When should post-transplantation proteinuria be attributed to the renal allograft rather than to the native kidney?
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Comment↗
Biomedical subjects
Christian Morath
Publications and source records attributed to Christian Morath.
No improvement of patient or graft survival in transplant recipients treated with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers: a collaborative transplant study report.
It was reported recently that treatment of kidney transplant recipients with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) is associated with strikingly improved long-term graft and patient survival. This finding has important implications for future posttransplantation therapy recommendations. In an analysis of 17,209 kidney and 1744 heart transplant recipients, an association of treatment with ACEI/ARB with improved transplant outcome could not be confirmed. It is concluded that recommendations for a widespread use of ACEI/ARB treatment in transplant recipients are unwarranted.
Aged↗
Pulmonary cavernae in Wegener's granulomatosis.
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Biopsy↗
Late referral--a major cause of poor outcome in the very elderly dialysis patient.
BACKGROUND: The population of incident dialysis patients is progressively ageing and dialysis outcome is particularly poor in the elderly. There is little documentation whether late referral is more frequent in the very elderly (> or =75 years) as compared with non-elderly patients and whether it contributes, at least in part, to their particularly poor outcome. METHODS: In a retrospective single center study we assessed all consecutive patients (n = 254) who had been admitted to haemodialysis between 1998 and 2001. Outcome in relation to the interval between the time of referral and start of dialysis was compared in very elderly and non-elderly patients. According to a previous analysis in our center major adverse outcome is seen in patients referred < or =8 weeks before the start of dialysis. For the present study this time interval was therefore operationally defined as 'late referral'. RESULTS: Expectedly 1 year after start of dialysis mortality was higher (31%) in the very elderly compared with younger patients (19%). The interval between referral and first dialysis was less in patients > or =75 years (median interval 3.5 weeks) compared with patients <75 years (median 20.5 weeks; P = 0.007). The difference in 1 year mortality between timely (>8 weeks) vs late (< or =8 weeks) referral, however, was as high in the very elderly (42% vs 16%) as in the younger patients (34% vs 9%). The relative risk of death conferred by late referral was also not significantly different in the very elderly (RR 1.80) compared with the younger (RR 2.32) patient. Using multivariate analysis timing of referral proves to be an independent factor with regard to the outcome and time of survival. CONCLUSIONS: We conclude that late referral is more frequent in the very elderly. Although the relative risk of death conferred by late referral is similar in the very elderly and non-elderly, due to higher frequency of late referral it accounts for a large proportion of excess mortality in the very elderly.
Aged↗
Lymphoid interstitial lung disease in a patient with acute tubulointerstitial nephritis and uveitis: a new facet of a rare syndrome?
We report for the first time the appearance of lymphoid interstitial lung disease in a patient with tubulointerstitial nephritis and uveitis (TINU) syndrome. A 41-year-old woman with a 9-month history of recurrent bilateral iridocyclitis was referred to our division for examination of renal dysfunction. Renal biopsy showed extensive interstitial CD3+ lymphocytic infiltration; glomerular structures were unaffected. After oral corticosteroid therapy, renal function remained stable during the next few years. Uveitis was controlled by using topical steroids. Five years after first presentation, the patient developed symptoms suggestive of interstitial lung disease, combined with a relapse of uveitis. Lung biopsy showed lymphofollicular bronchiolitis (CD3+) associated with florid alveolitis. There was no evidence for acute infection or systemic disease to be the cause of this pathological state. Lung disease proved to be steroid responsive. A new pulmonary flare-up 3 years later responded to renewed treatment. Accounting for the histological findings, we assume both TINU syndrome and interstitial lung disease to be manifestations of a common autoimmune disorder.
Acute Disease↗
Antifibrotic actions of mycophenolic acid.
Mycophenolic acid (MPA) is a highly selective, non-competitive and reversible inhibitor of the inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides. Mycophenolate mofetil (MMF, the ester prodrug of MPA) strongly inhibits both T- and B-lymphocyte proliferation and has now been widely used in the prevention of acute and chronic allograft rejection. Recent evidence, however, suggests that MMF is also capable of inhibiting the proliferation of non-immune cells. In various cell lines, e.g. smooth muscle cells, renal tubular cells, mesangial cells, and fibroblasts, MPA reduced or even abrogated proliferation in response to proliferative stimuli. In animal studies, MMF ameliorated renal lesions in immune-mediated disease, e.g. in the Anti-Thy 1.1 model and experimental lupus nephritis, but was also effective in non-immune-mediated renal damage, e.g. in the rat remnant kidney model or in a model of chronic cyclosporine nephrotoxicity in the rat. In humans, MMF reduced proteinuria in steroid-resistant nephrotic syndrome and had beneficial effects in the prevention and treatment of chronic allograft nephropathy and calcineurin inhibitor toxicity through the reduction of immune- and non-immune-mediated renal damage. MMF is well tolerated and has proven to be a relatively safe drug. Taken together, there is a growing body of evidence pointing to therapeutic applications of MMF other than immunosuppression, in particular the prevention of fibrosis.
