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b) Summary of Doctorate work

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  • 1. Riga Stradins University Aivars Pētersons Monograph HOW TO DISCOVER AND TREAT RENAL DISEASES: to contribute systemic scientific approach in nephrology with particular implication on introduction of peritoneal dialysis (renal replacement therapy) in Latvia and to expand the role of renal ultrasonoscopy in the nephrologists' practice Doctorate work for doctor degree of medical sciences in internal diseases /specialty - nephrology/ Riga, 2005
  • 2. The Doctorate work has been performed in the Centre of Nephrology of P. Stradiņš Clinical University hospital from 1996 to 1998 and continued till the year 2005 for works mentioned in the list of publications. Work manager: Prof. Aivars Lejnieks Reviewers: Prof. Andrejs Kalvelis Prof. Vytautas Kuzminskis, Kaunas, Lietuva Prof. Valdis Pīrags Introduction The Doctorate work is based on the book of A. Petersons, E. Veverbrants, I. Lazovskis "How to discover and treat renal diseases" (580 pages, published on 1998, Riga, author's edition of A. Petersons, impression 1800 copies). The book is made as a monograph of A. Petersons with participation of both inspirers of the work, teachers and nephrology experts - Prof llmars Lazovskis (chapter on the history of nephrology; 3% of the total amount)
  • 3. and Prof Egils Veverbrants (chapter "Acid/alkali balance"; 9% of the total amount). The basis of the Doctorate work, working with a monograph "How to discover and treat renal diseases" has been performed in P. Stradins Clinical University hospital, Center of Nephrology from 1996 till 1998 and continued till the year 2005 for works mentioned in the list of publications. The monograph has served as a mean both for introduction of peritoneal dialysis in Latvia and more extended integration of renal ultrasonoscopy in the nephrological practice. The amount of specific nephrological knowledge defined in the monograph has influenced the development of clinical practice based on scientifically justified evidences, including more extended use of glomerulonephritis morphological classification. In addition, the monograph has not lost its importance when evaluated after some time. Topicality of the work Nephrology as a specialty is undergoing rapid and radical changes over last 20 years. Among disciplines of internal medicine due to development of modern technologies, probably only in cardiology the same serious development and changes of the specialty content may be observed. At baseline nephrology science (Hamburger, 1963) was engaged in research and treatment of renal diseases, but nowadays 80% of the nephrologists's attention and time is devoted to renal replacement therapy (RRT) (haemodialysis, peritoneal dialysis, kidney transplantation) and associated problems that both clinically and scientifically include all organ systems of the human body. In the practical medicine in Latvia from vital organs at sufficient amount for public only kidneys may be replaced (at small amount also heart and stem cell transplantation is being performed). As known, in other developed countries also liver, lung and pancreas may be transplanted, but no technological replacement methods for these organs are available. RRT is a life saving therapy and its costs are very high.
  • 4. Therefore scientifically justified choice of the treatment method, control and development may not be overestimated. After recovery of independence in the nephrology in Latvia a big influence of soviet traditions has been observed. The clinical nephrology has developed separately from hemodialysis and kidney transplantation. Peritoneal dialysis for first patients was started only on 1994 with large organizational problems. In the resident program of nephrology established at Riga Stradins university on the basis of P. Stradins hospital Nephrology centers it was impossible to get all the necessary knowledge in Latvian, particularly detailed description of renal replacement methods, including peritoneal dialysis, morphological classification of glomerulopathies etc. Therefore availability of up-to-date scientifically grounded material was very important and actual for the development of the field. Figure 1. Principal sheme of peritoneal dialysis (Inflow bag on the right side, then intraabdominal dwell, and outflow (left), attaching system 4 times daily as a standart) Peritoneal dialysis (PD) is one of 3 (also hemodialysis and kidney transplantation) renal replacement therapy methods used when the patient kidneys are loosing their function due to disease.
