Transplant glomerulopathy | |
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Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. PAS stain. | |
Specialty | Nephrology |
Transplant glomerulopathy(TG) is a morphologic lesion of renal allografts that is histologically identified by glomerular basement membrane (GBM) duplication and/or multilayering. [1] Proteinuria, hypertension, and deteriorating graft function are the hallmarks of TG. [2]
Acute rejection, pre-transplant antibody levels, and de novo HLA antibodies are all linked to TG. There are further risks associated with HLA class II and/or donor-specific antibodies. [2]
Five years after transplant, TG is present in 5–10% of renal allografts; in rare cases, protocol biopsies may reveal TG as a subclinical finding. With chronic alloantibody-mediated injury, the lesion is particularly associated with a poor prognosis for the outcome of the graft. [3]
Transplant glomerulopathy (TG) may present as clinically silent and only be detected on biopsy. [4]
Low-level proteinuria and/or a slight decline in glomerular filtration rate are examples of early clinical manifestations. [5] However, as the lesion worsens, hypertension, a drop in glomerular filtration rate, and an increase in proteinuria, often into the nephrotic range, may occur. [6]
Numerous studies have linked reduced allograft survival to transplant glomerulopathy. [7] [8] [9]
TG is thought to be a morphologic expression of chronic antibody-mediated rejection (ABMR) in most cases and is well-documented as being correlated with a buildup of donor-specific antibodies (DSAs), particularly against HLA class II antigens. But TG is not exclusive to chronic ABMR; in one-third to one-fourth of cases, thrombotic microangiopathy (TMA), hepatitis C, and possibly T cell-mediated rejection (TCMR) appear to be the alternative etiologies. [10]
Transplant glomerulopathy (TG) is a slowly developing, long-lasting damage to the glomerular capillary walls that is thought to result from long-term glomerular endothelial activation and injury. The glomerular basement membrane is also repaired and remodeled in conjunction with this condition. [11] Reduced podocyte density and glomerular epithelial cell stress are also factors in transplant-related glomerular injury, which includes increased urine podocyte excretion in TG and significant podocyte detachment, both of which are linked to progressive glomerulosclerosis. [12]
Out of all the suggested mechanisms, the one that has been documented the most is the correlation between donor-specific antibody against the human leukocyte antigen (anti-HLA-DSA), antibody-mediated mediated rejection (ABMR), and endothelial damage that results in the development of TG. [13]
Clinical investigations have also demonstrated the connection between TG and humoral alloimmunity. [13] TG is first thought to be the characteristic lesion of chronic ABMR. Compared to other transplants, HLA-incompatible transplants that need to be desensitized have a higher prevalence of TG. [14] Patients with TG have consistently been found to have an increased prevalence of donor-specific anti-HLA antibodies (DSA) and an increased incidence of antecedent or concurrent ABMR. [15] [16] Apart from preformed DSA, de novo DSA development has also been linked to TG, indicating that pathogenetic relevance to TG also extends to either new or recurrent endothelial damage resulting from de novo DSA. [17]
The most compelling evidence for the theory that non-HLA antibodies could cause ABMR has come from studies on HLA identical renal allograft recipients who developed anti-donor endothelial reactive antibodies. [18] According to data, non-HLA auto- and alloantibodies may contribute to chronic graft loss either by themselves through cytotoxicity or in conjunction with anti-HLA antibodies. [19]
Clinical biopsy studies showing TG lesions in the absence of discernible acute or chronic ABMR have raised the possibility that non-humoral mechanisms may be responsible for the TG pathogenesis in these cases. [20]
It has long been believed that humoral immunity is the cause of microvascular inflammation (MVI), which occurs in conjunction with TG and ABMR. [21]
Transplant glomerulopathy (TG) is best recognized histologically by reduplications or "double contours" of the glomerular basement membrane in peripheral glomerular capillary loops; basement membrane stains (methanamine silver and periodic acid-Schiff) work best for this kind of identification. Since it is a focal lesion in the early stages and only affects a small percentage of glomeruli, sufficient glomerular sampling is required. The lesion becomes more diffuse over time, accompanied by secondary focal segmental and global glomerulosclerosis and hyalinosis, variable mesangial matrix expansion (without the formation of mesangial nodules or significant mesangial cell proliferation), and associated glomerular hypertrophy. Severe nodular hyaline arteriolosclerosis, arterial fibrous intimal thickening, and progressive interstitial fibrosis and tubular atrophy are typically linked to advanced TG. [3]
According to the Banff '97 criteria, double contours had to be present in at least 10% of the capillary loops in the most affected glomerulus in order to diagnose transplant glomerulopathy. [22]
Immunofluorescence (IF) results for TG show no diagnostic staining for IgG, IgA, or C1q, as well as mild-to-moderate glomerular mesangial along with capillary wall deposition of IgM and C3. [3]
Differential diagnosis (DDX) of transplant glomerulopathy includes thrombotic microangiopathies, recurrent membranoproliferative glomerulonephritis, and ischemia. [23]
The general management of patients with TG involves renin-angiotensin-aldosterone (RAAS) blockade, blood pressure and diabetes control, weight loss, and other strategies to lower intra-glomerular pressure. [13]
Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many unique HLA proteins on the surface of their cells, which signal to the immune system whether a cell is part of the self or an invading organism. T cells recognize foreign HLA molecules and trigger an immune response to destroy the foreign cells. Histocompatibility testing is most relevant for topics related to whole organ, tissue, or stem cell transplants, where the similarity or difference between the donor's HLA alleles and the recipient's triggers the immune system to reject the transplant. The wide variety of potential HLA alleles lead to unique combinations in individuals and make matching difficult.
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.
