IgA Nephropathy as a cause of End Stage Renal Disease

There are a variety of causes of end stage renal disease (ESRD) in teenagers and adults. Immunoglobulin-A (IgA) nephropathy could be a cause of end stage renal disease (ESRD) in around 25% of cases. There are five types of immunoglobulins in our body for protection against microorganisms and IgA provides defence at mucous membranes. Colostrum and breast milk are rich sources of IgA and protect us during infancy through breast-feeding. However, later in life, chronic mucosal inflammation (inflammation of respiratory, oral, or gastrointestinal mucous membranes) may lead to IgA-nephropathy (IgAN). Viral (including HIV), bacterial, yeast and parasitic infections have been found to be associated with IgAN. Environmental and food antigens have also been implicated in IgAN as these may mimic molecular structure of microbial antigens and lead to excessive IgA production, aggregation and breakdown of mucosal barrier. Patients affected by IgAN may present with hematuria (blood in urine) and/or proteinuria (protein in urine) with or without rise in serum creatinine. The most common initial symptom in children is microscopic hematuria. Some adults may present with acute or chronic renal failure.

IgA nephropathy is a common nephropathy, which could be detected on renal (kidney) biopsy evaluation through light and fluorescence microscopy. However, electron microscopic study of renal biopsy acts as a diagnostic adjunct as the location of immune complexes in the renal glomerulus could be pronounced on electron micrographs. Figures 1 and 2 are the electron micrographs from a proven case of IgAN, illustrating mesangial deposits of IgA.

Figure-1: Electron micrograph of an area of glomerulus of a case of IgAN showing electron dense deposits (D) in the mesangial (Mes) area. Glomerular basement membrane (GBM), capillary lumen (CL), podocyte or epithelial cell (EpC) and urinary space (US) are also exhibited; Original Magnification 4600x.

Figure-2: Electron micrograph of an area of glomerulus of a case of IgAN showing electron dense deposits (D) in the mesangial (Mes) area. Glomerular basement membrane (GBM), capillary lumen (CL), podocyte or epithelial cell (EpC) and urinary space (US) are also exhibited; Original Magnification 6000x.

The pathology of IgAN may be variable depending on underlying cause. Mesangioproliferative glomerulonephritis is the most common pattern in many renal biopsies; however, glomeruli may appear normal on light microscopy in some of the cases. Renal biopsies in a few cases may also show crescent formation in occasional glomeruli. Diagnosis of IgA nephropathy is established by direct immunofluorescence technique on renal biopsies and the pattern may be dominant or co-dominant for IgA staining. The incidence of ESRD has been found to be high in patients presenting with >1g/day proteinuria with increased level of serum creatinine as compared to those having proteinuria <1g/day with increased level of serum creatinine. Pathogenesis of IgAN is very complex. A variety of underlying diseases including hepato-biliary disease can be associated with IgA nephropathy. Defective detection and clearance by liver of polymeric immune complexes of IgA (IgA1) due to abnormal galactosylation of O-linked glycans is probably the major cause of IgAN in addition to loss of mucosal barrier and chronic mucosal inflammation. Recurrent tonsillitis may also lead to IgA nephropathy and tonsillectomy may be helpful in these cases to remove the mucosal foci of infection. Optimal treatment of tonsillitis and other oromucosal infections with antibiotics along with conventional treatment of IgAN would be helpful to put brakes on the progression of IgA nephropathy. Patients with acute or chronic renal failure due to advanced stage of IgAN may need hemodialysis or renal transplantation. Use of anti-oxidants and fish oil as food supplements in some cases of IgA nephropathy have been found beneficial.