  • 5. Using natural functions of peritoneum as a filter, with peritoneal dialysis it is possible to qualitatively maintain life for patients up to 20 years. In the middle of 80-ies due to development of PD technologies and reduction of the risk of major complications (peritonitis) this method has been used wider and wider all over the world. Proportion of PD among dialysis patients in different countries varies widely (see table 1), but on average it constituents approximately 20 to 40%. At most the frequency of PD is influenced by the medical funding model and the level of prosperity of the state (PD is cheaper by up to 30% than HD), religion, traditions, social situation. Table 1. Proportion of peritoneal dialysis among dialysis patients (National registers - ANZDATA, UK Renal Registry, ADR, USRDS 2002) The main advantages of PD in comparison to hemodialysis (HD) are the following: 1)low price - in developed countries up to -30%, 2)maintains residual renal function for long time allowing better control of fluid exchange, 3)gives an opportunity to live for people living far away from nephrology centers, 4)provides more active life style in the aspect of work and traveling, etc.
  • 6. Disadvantages of PD in comparison to HD are the risk of abdominal cavity infection, reduction of peritoneal function after 4 to 7 years, lower intensity and dose limitations for bigger individuals. Results of modern studies suggest that 3 renal replacement therapy methods do not compete mutually, but collaborate in the interests of the patient and where scientifically and medically motivated choice of RRT is implemented; all three of them are used in a dynamic complex. In addition, lege artis PD should be used as the first method (Fenton S. et al, 1997). Later when reduction of peritoneal function and/or residual renal function occurs, planned switch to hemodialysis may be performed. It is established that advantages of PD concerning the risk of mortality and morbidity in comparison to HD becomes equal after 2 to 4 years of dialysis (Vonesh E, 1997; Blake P, 1998). Possibilities of kidney transplantation may be used by maximum both in PD and HD patients. After transplantation, if necessary, patients mostly continue with hemodialysis or in the absence of vascular access - with peritoneal dialysis. Till 1994 in Latvia this third renal replacement therapy method was not available. Peritoneal dialysis has been introduced in the Nephrology centre of P. Stradins clinical university hospital from 1994, starting with 2 patients and meeting large organizational and financial difficulties. There was also no complete information on the scientific background of the method and possibilities of use in our conditions. They were characterized by poor social guaranties for inhabitants, questionable hygienic conditions, insufficient network of the out-patient medical care, lack of nephrologists and complete lack of information on peritoneal dialysis. When starting introduction of peritoneal dialysis a necessity of wide study on the scientific background of the method among other renal replacement therapy methods, as well as on practice of different centers in adaptation of the method for local conditions becomes actual. Ultrasonoscopy (US) is a non-invasive, informative, harmless, rapid and cheap image diagnostic method. With progression of US technology it as the one available only for radiologists in 80-ies now has been used also in other fields - particularly
  • 7. in gynecology and cardiology. The informativeness of the US method depends largely not only on the equipment quality, but especiallyon its user-specialist competence in particular specialty. Therefore large advantages has the nephrologists himself when examining a nephrological problem with US. From 1986 nephrologists have started to use US in their everyday practice in Kidney transplantation and Nephrology centers of P. Stradins hospital. This practice is introduced, gives invaluable information and operativeness, economic benefit and findings of additional symptoms. It was very essential to collect this experience, analyze it, offer for critical review of other colleagues as a methodological mean, include US as an integral part in the amount of specific nephrological knowledge. We considered that not less actual task is to advance particular hypotheses for further studies (diagnostic importance of renal pyramides in interstitial nephritis, the role of parenchymal oedema in evaluation of diabetes, the role of cortical hyperechogenicity in graduation of chronic renal disease etc.). Till the middle of 90-ies in the nephrology practice clinical classification of glomerulonephrites (GN) by Tareyev (Tapeeb EM, 1975) has been used. However in the USA and Western Europe glomerulonephrites are classified mostly by their morphologic picture or at the syndrome level - by the leading syndrome, also in everyday practice. Although the morphologic picture of GN has been outlined also in Latvian sources (Bruveris, Cernevskis, Lazovskis, 1990), however at the level of general classification with corresponding treatment methods and clinical syndrome it has not been used. Thus very actual is a scientifically grounded choice, introduction and use in the nephrology practice of CN classification by morphologic forms. In parallel to this process it was necessary to activate and optimize morphologic examination methods (PAS, immuno hystochemistry, electron microscopy), from which to a large extent depends nephrological quality in the light of morphological classification. Particularly actual in the aspect of clinical nephrology is correct detection of renal function, as well as detection of early renal dysfunction signs - minimally reduced glomerular filtration rate (GFR) and microalbuminuria. More and more studies indicate
