Diabetes is the leading cause of mortality and morbidity in the present era. It is marked by elevated blood glucose levels due to insulin deficiency. 10% of the cases of diabetes mellitus account for type 1 diabetes mellitus or insulin-dependent diabetes mellitus (IDDM). It is also called as juvenile -onset diabetes because it occurs at a very young age. Majority of the times, IDDM leads to serious complications like diabetic nephropathy which is the leading cause of death due to end stage renal disease in diabetic patients.
Case report: Christopher was diagnosed with type 1 diabetes mellitus at the age of 12. Some relatives of Christopher's father also had a history of juvenile onset diabetes. Although he was given insulin injections on daily basis, his blood glucose levels were often high and uncontrollable. At 35, he was diagnosed for hypertension and proteinuria. His serum creatinine test was found to be too high i.e. 7.5 mg/dl (normal <1.0 mg/dl). On the basis of these results, he was suspected of developing diabetic nephropathy. So he was given antihypertensive drugs and recommended a kidney biopsy which indicated extensive glomerulosclerosis, proving that Christopher had developed end stage renal disease. Thus, he had to undergo haemodialysis twice a week and was enlisted for a cadaveric kidney transplant. He got kidney allograft transplantation after 6 months, which seemed to be normal at first. But the graft underwent acute rejection due to compromised response to immunosuppressive therapy and heterogeneity in the genotypes of the donor and the patient.
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IDDM is caused due to autoimmune destruction of the insulin-producing β cells of islets of Langerhans in the pancreas by cytotoxic T cells. The immune-mediated attack on the β-cell results into impaired insulin production and its related functions. This attack is triggered by activated cytotoxic T-lymphocytes that target certain pancreatic islets for destruction. This results into the release of cytokines which thereby stimulate the migration of activated phagocytes and other immune cells like the autoantibodies to the site of inflammation leading to an immunological response. The overall reaction is responsible for the total destruction of the pancreatic tissue which brings about the consequent pathology.
Genetics plays a fundamental role in the autoimmune prospect. Generally, autoimmunity occurs when a person is genetically susceptible to a certain disease i.e. heredity. Most of the cases of genetic susceptibility to IDDM have the gene linked to HLA DR3, HLA DR4 and HLA DQ. According to the studies, it is observed that in case of identical twins, if one twin has IDDM, there are only about 50% chances of the other to develop it. This suggests that the genetics plays a major role in IDDM, but is not the sole cause of the disease. There are certain modifying factors that act as triggers for the development of the disease. It has been observed that several chemicals and viral infections contribute to the environment factors which stimulate the IDDM genes to express themselves. The diagram below shows the pathogenesis of IDDM under the influence of genetic and environment factors.
The pathophysiology of IDDM is a three step process. Firstly, due to idiopathic reasons, modified β-cell antigens are secreted and presented by MHC class I molecules. These antigens are presented by antigen-presenting cells (APCs) and are identified by CD8+ T cells causing destruction of cells that express MHC class I molecules by the release of cytotoxic cytokines. The secreted β-cell constituents are then taken up by immature dendritic cells in the islets of Langerhans of the pancreas and are transferred to the pancreatic lymph nodes, where antigen processing takes place and are presented to CD4+ T lymphocytes. This leads to an increase in the number of circulating auto reactive T cells. When clonal amplification is done, CD4+ effector T lymphocytes express adhesion molecules like intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1). Due to this, the effector cells adhere to the islet cells, tracking antigens and chemokines stimulated by the former CD8+ T-cell-mediated inflammation. The stimulated CD4+ T lymphocytes induce proliferation and activation of cells involved in inflammation, resulting into insulitis. β -cell destruction on the effector level is cytokine-mediated by stimulation of pro-apoptotic signaling in islet β-cells or by the expression of CD95 which induces direct apoptosis of β-cells. Free radicals are also involved in the above mechanism. The figure below is a representation of the underlying pathogenesis of IDDM.
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Christopher's paternal family had a history of juvenile-onset diabetes. This could be the possible cause of his genetic makeup susceptible to type 1 diabetes. IDDM requires an absolute intake of insulin on a regular basis for the treatment of hyperglycemia. However, there is a substantial lag time between the body's need for insulin and its dosing. Due to this the patients often suffer from elevated blood glucose levels for a longer period of time. Thus, Christopher suffered from chronic hyperglycemia in spite of regular insulin injections.
Prolonged exposure of the body to high blood glucose leads to damage to the vascular system and reduced peripheral circulation. Consequently, many serious complications take place which if left untreated, would result into the death of the patient. Diabetic nephropathy is one of them. Diabetic nephropathy is a broad term used for a set of renal structural and functional abnormalities resulting from long-term complications of diabetes. It is characterized by hypertension, proteinuria and decreased or loss of renal function. It usually manifests itself after 10-15 years of the first diagnosis of diabetes. Renal complications are more profound and severe in type 1 diabetes than in type 2 diabetes. About 30-40 percent of the diabetic patients develop diabetic nephropathy.
