Conservation Of Renal Function Research Articles

#1827 Myeloma cast nephropathy: is high cut-off hemodialysis effective?

Abstract Background and Aims Light-chain cast nephropathy is the result of intra-tubular precipitation of light-chains produced by a multiple myeloma. Treatment often includes high cut-off filters hemodialysis (HCO) with the purpose of purifying these chains until the chemotherapy response is achieved. The main goal of this study is to analyze our experience and determine if there is a correlation between the amount of chain purified and the conservation of renal function. Method We conducted a retrospective study that includes all patients suffering from myeloma cast nephropathy treated with hemodialysis in our hospital between 2008 and 2023. HCO filters were used in all of the cases and the diagnosis was established by clinical criteria. In the early stages of the study, only those patients who required kidney replacement therapy underwent dialysis. However, in recent years some cases which did not meet the renal replacement criteria were included. Results 27 patients received the treatment, 59,3% were male and the average age was 68,7+/-8 years. Even though the average of glomerular filtration rate (GFR) previous to the myeloma was 72,65+/-20ml/min, it should be underlined that 8 of them suffered from 3-4 stage chronic kidney disease. The mean follow-up was 55 months, after which 16 had passed away. 59,3% were kappa gammapathy and 75% of them had bone disease. Chemotherapy schemes were variable (85% included Bortezomib). The average of dialysis sessions was 8+/-3,8. 7 patients continued undergoing conventional hemodialysis during the hospital stay but only one of them remained in chronic dialysis. The average GFR at the beginning was 12,2+/-7ml/min. Despite the improvement of the renal function, when compared to the previous GFR, a statistically significant reduction in both hospital discharge (43,67ml/min) and after 1- and 2-year periods (51,94 and 39,91ml/min) was observed. No differences in renal function between patients who started dialysis prematurely (GFR>10ml/min) and those who did not were noticed. The light-chain reduction ratio in each dialysis was examined; it was remarkably variable (2-87%). In order to establish a connection between the amount of chain purified and the preservation of renal function, we conducted a correlation analysis between the intra-dialysis reduction of chains and the GFR at hospital discharge and after 1-year, but not statistically interrelations were observed (p=0,376 and 0,633 respectively). Lastly, no connection between the intra-dialysis light-chain reduction and the loss of GFR was detected. Conclusion In patients with myeloma cast nephropathy, a higher purification of light-chains in HCO hemodialysis is not associated with a better preservation of renal function.

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Renal Transplantation

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.

Familial clear cell renal cancer

Note: Renal cell carcinomas (RCC) represent 85% of all primary renal tumors. In general, RCCs are sporadic tumors but cases of familial RCC have also been reported. If detected early and without metastases, the disease can be cured surgically with conservation of renal function. Both familial and sporadic cases have in common the presence of abnormalities involving chromosome 3, suggesting a primary role for this chromosome in RCC causation, particularly the clear cell type. An early gene rearrangement due to translocation may be a primary event. Loss of 3p and somatic mutation(s) in a tumor-surpressor-gene(s) on 3p (e.g.VHL) may be recurring events related to tumor progression. Inheritance: The inherited form of renal cancer is characterized by: the tumor is found at an early age compared to sporadic tumors (see below) the tumors are found frequently bilateral multiple occurrence. Other (well known) classes of inherited renal cell carcinomas are: the Von Hippel-Lindau syndrome, and the Lynch syndrome II. Also chromosome abnormalities may be related to inherited renal cancer.

Intravital Two-Photon Microscopy Assessment of Renal Protection Efficacy of siRNA for p53 in Experimental Rat Kidney Transplantation Models

Renal ischemia-reperfusion (I/R) injury, which is unavoidable in renal transplantation, frequently influences both short- and long-term allograft survival. Despite decades of laboratory and clinical investigations, and the advent of renal replacement therapy, the overall mortality rate due to acute tubular injury has changed little. I/R-induced DNA damage results in p53 activation in proximal tubule cells (PTC), leading to their apoptosis. Therefore, we examined the therapeutic effect of temporary p53 inhibition in two rat renal transplantation models on structural and functional aspects of injury using intravital two-photon microscopy. Nephrectomized Sprague-Dawley rats received syngeneic left kidney transplantation either after 40 min of intentional warm ischemia or after combined 5-h cold and 30-min warm ischemia of the graft. Intravenously administrated siRNA for p53 (siP53) has previously been shown to be filtered and reabsorbed by proximal tubular epithelial cells following the warm ischemia/reperfusion injury in a renal clamp model. Here, we showed that it was also taken up by PTC following 5 h of cold ischemia. Compared to saline-treated recipients, treatment with siP53 resulted in conservation of renal function and significantly suppressed the I/R-induced increase in serum creatinine in both kidney transplantation models. Intravital two-photon microscopy revealed that siP53 significantly ameliorated structural and functional damage to the kidney assessed by quantification of tubular cast formation and the number of apoptotic and necrotic tubular cells and by evaluation of blood flow rate. In conclusion, systemic administration of siRNA for p53 is a promising new approach to protect kidneys from I/R injury in renal transplantation.

Safety and efficacy of tacrolimus rescue therapy in 55 kidney transplant patients treated with cyclosporine

To evaluate the efficacy and safety of conversion from cyclosporine to tacrolimus, we analyzed 55 kidney transplant patients who were converted due to cosmetic reasons in 42 patients, acute rejection in 2 patients, and other causes in 11 patients. At the doses and levels used, the development of diabetes mellitus was minimized. Disappearance of cosmetic side-effects and improvement of cardiovascular risk factors, together with conservation of renal function, encourage us to use tacrolimus as an efficacious and safe immunosuppressive therapy.

