Changes over the past 33 Years at Urayasu Hospital

in 1987, a few years after its establishment in May 1984. Since then, I have spent 33 years at the institution. The number of hospital beds has increased from 250 at its establishment to 785 at present. Initially, the Department of Internal Medicine was operated by around 10 staff members, and it was subsequently reorganized and subdivided by organ system in 2014. As of March 2020, the Department of Internal Medicine is operated by five staff members. In 2014, a blood purification center was established and I was appointed as the first head of the center. With the expansion of the hospital, I have gained experience by treating more patients. Over the past 30 years, there have been several major changes in the medical care of kidney diseases. These changes vary widely and include identification of chronic glomerulonephritis and diabetic nephropathy as the causative diseases of end-stage renal disease, approval of erythropoietin for the treatment of renal anemia, introduction of angiotensin II receptor blockers, establishment of the concept of chronic kidney disease (CKD), conceptualization of mineral and bone disorders in CKD, drug discovery for autosomal dominant polycystic kidney disease, and initiation of living-donor kidney transplants. I would like to describe the changes in clinical practice that I have experienced without discussing each disease in detail.


Introduction
Population aging is one of the major changes that I have observed over the past 33 years at this institution. The population aging rate in Japan has increased from approximately 10% to 28%.
Urayasu City has the lowest aging rate in Japan (approximately 10% lower than the national average).
Before coming to this institution, I worked for 2 years at the former Katsunan Municipal Hospital, also located in Urayasu City (now known as Tokyo Bay Urayasu Ichikawa Medical Center), while maintaining a good relationship with community medical care through the activities of the Japan Medical Association, the Health Insurance Claims Review and Reimbursement Services, and the Kanto-Shinʼetsu Regional Bureau of Health and Welfare. The treatments and understanding of kidney diseases have also changed significantly following the expansion of the hospital scale and subdivision of clinical departments. I describe notable changes in chronological order by year ( Figure-1).

1987: Renal Biopsy
Renal biopsy was an indispensable tool for the pathological diagnosis of kidney diseases, especially nephritis and nephrotic syndrome. At that time, it was still commonly performed under fluoroscopy with contrast medium. Due to the possibilities of insufficient tissue sampling and complications, such as bleeding, the procedure was replaced by ultrasound-guided automatic biopsy. This procedure was adopted rather early without serious issues. It was performed in as many as 80-90 cases each year, providing accurate diagnoses in cooperation with the Department of Pathology (Figure-2).

1990: Erythropoietin
The approval of erythropoietin greatly advanced  the treatment of kidney diseases. Prior to this, we had to rely on blood transfusions and anabolic hormones with unstable effects. Subsequently, erythropoietin came to be used during the chronic stage of renal insufficiency. In addition, depot preparations of erythropoietin were developed, which led not only to the amelioration of anemia, but also to the control of ischemic heart disease and congestive heart failure, and to the improvement of the quality of life of patients with renal insufficiency (Figure-3). Furthermore, hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors were introduced as the first oral agents in 2019, thereby increasing the number of treatment options. 1)

1998: Diabetic Nephropathy ⇔ Chronic Glomerulonephritis
When I first joined Urayasu Hospital in 1987, chronic glomerulonephritis was the most common causative disease for dialysis induction.
However, in 1998, diabetic nephropathy became the leading indication for dialysis. This change was unexpectedly fast (Figure-4). 2) At that time, the diagnosis of early nephropathy was a major issue due to the increasing number of diabetic patients. At present, urinary albumin levels are measured for diagnosis. However, it was a long time before quantitative and semiquantitative methods came to be widely used after their insurance coverage. Under these circumstances and the guidance of Professor (currently Professor Emeritus) Yasuhiko Tomino, serum soluble thrombomodulin (TM) levels were measured at different stages of diabetic nephropathy for the diagnosis of early nephropathy based on endothelial dysfunction. Serum TM levels are significantly correlated with the stages of nephropathy and may therefore serve as a valuable marker for diagnoses . 3) Glycosylated proteins detected in the forearm skin blood vessels and renal tissues in patients with diabetic nephropathy at the microalbumin stage were correlated with those at the overt proteinuria stage (Table-1

1998: Angiotensin II Receptor Blocker
The advent of angiotensin II receptor blockers (ARBs) was a major event that improved the treatments and prognoses of kidney diseases. The first ARB in Japan was candesartan, although the renoprotective effects of losartan were confirmed in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. 5) Subsequent subanalysis revealed superior renoprotective effects, particularly in Asian and Japanese patients. Overall, 96 of the 1,513 patients were Japanese, including three from our department.

