Viewpoint On
Suehiro T, Tsuruya K, Yoshida H, Tsujikawa H, Yamada S, Tanaka S, Tsuchimoto A, Eriguchi M, Fujisaki K, Torisu K, Nakano T, Kitazono T: Stronger Effect of Azilsartan on Reduction of Proteinuria Compared to Candesartan in Patients with CKD: A Randomized Crossover Trial. Kidney and Blood Pressure Research DOI 10.1159/000512365
The optimum dosage and preparation of renin-angiotensin system inhibitors (RASi) for slowing the progression of progressive proteinuric CKD remains somewhat uncertain, although it is generally appreciated that these agents exert their beneficial effects lately via lowering of systemic arterial and intra-glomerular capillary blood pressure. Both of these effects play a role in lowering the magnitude of proteinuria, and thus the rate of progression.
Suehiro and co-workers examined the relative effects of azilsartan and candesartan (both angiotensin receptor blockers; ARBs) on proteinuria and systemic arterial pressure in 111 patients with CKD (14% with diabetic kidney disease, 53% with chronic glomerulonephritis, and 28% with “hypertensive” nephropathy). The baseline proteinuria (urine protein to creatinine ratio; UPCR) was 1.8 ± 1.8 g/gCr and the eGFR was 42 ± 20 mL/min/1.73 m2. The average baseline blood pressure was 131/71 mm Hg. The dosage was 20 mg/day for azilsartan and 6 mg/day for candesartan. The trial was a randomized, cross-over design and the follow-up was 3 months. The primary endpoint was the percentage change in UPCR from baseline. Sodium chloride intake was not controlled.
At the end of study, the mean percentage change in UPCR was +6.1% in the azilsartan group and +25.8% in the candesartan group. Adverse events were similar. Average systolic blood declined at the end of the study in the azilsartan group and increased in the candesartan group. The change in UPCR was correlated with the decline in systemic arterial blood pressure.
This study confirms the generally well-known superior efficacy of azilsartan for blood pressure control, but only one dose (20 mg/day) was compared to one dose (6 mg/day) of candesartan. In the absence of a dose ranging study it is unknown whether the effects of higher doses of either agent would confirm this superiority of azilsartan over the entire range of commonly used dosages. Also, the lack of controlling for sodium chloride intake is a confounder in this study. The benefits on proteinuria track with the systemic anti-hypertensive effects, so it is unknown whether the superior anti-proteinuric effects of azilsartan are due to a systemic or an intra-renal effect (or both). The short duration of the study precluded any conclusions concerning beneficial effects on CKD progression. Nevertheless, this study does indicate that azilsartan might be the preferred agent for achieving blood pressure control and reducing proteinuria in patients with “generic” CKD. Larger and longer studies will be required to confirm this hypothesis and the beneficial effects may differ between the categories of CKD defined by etiology (particularly diabetic vs. glomerulo-nephritic CKD).
Quoted Karger Article
Stronger Effect of Azilsartan on Reduction of Proteinuria Compared to Candesartan in Patients with CKD: A Randomized Crossover Trial
Viewpoint On
Jiang J, Zhang Y, Chen J, Yang X, Mei C, Xiong F, Shi W, Zhou W, Liu X, Sun S, Zhang P, Zhang Y, Zhang Y, Liu S, Zhang Z, Lin Q, Yu Y, Tian J, Luo W, Qin X, Hou FF: Serum and Tissue Levels of Advanced Glycation End Products and Risk of Mortality in Patients on Maintenance Hemodialysis. American Journal of Nephrology DOI 10.1159/000512385
The relationships between tissue and circulating advanced glycan end-products (AGEP) maintained on chronic hemodialysis (HD) for kidney failure are uncertain. Serum levels of AGEP and skin autofluorescence (SAF; as a surrogate for tissue levels of bound AGEP) have been associated with an increased risk of mortality, particularly from cardiovascular disease (CVD), but the findings are inconsistent and meta-analyses have shown significant heterogeneity of outcomes.
Jiang and co-workers sought to clarify these uncertainties in a large (n = 1,634), multicenter, prospective cohort study of prevalent HD patients (median follow-up 5.2 years). N-carboxymethyl-lysine (CML) was measured in serum by spectrophotometry and SAF was assessed non-invasively by a cutaneous auto-fluorescence device. The mean age of the subjects was 57.4 ± 14.6 years with a mean dialysis ± vintage of 50.0 ± 48.4 months.
The baseline SAF positively correlated with all-cause and CVD mortality in a dose-response fashion, but baseline CML levels showed no such effect. Covariates, such as age, serum albumin, and diabetes, did not modify the effect of SAF on mortality. No assessment of glycated albumin or hemoglobin was performed. Adding SAF to the standard mortality risk prediction improved the C-statistic and risk classification, but only modestly. The reliability of the SAF device in individuals with varying skin colors/types was not examined.
These are interesting findings that need confirmation in a more ethnically diverse population. They very likely do not apply to incident HD or to peritoneal dialysis patients.
Quoted Karger Article
Serum and Tissue Levels of Advanced Glycation End Products and Risk of Mortality in Patients on Maintenance Hemodialysis
Viewpoint On
Lubennikov AE, Petrovskii NV, Krupinov GE, Shilov EM, Trushkin RN, Kotenko ON, Glybochko PV: Bilateral Nephrectomy in Patients with Autosomal Dominant Polycystic Kidney Disease and End-Stage Chronic Renal Failure. Nephron DOI 10.1159/000513168
Patients with autosomal dominant polycystic kidney disease (ADPKD) and advanced chronic kidney disease are not uncommonly considered as candidates for elective or emergent bilateral nephrectomy (BN) because of unrelenting abdominal discomfort or early satiety form massive kidney enlargement, infected cysts, persisting gross hematuria, suspected renal cell carcinoma, or to provide “more space” for a transplanted kidney. Open (midline laparotomy) or closed (laparoscopic) procedures are used but outcomes have seldom been compared.