  • 8. that these both symptoms are serious, independent factors of high cardiovascular risk (Ritz E. et al, 2004). If the prevalence of terminal renal failure requiring huge and increasing funding is relatively small, than cardiovascular diseases, the background of which probably is a minimal undiagnosed renal dysfunction, is a much more larger burden for society both in the aspect of survival, quality of life and medical expenses. Therefore research of issues associated with renal function and prescribing of treatment is invaluably actual problem of modern internal diseases. Targets of the job 1.To create a scientifically sound, contemporary, scientifically referenced minimum knowledge supply necessary for any nephrologist. 2.To analyze literature about optimal possibilities of PD usage in Latvia and to record the first experience about problems of implementation of this kidney replacement therapy method. 3.To implement and develop scientifically proven, common principles of PD usage in Latvia. 4.To trace the role of kidney US in nephrology practise and to highlight hypothesesis about US symptoms based on observations. 5.To create a scientifically sound classification based on GN clinical syndrome and morphological picture and to implement it in Latvia through motivations and descriptions. 6.To provide detailed analyses and information about early functional renal examinations (GFR, MAU), considering their significant effect on cardiovascular risk in population. Tasks of the job 1.To perform detailed analyses of literature about each target question. 2.To select, complement with experience of our centre and
  • 9. record conclusions in an easy to publish and understand way. 3.To create basis for further researches with references to originals, as well as to promote a discussion about problems of clinical nephrology basing on research studies. 4.To assess influence of the monograph on nephrological clinical studies and development of clinical practise. 5.To turn attention to language and terminology questions in the field considering the size of edition which includes all aspects of nephrology. Novelty of the job 1.For the first time in Latvia - selected, referenced in the text, essential and sufficient data intended for contemporary nephrologist have been included in one book. 2.For the first time in Latvia - a detailed review of scientific basis and practical usage of peritoneal dialysis method (kidney replacement therapy) has been created. 3.On the ground of basis worked out in monograph following has happened in Latvia: a. scientifically sound methodology has been created for PD usage, b. a stabile managerial structure of PD has been created on national level, c. a data base of dynamic observations of PD patients has been created in the Nephrology centre of P. Stradins Clinical Hospital. 4.Analyses, detailed descriptions and illustrations about usage and implementation of ultrasonography method in nephrology has for the first time been given in special literature of nephrology. 5.The job conveys hypothesis about relation between separate US symptoms and certain nephropathy, the meaning of which have been proved in clinical practise. 6.Close correlation of clinical syndrome and morphological picture has been used and implemented in classification of glomerulonephritis for the first time in Latvia.
  • 10. 7. Basis for referenced data base in nephrology field in Latvian has been created for the very first time. Job structure and size Monograph „How to discover and treat renal impairments" is written in Latvian language. It includes 20 chapters, 530 pages, 60 tables, 200 pictures, 660 references to the literature in the text Most of ultrasonography images have been fixed in the result of clinical observations of the author. Pictures illustrating essential data about morphology of glomerulopathia have been obtained due to cooperation with internationally well-known nephropathologists - Prof. Helmut Rennke and Prof. Jan Weening, as well as from personal archive of Prof. Egils Veverbrants. Results and discussion In the monograph „How to discover and treat kidney impairments" all aspects of modern nephrology have been considered, including clinical nephrology with arterial hypertension and renal pathomorphology, problems of water-salt balance, problems of alkaline-acid balance, kidney replacement therapy - either hemodialysis and peritoneal dyalisis, and principles of renal transplantation. All the themes are described in an analytical way basing on most important cognitive sources in nephrology, original research studies. Selection has been made basing on practical experience of authors in the field. Attempts are made to give most of the references straight in the text (referenced). It facilitates the reader to use source materials, promotes scientific discussion, creates basis for further elaboration of the data base. Similar contemporary monograph is not yet available in Estonia, Lithuania or Finland. It has been widely used not only in the references of other trials, in scientific and public articles, but has served as cognitive source of minimum necessary knowledge
  • 11. in Latvian for residents of internal diseases and nephrology, nephrologists, professionals who are trained in peritoneal dialysis method, e.c.t. Table 2. Dynamics of development of PD program in Latvia (data of LNSR) Successful development of state program of peritoneal dialysis may be considered as one of benefits from publication of the monograph. Program of peritoneal dialysis in Latvia was started with 2 patients in the Nephrology Centre of P.Stradins Clinical Hospital in 1994. Henceforward despite of all difficulties the number of patients treated with PD is growing (see table 2). By the help of our Nephrology Centre, PD method was initiated in Nephrology centres of Children's Hospital, Gailezers Hospital, which currently are acting as completely independent centres and also in Nephrology Centres of Valmiera and Liepaja Hospitals. PD problem investigation in the monography „How to discover and treat renal impairments?" serves as study aid for safe and precise usage and implementationofthe method in big Nephrologycentres. It has helped many people for whom dialysis and consequential survival was not possible before PD implementation. This mainly refers to patients who live far from Nephrology centres, elderly people and children, diabetics and persons with different special needs with moving difficulties, et c.
