pediatric Nephrology33(4), 573-584,
  4. Kielstein JT, Termühlen L, Sohn J, et al. Minimal change nephrotic syndrome in a 65-year-old patient following influenza vaccination. Clin Nephrol 2000;54:246–8.
  5. Gutiérrez S, Dotto B, Petiti JP, et al. Minimal change disease following influenza vaccination and acute renal failure: just a coincidence? Nefrologia 2012;32:414–5
  6. Macário F, Freitas L, Correia J, et al. Nephrotic syndrome after recombinant hepatitis B vaccine. Clin Nephrol 1995;43:349.
  7. Işlek I, Cengiz K, Cakir M, et al. Nephrotic syndrome following hepatitis B vaccination. Pediatr Nephrol 2000;14:89–90.
  8. Kikuchi Y, Imakiire T, Hyodo T, et al. Minimal change nephrotic syndrome, lymphadenopathy and hyperimmunoglobulinemia after immunization with a pneumococcal vaccine. Clin Nephrol 2002;58:68–72.
  9. Clajus C, Spiegel J, Bröcker V, et al. Minimal change nephrotic syndrome in an 82 year old patient following a tetanus-diphteria-poliomyelitis-vaccination. BMC Nephrol 2009;
  10. Kuzemko JA. Measles vaccination and the nephrotic syndrome. Br Med J 1972;4:665–6,
  11. Bomback AS, Kudose S, D’Agati VD. De novo and relapsing glomerulardiseases after COVID-19 vaccination: what do we know so far? Am J Kidney Dis. 2021;78(4):477-480.
  12. Niel O, Florescu C (2021) IgA nephropathy presenting as rapidly progressive glomerulonephritis following first dose of COVID-19 vaccine. Pediatr Nephrol.
  13. Wu HHL, Kalra PA, Chinnadurai R (2021) New-onset and relapsed kidney histopathology following COVID-19 vaccination: a systematic review. Vaccines.
  14. Nakawaza E.,Uchimura T., Hirai Y., Togashi H., Oyama Y., Inaba A., Shiga K., Ito S. New onset pediatric nephrotic Syndrome following Pfizer -BioNTech SARS-CV-2 vaccination: a case report and literature review. CEN Case rep
  15. Pondtip Jongvilaikasem and Pornpimol Rianthavorn. Minimal change disease and acute interstitial nephritis following SARS-CoV-2 BNT162b2 vaccination. Pediatr Nephrol. 2022 Jun
  16. Pella E, Sarafidis P, A, Alexandrou M, -E, Stangou M, Nikolaidou C, Kosmidis D, Papagianni A: De novo Minimal Change Disease in an Adolescent after Pfizer-BioNTech COVID-19 Vaccination: A Case Report. Case Rep Nephrol Dial 2022:44-49.

Kidney involvement in Waldenström’s disease – case report


Waldenström’s disease is a rare haematological neoplasm involving B lymphocytes, characterized by medullary infiltrated lymphoplasmacytic lymphoma and by the presence of a monoclonal M paraprotein. Although rarely, this condition may lead to heterogeneous renal involvement and cause severe renal failure.

We report the clinical case of a patient with overt nephrotic syndrome in Waldenström’s disease treated with a combination chemotherapy (rituximab, cyclophosphamide, dexamethasone) until complete renal and haematological remission.


Keywords: Waldenström’s disease, nephrotic syndrome, rituximab, cyclophosphamide, dexamethasone

Sorry, this entry is only available in Italian.


La malattia di Waldenström (WM) è una rara neoplasia ematologica coinvolgente i linfociti B, caratterizzata da un linfoma linfoplasmocitico con infiltrato midollare e dalla presenza di una paraproteina M monoclonale [1]. Essa rappresenta il 2% di tutte le neoplasie ematologiche, con un’incidenza annuale negli Stati Uniti di 0.57 su 100,000 persone, una età mediana di 71.5 anni al momento della diagnosi ed una maggiore prevalenza nel sesso maschile e nella etnia caucasica [2,3].

