The tandem endocytic receptors megalin and cubilin are important proteins in renal pathology. The molecular mechanisms controlling proximal tubule reabsorption of proteins have been much elucidated ...in recent years. Megalin and cubilin constitute two important endocytic receptor proteins involved in this process. Although structurally very different the two receptor proteins interact to mediate the reabsorption of a large number of filtered proteins, including carrier proteins important for transport and cellular uptake of several vitamins, lipids and other nutrients. Dysfunction of either protein results in tubular proteinuria and is associated with specific changes in vitamin metabolism due to the defective proximal tubular reabsorption of carrier proteins. Additional focus on the two receptors is attracted by the possible pathogenic role of excessive tubular protein uptake during conditions of increased filtration of proteins, and by recent findings implicating members of the low density lipoprotein-receptor family, which includes megalin, in the transduction of signals by association with cytoplasmic proteins.
Abstract Background and Aims Prednisolone monotherapy is the most used initial immunosuppressive treatment for nephrotic syndrome in adults with Minimal Change Disease (MCD) but choice of treatment ...in relapsing MCD is not as well described. With the introduction of new drugs and increased concern relating to the adverse events of prednisolone, treatment might have changed over time. The aim of this study is to describe changes in daily clinical practice of relapsing MCD within the last 35 years. Method A multicenter, retrospective analysis of adult patients with biopsy proven MCD from 13 hospitals from 1987-2022 in Denmark and the Netherlands. Patients were identified from the pathology registers. Information on treatment and clinical outcomes was retrieved from health records. Relapse is defined when the nephrologist found indication to restart an immunosuppressive treatment or increase the ongoing immunosuppression in patients in partial or complete remission. Results We included 167 Dutch and 72 Danish patients (n = 239) with MCD. Most patients (n = 205, 86%) were initially treated with prednisolone monotherapy. Overall, 93% (n = 220) gained remission and 56% (n = 123) of those who went into remission had one or more relapse with 68% of these occurring in the first year after remission. At the time of relapse, 89% were in complete remission and 11% were in partial remission. At first relapse, prednisolone monotherapy was the most prescribed treatment both before and after 2010 (69% and 45%, respectively), while the use of CNI tripled after 2010 (p = 0.002) (10% to 32%). At second relapse, prescription of CNI after 2010 showed a five-fold increase compared with before 2010 (49% vs 10%, respectively) while the use of prednisolone monotherapy was halved (50% to 24%). The use of cyclophosphamide decreased by two-thirds (32% to 10%) after 2010. Before 2010, 54% of patients received prednisolone monotherapy for their third to 14th relapse, but after 2010 this decreased to 26%. The use of rituximab and CNI both increased and after 2010 these were both prescribed to about one third of patients at third to 14th relapse. The use of cyclophosphamide decreased from 30% to 2% comparing before and after 2010. Rituximab was only used after 2010, and more frequently with the number of relapses (6% at first relapse and 36% at third to 14th relapse). Regardless of the choice of treatment the rates of remission were high. Conclusion The treatment of relapses has changed over time with a reduced use of prednisolone monotherapy and cyclophosphamide and increased use of CNI and rituximab.
Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common cause of kidney failure among glomerulopathies worldwide and it is reported that approximately 6-7% of all kidney ...transplantation is due to IgAN. It is well known that IgAN can recur in the kidney allograft and previous studies suggest that recurrent IgAN is the third most common cause of graft loss in patients with IgAN as primary disease. There is currently no effective treatment for recurrent IgAN, and the main goal is therefore to prevent recurrence in the allograft. Post-transplant steroid therapy is a cornerstone in many immunosuppressive regimens, but steroid treatment also come with several side effects leading to the use of steroid-free protocols. Controversy remains as to whether the use of steroid affects the risk of recurrent IgAN. Previous, retrospective studies report widely divergent associations between the use of steroids and the risk of recurrent IgAN and thus, more research on the association between steroid use and the risk of recurrent IgAN is warranted. We examined this by taking advantage of the fact that two different standard immunosuppression protocols have been employed at two Danish transplantation centers, of which one included steroids and the other did not. The patients treated at the two transplantations centers were otherwise similar with respect to ethnicity, socio-economic status and other aspects of treatment differing only by regional residency. This provided a unique opportunity to compare the association between steroid use, recurrence rate and graft survival. We furthermore aimed to identify potential risk factors for recurrent IgAN. Method A retrospective cohort study including all adult patients (age ≥ 18 years) with biopsy-proven IgAN and a first-time kidney-only transplantation from 1990 to 2020 at either Aarhus University Hospital or Odense University Hospital using a steroid containing or a steroid free post-transplant immunosuppressive protocol, respectively. Renal transplant patients with IgAN were identified from the Danish Nephrology Registry and data on medical treatment, graft survival and histopathological evidence of recurrent IgAN were extracted from electronic medical journals. Data is presented by Aalen-Johansen and Kaplan-Meier plot, and associations between risk factors for recurrent IgAN were analyzed by cox-regression. Results A total of 120 first-time kidney recipients were included in the study. Biopsy-proven, recurrent IgAN was identified in 17 (14.2%) recipients. The median time from transplantation to recurrence was 2.91 years (IQR 0.89−5.60). Only one of 18 (15%) recipients adhering to steroid-free protocol was diagnosed with recurrent IgAN during the study period. The accumulated use of steroid as part of the immunosuppression regime was not associated with the risk of recurrent IgAN (unadjusted HR (95% CI) =1.02 (0.94−1.12)). Transplantation with genetically related living donor was associated with a greater risk of recurrent IgAN compared with non-genetically related ((unadjusted HR (95% CI) = 3.90 (1.37−11.10)) and recipients with recurrent IgAN were more likely to be younger at time of been diagnosed with IgAN and had a shorter time from being diagnosed to kidney failure when compared to recipients with non-recurrent IgAN. There were no associations between the risk of recurrent IgAN and induction therapy or HLA-mismatches. The 10-year death censored graft survival was 45% for recipients with recurrent IgAN, compared to 80% for recipients with non-recurrent IgAN. Conclusion The risk of recurrent IgAN after kidney transplantation was not associated with the use of steroids as part of the immunosuppression protocol, whereas recipients receiving a kidney from a genetic related donor appeared to have a higher risk of recurrent IgAN.
Renal ischemia/reperfusion (I/R) can lead to impaired urine concentration ability and increased fractional excretion of sodium (FeNa). Local ischemic preconditioning improves renal water and sodium ...handling after I/R injury. Here, we investigate whether remote ischemic perconditioning (rIPeC) prevents dysregulation of renal water and salt handling in response to I/R injury and mechanisms that may be involved. Rats were subjected to right nephrectomy and randomized into a sham group or an I/R group. In the I/R group, rats were subjected to 37 min of renal ischemia and 3 days of reperfusion. rIPeC was applied to the abdominal aorta. Blood and urine were collected on day 3 postoperatively for clearance studies. The expression of aquaporins (AQPs) and the sodium transporter Na–K‐ATPase were analyzed using immunoblotting and immunohistochemistry. I/R injury resulted in polyuria, increased FeNa, and decreased urine osmolality compared to sham rats. rIPeC attenuated the increase in FeNa and the decrease in urine osmolality. Expression of AQP1, AQP2, phosphorylated AQP2 (pAQP2), and Na–K‐ATPase was downregulated in I/R rats. rIPeC attenuated the reductions in AQP2 and pAQP2 expression. Immunohistochemistry revealed decreased labeling of Na–K‐ATPase in the outer medulla in I/R kidneys compared to kidneys from sham and I/R + rIPeC rats. After renal ischemia, the expression of Na–K‐ATPase was substantially reduced in the outer medullary thick ascending limb. In conclusion, our data suggest that rIPeC might prevent dysregulation of renal water and salt handling via regulation of AQP2 expression and phosphorylation as well as via regulation of Na–K‐ATPase expression in I/R rat kidneys.
Renal ischemia/reperfusion (I/R) can lead to impaired urine concentration ability and increased fractional excretion of sodium (FeNa). This study investigated whether remote ischemic perconditioning (rIPeC) prevented dysregulation of renal water and salt handling in response to I/R injury. Our data suggest that rIPeC might prevent dysregulation of renal water and salt handling via regulation of AQP2 expression and phosphorylation in I/R rat kidneys.
