Michael J. Choi

Lymphocyte responsiveness to glucocorticoids, cyclosporine, or both

The reason why some patients with glomerular diseases respond to steroid treatment and others do not remains obscure, and it is not possible to prospectively evaluate the probability of response in individual patients. One factor that might contribute to the clinical response to treatment could be the relative sensitivity of a patients immune system to the suppressive effects of steroids or other immunosuppressive agents. To evaluate this possibility, phytohemagglutinin (PHA)‐stimulated peripheral blood mononuclear cells (PBMC) from 16 patients with various biopsy‐proven glomerulopathies were cultured with prednisolone or methylprednisolone in final concentrations of 10−5 to 10−8 mol/L. From the dose—response curves, the concentration of steroid required to cause 50% inhibition (IC50) of the PHA‐induced proliferative response was determined. The PBMC from 10 patients also were cultured with 400 ng/mL cyclosporine both alone and with 10−7 mol/L steroid, and the inhibitory effects were calculated. There was considerable heterogeneity in the sensitivities of individual patients to steroid inhibition, and the mean ± SEM IC50 was significantly lower for methylprednisolone than for prednisolone. Cyclosporine caused 50% or greater inhibition in 6 of the 10 patients but had <10% inhibitory effect in 2 patients. In most patients studied, cyclosporine plus steroid was significantly more inhibitory than cyclosporine alone, but the combination was usually no more effective than 10−7 mol/L methylprednisolone alone. These results are consistent with the hypothesis that differences in the sensitivity of individual patients immune systems to the immunosuppressive effects of steroids and cyclosporine might contribute to differences in their clinical responsiveness to treatment.

Relationship between lymphocyte and clinical steroid responsiveness in focal segmental glomerulosclerosis

A remission in nephrotic proteinuria with steroid treatment appears to favorably alter the natural history of focal segmental glomerulosclerosis (FSGS). It is not known why some patients have a favorable response to steroid treatment whereas others do not. Considering the possibility that differences in the pharmacodynamic responsiveness to steroids among patients might be one factor, the authors examined the relationship between the pretreatment suppressive effect of steroids on lymphocyte proliferation (% inhibition) in vitro and the short‐ and intermediate‐term responses of creatinine clearance (Clcr and/or nephrotic proteinuria (urine protein/creatinine ratio = Up/c in 13 patients with FSGS. There were significant correlations between % inhibition and the changes in Clcr at 3 (r = 0.92, p < 0.001) and 6 (r = 0.86, p < 0.01) months and the changes in Up/c at 3 months (r = −0.74, p = 0.02). Thus, the greater the pretreatment lymphocyte steroid sensitivity the greater the increase in Clcr or decrease in Up/c. The changes in these parameters could not be accounted for on the basis of steroid dose or histopathology The in vitro sensitivity of FSGS patients lymphocytes to steroids may be of value in anticipating their clinical response to treatment.

Lymphocyte suppression by glucocorticoids with cyclosporine, tacrolimus, pentoxifylline, and mycophenolic acid

Methylprednisolone has been found to be significantly more suppressive than prednisolone (the pharmacologically active metabolite of prednisone) of mitogen‐stimulated human lymphocyte proliferation. In this study, peripheral blood mononuclear cells (PBMC) from end stage renal disease patients were cultured with phytohemagglutinin (PHA) alone and with methylprednisolone and prednisolone individually, as well as each glucocorticoid (10−7 mol/L) in combination with 300 ng/ml cyclosporine, 10 ng/ml tacrolimus, 25 μg/ml pentoxifylline, and 10−7 mol/L mycophenolic acid. Under each experimental condition, the mean ± SD % inhibition of PHA‐stimulated 3H‐thymidine incorporation was significantly greater with methylprednisolone than with prednisolone: methylprednisolone 55 ± 17 versus prednisolone 28 ± 14, p < 0.001; methylprednisolone + cyclosporine 76 ± 18 versus prednisolone + cyclosporine 52 ± 18, p < 0.001; methylprednisolone + tacrolimus 74 ± 18 versus prednisolone + tacrolimus 50 ± 20, p = 0.001; methylprednisolone + mycophenolic acid 69 ± 14 versus prednisolone + mycophenolic acid 46 ± 15, p < 0.001. These results confirm and extend previous observations and suggest that methylprednisolone might be more effective than prednisone in treatment protocols used to suppress allograft rejection.