L’eziologia della WM non è conosciuta e le basi genetiche non sono ancora del tutto chiare. La cellula da cui origina la malattia sembra essere il linfocita B maturo ed attivo; attraverso fasi consecutive di mutazioni genetiche tale cellula dà origine ad un clone, dapprima benigno come gammopatia monoclonale di significato incerto (MGUS IgM) e successivamente maligno (WM) [4].


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The complex etiopathogenesis of focal segmental glomerulosclerosis


Focal segmental glomerulosclerosis (FSGS) is a pathological spectrum subtended by heterogeneous etiologies. A good knowledge of FSGS and its causes should be included in the nephrologists’ clinical background, as it deeply influences the subsequent management of the affected patients. In fact, while immunosuppressive treatment should be considered in idiopathic FSGS, the treatment of secondary forms should primarily aim at curing or containing the underpinning etiologic factors. Furthermore, in contrast to secondary FSGS, idiopathic FSGS tends to relapse after kidney transplantation.

Although FSGS has a wide spectrum of etiologies, several pathogenetic “moments” are shared. Furthermore, recent studies have identified a pool of glomerular cells potentially capable of regenerating lost podocytes; these cells might represent a promising therapeutic target.

The primary aim of this review is to describe the etiologic factors associated with FSGS, with a focus on the main pathogenetic mechanisms involved in its development.

Keywords: focal segmental glomerulosclerosis, nephrotic syndrome, podocytopathy

Sorry, this entry is only available in Italian.


La glomerulosclerosi focale segmentaria (GSFS) è stata storicamente definita come un pattern di danno glomerulare caratterizzato da sclerosi in parte del flocculo (segmentale) di una porzione variabile di glomeruli (focale) alla microscopia ottica di una biopsia renale [1]. Essa è attualmente una delle più frequenti cause di sindrome nefrosica, entità clinica con incidenza di 20-70 casi su 1000000 di persone/anno e prevalenza di 160 casi su 1000000 di persone; la GSFS, infatti, arriva a costituire fino al 25-40% dei casi totali di sindrome nefrosica dell’adulto e il 20% dei casi totali dell’infante [13], con una lieve predilezione per il sesso maschile (rapporto M:F = 1.5-2:1) [4, 5]. I tassi di incidenza medi riportati in letteratura globalmente sono compresi tra 2 e 11/1000000 di persone/anno [6]; è tuttavia importante sottolineare come, nelle ultime decadi, l’incidenza della GSFS abbia subito un incremento complessivo di 3-13 volte, a fronte di un relativo calo nella diagnosi di altre glomerulonefriti [2, 4, 7]. La GSFS è inoltre la glomerulonefrite primitiva associata al più elevato tasso di progressione verso l’insufficienza renale avanzata (end stage renal disease – ESRD), anch’esso in progressivo incremento: dal 1980 al 2000 è stato infatti riportato un incremento complessivo della proporzione di ESRD attribuibili alla GSFS di 11 volte (da 0.2% a 2.3%) [8]. Nel 2010 tale stima è ulteriormente salita al 4% [9].

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The application of philosophy and history of medicine in current medical practice. The Nephrotic Syndrome Example


Current medicine has banished all philosophical theories and systems and preserves only the facts, the data and the results of experience. However, according the belief of authors medical history and philosophy still continue producing apparent results upon the treatment of dilemmas in current medical practice. As an evidence of this belief a peculiar approach of nephrotic syndrome (one of the most debated issues in nephrology) in parallel with the aspects of medical history and philosophy was attempted.

The first empirical references from the earliest times of medical art, follow more defined rational and methodic classifications such as the clinical-etiological of Bright, the current histological and probably the forthcoming omics classification, of medical science.

The mystic period and the sacred numbers of Egyptians and Babylonians, the mathematical theories of Pythagoras have now been replaced by the sacred number of p<0,001 and the mystic of statistic values of random controlled clinical trials (RCT). According to the mentioned above current doctors could be considered as “eclectic” ones: they adopt the reports of beneficial experience (clinical guidelines), carefully and methodically controlled by RCT and follow the modern dogmas such as the individualization of therapy and cost/effectiveness relation combined with the diachronic one “the beneficence of the patient”. The remains of medical antiquity may now have little interest, especially in a didactic point of view; but they will always interest the “erudite” doctor, indicating the route followed by the science where the past is “dogmatic” in present and the present will be “empirical” in the future.


