Links of interest: National Kidney Foundation. Web MD
Companies: Rockwell Medical
See also: Reperfusion injury under inflammatory diseases
Introduction:
Examples of kidney diseases include end stage renal disease, acute renal failure, chronic renal failure, polycystic kidney disease, chronic kidney disease, acute tubular necrosis (e.g., renal artery stenosis), infections that reduce kidney function kidney transplantation rejection and urinary tract obstruction. In addition, there are various disorders which are associated with such disorders.
Hemolytic uremic syndrome (HUS): See outline
Autosomal dominant polycystic kidney disease (ADPKD):
ADPKD is among the most prevalent dominant human disorders. The major manifestation of the disorder is the progressive cystic dilation of renal tubules, leading to renal failure in half of affected individuals by age 50. ADPKD associated renal cysts may enlarge to contain several liters of luid and hte kidneys usually enlarge progressively cuasing pain.
Reeders (US 5,891,628) disclose a novel gene called the PKD1 gene and mutations within this gene which are responsible for about 90% cases of ADPKD. In addition, the gene product and antibodies directed against the product are described as well as methods and compositions for the diagnosis and treatment of ADPKD.
Chronic kidney disease (CKD):
CKD affects more than 20 million Americans and is associated with high morbidity and mortality. The progressive deterioration of kidney function in CKD leads to retention of many substances, including phosphorus (P) that are normally excreted by the kidney. ADPKD is inhreited as an autosomal dominant disorder. Three distinct loci have been shown to cause phenotypically indistinct forms of the disease, with greater than 85-90% of the disease incidence being due to mutations which map to the short arm of chromosome 16.
CKD is a condition characterized by a gradual loss of kidney funciton over a period of months to years. It is characterised by nutritional disorders and systemic inflammation, which is accompanied by an increased catabolism, increasing morbidity and mortality. When a CKD patatient needs renal replacement therapy, the condition is called end0-stage renal disease. It is generally associated with old age, diabetes, hypertension, obesity, and CVD.
Causes:
The intestinal microbiota has emerged as an important trigger for progression and complications of CKD. Prolonged retention and undigested protein in the intestines triggers immune response cuasing discomfort and inflammation in the gut and formation of uremic toxins like p-cresol (“para-cresol”) sulfate and indoxyl sulfate, which play an important role in the genesis of cardiovascular complications and progression of rengal damage in CKD. The CKD induced changes in the composition and funciton of the gut microbiota represent a dysbiotic state that has adverse consequences. For example, increased generation of toxic solutes (e.g., indoxyl sulfate, p-cresol sulphate and trimethylamine-N-oxide) and dminsihed production of beneficial micronutrients may contribute to systemic inflamation, CDK progression and cardiovascular complications.
Uremic toxins can be divided into three categoreis depnding on the biochemical and physical properties. The first group includes water-soluble non-protein binding, LMW compounds, such as urea and creatine. The second group includes arger or medium MW compounds such as 2-microglobulin. The thrid group includes protein, binding, LMW compounds such as indoxyl sulphate, p-cresol or p-cresyl sulphate. Among the uremic toxins, the protien binding compounds such as indoxyl sulphate are difficult to remove via classical dialysis because of their strong prtoein-binding capabilities. The increase in p-cresol and indoxyl sulphate toxin production in CKD patients, coupled with inadequate renal clearant, results in high serum levels.
Glomerulonephritis:
Glomerulonephritis is a renal disease characterized by bilateral inflammatory changes in the glomeruli of the kidneys. Rapidly progressive glomerulonephritis (RPGN) can be caused by any of several underlying conditions, including necrotizing and/or crescentic glomerulonephritis with scant or no immune deposits (pauci-immune NCGN), anti-glomular basement mebrane nephritis (anti-GBM nephritis), IgA nephropathy, lupus nephritis and post-streptococcal glomerulone-phritis. In addition, certain diseases other than glomerulonephritis, such as hemolytic uremic syndrome or acute interstitial nephritis, may produce the clinical picture of RPGN. Pauci-immune NGGN can be restricted to the kindey (primary NCGN) or associated with Wegener’s granulmatosis or a systemic disease often classified as microscopic polyarteritis nodosa. (Arnaout US 5,200,319).