  • 12. Table 3. Penetrance of PD method in dialysis (data of LNSR) Either in the monograph and after it's publishing it was practically proved that PD method does not compete with other RRT methods, but mutually reinforce each other. Good renal transplantation results were observed in patients who had received PD. It has proved to be beneficial as also first RRT in patients with maintained residual function of kidneys. Patients, who have protractedly received hemodyalisis (which is the main and most intensive method of dialysis) may experience vascular problems and if transplantation is impossible, only PD may be helpful. The above mentioned and several other criteria, including financial aspects, form rational proportion of peritoneal dialysis and hemodialysis in countries where choice of a certain RRT method is not influenced by private financial interests. PD is at optimum used in 20 - 30% of dialysis patients. Due to scientific approach and education, which has been promoted by this monograph, proportion of PD among the other dialysis methods in Latvia comes close to optimum (see Table 3) Detailed studies, selection and pictorial description of US symptoms characteristic to renal diseases has been performed. Algorithms of interpretation of similar US examination results depending on a patient's clinical condition have been offered. It is suggested to implement a 4 stage classification for cortical
  • 13. echogenity US description (Hricak H, 1982). It's advantages have been tested in long-term practical observations as well as through analyses of cortical echogenity related available literature. Looking retrospectively classification of Hricak has turned out to be useful and has widely spread among nephrologists and radiologists in Latvia. Figure 2. - 5. Grading of renal cortical echogenicity (Grade 0-3, Hricak) A conception about usage of US in nephrology practise has been risen and motivated. Such approach in 1998 was observed only in some centres of Germany (Koeppen-Hagemann, 1992) and France, but in other countries, especially in USA ultrasonoscopy was under responsibility of radiologists, moreover radiologists
  • 14. were only analyzing standard images obtained by technicians. Recently (Neil, 2002) USA also starts developing gradually the nephrological way of US examination which is particularly described in our monograph. Morphological classification of glomerulopathias has been used for detailed analyses of pathogenesis and therapy possibilities of separate diseases. It has for the first time been completely reviewed and used as basic classification for glomerulonephritis. Associations with clinical glomerulal syndomes - nephrotic and nephritic - have been highlighted and motivated. Figure 6. FSGS in light microscopy (PAS) Figure 7. IgA nephropathy (immunperoxidase)
  • 15. Pathologies with variable study results or contradictory opinions of different authors have been handled through scientific discussion and open polemics. It has been reflected in the job. For example, 1) status of minimal change glomerulonephritis (MCG) as an independent disease or as part of focal segmental glomerulosclerosis (FSGS), 2) debated hypothesis about similarity or direct pathogenetic relation of IgA nephropathy to Henoch-Scheonlein purpura (HSP). 3) Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura are included in a wider pathogenically sound group - thrombotic microangiopathy (TMA), 4) Not so widely used, but very practical 3-type division of rapidly progressive glomerulonephritis (RPGN) has been used. The significant role of AKI for almost all patients with increased blood-pressure or chronic renal disease has been highlighted in the job. After 1998 when the monograph was published the meaning of this therapy has been proven in new controlled studies Additional hypothesis raised in the job 1.US oedema symptoms of renal parenchyme (thickness > 15 mm; kidney length > 12 cm; and cortical hypoechogenity) in patients with short medical history of Type 1 diabetes mellitus can indicate to diabetic metabolic decompensation and glomerular hyperfiltration. 2.Increased echogenity of medullar pyramids may indicate to an acute intersticial nephritis and may help in differential diagnosis between mostly intersticial or glomerular impairment. 3.US of kidneys should be preferably performed by the nephrologist him-/herself on everyday basis.