Delayed graft function and primary non-function are serious complications following transplantation of kidneys derived from deceased brain dead (DBD) donors. α-melanocyte stimulating hormone (α-MSH) ...is a pleiotropic neuropeptide and its renoprotective effects have been demonstrated in models of acute kidney injury. We hypothesized that α-MSH treatment of the recipient improves early graft function and reduces inflammation following DBD kidney transplantation. Eight Danish landrace pigs served as DBD donors. After four hours of brain death both kidneys were removed and stored for 18 hours at 4°C in Custodiol preservation solution. Sixteen recipients were randomized in a paired design into two treatment groups, transplanted simultaneously. α-MSH or a vehicle was administered at start of surgery, during reperfusion and two hours post-reperfusion. The recipients were observed for ten hours following reperfusion. Blood, urine and kidney tissue samples were collected during and at the end of follow-up. α-MSH treatment reduced urine flow and impaired recovery of glomerular filtration rate (GFR) compared to controls. After each dose of α-MSH, a trend towards reduced mean arterial blood pressure and increased heart rate was observed. α-MSH did not affect expression of inflammatory markers. Surprisingly, α-MSH impaired recovery of renal function in the first ten hours following DBD kidney transplantation possibly due to hemodynamic changes. Thus, in a porcine experimental model α-MSH did not reduce renal inflammation and did not improve short-term graft function following DBD kidney transplantation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney.
Reabsorption of albumin from the glomerular filtrate occurs via receptor-mediated endocytosis in ...the proximal tubule. This process is initiated by binding of albumin in apical clathrin-coated pits, followed by endocytosis and degradation in lysosomes. Although binding sites have been characterized by kinetic studies, the receptors responsible for the binding of albumin have not been fully identified. Two giant glycoproteins, cubilin and megalin, constitute important endocytic receptors localized to the kidney proximal tubule.
In the present study, we examined the colocalization of cubilin and megalin in the endocytic pathway and the relationship between the uptake of albumin and the expression of cubilin and megalin in opossum kidney (OK) proximal tubule cells by immunocytochemistry and immunoblotting.
OK cells expressed both cubilin and megalin. The light microscope labeling patterns for cubilin and megalin were almost identical and were mainly located at the surface area of the cells. Cubilin and megalin were also shown to colocalize on cell surface microvilli, in coated pits, and in endocytic compartments at the electron microscope level. Endocytosed bovine serum albumin (BSA) was identified exclusively in cells expressing megalin and cubilin. Uptake of BSA-FITC was saturable and inhibited by receptor-associated protein (RAP) and by intrinsic factor-vitamin B12 complex (IF-B12) at high concentrations. Significant inhibition was also observed by specific antibodies to cubilin, and megalin and cubilin antisense oligonucleotides likewise significantly reduced albumin uptake. Egg albumin did not affect the uptake of BSA.
The present observations suggest that the two receptors cubilin and megalin are both involved in the endocytic uptake of albumin in renal proximal tubule cells.
Abstract
Background and Aims
Acute kidney injury (AKI) is associated with increased risks of chronic kidney disease (CKD) and cardiovascular disease (CVD). The duration of AKI may be an important ...clinical marker of individuals at high risk of adverse outcomes; however, the potential links between AKI duration and CKD and CVD remain unresolved. Therefore, we examined the associations between AKI duration and CKD and CVD in a population-based setting.
Method
Using population-based plasma creatinine (pCr) data, we identified individuals with first-time AKI in Denmark from 1 January 1990 to 31 December 2018. AKI was defined in accordance with the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. To allow for determining AKI duration, analyses were restricted to individuals with an assessment of baseline kidney function by pCr within the prior year and evaluation of AKI duration by pCr within seven days after AKI onset. In accordance with the Acute Disease Quality Initiative (ADQI) 16 Workgroup criteria, AKI duration was categorized as “rapid reversal” if a pCr test within two days after AKI onset did not fulfill the AKI definition, as “persistent” if a pCr test between two and seven days after onset did not fulfill the AKI definition, and otherwise as “acute kidney disease” (AKD). CKD was defined by in- or outpatient hospital diagnoses codes or as ≥2 outpatient eGFR <60 ml/min/1.73 m2 separated by a least 90 days. CVD was defined by diagnosis codes and evaluated overall and as individual conditions including atrial fibrillation and flutter, ischemic heart disease, heart failure, stroke, and hypertension. When examining CKD, overall CVD, and specific CVDs only individuals without the condition were included in the analyses. Twenty-year cumulative risks and hazard ratios (HRs) were computed and compared across the three AKI duration groups.
