December 26, 2017

Kidney & Urinarytract

Urinary incontinence

Urinary incontinence is a main health problem that affects more than 200 million patients in the world. This disorder has been seen in a middle-aged women which devoted 25% of the patient’s population. In the absence of treatment, this disease will make negative psychosocial effects and social isolation in the affected person, as well as impose economic costs on society.

The most common type of this disease is stress urinary incontinence, and the risk factors are including the age of over 40, the number of pregnancies and the number of vaginal births. There is no drug therapies efficacy to treat urinary incontinence. In addition, the injection of volumetric materials into the ureter and bladder as a non-surgical procedure, while having several side effects, also have a lower rate of response. Finally, surgical methods have 30-50 % of side effects and sometimes lead to failure of treatment or recurrence of the disease. Since this complication has a high incidence among women, it has always been a concern of urological researchers to solve this problem. Todays, some methods such as open surgery and laparoscopic surgery are common to use in treatment of the disease. In other case, the outpatient treatments with peripetal injection and less side effects, which are ineffective or short-lived in woman. Therefore, muscle stem cell injection to sphincter have been considered as a new treatment method which has promising early hope outcomes.

Study 1

In the kidney and urinary tract of the Royan Institute, a research was conducted on muscle derived stem cell transplantation in stress urinary incontinence in the urology clinic of Labafinejad Hospital.

Patients selection:

In this study, 20 urinary incontinence patients in aged 18-65 years have been admitted on Urology clinic of Royan Institute based on inclusion and exclusion criteria, and their informed consent was obtained.

 

Inclusion criteria:

The presence of urinary incontinence symptoms

The aerodynamic stress incontinence have been submitted by multi aerodynamic tests

The positive result of cough stress test

Requirement of urinary incontinence surgery repair

 

Exclusion criteria:

The amount of urine remaining after urination over 100 cc

History of using biologically or synthetic sub-urethral signs

Tendency to be pregnancy in feature

Having chronic inguinal and vulvar abscess with hidradenitis history

Bleeding history or recent anticoagulant therapy

Inguinal lymphadenopathy or inguinal/vulvar tuberculosis

Recent history of diverticulosis or genitourinary fistula

Recent cystocele and rectocele history

Urinary infection

Neuromuscular diseases

Diabetes

Reversible incontinence (such as a medical complication)

Surgical Prohibition

 

Cell preparation:

In order to obtain muscular stem cells (MDSCs), a 1 × 1 biopsy was taken from a patient’s deltoid muscle. Muscle Stem Cells (MDSCs) were isolated and cultured according to GMP standards, and cell suspension with 30 million prepared cells was injected through internal sphincter.

Cell injection:

After 7 to 8 weeks of sampling, autologous muscle cells were injected to submucosa sphincter area in outpatient treatment.

 

Study Description:

In this study, 20 urinary incontinence woman were administrated under autologous muscle stem cells in their urethral duct. They were under follow- up at 1, 3, 6, 9, 12 months after injection. These assessments included standard questionnaires were evaluated based on their weight, the number of daily incontinence and mild or severe cough.

Results:

All patients were followed up in 1, 3 and 6 months after injection, and 11 patients were followed during 12 months. 3 patients were excluded from the study due to lack of access to follow up. In overall 11 patients, 5 (45%) of patients completely recovered, 4 (36%) of patients improved, and 2 (8%) did not respond to treatment. In 6 patients were followed during 6 months, 4 (66%) patients treated partial relief, 2 (33%) did not respond to treatment. No severe complications or side effects were observed in this method of treatment.

سلول درمانی- بی اختیاری ادرارFigure 1: Test pad changes in patients after intervention

سلول بنیادی-بی اختیاری ادرارFigure 2: Changes in clinical symptoms of patients after intervention

سلول درمانی- نفرولوژیFigure 3: The number of patients responding to treatment based on the test of the pad in different months of follow up

سلول درمانی-بیماری کلیویFigure 4: Coughing Test Changes in Patients After Intervention

 

 

Polycystic kidney disease

Polycystic kidney disease with dominant autosomal inheritance is one of the most common single-gene diseases that is characterized by the cysts formation in the kidneys and other organs, ultimately leading to end-stage kidney disease. The mutation in the two PKD1, PKD2 genes causes the disease.

Therapeutic steps:

Diagnosis of this disease is based on medical imaging and Ravin criteria. There is no definitive treatment for the disease, and the goal of these therapies is to reduce the incidence of morbidity and mortality. The therapeutic interventions have included cysts aspiration and antibiotic therapy, and in other cases dialysis and kidney transplantation.