Ultrafiltration Rate Thresholds in Maintenance Hemodialysis: An NKF-KDOQI Controversies Report

High hemodialysis ultrafiltration rate (UFR) is increasingly recognized as an important and modifiable risk factor for mortality among patients receiving maintenance hemodialysis. Recently, the Kidney Care Quality Alliance (KCQA) developed a UFR measure to assess dialysis unit care quality. The UFR measure was defined as UFR≥13mL/kg/h for patients with dialysis session length less than 240 minutes and was endorsed by the National Quality Forum as a quality measure in December 2015. Despite this, implementation of a UFR threshold remains controversial. In this NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) Controversies Report, we discuss the concept of the UFR, which is governed by patients interdialytic weight gain, body weight, and dialysis treatment time. We also examine the potential benefits and pitfalls of adopting a UFR threshold as a clinical performance measure and outline several aspects of UFR thresholds that require further research.

Suppression of lymphocyte interleukin-2 receptor expression by glucocorticoids, cyclosporine, or both.

Although glucocorticoids and cyclosporine are frequently used to treat patients with various types of glomerulopathy, clinical responses to treatment vary considerably. Considerable interindividual heterogeneity in the suppressive effects of glucocorticoids on lymphocyte proliferation in vitro has been previously reported, suggesting that differences in the pharmacodynamic responsiveness of the immune system to these agents might be an important determinant of how well an individual patient responds to treatment. It also has been shown that methylprednisolone is significantly more suppressive than prednisolone. To identify cellular mechanisms by which these drugs act, a study of the suppressive effects of prednisolone, methylprednisolone, and cyclosporine on lymphocyte proliferation and the expression of the cell surface receptor for interleukin‐2 (IL‐2R) was conducted using phytohemagglutin‐stimulated peripheral blood mononuclear cells (PBMCs) from 13 patients with glomerulopathy and 12 control subjects. Heterogeneity among individuals in both parameters of lymphocyte responsiveness to these drugs was again found, and the significantly greater suppressive effect of methylprednisolone was confirmed for both proliferation and IL‐2R expression in patients and control subjects. Cyclosporine alone was moderately suppressive. For most individuals, the greatest degree of suppression occurred when cells were exposed to both cyclosporine and glucocorticoid. Further studies are being conducted to determine whether pretreatment assessment of in vitro lymphocyte responsiveness has any predictive value regarding therapeutic efficacy of each drug in individual patients and to identify of those patients likely to require a more intensive or multidrug immunosuppressive regimen.

Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report

Rationale: Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAFs unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF. Lessons: This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF.

Use of Renin-Angiotensin System Blockade in Advanced CKD: An NKF-KDOQI Controversies Report

Multiple clinical trials have demonstrated that renin-angiotensin system (RAS) blockade with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers effectively reduces chronic kidney disease (CKD) progression. However, most clinical trials excluded participants with advanced CKD (ie, estimated glomerular filtration rate [eGFR]<30mL/min/1.73m2). It is acknowledged thatxa0initiation of RAS blockade is often associated with an acute reduction in eGFR, which is thought to be functional, but may result in long-term preservation of kidney function through the reductions inxa0glomerular intracapillary pressure conferred by these agents. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) report, we discuss the controversies regarding use of RAS blockade in patients with advanced kidney disease. We review available published data on this topic and provide perspective on the impact of RAS blockade on changes in eGFRs and potassium levels. We conclude that more research is needed to evaluate the therapeutic index of RAS blockade in patients with advanced CKD.