Key words: History, medicine, philosophy, nephrotic syndrome


The nephrotic syndrome (NS), the glomerular disease (GD) in generally, is one of the most debated and challenging issue for the clinical nephrology. The uncertainty concerning the GD is reflected by the low grade of the existed clinical guidelines, (only 2% of clinical guidelines are grade as A (1) and the unwilling of nephrologists, (15-46%) to adopted them as it was recorded from a Canadian study (2) two years after the KDIGO guidelines.

The clinical nephrologist stands uncertain in front of the GD, where the cause is unknown, the treatment unsafe and the future uncertain. This uncertainty was expressed in ancient Greek philosophy (the aphorism quotes the first two lines of the Aphorismi) (3) by the ancient Greek physician Hippocrates:

“Life is short, and art long, opportunity fleeting, experimentations perilous, and judgment difficult.”

The above mentioned observations were the trigger of wondering about the utility of medical history and philosophy in facing current dilemmas in daily medical practice. The belief that philosophy is a matter of great value when it can be redeemed in daily life and practice and additionally that philosophical theories still produce apparent results upon the current practice of medicine overarches the text below. In order to support this, a peculiar approach was attempted. The retrospection of history of medical science and philosophy in parallel with the history of NS and GD. This was an interesting challenge to consider: both continuity and change in the practices of medicine (what traditions did medical practitioners draw upon – even as they made radical innovations) and the relationship of medicine to its wider culture.



Science represents the only robust and trustworthy way of knowing both the world and the Mankind and could be a part of “… a new humanism a project that could bridge social, national and intellectual divisions just as the humanist movement had done a millennium earlier…” (6). Anciently philosophy embraced the whole human knowledge (physics, natural history, medicine, morals, metaphysics, theology, mathematics etc). Gradually many of these branches have been detached from the main trunk and constituted separate sciences. Historians take also seriously the point that before the early 19th century there was no such a thing as science but instead there was something called, natural philosophy, with much broader ultimately religious aims.

The discipline of the history of science concerns the history of the way nature has been manipulated, modeled and understood by different societies. History of science constantly reattaches itself to other disciplines in the humanities and social sciences and embraces a wide range of approaches. These link history of science to history of philosophy, medical history, social history, history of technology and many other historical disciplines.

In Europe a number of scientists turned to history to support their theories of scientific method what called philosophy of science. The assumption that the method and object of scientific practice demarcates it from all other human activities drew history of science and philosophy of science closely together. One could best discover a particular world view at any period or culture by looking at the sorts of problems addressed by its philosophers. In addition the central concepts of philosophy at any given time may be determining element of the nature of the scientific thought of that age. In the history of medicine, most of the medical theories derived more or less directly from some system of philosophy; consequently in estimating the merits of any theory or method of practice it becomes prominent to know from which of these emanated.

History of science has also allied itself move closely with developments in sociology of science and other historical disciplines (imperial history, economic and global history). This approach has to balance the intellectual history of science first to its social context (social history of science) and secondly to the technical accomplishments by adopting a more materialist view, with the integration of scientific instruments and their use (science of technology).

It is obvious that science has never flourished and been cultivated in the highest degree in any place where it has had no legal recognition. Science was usually conditioned by its social and historical contexts. In Ancient world the condition of organized theoretical knowledge or “episteme” had been that members of “leisured” classes devoted themselves to theory. Science had developed in the West from this disengaged basis and not elsewhere where there were great “bureaucracies” that were always hostile to independent scientific thought. The signal contribution of history of science has been to show the significance of relations between philosophical, historical, religious, social values in the development of science.