Animals↗
Real-time contrast-enhanced sonography in renal transplant recipients.
Conventional colour Doppler ultrasonography (CDUS) is a well-established and the most frequently used imaging procedure to diagnose kidney allograft dysfunction. Unfortunately, this technique is limited to the estimation of the allograft perfusion in large arteries. Early diagnosis of vascular damage, i.e., chronic allograft nephropathy is essential for an early therapeutic intervention. CDUS is still limited in interpreting vascular integrity. In contrast-enhanced sonography (CES) is a feasible technique for quantitative analysis of kidney perfusion and early diagnosis of biopsy proven chronic allograft nephropathy. CES does not provide only quantitative information on microvascular perfusion of the renal allografts but also represents improved diagnostic significance compared with CDUS for the detection of chronic allograft nephropathy.
Contrast Media↗
Salt--a potential 'uremic toxin'?
It has been known for decades that salt (NaCl) determines extracellular volume as well as blood pressure and is one cause of hypertension. The difficulty to control the NaCl balance and thus treat sodium overload and hypertension in patients on dialysis has been recognized by Scribner in the early days of dialysis. In recent years, an impressive body of evidence has accumulated indicating that in essential hypertension, NaCl--blood pressure independently--causes target organ damage such as left ventricular hypertrophy, microalbuminuria, and increased aortic stiffness. It has further been recognized that NaCl increases oxidative stress and, again blood pressure independently, amplifies tissue injury induced by aldosterone. In renal damage models, progression is dramatically accelerated by high NaCl intake. Sodium as a potential culprit in progression to target organ damage in terminal renal failure has not been well investigated so far. However, it is possible, and indeed likely, that sodium plays an adverse role in the genesis of target organ damage in terminal renal failure.
Albuminuria↗
Color doppler ultrasonography in the diagnostic evaluation of renal allografts.
Color Doppler ultrasonography of large allograft vessels and renal parenchyma is established firmly in the diagnosis of renal allograft perfusion. While conventional color Doppler ultrasonography has proven itself to be an indispensable, rapid, highly valid and practicable method, e.g. in the diagnosis of allograft artery stenosis or allograft vein thrombosis, the diagnostic usefulness of this method with regard to allograft perfusion is considerably limited. With contrast-enhanced sonography, a simple and readily implementable method that enables the early diagnosis of chronic allograft nephropathy is now available. The timely diagnosis of vascular damage prior to a rise in S-creatinine offers the possibility of early therapeutic intervention and thus at least the potential for the improvement of allograft survival.
Blood Vessels↗
Damage to the peritoneal membrane by glucose degradation products is mediated by the receptor for advanced glycation end-products.
Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE-receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3+ T cells, increased NF-kappaB binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-beta1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3+ T cells and NF-kappaB binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-beta1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE-RAGE interaction.
Animals↗
An oral load of the early glycation compound lactuloselysine fails to accumulate in the serum of uraemic patients.
BACKGROUND: It has been hypothesized that in renal failure, exogenous glycation compounds from food accumulate and play a major pathogenetic role when renal excretion is impaired. METHODS: To address this, a diet containing a defined amount of the lysine Amadori product (AP) lactuloselysine was used. Plasma concentrations and cumulative urinary excretion of AP were assessed in 16 healthy subjects, 12 renal failure patients and 6 continuous ambulatory peitoneal dialysis (CAPD) patients. Amadori product was measured as furosine using reverse phase high performance liquid chromatography (RP-HPLC) after acid hydrolysis. RESULTS: A diet low in glycation compounds significantly decreased excretion of APs in healthy subjects. In healthy individuals, ingestion of lactuloselysine bound to food proteins caused only a minor acute increase (8.24+/-1.11 mg/day, 2% of the administered dose) of AP excretion in the urine; in patients with renal failure not yet on dialysis, the increase in AP excretion in the urine was significantly less (4.0+/-0.51 mg/day) and the same was true in CAPD patients (0.21+/-0.09 mg/day). The plasma concentration of total APs, i.e. the sum of APs as free amino acids and residues bound to plasma proteins, did not change in any of the three groups, however. CONCLUSION: Dietary APs do not accumulate in the blood even in advanced renal failure. The amount of APs measured as furosine excreted in the urine is significantly less, however, in renal failure and CAPD patients compared with healthy subjects. Although the findings exclude accumulation of lactuloselysine in renal failure, they do not generally exclude accumulation of other food-derived advanced glycation end products (AGEs).
