Arrigo Schieppati

Progression, remission, regression of chronic renal diseases

The prevalence of chronic renal disease is increasing worldwide. Most chronic nephropathies lack a specific treatment and progress relentlessly to end-stage renal disease. However, research in animals and people has helped our understanding of the mechanisms of this progression and has indicated possible preventive methods. The notion of renoprotection is developing into a combined approach to renal diseases, the main measures being pharmacological control of blood pressure and reduction of proteinuria. Lowering of blood lipids, smoking cessation, and tight glucose control for diabetes also form part of the multimodal protocol for management of renal patients. With available treatments, dialysis can be postponed for many patients with chronic nephropathies, but the real goal has to be less dialysis-in other words remission of disease and regression of structural damage to the kidney. Experimental and clinical data lend support to the notion that less dialysis (and maybe none for some patients) is at least possible.

Prognosis of Untreated Patients with Idiopathic Membranous Nephropathy

Background Defining the most appropriate treatment for patients with idiopathic membranous nephropathy is a matter of controversy. The course of the disorder is often benign, and the immunosuppressive regimens used in some patients have uncertain benefits and substantial risks. We studied the natural history of idiopathic membranous nephropathy in patients who received only symptomatic therapy. Methods We prospectively studied 100 consecutive patients (68 men and 32 women; mean [±SD] age, 51 ±17 years) with biopsy-proved idiopathic membranous nephropathy. The patients received diuretic or antihypertensive drugs as needed, but no glucocorticoid or immunosuppressive drugs. We examined the patients and measured their urinary protein excretion and serum creatinine concentrations every 6 months for a mean of 52 months. Results Twenty-four (65 percent) of the 37 patients followed for at least five years had complete or partial remission of proteinuria; in 6 others (16 percent), end-stage renal disease developed...

Why rare diseases are an important medical and social issue.

Rare diseases aff ect a limited number of individuals (defi ned as no more than one in 2000 individuals in the European Union and no more than about one in 1250 in the USA), but the number of disorders that fi t this defi nition is very large (>5000 according to WHO). Therefore, the number of patients aff ected by a rare disease could be about 30 million in Europe and 25 million in North America. The true burden of rare diseases in Europe and elsewhere is diffi cult to estimate, since epidemiological data for most of these diseases are not available. Rare diseases are an important public-health issue and a challenge for the medical community. They are called health orphans, because rare diseases were neglected for many years. Similarly, before the USA passed the Orphan Drug Act in 1983, the pharmaceutical industry had neglected the development of treatments for rare diseases, hence the name orphan drugs. Public awareness about the diffi culties of patients with rare diseases was fi rst raised by the report of the National Commission on Orphan Disease of the US Government in 1989. The Commission’s hearings with hundreds of stakeholders highlighted issues that aff ected patients’ care, such as little information on rare diseases, diffi culties of fi nancing research, drawbacks of providing adequate health insurance and coverage of medical expenses, and the limited availability of eff ective treatments. The International Classifi cation of Diseases (ICD) that is used in most countries is not convenient for rare diseases. The absence of a universally recognised coding system is an obstacle for reliable registration of patients in national or international databases, preventing assessment of the economic and social eff ects of rare diseases. For some disorders, national or international registries are available, which have been set up and maintained by researchers, patients’ associations, public institutions, or drug companies. The European Rare Disease Task Force of the Health and Consumers Protection Directorate General of the European Commission has set up a working group to collaborate with WHO on ICD-10, and is considering all other existing classifi cations to provide the rare-diseases community with a uniform system. Assessment of the prevalence of rare diseases was attempted by the European Organization for Rare Diseases (Eurordis), and Orphanet, with the support of the European Commission. This study not only provided an estimate of the prevalence of several rare diseases (table), but also showed the absence of reliable data, low consistency between sources of information, and poor methodological quality of epidemiological studies. Additionally, facilities for biochemical or genetic testing are scarce. We use the collective term of rare diseases to include a very heterogeneous group of disorders that can aff ect any system. Most rare diseases are genetic disorders, which are often severely disabling, substantially aff ect life expectancy, and impair physical and mental abilities. These disabilities result in reduced quality of life, and aff ect an individual’s potential for education and earning capabilities. One example is inborn errors of metabolism, most of which are rare (prevalence between 1 in 1400 and 1 in 5000 livebirths). An Italian prospective study (1985–97) on patients aged 0–17 years revealed that, of the 1935 newborn babies with inborn errors of metabolism identifi ed by the study, only 11% reached adulthood. Rare diseases also pose a considerable burden on the aff ected families. This burden was assessed by sending a questionnaire to 2500 patients with chronic diseases (8·2% of which were rare diseases). Patients with rare disorders had the worst exper ience in terms of loss of social and economic oppor tunities, and of medical care. Patients with rare diseases face diagnostic delays. This issue was shown in a survey of eight rare diseases (Crohn’s disease, cystic fi brosis, Duchenne muscular dystrophy, Ehlers-Danlos syndrome, Marfan’s syndrome, Prader-Willi syndrome, tuberous sclerosis, and Lancet 2008; 371: 2039–41