Urea Synthesis and Clearing: Role of Liver and Kidneys

The proteins we eat contain about 20% nitrogen. A person consuming around 100g proteins daily will excrete about 17g of nitrogen daily in the form of urea. In man and other vertebrate animals the major excretory product of protein metabolism is urea, and they are classified as ureotelic animals. Birds and reptiles excrete the waste nitrogen in the form of relatively insoluble uric acid as the end product of nitrogen metabolism and are called uricotelic animals. Urea is synthesized in liver and is released into the blood and cleared by kidneys in the urine.
Urea synthesis in the liver involves five enzymes: (1) Carbamoyl phosphate synthetase 2) Ornithine carbamoyl transferase (3) Argininosuccinate synthetase (4) Argininosuccinate lyase and (5) Arginase. Deficiency in any of these enzymes may lead to metabolic disorder. The sole function of urea cycle is to convert the ammonia to non-toxic compound urea. All metabolic disorders of urea synthesis cause ammonia intoxication. Catabolism of amino acids in the most of cells produces ammonia. Considerable quantity of ammonia is produced by intestinal bacteria from the dietary proteins and from the urea present in cellular fluids secreted into the gastrointestinal tract. The ammonia produced in the intestine is absorbed into the portal venous blood and is promptly removed by the liver, where urea is synthesized from the ammonia. At first step, carbamoyl phosphate is produced by condensation of one molecule each of ammonia, carbon dioxide and phosphate, under the action of intramitochondrial carbamoyl phosphate synthetase-1 (CPS-1) in the presence of Mg⁺⁺ and N-acetyl glutamate. Now citrulline is formed from the carbamoyl phosphate by union of carbamoyl phosphate and ornithine under the action of another intramitochondrial enzyme called ornithine carbamoyl transferase. The rest of the steps in the urea synthesis take place in cytosol. Citrulline diffuses out from the mitochondrial membrane into the cytosol, where it is linked with aspartate to form argininosuccinate under the action of enzyme argininosuccinate synthetase in the presence of Mg⁺⁺ ions and ATP. There after the cleavage of argininosuccinate to arginine and fumarate is catalyzed by argininosuccinate lyase. The final step in the urea synthesis is the hydrolysis of arginine to urea and ornithine. Ornithine from the cytosol enters the mitochondria and is recycled in urea synthesis. Though other body tissues also exhibit the presence of urea synthesis enzymes but the physiologic contribution of extrahepatic urea synthesis is very low. Urea produced by the hepatic cells enters the blood and is excreted in the urine by the kidneys. Low level of blood/plasma urea and respiratory alkalosis are indicative of urea cycle disorders. Free "Human Body Maps"

Renal Transplantation and Immune Profiling

Organ transplantation is analogous to blood transfusion and we need to detect and match the tissue antigens of the donor and the recipient before transplantation of an organ, say kidney. Tissue antigens are known as human leucocyte antigens (HLA). There are four loci called A, B, C and D on the 6th chromosome, which govern these tissue antigens or HLA. We inherit one gene (each gene has sub-genes) each on each locus from our mother and father. There is antigenic polymorphism at each locus (A, B, C, and D). Unless the kidney donor and the recipient (patient) are identical twins, a 100% match of these HLA is not possible. There is 50% match of HLA amongst parents and children, and the siblings. Unrelated donor and recipient may also have 50% matching of tissue antigens or HLA. The participation of immune mechanisms in allogenic kidney transplant begins with the identification and appropriate reaction to the donor organ, by the recipient, depending on the degree of HLA mismatch. Immunosuppressive therapeutic protocols are prescribed for the adoption and survival of grafted/transplanted kidney. There is very complex immune pathway in our body involving antigen presenting cells and T & B cells (Lymphocytes), which get activated and lead to injury of the target cells. The intragraft cell trafficking and their effector mechanisms may have serious implications. Post transplant immune profiling is a way of monitoring the allograft function and to elucidate pathogenic mechanisms and molecular pathways causing tissue injury and disease.

Transplant tolerance could only be achieved through sincere compliance of immunosuppressive therapy. The immune system of the recipient following renal transplantation, though challenged by the exposure to donor antigens to initiate an early sub-clinical or acute rejection process, attempts to regulate the inflammatory processes or maintain homoeostasis in the body. The acute rejection may be cell or antibody mediated. The transplant tolerance is defined as maintenance of stable allograft function without clinical evidence of immunosuppression. There are many therapeutic approaches to achieve the transplant tolerance, however, the best one is donor specific transfusion or hematopoietic cell infusion. Almost all the transplant recipients have to depend on a variety of immunosuppressive protocols to ward of any chance of allograft rejection.