2002: Chronic Kidney Disease
The concept of chronic kidney disease (CKD) was proposed in 2002 by the National Kidney Foundation in the United States. Thereafter, the Kidney Disease Improving Global Outcomes (KDIGO) was established, which presented a stage classification based on renal function and urinary protein levels. It played large roles in the early detection of renal diseases, inhibition of progression to end-stage renal diseases (ESRD), and prevention of cardiovascular diseases. I previously gave community lectures for non-specialists in renal diseases. However, as revealed by a survey of CKD patients, they were referred to our outpatient clinic rather late, suggesting the necessity of further improvement (Table-2).

2004: Blood Purification Center
Urayasu Hospital has expanded since 2004. A blood purification center was established in addition to the increased number of beds. Due to the increasing numbers of hemodialysis patients, the newly established medical department, and the start of emergency and critical care center, the number of patients who required blood purification steadily increased. In addition to hemodialysis, simple plasma exchange (PE), double filtration  plasma exchange, plasma adsorption, and leukocytapheresis/granulocytapheresis were started. Currently, at least 7,000 procedures are performed annually (Figure-6). During the Great East Japan Earthquake in 2011, Urayasu City was highly damaged due to liquefaction. The center was unable to secure water for dialysis and was forced to discontinue dialysis treatment for 4 days because of failure of the drainage system. This was a good lesson for future disaster countermeasures.

2009: CKD Mineral and Bone Disorders
Concepts and guidelines were presented by the KDIGO this year. 6   of parathyroidectomy procedures for secondary hyperparathyroidism, although ectopic calcification remains challenging.

2010: Diabetic Nephropathy ⇔ Chronic Glomerulonephritis
In 1998, diabetic nephropathy was the most common causative disease for dialysis induction. In 2010, it became the leading indication for all dialysis patients (Figure-7). At the end of 2018, of approximately 340,000 dialysis patients, 39.0% had diabetic nephropathy and 26.8% chronic glomerulonephritis. The number of dialysis patients is still increasing, with the mortality rate increasing for an increasing number of complications of cardiovascular lesions, in addition to aging. Although immunoglobulin A (IgA) nephropathy is the most common chronic glomerulonephritis, its proportion among major causative diseases was reduced by early diagnosis using kidney biopsies and advances in treatment. However, the prognosis after the start of dialysis and the effects on the entire medical expenditure for dialysis must be considered.

2014: Autosomal Dominant Polycystic Disease
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary renal disorder, which progresses to ESRD in approximately half of patients at around 60 years of age. However, until 2014, no therapy was available. Therefore, patients were placed on follow-up with focus on the management of hypertension and the early detection of complications. Tolvaptan was approved in 2014 as a therapeutic agent to suppress the increases in cyst and total kidney volumes, and to slow the decline in renal function. 7) As ADPKD was subsequently designated as an intractable disease, the drug was immediately introduced at our department. To date, we have administered it to approximately 30 patients, with high tolerability and long-term effects expected.

2015: Kidney Transplantation
Kidney transplantation has been performed since 2015 at Urayasu Hospital. Living-donor kidney transplantation was started in the Department of Urology at our institution. Our department has also requested it as preemptive transplantation, with favorable results. To date, 26 patients, including 13 with ADPKD, 4 with nephrosclerosis, 2 with IgA nephropathy, 1 with hypoplastic kidney, and 6 with unknown primary diseases, have undergone the procedure. The mean ages of the recipients and the donors were 52.6 and 59.5 years, respectively. The Nephrology and Hypertension Department also played a role in preoperative and postoperative PE for blood group incompatibility transplantation and perioperative blood purification.

Conclusion
The changes at Urayasu Hospital over the past 33 years after its establishment were described. The Department of Nephrology started with just one staff member and has provided medical care in conjunction with the Department of Cardiovascular Medicine. Today, the department is reorganized independently as the Nephrology and Hypertension Department with five medical staff members. I discussed the major changes in actual medical care during my long career. All of these changes were revolutionary and I am honored to have personally witnessed them. I am also looking forward to possible changes in the next 10 to 20 years.