Mycophenolate Mofetil for the Treatment of Takayasu Arteritis: Report of Three Cases

I wet my bed. Thats how it all starts. It was an accident, I tell myself. I am embarrassed. No more water before bed; maybe I was drinking too much beer. I am resolved. I am good. In the morning the bed is wet. Peeing in the bed? Humiliation. Hide it from my wife. Put a towel down. Stay on my side. Dont turn. Give up sleep. Mention it to one of my pals, boyhood friend, like a brother, big-time CEO. Go to see my doctor. Weve just given him a big grant. Hes been anointed by a major magazine. Hes just the best. I dont need the best. I dont deserve the best. I cant afford the best. Nonsense, nothings more important than your health. He calls. The earth moves. I have an appointment the next day at a major metropolitan hospital, famous for its care of celebrities. The waiting room is packed. Patients in two treatment rooms with another patient in the office. This guy doesnt have time to pass wind. My instinct is to flee but my friend made the call . Finally in his office. I am charming. Hell see Im special. Hell want to take care of me. He stares at my shoulder as I talk. Not a good sign. I wet the bed. He looks past me, then speaks. He radiates confidence, experience, and enthusiastic energy. I havent got time for this but for a friend of. Instant diagnosis. My bladder is overflowing. My prostate must be enlarged. Assume the position. Invade my privates. We need some tests. Blood urine ultrasonography of my bladder. Make an appointment with my secretary. Well start with medication to see if we can reduce the size of the prostate. If it doesnt work, we may have to do a simple procedure. Bing bang, hes off to the next treatment room and Im on the street with a prescription for terazosin hydrochloride, dates for a variety of tests, a bag attached to my leg, and a tube in my penis. During the next weeks, a new regimen takes over my life. I take my medication religiously. I talk on the phone a lot, and Ive learned a new dance of avoidance. My wife, my plastic bag, and me. In the always clogged doctors office, I have become whats his name at my weekly morning visit. The bag is removed. Zip, zap, in and out. I go home and wait to see if I can pee by myself. Come back at 3:00 if it doesnt work. I drink water like its going out of style. I walk the living room. Lie on the bed. Stare at the ceiling. I hover over the toilet bowl praying. Nothing. I rush back to the hospital. The tube is reinserted. This is done by a young associate. The doctor is off lecturing in Paris at a symposium in Berlin or a special assignment on the dark side of the moon. Im assured that insertion of the tube is a purely mechanical process and that the physician is fully informed of my progress. And so it goes for 6 disappointing weeks. By the time I reach the elevator on my last visit, I am in agony. Every step is excruciating. I go back to the young associate once again wait my turn. Finally, he, smiling, adjusts my apparatus. The bill comes in later. Two visits

Reduced Platelet Thromboxane Formation in Uremia. EVIDENCE FOR A FUNCTIONAL CYCLOOXYGENASE DEFECT

260. This is no fun. The following week quick visit, drop off a specimen. Physician runs by: How are you? Waves. Billed

Prostacyclin and human foetal circulation.