Various hemodynamic and metabolic mechanisms contribute to the development of diabetic nephropathy. Chronic hyperglycemia leads to nephropathy characterized by glomerular hypertrophy and thickening of the basement membrane, increased endothelial permeability to albumin, and increased matrix protein synthesis. Hyperglycemia may also lead to high amounts of prostaglandins causing vasodilation. As a consequence to this, hyper filtration occurs due to renal perfusion and intraglomerular pressure. Prolonged hyperglycemia is also related with the production of advanced glycated end products (AGE). The aggregation of these AGE products in the kidney results into cytokine formation and eventually leads to mesangial hyperplasia. Extra glucose is converted to sorbitol by aldose reductase enzyme through the polyol pathway in the kidney. A considerable hike in the intracellular sorbitol quantities results in decrease of intracellular myoinositol, resulting into elevated renal blood flow, and an increase in pressure in the glomerular capillary. The polyol pathway also contributes to the increase in oxidative stress and kidney damage. Elevated blood glucose leads to hyperactivity of protein kinase C in vascular smooth muscle and endothelial cells which also causes diabetic nephropathy. Hemodynamic factors contribute to the development of the disease by changing the function of glomerular, mesangial, and epithelial cells in such a way that this leads to increase in mesangial matrix production and consequent thickening of the basement membrane. Thus, chronic hyperglycemia results into increased glomerular permeability, proteinuria, and glomerulosclerosis leading to symptoms of diabetic nephropathy. The pathogenesis of the diabetic nephropathy has been summarized below:
The same was the case with Christopher. At the age of 35, he was observed to be hypertensive and his urine marked the presence of a protein indicating proteinuria. Creatinine is formed in the muscles and is the end product of the metabolism of a compound called creatine. All of the creatinine is excreted out of the body by the means of kidneys. So the serum creatinine levels are a good test for kidney function with their normal range as less than 1 mg/dl. Christopher's creatinine levels were on a hike i.e. 7.5 mg/dl. This prompted that he was suffering from diabetic neuropathy. On kidney biopsy, his results revealed extensive glomerulosclerosis. This indicated that he had been suffering from diabetic nephropathy for a very long time which had eventually resulted into end stage renal disease.
End stage renal disease (also called as chronic glomerulonephritis) is the final stage of the kidney wherein irreversible damage to the renal structure and function takes place. In such cases, dialysis and kidney transplant are the only options for treatment available to the patient. In accordance with this, Christopher was called for dialysis on a day-to-day basis. But as the cost for regular dialysis is very high, he was also enlisted for a cadaveric kidney transplant.
For a transplant, genetic relationship of the donor and the recipient are taken into account. For any successful transplantation, matching of the human leucocyte antigens (HLA) of the donor and the recipient are of utmost importance. HLA antigens regulate the processes by which the body recognizes and rejects foreign tissue.
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Christopher was of blood group B positive which matched the one of the donor. However, his HLA-type was A2, 24; B50, 51; DR3, 4. DR3 and DR4 are the variants associated with IDDM. The HLA-type of the donor was A2, 11; B7, 35. The DR antigen was not obtained from the donor. As they were unrelated biologically, they had different genotypes. This resulted into an allograft transplant (donor is from the same species but a different genotype). Allograft transplants can only be possible under the influence of immunosuppressive drugs. Hence, when he was operated for renal transplantation, he was given 100 mg methylprednisolone and 40 mg of anti-ICAM monoclonal antibody. Methylprednisolone is a corticosteroid given to suppress inflammation. Anti-ICAM antibodies are used to target ICAM molecules, which are cell adhesion molecules, to impair leucocyte invasion of the graft. After the surgery, his urine output was 200 mL on the first day. This was normal for a newly transplanted kidney but was one-fifth of the normal output from a healthy person.
Christopher was then given a dose of 450 mg cyclosporine, 100 mg azathioprine, 160 mg methylprednisolone, and 40 mg of anti-ICAM antibodies. Cyclosporin inhibits the phosphatase calcineurin, which restricts interleukin release, impairing function of effector T-cells. Azathioprine inhibits DNA synthesis by acting as a purine analogue and is the most important immunosuppressive agent. After 5 days, the dose of anti-ICAM antibodies was discontinued and he was given 100 mg azathioprine, 400 mg cyclosporine, and 20 mg prednisone. Prednisone is a steroid which decreases inflammation. Steroids cannot be given for a longer period of time and their dosage should be reduced as soon as possible. He was then diagnosed normal for serum creatinine test. After 10 days of the surgery, he was discharged as his creatinine levels and blood pressure was stable and normal. On ultrasonography, the graft was found to be normal. A week later after discharge his urine output fell to half of normal. He was then tested for creatinine which had risen to 2.5 mg/dl. The transplant had enlarged and had become tender. This showed that the kidney was undergoing acute rejection.
Acute rejection occurs due to HLA reaction of the donor with the host T-cells triggering a chain of immune responses. The reason it takes place after 10-15 days of transplantation is because T cells need to differentiate in the bone marrow before maturation and specific antibodies have to be formed. T cells are majorly responsible for the cell-mediated immune response. When the T-lymphocytes of the recipient come in contact with the HLA antigens of the donor, they become irritated. These aggravated cells invade the graft by means of hypersensitivity reactions mediated by helper T cells. Acute rejection is marked by extensive infiltration of the graft by lymphocytes. It occurs mainly due to poor response to the immunosuppressive drugs.
The number of incidences of end stage renal disease is increasing rapidly with time. The cost of the present treatment is unaffordable and does not even guarantee complete success. Hence, there is a need for better and more promising methods. Thus, alternative approaches to cadaveric organ transplants must be designed and brought to practice. There is scope for the use of stem cells which have the potential to regenerate and help in maintaining structural and functional integrity of the tissue. Lot of research has been done and is still ongoing on the plausibility of administering bone marrow derived adult stem cells for the treatment of kidney failure. Embryonic progenitor cells originated from the blastocyst can possibly be useful for such alternative treatments. The resident renal stem cells which have the ability to regenerate and differentiate into many types of cells of the nephron and reverse the effects of functionally impaired renal tissue indicate that they might be the best element for stem cell therapy of kidney failure.