History of philosophy and medical science (7, 8) versus history of NS and GD

Science has been held to have a unique capacity to progress by providing us with true statements about nature. Scientific progress began when knowledge became more abstract and freed itself from its craft origins and then from unnecessary remaining metaphysical elements. Gradually became distinctive from other forms of human activity and progressed through operations that elevated it above and extricated itself from the plethora of superstitious metaphysical occultist and religious opinions that always held back its advance. The tenacious obedience to authority was disputed and there was a shift of human mind from the domain of purely speculative vague conjectures and dogmas to the actual study and collation of facts. New doctrines and scientific discoveries disputed the “authority” of the former time and surpassed dogmas which were not eliminated but attempts were made to reconstruct medicine upon “scientific” basis. Dogmatics who devoted themselves to philosophical speculations and the formation of theories gave their place to Empirics who gave their attention to the observation; their reasoning did not go beyond the observation and experience and placed nothing in the rank of positive and certain knowledge but the sensations.

The “scientists” started to observe the “unknown” and report the experience. Observation and memory which constitute experience were the principal faculties put in exercise: reason entered very little into their considerations.

Reports about NS dating back to Hippocrates. Generalized edema, referred to as dropsy in the earlier literature, and its correlation with renal disease has been documented by his observation: “when bubbles settle on the surface of the urine, it indicates a disease of the kidney and that the disease will be protracted (9). A rich history of observations and interpretations followed over the course of centuries until finally in 1827, an English clinician, Richard Bright, published his first book “Diseased Kidney in Dropsy” where a causal relationship between dropsy and anatomic changes in the kidney was established and the triad of generalized edema, proteinuria and kidney disease were the dominant features that defined the disease which from that time was called “Bright’s disease” (10). In 1833 Bright gave the Goulstonian lectures and he first described the rising of blood urea with advancing renal impairment (11). The full description of the clinical and gross morbid anatomical features of all stages of glomerular disease in Bright’s paper of 1836 is regarded as one of the classics of medical literature (12). The impact of his work was remarkable. His observations were quickly repeated in several centers and widely extended over the next decade. This was the empirical era of NS constituted only by observations concerning macroscopic symptoms where suggestions about reason were very cautious.

As the observations multiplied it became necessary to arrange them after a method which would impress them upon the previous acquired memory and experience. This was the origin of the first pathological classification. Mere experience report by occasional instinctive observations taken at hazard and gathered generally without taste or method; without the luxury of harmonious thought and premeditated design is an Art. It’s the combination of intelligence that investigates beyond the phenomena, the reason and the systematically arrangement of observations that transforms Art into Science. The Empirics were succeeded by the Methodists and observations that tend towards a common end were arranged systematically; both signaled the passage from Art to the Science of Medicine. In accordance with the above mentioned, as the experience concerning GD increases and the information multiplies, it becomes more obvious the need of classify them under some system and method. The method used to classify GD was based on three axes: clinical observation, etio/pathogenesis and histological findings. The initial “rough” clinical classification based on Bright’s Reports described cases of chronic NS. Acute nephritic related cases were also reported later. Another classification based on etio/pathogenesis arises as our knowledge and information about the causes of GD accumulated. Other immunological, genetic, metabolic causes are also involved in the pathogenesis of GD. However the “unknown” pathogenesis still has a dominant place and gives trigger for development of new theories and raising of new dilemmas and controversies.

The entrance of renal biopsy in 1950 was a revolution in the area of kidney disease and led to the emergence of a new specialty of nephropathology. There was a shift from the clinical/etiopathogenetic approach to the analysis of histological patterns. A grade range of morphological features appeared from “gross” findings on light microscopy (minimal change lesions, focal or diffused hypercellularity) to more complex and enriched descriptions with the support of immunofluorescence techniques and high revolution electron microscopy. Consequently the field of glomerular diseases dramatically augmented. New data are added in old clinical-histological entities and new diseases emerge such as immunotactoid GD, hereditary forms of GD, C3 glomerular disease. One the other hand the histological classification has its limitations; the most prominent one is that we don’t classify diseases but histological patterns and indeed patterns of limited “repertoire” since kidneys respond in a limited way to kidney damage. Therefore, certain histological patterns may be the end result of many different renal diseases and molecular pathways of progress of kidney injury. In other words different clinical manifestations may have similar histological findings while different histopathologies may be present to the same clinical entity. Consequently it became obvious in Renal Consensuses (13) that although the histological patterns are the only “scientific, objective observation” criteria we need to go beyond that to a more comprehensive classification where new data will be incorporated on the etiology/pathogenesis basis. Observation and classification are not enough in treating the GD. They may not be related to either clinical severity or prognosis and they do not always guarantee a clinical utility by determining the course of treatment.

