Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece.

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

Tracing the roots of the idea of dialysis: a leap of 20 centuries--from "catharsis" to dialysis.

In this article, we comment on a primitive foresight of Galen's regarding the value of blood purification. His main arguments are based on: (i) The disease-blood concept, i.e., the idea that blood can be unclean (with an either excess or bad-quality humor) and thus cause a disease; (ii) Cure can be achieved if elimination (catharsis in Greek) of the humor (toxin) is possible; (iii) If the toxins are limited in the intravascular space, their elimination will be sufficient for cure by just a single attempt of replacing the unclean blood with pure; (iv) If the toxins have also affected the extravascular space, then repeated attempts will be needed; (v) The whole procedure can be compared with the insufficiency of washing once a dirty clay pot and immediately filling it with a pure liquid. The dirt that has adhered to the pot's walls will contaminate the pure liquid. Thus, repeated washing is needed to achieve cleanliness. Galen's metaphor of washing a dirty pot for a long period and eventually achieving a pure content is strikingly similar to the theory of hemodialysis. According to this, uremic toxins are spread both intravascularly and extravascularly. To eliminate them, long and repeated "washing" of the blood is needed. One of the reasons the first attempts to dialyze failed was that this "washing" procedure was inadequate (the other reasons were clotting of the blood, infections and access problems).

On some exotic urine colors in ancient and Byzantine Greek literature.

This work does not analyze the entire subject of uroscopy but focuses on a very small part thereof: i.e., some rare urine colors, in particular green and blue. These are so rare that most modern nephrologists have never encountered them. We conducted a small survey comparing contemporary knowledge with that of the past, with the participation of 40 Greek nephrologists (25 juniors and 15 seniors). Of these, 63% rejected the notion that green or blue urine even exists, while of those who were aware of them, only 20% had personally encountered them. According to our search of the modern literature, such colors result from either consumption of green or blue pigments, liver dysfunction or urine infection by certain bacteria. We searched and traced several passages on these rare urine colors, referred to in ancient Greek fewer than 7 different names, in the Greek medical literature of the Classical, Roman and Byzantine eras. In these passages, the authors not only gave detailed descriptions of the medical conditions of the corresponding patients but also explained this appearance of the urine. Surprisingly, in the studied texts we also found identical explanations with those in modern texts: consumption of certain foods, liver disease and inflammation. We present and comment on these passages, concluding that many uroscopical findings of antiquity were not quackery, but rather reliable medical statements based on thorough observation and rational reasoning.

The late Greco-Roman and Byzantine contribution towards the evolution of laboratory examinations of bodily excrement. Part 2: sputum, vomit, blood, sweat, autopsies.

Although the establishment of medical laboratory institutions was a continuous process that matured only after the 16th century, several attempts had already been made to attain a diagnosis by investigating bodily excrement. In the first part of our work, published in a previous issue of this journal, we presented data on urine, sperm, menses and stools. In this paper we present data on sputum, vomit, blood, sweat, and autopsies, thus completing the list of human materials used for laboratory examinations. All the data used are extracted from codices of Late Antiquity and Byzantium and translated by us. We did not study medical texts from the other great ancestors of Western medicine, namely Arabic and Jewish writings. From the texts cited, it is apparent that the lack of technological means was no obstacle for the doctor to create an "examinational" mind, i.e., to try to correlate the macroscopic findings in the excrement with the pathophysiological mechanism that induced them, solely with the use of the senses. This not only applies to the examination of urine, as is commonly assumed, but also to many other excrements of the upper and lower orifices of the body, as well as the human body as a whole.

The late Greco-Roman and Byzantine contribution to the evolution of laboratory examinations of bodily excrement. Part 1: Urine, sperm, menses and stools.

It is a common belief that laboratory investigation processes were developed after the 16th century and that before that time no attempts were made to attain a diagnosis by investigating material coming from the human body. In this paper we present data extracted from Byzantine codices that support the following thesis: The idea of examining human excrement for diagnostic purposes has its roots in the Roman and Byzantine eras. The lack of technological means was no obstacle for the doctor to create an "examinational" mind, i.e., to try to correlate the macroscopic findings in the excrement with the pathophysiological mechanism that induced it, using only the human senses.