Glomerulonephritis is a disease of the kidney characterized by inflammation and resulting enlargement of the glomeruli that is typically due to immuen complex formation. The accmulation of immune complexes in the glomeruliresults in inflammatory resopsnes, involving inter alia hypercellularity, that can cause total or partial blockage of the glomerulus through, among other factors, narrowing of the capillary lumens. One result of this process is the inhibition of the normal filtration function of the glomerulus. Blockcage may occur in large numbers of glomeruli, directly compromising kidney funciton and often causing the abnormal deposition of proteins inthe walls of the capillaries making up the glomerulus. Such deposition can, in turn, cause damage to glomerular basement mebranes. Those glomeruli that are not blocked develop increased permeability, alloiwng alrge amounts of protein to pass into the urine, a condition referred to as protienuria. (US63555245)
C3 glomerulpathy, C3G, is a rare disease and encompasses a heterogenous gorup fo syndromes encompassing dense deposit disease and C3 glomerulonephritis (C3GN). As with aHUS, C3G is a disease in whihch the complement system is dyregulated, typically within the amplificaiotn look. Unlike in aHUS, the dysregulaion usually affects fluid phase acitvaition. It is clear that systemic acitvaiton of complement leads to high levels of complement deposition in the kindey, particularly as teh glomerular basement membrane. (Ricklin, Molecular Immunogloy 102 (2018) 89-119).
C3G is primarily driven by excessive complement turnover in the ciruclation due to convertase stabilizing autoantibodies, which mainfests in massive deposition of C3 activaiton fragments in the kidney (mostly on the glomerular basement membrane in the case of dense deposit disease). (Lambris, “The renaissance of complement therapeutics” (2018)).
Immune complexes in the kidney are notable absent in aHUS and C3G, but are present in other diseases of the kidney. In immune complex glomerulonephritis (IC-MPGN), immune complexes activate the classical pathway and deposits of activated C3 and immunoglobulin are found in the kidney. The disease is heterogenous with varialbe presence or absence of complement gnee mutations, autoantibodies and complement abnormalities in the circulation. (Ricklin, Molecular Immunogloy 102 (2018) 89-119)
Lupus nephritis is a common clinical manifestation and casue of morbility in systemic lupus erythematosus (SLE) in whcih immune complexes deposit in the kidney causing complement activaiton, renal cell damage and thrombotic microangiopathy (TMA). Up to 50% of patiens with SLE will have clinically evident kidney dsiease at presentation during follow-up, renal involvement occurs in up to 75% of patients. (Ricklin, Molecular Immunogloy 102 (2018) 89-119.pertension. (US63555245)
GN is the third leading cause of death in end stage renal disease patients, exceeded only by diabetes and h
Diagnosis of glomerulonephritis:
Diagnosis of the condition causing RPGN is essential for teh initiation of appropriate treatment. Renal biopsy has generally been considered to be the msot definite diagnostic procedure in patients exhibiting RPGN. However, the procedure invovles risk and sometimes fails to provide the correct diagnosis because the lesions in the NCGN are often focal and can be missing from a small biopsy specimen.
Serologic test have diagnostic value in some forms of RPGN. In particular, patients exhibiting RPGN often have circualting auto-antibodies directed against neutrophils and monocytes. the presence of these auto-antibodies, generally referred to as anti-neutrophil cytoplasm antibodies (ANcA) ahs been used as a diagnostic tool ANCA are detected by means of an indirect immunofluorescence assay suing ethanol fixed normal human neutrophils as a substrate. (Arnaout US 5,200,319) discloses a substantially pure protein )p29) which can be isolated from human neutrophils and is capable of binding to auto-antibodies present in the sero of individuals aflficted with Wegener’s granulomatosis. A method of detecting auto-antibodies diagnsotic for Wegener’s granulomatosis is discloses which includes the step fo contacting a biological fluid to be tested to p29. Any immune complexes formed are detected and used as an indication for the presence of auto-antibodies diagnostic for Wegener’s granulomatosis. A separate method is disclosed for detecting auto-antibodies diagnostic for pauci-immune necrotizing and/or crescentic glomerulonephritis which involves contacting a sample with myeloperoxidase and detecting immune complexes formed.