Going back to the past. The Empirics assumed that in any given case only such remedies as had appeared to be valuable in similar cases, should be employed without any regard to the proximate cause of which they nothing reveals to us the mode of action. It was sufficient enough to show that they were able to cure in order to feel authorized to apply the same treatment to analogous cases. It was naturally supposed that the same remedy would relieve of a similar trouble and all similar cases should be treated in a like manner. No inquiry was made as to the mode of cure by the remedy. This attitude «treating without knowing” does not sound unfamiliar in medical practice even in recent days, representative examples the “early” use of aspirin and corticosteroids. The initial treatment of NS included resting and lowering the protein uptake in order to reduce the renal load, a therapeutic strategy that is followed even in now days. In 1950 the Nobel Prize in Physiology or Medicine was awarded jointly to Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”. The whole story began by an observation. Kendal in the course of his work he observed the favorable effects of jaundice on arthritic patients, causing remission of pain. Other bodily changes, for example pregnancy produced the same effect. These and other observations led him gradually to the conclusion that the pain-alleviating substance was steroid. In the period 1930-1938 Kendal and his collaborators had isolated several steroids from the adrenal gland cortex one of which was initially called Compound E. Working with physician Philip Showalter Hench, Compound E was used to treat rheumatoid arthritis. The compound was eventually named cortisone (14). The excellent response to new treatment mainly in cases of minimal change GD in pediatric patients and other types of GD had established corticosteroids as a corner stone not only for the treatment but also as a prognostic marker of the outcome of GD.

However, it was proved, once again that observation and empirical treatment is not enough. It has been several decades since then but there are still dilemmas that oscillate the clinicians. There is a need once again to go beyond the experience, behind the phenomena discovering new pathogenetic pathways. New players of humoral and cellular immunity are introduced in the field of renal injury. The recognition and understanding of their role has led to the introduction of new more specific, effective and targeted therapies (15). But the response to therapy is not always the desirable one. Except the cortico-resistant forms of GD, new forms of resistant nephrotic syndrome appear like cyclosporine, mycophenolate resistant forms. We could say that treatment strategies offer a picture of a republic delivered up to many rival factions which dominate but turns without ever obtaining lasting power. What exactly is going on? Maybe the past will help us to find the answer. A basic doctrine of the philosophy of causes says that the same factors placed under identical conditions will always produce the same result. But in medicine this is different: here nature and accidents ie. diseases, furnish us the opportunities of experimenting: but in the first place the elements (patients) of these experiments and the diseases (glomerulopathies with great heterogeneity) are never identical; and secondly it is impossible to isolate the patients from a multitude of influences that alter the therapeutical results. Another fundamental principal is expressed by the aphorism: contraria contrariis curantur. It was held that always exists a species of antagonism between the cause of the morbid phenomena and the active properties of the remedies that cured them; or rather between the pathological modification of the organism and the curative impulse given to the economy by the treatment.

Freedom of thought and expression are necessary prerequisites for any science to flourish. The right of free choice is the most dominant one. The history of medicine teach us that in the face of dilemmas about theories and treatments there was a cast of physicians the Eclectics who professed to select such principles and modes of practice as appeared to them the most valuable and beneficial for the patient. Their object seemed to be a reconciliation of the tenets of Methodists (classification of knowledge) with those of the Dogmatics (dogmas, principles and theories) and Empirics (observation and experience). Current doctors could be considered as “eclectic” ones: they adopt the reports of beneficial experience (clinical guidelines), carefully and methodically controlled by random controlled trials (RCT) and follow the modern dogmas such as the individualization of therapy and cost/effectiveness relation combined with the diachronic one “the beneficence of the patient”.