  • 16. Conclusions 1.The extent of specific knowledge and scientific conclusions in nephrology should include the minimum which is reviewed in the monograph and basically complies with UEMS recommendations. 2.Also in Latvia PD is an effective kidney replacement therapy method which does not compete with other methods, but successfully incorporates in the common therapy complex. 3.The inclusion of US in the range of routine examinations of nephrologists, especially if it is performed by a specialist him-/herself significantly improves quality of diagnostics and rate of examinations. 4.Cortical echogenity of kidneys, signs of oedema and the type of medullar pyramids in US are relatively specific symptoms for certain renal diseases and for clinical condition of a renal patient. Practical recommendations 1.In everyday diagnostics of glomerulopathies morphological classification approved by renal biopsy should be used. 2.Peritoneal dialysis in patients without contraindications should be used as first or initial renal replacement therapy method, incorporating the two other methods later on during. 3.Nephrological or „blind" implantation of peritoneal dialysis catheter is effective, quick, safe in all cases, when surgical implantation is not indicated. 4.In all cases when US equipment is available, it is recommended that a nephrologist him-/herself should perform this examination. 5.Indirect US renal biopsy method combined with automatic single-use biopsy needles (e.g. COOK) is good to be used in everyday conditions of a nephrology unit to minimize the risks of obtaining a qualitative bioptate.
  • 17. Publikāciju saraksts 1.A. Pētersons - nodaļa „Nieru slimības", 120 Ipp. grāmatā "Internās slimības" A. Lejnieka redakcijā. 2005., NMA, Rīga, (pieņemts publicēšanai). 2.A. Pētersons - nodaļa „Nefroloģiskās rīcības labas prakses vadlīnijas" 21 lpp., grāmatā „P. Stradiņa slimnīcas Interno slimību ārstēšanas prakse" V. Pīrāga redakcijā, 2005., ISSA (pieņemts publicēšanai). 3.A. Pētersons, I. Daņiļēviča, H. Čerņevskis. Akūtas nieru mazspējas īpatsvars pacientu ar samazinātu nieru funkciju vidū Rīgā. RSU Zinātniskie raksti, 2005., (pieņemts publicēšanai). 4.Michule L, Adamsone I, Krastina E, Mihailova V, Petersons A, SpudassA, Babarykin D. Impact of predialysis erythropoietin treatment on the left ventricular hypertrophy, hospitalization rate and mortality in end stage renal disease (ESRD) patients after initiation of dialysis: a pharmacoeconomic analysis. 3rd Baltic Atherosclerosis congress 2004, Riga, Abstract, 57.lpp. 5.Diabētiskās nefropātijas diagnostika, ārstēšana un pacientu aprūpes principi (vadlīnijas) - autoru grupa - H. Čerņevskis, A. Galviņš, A. Helds, S. Lejniece, A. Lejnieks, A. Pētersons, V. Pīrāgs, 2004.g., 30. lpp., Rīga. 6.I. Mihailova, A. Pētersons, I. Jaunalksne, V. Mihailova, V. Priedīte. Perifēro mononukleāro šūnu apoptozes un aktivācijas izpēte hroniskas nieru mazspējas slimniekiem ar peritoneālo dialīzi. RSU, Zinātniskie raksti, 2003. 7.Mihailova I, Petersons A, Jaunalksne I, Priedite V. Increased level of apoptotic CD95+(Fas) and activated CD25+(IL-2RI) peripheral mononuclear cell (PMC) in patients with ESRD treated with PD. Nephrology Dialysis Transplantation 2003 Jun; 18(Suppl. 4), 767. 8.Petersons A., Stifts A., Tretjakovs P., Martinsons A., Jurka A. Skin microhemodynamics in patients with micro and macroproteinuria. Nephrology Dialysis Transplantation 2002; 17 (suppl) 225-225.