Administration, Oral↗
Transmission of malignancy with solid organ transplants.
Donor-derived malignancy is found in about 0.02-0.2% of allograft recipients. With an increasing number of older donors, this problem will gain more relevance in the future. We wish to review the current literature on tumor transmission with solid organ transplants and focus on the consequences of an extension of the donor pool, such as by the use of donors with a history of cancer. Finally, suggestions are made for screening regimens for living as well as cadaveric donors to minimize the risk of inadvertent tumor transmission.
Central Nervous System Neoplasms↗
Transmission of donor-derived small-cell carcinoma cells by a nontumor-bearing allograft.
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Adult↗
Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study.
Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 +/- 12.6 yr) with nondiabetic kidney diseases and mild to moderate renal failure. Progression assessed as doubling of serum creatinine and/or renal replacement therapy was evaluated prospectively. Baseline plasma ADMA concentrations in renal patients correlated significantly with serum creatinine (r = 0.595), GFR (r = -0.591), age (r = 0.281), and proteinuria (r = 0.184; all P < 0.01). Patients who reached an end point during follow-up were significantly older (P < 0.05) and had significantly higher creatinine, ADMA, and parathyroid hormone blood concentrations and protein excretion rates at baseline, whereas GFR and hemoglobin were significantly lower (all P < 0.01). Cox regression analysis revealed baseline serum creatinine (odds ratio 2.00; 95% confidence interval [CI] 1.61 to 2.49; P < 0.001) and ADMA (odds ratio 1.47; 95% CI 1.12 to 1.93 for an increment of 0.1 mumol/L; P < 0.006) as independent predictors of disease progression. In patients with ADMA levels above median, progression was significantly faster (P < 0.0001), and their mean follow-up time to a progression end point was 52.8 mo (95% CI 46.9 to 58.8) as compared with 71.6 mo (95% CI 66.2 to 76.9) in patients with ADMA levels below the median. The endogenous NO synthase inhibitor ADMA is significantly associated with progression of nondiabetic kidney diseases. Lowering plasma ADMA concentrations may be a novel therapeutic target to prevent progressive renal impairment.
Adult↗
Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study.
The relationship among insulin resistance, adiponectin, and cardiovascular (CV) morbidity in patients with mild and moderate kidney disease was investigated. Insulin sensitivity (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]) and adiponectin plasma levels were assessed in 227 nondiabetic renal patients at different degrees of renal dysfunction and in 76 healthy subjects of similar age and gender distribution and body mass index. In renal patients, association with prevalent CV events was evaluated, and incident CV events were evaluated in a prospective study. HOMA-IR was markedly higher in patients than in healthy subjects (3.59 +/- 3.55 versus 1.39 +/- 0.51; P < 0.01). In renal patients, HOMA-IR was significantly correlated with body mass index (r = 0.477; P < 0.01), triglycerides (r = 0.384; P < 0.01), adiponectin plasma levels (r = -0.253; P < 0.01), and age (r = 0.164; P < 0.05), but not with renal function (GFR by iod-thalamate clearance). Patients with previous CV events were significantly older, had higher HOMA-IR and serum triglycerides, and had lower adiponectin plasma levels (all P < 0.05). Logistic regression analysis revealed age (P < 0.001) and adiponectin (P < 0.002) as independent variables related to prevalent CV events. In the prospective study, median follow-up was 54 mo. Patients who experienced CV events had significantly higher serum glucose and lower adiponectin plasma levels (both P < 0.05). In patients with chronic kidney diseases, a syndrome of insulin resistance is present even in the earliest stage of renal dysfunction, and several components of this syndrome are associated with CV events. Moreover, hypoadiponectinemia is a novel putative CV risk factor in patients with mild and moderate renal failure.
Adiponectin↗
A generalized seizure in a renal allograft recipient.
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Brain Neoplasms↗
Acquired Glanzmann's thrombasthenia variant and immune thrombocytopenia in a renal transplant recipient receiving tacrolimus.
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Graft Rejection↗
The long-term consequences of living-related or unrelated kidney donation.
Since the frequency of living-related and unrelated kidney donation has increased in the past decade, the risk of uninephrectomy should not be neglected. Major complications after kidney donation are rare. No serious problems like infection or bleeding are common with an overall perioperative complication rate of 14%. Risk of long-term mortality is lower compared to the expected mortality. Little decrease of glomerular filtration rate immediately after transplantation occurs with no further decline. Risk of end-stage renal failure in living donors is approximately 0.2-0.5%. Only a few patients develop proteinuria. After age adjustment, no increase of blood pressure is noted. The benefit of living kidney transplantation is superceding the potential risks. After careful work-up of the donor short- and long-term risks are minimal.
Aged↗