According to Franchi’s observations, intracerebroventricular injection of mesenchymal stem cells derived from bone marrow in rats with polymicrobial kidney improves creatinine clearance and maintains vascular density, as well as glomerular diameter, and reduces fibrosis in kidney.

Study 1

In this study, 6 patients were admitted to the study from patients with a polycystic kidney who were referred to the Royan Institute. The results showed that after the injection of these cells, no serious complications were observed for the patients and the results were satisfactory.

Patients selection:

In this study, out of 27 patients, only 6 patients with inclusion criteria were selected and informed consent was obtained from them.

 

Inclusion criteria

Ranging in age of 18-65 years

1.73 m2 / min/ GFR 25-60 mL

Informed consent

 

Exclusion criteria:

Pregnancy or breastfeeding

Vascular disease

Diabetes requiring medical intervention

Other systemic kidney diseases, such as cancer, autoimmune diseases, blood diseases, liver disease and …

Hospitalization of patients due to severe illness in the past two months

Lifespan less than two years

Any sensitivities to the compounds of cell culture process

 

Cell Preparation:

Mesenchymal stem cells are derived from adipose tissue. Abdominal adipose tissue samples are presented in sterile plate containing buffer, penicillin and streptomycin antibiotics to the laboratory for cultivation, duplication and preparation for injection, and then is dissolved in a solution containing collagenase enzymes of the cells for injection.

 

Cell injection:

Prepared cells are injected into the patient by intravenous injection of 1 × 106 cells in 50 cc normal saline.

 

Study Description:

27 patients with autosomal polycystic kidney disease were evaluated based on Ravin criteria, 6 patients have been admitted with inclusion criteria to enter in program and 25-60 glomerular filtration. The patients received 2 × 106 mesenchymal stem cells derived from autologous adipose tissue/ kg body weight. The early outcomes, type, side effects and secondary outcomes of glomerular filtration were reviewed after 12 months. The total volume of the kidneys as well as the size of the largest cysts were determined by ultrasonography and glomerular filtration was determined by MDRD and DTPA scan.

 

Results:

There is no side effects in administration of mesenchymal stem cells of bone marrow in 6 selected patients (Table 1). There is no change in blood pressure and kidney size after 1 year of follow-up.

However, the mean glomerular filtration showed a significant decrease in pre-intervention time compared to one year ago (p = 0.320). In this study, there is a slight decrease in the glomerular filtration rate from injection time to one year later, which is not noticeable. (Figure 1)

Patients Parameters Baseline (Mean ± SD) Months (Mean ± SD) Value (Paired t-test)
Leukocytes/ul) 5700 ± 855 6468 ± 2153   0/238601
Hemaglobin(g/dl) 12/80 ± 1/71 13 ± 1/25 0/551017
HCT (%) 37/40  ± 3/81 39/46 ± 3/40 0/148000
MCV(fl) 88/76 ± 9/36 89/51 ± 3/32 0/822798
Platelets(*103/ul ) 211/66 ± 56/77 187/33 ± 41/96 0/252030
FBS(mg/dl) 96/83  ± 10 90/33 ±  12/83 0/058904
Hba1c (%) 5/20 ± 0/35 5/15 ± 0/39 0/295559
Sodium (mEq/l) 141/83 ± 1/94 141/33 ± 1/96 0/363217
Potassium (mEq/l) 4/45 ± 0/47 4/31 ± 0/46 0/414238
Calcium (mg/dl) 9/28 ± 0/58 9/37 ± 0/31 0/794856
Phosphorus (mg/dl) 3/73 ±  0/56 3/70 ± 0/51 0/894896
TSH (MIU/ml) 2/28 ± 1/06 2/40 ± 1/30 0/861074
PTH (pg/ml) 140/26 ± 70/08 111/08 ± 48/34 0/252263
ESR 1hr (mm/hr) 22/16 ± 18/79 15/50 ± 10/34 0/161790
CRP(mg/l) 5/06 ±  8/66 0/33 ± 0/81 0/230797
Albumin (g/dl) 4/27 ± 0/26 4/38 ± 0/45 0/684411
Uric acid (mg/l) 6/48 ± 2/14 7/16 ± 1/29 0/381549
ALT (U/I) 24/33 ± 9/81 19/33 ± 6/62 0/337149
AST(U/I) 29/67 ± 18/54 20/50 ± 5/85 0/253489
Alkaline phosphatase(U/I) 231/17 ± 62/52 155/83 ± 53/82 0/079215
Total cholesterol (mg/dl) 177 ± 44/21 172/50 ± 42/03 0/660475
Triglycerides (mg/dl) 191/66 ± 150/67 192/51 ± 108/17 0/974849
LDL cholesterol (mg/dl) 99/5 ± 34/02 96 ±  30/21 0/667696
HDL cholesterol (mg/dl) 39/16 ± 11/01 41/33 ± 12/29 0/611604
Dipstick proteinuria 1/66 ± 0/81 1/33 ± 0/51 0/465

Table 1- Laboratory parameters of patients at the beginning of the plan and the end of 1 year follow up.