Symptoms of glomerulonephritis: include proteinuria, reduced glomerular filtartion rate, serum electrolyte changes including azotemia (uremia, excessive blood area nitrogen-BUN) and salt retention, leading to water retention reuslting in hypertension and edema, hematuria and abnormal urinary sediments including red cell casts, hypoalbuminermia, hyperlipidemia and lipiduria. (US63555245).
Treatment of Glomerulonephritis:
–anti-C5 anibodies:
(US63555245) disclsoes anti-C5 antibodies taht bind to complement component C5 which can be admisntiered after the appearance of GN smptoms.
Diabetic nepthropathy (DN):
Diabetic nepthropathy is a progressive kidney disease associated with longstanding diabetes mellitus. It causes abnormal fluid filtration and increased urinary albumin excretion, eventually leading to kidney failure. Although several treatment have been proposed in addition to the strict control of blood glucose levels, the prognosis of patients with diabetic nephropahty reamins poor as compared to other causes of renal failure. One of the mechanisms involved in DN is a hypercoagulation state that produces numerous microthrombi in the glomeruli. Ishii showed that administration of annexin-2 significantly reduced microalbuminuria and the development of glomerular lesions in a murine model of type 2 diabetes.
IgA and IgM Mediated Kidney Diseases: See outline
Membranoproliferative glomerulonephritis (MPGN):
MPGN mainly affects children and adults (median age at onset of disease about 10 years. 50% of the patients present with nephrotic syndrome, the others with mild proteinuria, 20% with macrohematuria. 30% of the patients develop hypertension with onself of disease. Children with MPGN have an unfavourable late prognosis and develop end stage renal disease (ESRD) after about 8-16 years. chronic nephropathies
MPGN type II (MPGN II): MPGN II, also termed “dense deposit disease” is a rare disease which is characterized by complement containg dense deposits within the basement membrane of the glomerular capillary wall and followed by capillary wall thickening, mesangial cell prolfieration and glomerular fibrosis.
MPGN & MPGNIII: are two more subtypes of MPGN characterized by mesangial cell proliferation and increase in mesangial matrix compbined with a thickening of the glomerular capillary walls.
Renal Ischemia:
Renal Ischemia may occur in the setting of hypovolemia, hypotension or renal transplantation. Ischemia reperfusion (I/R) injury in the kidney is a common cause of acute renal fialure (ARF). Hemodialysis is currently the only treatment of ARF that is approved by the FDA.
Student of renal I/R injury have demonstrated that mice deficient in complement are protected from injury. Deposition of C3 occurs primarily at the tubular basement membrane and teh reas of deposition correspond with morphologic injury. Thurman (J. Immunology, 2003, 170: 1517-1523) showed that mice deficient in complement factor B, an essential component of the AP pathway, developed substantially less injury after I/R.
Stable Renal Function:
Stable renal function refers to renal function which may be estimated by Glomerual Filtration Rate calculated by Modification of Diet in Renal Disease 7 (MDRD7) or serum creatinine. Generally, stable renal funciton refers to renal funciton which varies by less than 60% between repeated measurements of estimated by Glomerular Filtraiton Rate and serum creatinine. (Frey, US Patent Applicaiton No: 16/340,453, published as US 2019/0276524).
Conditions Associated with Renal Failure See outline
1. Erythropoietin (EPO) deficiency: See outline
2. Hyperphosphatemia: See outline
3. Proteinuria: See outline
4. Hyperparathyroidism (HPT): see outline
5. Vitamin D Deficiency: See outline
6. Complement System Upregulation: See outline
Treatment:
Probiotics:
Pandurangan (US 2023/0148645) discloses a method of reducing protein bound uremic toxins in a subject and treating renal diseases that includes administering to a subject in need thereof a therapeutically effective amount of an enzobiotic composition which includes a therapeutically effective amount of a (1) synbiotic that includes at least one probiotic selected from the group consisting of L. acidophilus, L. brevis, L. bulgaricus, L. casek, L. fermentum, L. helviticus, L. plantarum, L. Leichmannii, L. salivarius and L. cellobiosus and at least one prebiotic comprising at elast one ogligosaccharide and a proteolytic enyme which is capable of reducing the concentration of protein bound uremic toxins, p-cresol and indoxyl sulphate.