Results
We identified 165,334 individuals with first-time AKI and with an assessment of baseline kidney function and AKI duration. Among these 36,514 (22%) had rapid reversal AKI, 22,619 (13%) had persistent AKI, and 110,499 (65%) had AKD. The median age was 72 years (interquartile range (IQR)), 62-80) and 52% were females. The most common comorbidities were CKD (37%) and hypertension (43%). Among the 106,916 individuals without prevalent CKD, the 20-year risks of CKD were 18.9% (95% confidence interval (CI), 18.2-19.6) for rapid reversal AKI, 23.2% (95% CI, 22.1-24.2) for persistent AKI, and 22.0% (95% CI, 21.6-22.5) for AKD. The adjusted HRs for CKD were 1.23 (1.17-1.30) for persistent AKI and 1.33 (1.28-1.39) for AKD when compared with rapid reversal AKI. Among the 59,949 individuals without prevalent CVD, the overall 20-year risks of CVD were 36.0% (95% CI, 34.0-38.0) for rapid reversal AKI, 33.2% (95% CI, 31.6-34.9) for persistent AKI, and 32.2% (95% CI, 31.4-33.0) for AKD. This corresponded to adjusted HRs of 1.02 (95% CI, 0.96-1.09) for persistent AKI and 0.97 (95% CI, 0.93-1.02) for AKD when compared with rapid reversal AKI. Findings were consistent across outcomes of atrial fibrillation or flutter, stroke, and hypertension. For ischemic heart disease and heart failure, persistent AKI was associated with adjusted HRs of 1.10 (95% CI, 1.01-1.20) and 1.13 (95% CI, 1.05-1.20), respectively, and AKD with adjusted HRs of 1.08 (95% CI, 1.02-1.15) and 1.08 (95% CI, 1.02-1.13), respectively, compared with rapid reversal AKI.
Conclusion
In conclusion, longer AKI durations were associated with increased long-term rates of CKD. AKI duration was not associated with rates of overall CVD; however, rates of ischemic heart disease and heart failure increased with longer AKI durations. The distinct increase in rates of CKD and specific CVDs with longer AKI durations illustrates the potential for using AKI duration as a risk marker when planning nephrology follow-up after AKI. Further studies examining whether interventions to shorten AKI duration prevent outcomes are warranted.
Albuminuria in kidney transplant recipients (KTRs) is associated with hypertension and aberrant glomerular filtration of serine proteases that may proteolytically activate the epithelial sodium ...channel (ENaC). The present non-randomized, pharmacodynamic intervention study aimed to investigate if inhibition of ENaC increases Na
excretion and reduces extracellular volume in KTRs dependent on the presence of albuminuria. KTRs with and without albuminuria (albumin/creatinine-ratio > 300mg/g, n=7 and < 30mg/g, n=7, respectively) were included and ingested a diet with fixed sodium content (150mmol/d) for five days. On the last day amiloride 10mg x 2 was administered. Body weight, 24h urine electrolyte excretion, body water content and ambulatory BP, as well as plasma renin, angiotensin II, and aldosterone concentration, were determined before and after amiloride. Amiloride led to a significant decrease in body weight, increase in 24h urinary Na
excretion and decrease in 24h urinary K
excretion in both groups. Urine output increased in the non-albuminuric group only. There was no change in plasma renin, aldosterone, and angiotensin II concentrations after amiloride while a significant decrease in nocturnal systolic BP and increase in 24h urine aldosterone excretion was observed in albuminuric KTRs only. There was a significant correlation between 24h urinary albumin excretion and amiloride-induced 24h urinary Na
excretion. In conclusion, ENaC activity contributes to Na
and water retention in KTRs with- and without albuminuria. ENaC is a relevant pharmacological target in KTRs. Larger and long-term studies are needed to evaluate whether the magnitude of this effect depends on the presence of albuminuria.
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