130. I notice that the nurses in his office mirror his attitude arrogant aloof superior after all, they are the attendants to a star. I am lucky. Be happy he made time for you at all. The medication doesnt work. I go in for the simple procedure, affectionately called a rotor rooter. There I am, lying on my back, spread eagle, my feet sticking up into stirrups, tubes inserted, television monitor tuned to this scintillating spectacle. The star enters the operating theater, gloves and mask in place. The lights are fixed. There is a hush. He looks at the monitor dramatically pauses. Oh, look, theres a stone in the bladder. A stone? They had enough photos of my bladder to start an exhibition. It was hiding. Where? In my armpit? Undeterred, he does something or other. It shouldnt be a total loss, he says. He stares at the overhead clock all the while and tells me he has to catch a plane for the Virgin Islands. Finished. Thats it and hes off. Over his shoulder, a parting shot: Dont worry If you get into trouble Ill fly back. Trouble what trouble? I wasnt told about trouble. This was going to be a simple procedure. We do it all the time. I need a day for my body to heal before the stone can be removed. I am lying in bed contemplating my fate when this new spiffy doctor comes in to see me. One of the blood tests showed that I was a bit anemic, and my star had left an order for me to be seen by a blood man. He asks me a few questionsage, weight, easy stuffthumps my chest, listens to my heart, then tells me about all the blood tests we are going to do when I visit him at his office. If that doesnt show anything, he says, there are tons of bone marrow tests we can try. He is there all of maybe 3 minutes. Later, the bill comes for my comprehensive examination

Plasmatic regulation of vascular prostacyclin in pregnancy.

500. Whats the difference what is charged, they tell me. The insurance company will pay. Insurance industry medical facilitators thats what they seem to be. But I dont have any insurance. After 1 day of rest, I am wheeled down to the operating room for a second go-around. The stars associate, an experienced physician who grumbles about having to take over the problem, steps into the breech. He is concerned and efficient and blasts the stone. It was huge. They show me a test tube full of fragments. The star comes back from his trip and calls to see how I am. Every time I try to skip a procedure take a short cut, he says, it comes back to bite me on the ass. He had left out the cystoscopy, a procedure in which they look through a tube inserted in the penis to see what is going on inside. If he did this procedure, he would have seen the egg. Oh, poor guy. What about me? I am the one who needed another 3 days in the hospital, another spinal, another set of tests, and the procedure, unpleasant at best, to blast the dinosaur egg. Not a word about my discomfort about the effect on my body about my anxiety. I wont even talk about the cost yet. A week later, I go in for a check-up. The stone had caused the blockage, and it had been removed. The biopsy shows no signs of cancer. Good news indeed. If all remained the same after 6 months, Id come in once a year to watch it, and that was that. End of story. Three weeks later, I start to bleed when I urinate. Not a few tricklesgushes, streams of my blood pouring out. I call the great man. I tell him I must come to the office immediately. Immediately takes a week and a half. I call the office. Urgent, I tell them, Im bleeding. The physician says, . But but but. Im sorry, the earliest I can possibly squeeze you in. But. To no avail. I consider going to another physician or to an emergency room. Then I think of the explanations theyll want to see records and do more tests to verify. Anyway, he is the one who had. A week and a half later, after a 3.5-hour wait we meet. He takes blood and urine samples. Well find out why I was bleeding. He calls the next day, somewhat agitated. I had lost nearly a pint of blood. Really? He does more tests more ultrasonography to see whether the dinosaur egg spawned offspring or whether some other internal calamity is causing my blood to flow. The test results all prove negative. A cystoscopy then. We didnt do it the first time. Well do it now. So there I am, back spread eagle in the stirrups with more tubes in my penis. After a quick 10 minutes, wemy wife and Iare in a little cubicle for consultation. It is the prostate. The one that was supposed to have been taken care of. It had grown back, it had regenerated, it had multiplied it was there rubbing against itself causing the bleeding. The physician draws diagrams curved mountains who knows. He is going to prescribe something that will stop the bleeding. The good news is that it has been known to stop or at least inhibit the loss of hair. It may even cause hair to grow. Terrific. The bad news is that it might, on occasion, slow my orgasm. The flow wont be as strong, thats all. That seems fair a few hairs for a weak ejaculation. I dont know whether I am supposed to laugh or cry. I am numb, and I am still bleeding. How long will I have to take this wonderful drug? For the rest of my life, the physician tells me. So I start to take finasteride. The bleeding stops and my body changes. I cant feel it anymore. Nothing. Slow the ejaculations? What ejaculations? I feel as if I am detached from the lower part of my body. I call the physician. I dont feel anything. Im walking around in someone elses body. Oh, he says. Stop taking the medication. Casual calm an answer for everything. The medicine I was going to take for the rest of my life is no longer important. Whats going to replace it? I ask. Nothing. Thats it? The bleeding has stopped. Thats the important thing. Make an appointment in 3 months. Well schedule another cystoscopy do a biopsy maybe do another rotor rooter. Youll be fine. Then the bills come and come and come. I was originally told that I would have to pay for two hospital days, one procedure, and one physician: around

Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome

8000. Instead, four hospital days, two procedures, and all that they entailed will cost me more than

Prevention programmes of progressive renal disease in developing nations (Review Article)

30 000. My fault no insurance. Thats what I get for being an independent. I should have listened to my mother and become a dentist. But what bothers me, besides the money, is the attitude. The physicians, the nurses, and the hospital couldnt have cared less about me. Health was just a six-letter word left out of the bill. And the great man ? He may be a star, but hes no longer cast in my life story.Mycophenate mofetil may be an alternative to steroids and cytotoxic agents in patients with Takayasu arteritis.

Kidney failure: aims for the next 10 years and barriers to success

A qualitative platelet abnormality and a bleeding tendency are frequently associated with renal failure and uremia. We demonstrated previously that uremic patients display an abnormal platelet aggregation to arachidonic acid and reduced malondialdehyde production in response to thrombin and arachidonic acid. The objectives of this investigation were: (a) to compare platelet prostaglandin (PG) and thromboxane (TX) production in whole blood and in platelet-rich plasma (PRP) of 21 uremic patients and 22 healthy subjects; (b) to evaluate the concentration and activity of platelet PG- and TX-forming enzymes; (c) to assess the functional responsiveness of the platelet TXA(2)/PGH(2) receptor; (d) to explore the hemostatic consequences of partially reduced TXA(2) production.Platelet immunoreactive TXB(2) production during whole blood clotting was significantly reduced, by approximately 60%, in uremic patients as compared to age- and sex-matched controls. Exogenous thrombin (5-30 IU/ml) failed to restore normal TXB(2) production in uremic platelets. Uremic PRP produced comparable or slightly higher amounts of TXB(2) than normal PRP at arachidonate concentrations 0.25-1 mM. However, when exposed to substrate concentrations >2 mM, uremic PRP produced significantly less TXB(2) than normal PRP. To discriminate between reduced arachidonic acid oxygenation and altered endoperoxide metabolism, the time course of immunoreactive TXB(2) and PGE(2) production was measured during whole blood clotting. The synthesis and release of both cyclooxygenase-derived products was slower and significantly reduced, at all time intervals considered. Furthermore, PGI(2) production in whole blood, as reflected by serum immunoreactive 6-keto-PGF(1alpha) concentrations, was significantly reduced in uremic patients as compared with healthy subjects. PGH synthase levels, as determined by an immunoradiometric assay, were not significantly different in platelets from uremic patients as compared to control platelets. A single 40-mg dose of aspirin given to five healthy volunteers reduced their serum TXB(2) to levels found in uremic patients. This was associated with a significant increase of threshold aggregating concentrations of ADP and arachidonic acid and prolongation of bleeding time. Substantially similar threshold concentrations of U46619, a TXA(2) agonist, induced aggregation of normal and uremic platelets. Prostacyclin induced a significant elevation of uremic platelet cyclic AMP, which was suppressed by U46619, further suggesting normal responsiveness of the TXA(2)/PGH(2) receptor. WE CONCLUDE THAT: (a) an abnormality of platelet arachidonic acid metabolism exists in uremia, leading to a reduced TXA(2) production; (b) the characteristics of this abnormality are consistent with a functional cyclooxygenase defect; (c) reduced TXA(2) production may partially explain the previously described abnormality of platelet function in uremia.