 

سلول درمانی- سندرم کلیه

Fig 1- EGFR changes in patients over two years, from one year before and one year after mesenchymal stem cells injection

 

 

Ultrafiltration failure in peritoneal dialysis

Peritoneal dialysis is one of the option in treating severe kidney patients, which uses the peritoneum as a semi-permeable membrane for ultrafiltration (UF) and drug trafficking. According to available data, peritoneal dialysis accounts about 6.8% of all alternative renal treatments. However, there is a wide various scale in different country. In our country, an increase in the number of peritoneal dialysis patients has been observed over time. It should be noted that, like any other therapeutic treatment, peritoneal dialysis can have short or long term complications. Some of the most important complications which observed in long term of peritoneal dialysis are ultrafiltration failure (UFF) and peritoneal fibrosis. In fact, UFF is the most common functional disorder that occurs in about 20% of patients who have had peritoneal dialysis for at least two years. There are no methods for postponing fibrosis and thus preventing ultrafiltration failure in peritoneal dialysis patients till now.

Recent studies have shown that the MSCs regulate the properties of mesenchymal stem cells (MSCs), which are responsible for the effects of these cells on the types of immune cell lines, and their repair effects may be useful in the treatment of various inflammatory diseases.

Indeed, confirming the anti-inflammatory effect of paracrine stem cells can produce immune regulating solutions in the future, so that anti-inflammatory effects can be quickly and easily used without requirement of cell infusion. There is serious need to fine a treatment intervention which can be used to prevent long-term PD complications a peritoneal fibrosis while keeping peritoneal function as a normal situation.

 

 Therapeutic steps:

In the first stage patient should examine by specialist and after confirmed the peritoneal dialysis symptoms, subsequent examination are done on the patient. In cell therapy process, the stem cells derived adipose sample was taken and dissolved in a solution containing collagenase enzyme, then the isolated cells were cultured and injected to lesion site about 1 million cells per body weight.

 

Study 1

In the case of mesenchymal stem cells derived adipose tissue transplantation, patients have been admitted to Royan institute in 1394. There was no side effects including redness at the injection site, warmth, sensitivity, anaphylaxis, hypotension, headache, dizziness.

 

Patient selection:

In this study, peritoneal dialysis patients who have been admitted to the Shariati Hospital and Royan institute. Based on inclusion and exclusion criteria, 8 patients in both of gender were selected and informed consent was obtained from them.

 

Inclusion criteria:

1- Peritoneal dialysis patients

2-Ranging in age of 18-65 years

3- In both of gender

4- Use of peritoneal dialysis as RRT at least 2 years ago

5- Having UFF

 

Cell Preparation:

Mesenchymal stem cells are derived from adipose tissue. Abdominal adipose tissue samples are presented in sterile plate containing buffer, penicillin and streptomycin antibiotics to the laboratory for cultivation, duplication and preparation for injection, and then is dissolved in a solution containing collagenase enzymes of the cells for injection.

 

Cell injection:

Prepared cells are injected into the patient by intravenous injection of 1 × 106 cells in 50 cc normal saline.

 

Study Description:

This study included 8 patients with filtration defects in peritoneal dialysis, which were injected according to the criteria mentioned above. The 6-month follow-up period of mesenchymal stem cells was considered in this study from the patient’s own adipose tissue.

Results:

The mean age of the patients was 56 years, of which 8 were 6 women, 2 of whom completed the follow-up period without any complications. Five patients undergo follow-up and a patient is waiting for the cells to be injected. The table below summarizes demographic characteristics of patients.

 

Number Age (year) Duration of dialysis (year) Kidney failure cause Weight No urine UF in 24 hours (cc) Number of dialysis in 24 hours
1 49 8 Unknown 45 Yes 1200 5
2 70 9 Polycystic Kidney 63 Yes 950 4
3 68 4 Chronic UI 73 No 600 3
4 43 3 Diabetic 62 Yes 950 4
5 69 5 Blood pressure 67 No 600 4
6 63 5 Blood pressure 63 No 700 4
7 44 5 Unknown 85 Yes 1200 4
8 45 4 75 Yes 4