Cistinosis nefropática infantil

Nephropathy caused by cystinosis is a rare recessive disorder produced by a defect in the lysosomal transport of cysteine. This results in intracellular crystal deposits in the kidneys, cornea and other tissues. It constitutes the commonest congenital cause of Fanconi's syndrome and progresses during the first decade of life to chronic renal failure. The diagnosis is confirmed by the detection of cystine in circulating leucocytes and lymphoblasts. The treatment consists in replacing the losses caused by the tubular defect and the oral administration of cystamine which depletes cystine and favours its transport across the lysosomal membrane. The objective of this report is to present the first case of cystinosis diagnosed and treated in Chile. The patient was hospitalized at the age of 15 months with advanced disnutrition, clinical rickets, severe dehydration, hypokalaemia, hypophosphataemia, metabolic acidosis consistent with Fanconi's syndrome. An elevated concentration of cystine was found in the polymorphic leucocytes confirming the diagnosis. After 2 years of treatment with oral cystamine the patient demonstrates an excellent evolution with regards to stature and conservation of renal function, although the tubular defect persists.

Relapsing Membranous Nephropathy

Background: Although controversial, treatment of membranous nephropathy appears to yield a reduction in the degree of proteinuria and conservation of renal function. Methods: We report herein our experience with the treatment with steroids alone (group II, n = 13), or in combination with immunosuppressants (group III, n = 19) of patients with membranous nephropathy and the nephrotic syndrome, with a mean follow-up of 8.37 years. Results: All patients underwent a first remission, with 24-hour urine protein excretion falling to 0.63 ± 0.25 g in group II and 0.62 ± 0.26 g in group III (p = NS) after 12.69 ± 10.94 months of treatment in group II and 18.95 ± 13.17 months in group III (p = NS). Three patients from group II (23%) and seven patients from group III (36.8%) experienced four and eight relapses, respectively (proteinuria in 24 h 4.0 ± 0.80 g in group II relapsers and 4.4 ± 0.87 in group III relapsers; p = NS). On treatment, all relapses remitted (second remission) after 7 ± 6.93 months of therapy for group II and 8.6 ± 6.70 months of treatment for group III (p = NS). Thereafter, no patients from group II, but 3 patients from group III (33.3%) had a second relapse. After treatment, all relapses remitted (third remission) in 3.3 ± 1.53 months of therapy. Conclusions: These studies show that relapses, which occur in one-third of patients, respond favorably to treatment albeit remitting in approximately half the time, and that the duration of remission gets progressively longer in the later compared to the earlier remission.

Influence of anti-hypertensive drugs on glomerular hemodynamics.

Alterations in glomerular hemodynamics may play an important role in the progression of renal dysfunction. Accordingly, treating not only systemic hypertension, but also glomerular hypertension is important for conservation of renal function in patients with renal disease. However, glomerular capillary pressure does not necessarily change in parallel with systemic blood pressure due to unique mechanisms that control the resistance of glomerular afferent and efferent arterioles. While myogenic response and tubuloglomerular feedback play an important role in controlling afferent arteriolar resistance, angiotensin II is a major determinant of efferent arteriolar tone. Calcium antagonists block almost all mechanisms that constrict the afferent arteriole, rendering glomerular capillary pressure dependent on systemic pressure. On the other hand, angiotensin-converting enzyme inhibitors dilate efferent arterioles, thereby lowering glomerular capillary pressure. Such differences should be taken into account when selecting adequate drugs for the treatment of hypertension with various degrees of renal dysfunction.

Hyperfiltration and Conservation of Renal Function in Hypertensive Nephrosclerosis Patients

Renal glomerular hyperfiltration has been proposed as an important contributing factor to the progression of hypertensive nephrosclerosis in rats with reduced renal mass. However, no clinical studies have assessed the role of glomerular hyperfiltration in the pathogenesis of hypertensive nephrosclerosis in humans. In a prospective, randomized, long-term blood pressure control study with up to 3 years follow-up, we showed that good blood pressure control with a mean diastolic blood pressure < or = 95 mm Hg preceded by a 2- to 4-month period of diastolic blood pressure < or = 80 mm Hg improved renal function in hypertensive nephrosclerosis patients. Patients treated with minoxidil, an angiotensin-converting enzyme inhibitor (enalapril), or a calcium entry blocker (nifedipine) had improvement in renal function, as indicated by a positive slope of the reciprocal serum-creatine concentration versus time and an increment in glomerular filtration rate. These results suggested that improvement in renal function occurred with these major types of antihypertensive drug treatment. To assess the renal hemodynamics of minoxidil, enalapril, and nifedipine, eight patients with hypertensive nephrosclerosis were admitted to the General Clinical Research Center for renal clearance studies on each drug while ingesting a fixed-calorie, 12% protein, 40% fat, and 100 mEq Na/d diet. Mean blood pressure, effective renal plasma flow, and renal vascular resistance did not change during the three phases of treatment. However, minoxidil treatment increased the glomerular filtration rate by 48% versus enalapril and by 79% versus nifedipine. Since minoxidil treatment improves renal function while causing a relative hyperfiltration, glomerular hyperfiltration per se is an unlikely mechanism for the progression of hypertensive nephrosclerosis in humans.

Prevention of Renal Disease and Conservation of Renal Function

In summary, we have reviewed some of the most frequently encountered areas of prevention of renal failure in the elderly. They include obstruction, hypertension, drug interaction, and inappropriate use of drugs and the silent killer of the elderly, renal carcinoma. Only by a thorough understanding of the altered physiology of the aging kidney can the physician avoid making the same mistakes when new drugs are developed or new types of diseases are encountered. Proper early diagnosis and understanding the guidelines to therapy in these conditions, can save huge human costs in terms of mortality, morbidity, and money.