End Stage Renal Disease and Renal Transplantation

Chronic glomerulonephritis, diabetic nephropathy, chronic tubulointerstitial disease, benign nephrosclerosis and polycystic kidney disease are the major causes of end stage renal disease (ESRD) and renal failure. Patients with ESRD exhibit a variety of abnormalities in their autonomic functions. Precise mechanisms of evaluating autonomic functions have revealed abnormalities in efferent parasympathetic pathway and baroreceptor sensitivity in patients with end stage renal disease. An increase in expiration-inspiration, lying standing and valsalva ratios, and baroreceptor sensitivity slope have been well documented in ESRD. Uremic patients with ESRD respond poorly to antihypertensive drugs as compared to otherwise healthy controls. Renal involvement in multiple myeloma is an other cause of ESRD and renal failure. Dialysis is an adoptive procedure in patients having end stage renal disease and ultimate surgical measure is renal (kidney) transplantation. Adequate dialysis in patients with ESRD reverses the elevated levels of urea, creatinine and electrolytes in blood.

Though renal transplantation is must in patients with ESRD, but it needs a lot of medication and post transplantation care for the successful adoption and survival of renal allograft. Systemic fungal infections (cryptococcosis, mucuromycosis, candidiasis, aspergillosis and mixed infections) have been documented after renal transplantation. Though these infections are treatable but may complicate the post operative care as additional medication will be required in addition to immunosuppressive therapy. High incidence of tuberculosis has also been observed in recipients of renal transplant along with viral infections like BK virus and cytomegalovirus (CMV). Adverse impact of pre-transplant polyoma virus (BK virus) infection on the graft survival has also been documented. Molecular technology has been developed for the early detection and identification of these viruses from the time of renal transplantation onwards by using protocol biopsies from the grafted kidney.

Acute Renal Failure: Medical and Other Causes

If we look at the spectrum of acute renal failure (ARF), we find that in more than 65% of cases medical causes or ailments are associated. Around 20% of cases generally have obstetrical causes and 15% of cases of acute renal failure may have surgical or other causes. Diarrhoea, mismatched blood transfusion, intravenous hemolysis in glucose-6-phosphate dehydrogenate (G-6-PD) deficient patients, hemolytic uremic syndrome (HUS), severe glomerulonephritis, falciparum malaria, snake bite, insect stings, septicemia and copper sulphate, mercuric chloride and zinc phosphide poisoning are some medical conditions in which if effective treatment is delayed may lead to acute renal failure. Intake of nephrotoxic drugs can also cause acute renal failure. Obstetrical causes include toxemia of pregnancy, postpartum hemorrhage, puerperal sepsis and post abortal sepsis. Major surgery may cause ARF in some cases. Nephrotoxic drugs and sepsis could be compounding factors in cases ARF with surgical cause.

Acute gastroenteritis, septicemia and HUS may singly or in combination be the major cause of ARF in tropical countries. Rhabdomyolysis has been observed to play a significant role in causing ARF in a variety of conditions including toxemia of pregnancy, status asthmaticus, status epilepticus, hypothermia, burns, dermatomycosis, wasp and hornet strings, and copper sulphate, mercuric chloride and zinc phosphide poisoning. The main causative factors for intravenous hemolysis in G-6-PD deficient patients include the commonly used drugs like aspirin, chloramphenicol, chloroquine, quinine and phenylbutazone. Bilateral mucuromycosis has also been documented to cause ARF even in non-immunocompromized subjects. Sometimes nephrectomy may be required in cases of ARF due to mucuromycosis. The spectrum of community acquired acute renal failure and hospital acquired acute renal failure is almost similar throughout the world. Decreased renal perfusion in cases of hypothermia and hypotension (low blood pressure) may cause ARF if not treated well in time. Timely treatment and hemo-dialysis or peritoneal dialysis can definitely benefit the patient in restoration of renal function and reversal of acute renal failure.