As medical science gradually detached from philosophy and humanities was influenced and supported by other “applied” sciences such as physics, chemistry, mathematics. The first link was made at the time of Pythagoras, but the few fragments of this mathematical system that are left serve more as proof of its existence than for its understanding,. Those who wrote them use a “jargon” that is supposed to be known in the same way that modern scientists use algebraic, statistical characters etc. The language of the numbers used by the Pythagoreans is lost. Now days the sacred numbers 1, 2, 3 7 have been replaced by the sacred number of p<0.001 and the mystery of statistic values of randomized double blind studies. But in the case of GD they are “weak” due to: a) the few number of patients b)the slow progression of the disease c) the differences in data classification as well as in types of histological patterns. All these impede the reliable comparison of the data and the creation of a basic reliable multicenter study. Consequently the mathematically “evidence –based” well doing of treating GD has been limited by poor availability of large comprehensive registries.

The basic sciences, systems biology, molecular biology and omics are the rapidly advancing, innovating and promising fields in molecular mechanisms underlying the diverse etiologies of GD. It is the answer of now days offering a “storm” of new information and entirely new fields in its investigation. Large-scale gene, protein and metabolite measurements (‘omics’) have driven the resolution of biology to an unprecedented high definition. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these high-throughput technologies unveiling their full potential. The omic cascade, from the potentiality of ‘what can happen’(genome) through ‘what appears to happen’ (transcriptome) and ‘what makes it happen’ ( proteome) to ‘what has happened’ (metabolome), embodies the paradigm of what needs to be modelled. Integration will unveil the full potential of these high-throughput technologies leading to a comprehensive decoding of the upper emergent level, the phenotype and the key to decoding the underlying principles that govern the complex functions of living systems. Systems biology is a novel field pitched at decoding -omic dynamic interactions and adding an additional dimension to that of a classical homeostatic model of physiology (16, 17). In the near future omics will improve the classification of GD (in addition to clinical, etio/pathogenesis, histological the omics one) to a more sophisticated model. Finally there will be a radical moving from empirical to stratified and individualized medicine which will depend on refined molecular fingerprints.

These modern sciences will modify the traditional deductive model of scientific knowledge (scientific knowledge is hypothesis established on valid rationally and after research proven true statements) or even the more radical one related to Popper’s philosophy of empirical falsification (A theory in the empirical sciences can never be proven, but it can be falsified) to an unbiased model without prior hypothesis but first gathering data and then generating hypothesis after analysis and modeling.

Churchill once said as he was “bombarding” by the claims of the Balkan nations that … “they produce more history than they can consume…” In analogy we now produce more information and data than we can incorporate into the daily clinical practice. This creating a demand for effective storage (data bases), management and exchange of rapidly generated data and research discoveries. Databases are divided into two categories: general databases with a broad information scope and kidney specific databases distinctively concentrated on kidney pathologies. In research, databases can be used as a rich source of information about pathophysiological mechanisms and molecular targets. In the future, databases will support clinicians with their decisions, providing better and faster diagnoses and setting the direction towards more preventive, personalized medicine.

It is a fact that modern medicine rejects from medical practice any kind of system and philosophical theories and insists on the value of pure scientific evidence based data alone. However this may sound utopian when the “philosophy of physician’s attitude” about the welfare, disease and health determines his attitude towards healing. A science that deals with the mystery of life cannot be complete if it deals only with its empirical/scientific part. A major part of individualization of treatment in medicine relies on the “holistic” view of life and disease.

The clinical nephrologist still wanders around in the labyrinth of NS resulting usually in “minotauric dead ends” searching for the ball of yam (mitos) in order to find his way out.



This retrospection does not allude that that the progress of the science and the acquisition of knowledge is a circular game incessantly repeating. From Aristotle and Kant to Popper and model of systems biology, each era has its own “cognitive” model of approaching knowledge. Nevertheless knowing the history and philosophy of the science that we practice, it is not only a privilege of an erudite man but also make us more broad minded in, understanding, individualizing and treating current unknown under research issues indicating the route followed by the science where the past is dogmatic in the present and the present will be empirical in the future so that every current generation will be the empirical candidate of the future.



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