Xenotransplantation, or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenografts or xenotransplants. It is contrasted with allotransplantation, syngeneic transplantation or isotransplantation and autotransplantation. Xenotransplantation is an artificial method of creating an animal-human chimera, that is, a human with a subset of animal cells. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid.
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ. Living-donor kidney transplants are further characterized as genetically related (living-related) or non-related (living-unrelated) transplants, depending on whether a biological relationship exists between the donor and recipient. The first successful kidney transplant was performed in 1954 by a team including Joseph Murray, the recipient’s surgeon, and Hartwell Harrison, surgeon for the donor. Murray was awarded a Nobel Prize in Physiology or Medicine in 1990 for this and other work. In 2018, an estimated 95,479 kidney transplants were performed worldwide, 36% of which came from living donors.
Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive metabolic disorder caused by mutations of the APRT gene. Adenine phosphoribosyltransferase (APRT) catalyzes the creation of pyrophosphate and adenosine monophosphate from 5-phosphoribosyl-1-pyrophosphate and adenine. Adenine phosphoribosyltransferase is a purine salvage enzyme. Genetic mutations of adenine phosphoribosyltransferase make large amounts of 2,8-Dihydroxyadenine causing urolithiasis and renal failure.
Tissue typing is a procedure in which the tissues of a prospective donor and recipient are tested for compatibility prior to transplantation. Mismatched donor and recipient tissues can lead to rejection of the tissues. There are multiple methods of tissue typing.
The TCIRG1 gene encodes for the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.
Paul Ichiro Terasaki was an American scientist in the field of human organ transplant technology, and professor emeritus of surgery at UCLA School of Medicine.
Human leukocyte antigens (HLA) began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences. An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.
Glomerulopathy is diseases that impact the glomeruli in the nephron, either inflammatory or noninflammatory. Glomerulopathy includes collapsing glomerulopathy, glomerulocystic kidney disease, glomerulomegaly, membranous nephropathy, and tip lesion glomerulopathy.
Necrotizing vasculitis, also called systemic necrotizing vasculitis, is a general term for the inflammation of veins and arteries that develops into necrosis and narrows the vessels.
Bernd Schröppel is a German former transplant nephrologist at the Mount Sinai Medical Center and the former medical director of the kidney pancreas transplant program at the Recanati/Miller Transplantation Institute at the Mount Sinai Medical Center in New York City. He is also a former assistant professor of nephrology at the Mount Sinai School of Medicine.
Eosinophilic cystitis is a rare type of interstitial cystitis first reported in 1960 by Edwin Brown. Eosinophilic cystitis has been linked to a number of etiological factors, including allergies, bladder tumors, trauma to the bladder, parasitic infections, and chemotherapy drugs, though the exact cause of the condition is still unknown. The antigen-antibody response is most likely the cause of eosinophilic cystitis. This results in the generation of different immunoglobulins, which activate eosinophils and start the inflammatory process.
Glomerular hyperfiltration is a situation where the filtration elements in the kidneys called glomeruli produce excessive amounts of pro-urine. It can be part of a number of medical conditions particularly diabetic nephropathy.
The National Kidney Registry (NKR) is a national registry in the United States listing kidney donors and recipients in need of a kidney transplant. NKR facilitates over 450 "Kidney Paired Donation" (KPD) or "Paired Exchange" transplants annually.
Kidney paired donation (KPD), or paired exchange, is an approach to living donor kidney transplantation where patients with incompatible donors swap kidneys to receive a compatible kidney. KPD is used in situations where a potential donor is incompatible. Because better donor HLA and age matching are correlated with lower lifetime mortality and longer lasting kidney transplants, many compatible pairs are also participating in swaps to find better matched kidneys. In the United States, the National Kidney Registry organizes the majority of U.S. KPD transplants, including the largest swaps. The first large swap was a 60 participant chain in 2012 that appeared on the front page of the New York Times and the second, even larger swap, included 70 participants and was completed in 2014. Other KPD programs in the U.S. include the UNOS program, which was launched in 2010 and completed its 100th KPD transplant in 2014, and the Alliance for Paired Donation.
Donor-specific antibodies (DSA) are a concept in transplantation medicine and describe the presence of antibodies specific to the Donor's HLA-Molecules. These antibodies can cause antibody-mediated rejection and are therefore considered a contraindication against transplantation in most cases. DSA are a result of B cell and plasma cell activation and bind to HLA and/or non-HLA molecules on the endothelium of the graft. They were first described in 1969 by Patel et al., who found that Transplant recipients who were positively tested for DSA using a complement-dependent cytotoxicity crossmatch assay had a higher risk of transplant rejection. DSA can either be pre-formed or can be formed as a response to the transplantion.
Cardiac allograft vasculopathy (CAV) is a progressive type of coronary artery disease in people who have had a heart transplant. As the donor heart has lost its nerve supply there is typically no chest pain, and CAV is usually detected on routine testing. It may present with symptoms such as tiredness and breathlessness.
Alexandre Loupy is a French nephrologist, a university professor and hospital practitioner at the Necker Hospital of the Assistance Publique - Hôpitaux de Paris, in the kidney transplant department. He is known for his discoveries on the topic of graft rejection.,, Its approach proposing innovative methodological tools has led to a better understanding but has also led to important changes in the international classification of graft rejection., These discoveries allow to improve the performance of clinical trials and to consider new therapeutic innovations in transplantation.
Gaetano Ciancio is an Italian American surgeon at the University of Miami who specializes in kidney transplant. He is the chief medical and academic officer of the Miami Transplant Institute and the director of its Kidney & Kidney-Pancreas Programs. His most significant contributions to medicine are related to surgically treating kidney cancer once it has spread to the inferior vena cava and in optimizing the immunosuppression protocol after kidney transplant.