  • 18. 9.Donaldson K, Rossi M, MacLeod A, Petersons A et al. Incidence, prevalence and outcome in chronic renal failure in Eastern Europe - the results of the NACE study. Nephrology Dialysis Transplantation 2002; 17 (suppl) 246-247. 10.Hroniskas nieru mazspējas slimnieku ārstēšana. Kvalitātes standarts (vadlīnijas) - autoru grupa A. Pētersona vadībā, 1999., 7 Ipp., Rīga. 11.Petersons A, Ritz E. Nephrology in the Baltic countries. Nephrology Dialysis Transplantation 1998; 13: 2779-2780. 12. A. Pētersons, E. Vēverbrants, I.Lazovskis „Kā atklāt un ārstēt nieru slimības", zinātniska monogrāfija, 520 Ipp., 1998., Rīga, autorizdevums. 13. A. Pētersons. Nefroloģija Latvijā ārstu kongresu starplaikā. Latvijas Ārsts 1997; 6: 368-369. lpp. 14. A. Pētersons, Dz. Krugale. Peritoneālā dialīze Latvijā. Latvijas Ārstu žurnāls 1997; 9: 66-67.lpp. 15.ПЕТЕРСOНС А.А., ЛАЗОВСКИС И.Р. РОЛЬ УЛЬТРА- СОНОГРАФИИ В ДИФФЕРЕНЦИАЛЬНОЙ ДИАГНОСТИКЕ ГЕМАТУРИЧЕСКОГО ГЛОМЕРУЛОНЕФРИТА — 4. PSRS Nefrologu kongresa materiāli, Novosibirska, 1989.
  • 19. Darba aprobācija (uzstāšanās, referāti): 1.Mnogrāfija KĀ ATKLĀT UN ĀRSTĒT NIERU SLIMĪBAS: sistēmiskas zinātniskas pieejas veicinātāja nefroloģijā ar īpašu ietekmi peritoneālās dialīzes (nieru aizstājterapija) metodes ieviešanā Latvijā un nieru ultrasonoskopijas lomas padziļināšanā nefrologa praksē. - Iekšķīgo slimību katedras sēde 2005.g. rudenī 2."Earlv Renal Dvsfunction: pathogenetic link to arterial hvpertension" 3rd Baltie Nordic Meeting on Hvpertension, Vilnius, October 21, 2005. 3.Modernās nefroloģijas attīstība Latvijā - 5. Pasaules latviešu ārstu kongress, Rīga, 2005. 4.„Minor renal dysfunction: how to diagnose and treat" - 7th Baltic Conference of Nephrology, 2004., Riga 5.„How to Develop Peritoneal Dialysis Programme" - 1st Baltic Peritoneal Dialysis Meeting, 2003, Pernava, Igaunija 6."Specificity of Development of Nephrology in Latvia" - 6th Conference of Baltic Societies of Nephrology, 2002, Kaunas, Lietuva 7."Importance of Dialysate Quality in Peritoneal Dialysis"- Gambro Baltijas valstu konference, 2002., Rīga" 8.Hypertension in Kidney Disease" - 2nd Baltic - Nordic Meeting on Hypertension, 2001. g., Rīga. 9.„Nieru aizstājterapija Latvija: nepieciešamība un iespējas" - 4. Pasaules latviešu ārstu kongress, 2001., Rīga. 10.„Renal replacement therapy in Latvia: era of rapid evolution" - Rochester General Hospital, University of Rochester, 2001., ASV, Rocestra. 11.Organization and epidemiology of RRT in Latvia" - NACE Study group, Aberdeen University, 2000, Aberdīna, AK. 12.„Epidemiology of ESRD in Latvia" - 4th Baltic Seminar of Nephrology, ERA-EDTA un ISN organizets, 1998., Rīga 13.Par monogrāfiju - KĀ ATKLĀT UN ĀRSTĒT NIERU SLIMĪBAS -RSU Iekšķīgo slimību katedras sēde (vad. Prof. J. Anšeļēvičs) 1998.g. novembrī 14.Par monogrāfiju - KĀ ATKLĀT UN ĀRSTĒT NIERU SLIMĪBAS - Latvijas Nefrologu asociācijas sēde, 1998.g. novembrī.

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