Lubennikov and colleagues retrospectively analyzed their single-center experience with both procedures for BN in 108 patients with ADPKD – 36 with a laparoscopic approach and 72 with open midline laparotomy, specifically addressing complications and mortality. About 35% of the cases were elective and 80% were performed because of infected cysts and urinary tract infections.
Postoperative complications were equal with both procedural approaches and postoperative mortality was only observed in the emergent group (usually associated with bowel injury and sepsis. Laparoscopic surgery was the preferred procedure in elective BN. Incidental renal cell carcinoma was found in 6.4% of cases. The duration of surgery was longer with laparoscopic BN due to the time needed to “flip” the patient during the procedure, but these patients rehabilitated sooner and had a shorter hospital stay. C-reactive protein levels above 173 mg/L preoperatively were associated with a higher risk of mortal complications. This descriptive study provides valuable data on the risk of complications among patients with ADPKD undergoing elective or emergent BN. Whether the type of procedure used influences this risk will likely depend on the indications for the procedures and the experience of the surgical team performing them.
Quoted Karger Article
Bilateral Nephrectomy in Patients with Autosomal Dominant Polycystic Kidney Disease and End-Stage Chronic Renal Failure
Viewpoint On
Sousanieh G, Whittier WL, Rodby RA, Peev V, Korbet SM: Percutaneous Renal Biopsy Using an 18-Gauge Automated Needle Is Not Optimal. American Journal of Nephrology DOI 10.1159/000512902
Percutaneous biopsy (PB), of either native or transplanted kidney, is commonly performed using a variety of needle sizes (14, 16 or 18 G), according to the preferences, training, and experience of the operator (nephrologist or interventional radiologist). The complication rate (primarily bleeding) and adequacy of the kidney tissue specimens for pathologic evaluation are competing variables in the choice of needle size.
Sousanieh and coworkers conducted a single-center (Rush University Medical Center, Chicago, USA), retrospective review of their experience with both native and transplant kidney PB between 2010 and 2020 (native PB, n = 592; transplant PB, n = 1,023). The PBs were carried out using 14-G (n =337, native only), 16-G (n = 255 in native and n = 892 in transplant), and 18-G needles (n = 131, transplant only), using a spring-loaded automated biopsy device. All PBs were performed by a nephrologist or a trainee under the direct supervision of a nephrologist.
The needle size employed was compared to the complication rate (hematoma by ultrasound at 1 h post-PB and transfusion requirement) and adequacy assessed by the number of glomeruli by core and total yield of glomeruli. As noted above, all of the native kidney PBs were performed using 14- or 16-G needles, none used 18-G needles, and all of the transplant kidney PB used a 16- or 18-G needle, none used 14-G needles.
The complication rates were statistically similar, regardless of needle size, but 18-G needles in transplant kidney PB showed a non-significant trend for fewer complications. This could not be further evaluated in native kidney PBs. The study may have been underpowered to show a safety superiority of 18-G needles in transplant kidney PBs. The number of cores obtained was somewhat lower when higher-gauge needles were used in native and transplant kidney PB. The total number of glomeruli (combining light, immunofluorescence, and electron microscopy) were lower with higher-gauge needles (14 vs 16 G in native and 16 vs 18 G in transplant), suggesting that the adequacy of the specimens obtained might be improved by the use of lower-gauge needles. Specimens containing >20 glomeruli were found in 85%, 82/83%, and 46% of the PBs obtained by 14-, 16-, and 18-G needles, respectively. Optimal safety and adequacy were associated with the use of 16-G needles, but the absence of data on 18-G needles in native kidney PB and 14-G needles in transplant kidney limits generalization of this conclusion to all needles and all kidney types. Nevertheless, the lack of association of needle size with complication rates (except for the proviso mentioned above), and the better adequacy of specimen collection with lower-gauge needles, supports their preferential use.
Quoted Karger Article
Percutaneous Renal Biopsy Using an 18-Gauge Automated Needle Is Not Optimal
Viewpoint On
Carrara C, Cravedi P, Perna A, Peraro F, Villa A, Carrara F, Cortinovis M, Gotti E, Plati AR, Amaduzzi A, Rota G, Lacanna F, Rossini G, Abelli M, Remuzzi G, Ruggenenti P: Preimplantation Histological Score Associates with 6-Month GFR in Recipients of Perfused, Older Kidney Grafts: Results from a Pilot Study. Nephron DOI 10.1159/000512341
The selection of donor kidneys for optimal post-transplant outcomes is an important issue, and discarding kidneys based on clinical criteria decreases the availability of organs. Pre-implantation biopsies of potential donor kidneys combined with pulsatile machine perfusion may help to improve marginal kidney donor use in transplantations.
Carrara and co-workers examined this issue in a single-center, prospective cohort study of 20 deceased donor kidney transplants for >60-year-old donors. The Kidney Donor Profile Index (KDPI) was >80% in 19 out of 20 cases. All grafts were hypothermically pulsatile machine perfused. A wedge biopsy was fixed in formalin and evaluated by a single pathologist. The global histological findings (glomeruli, tubule-interstitium, vascular) were scores on a scale of 0–12. Kidneys with a score of 0–4 were eligible for a single transplant, scores from 5 to 7 were eligible for a dual kidney transplant, and kidneys with a score of 8 or greater were discarded. Flow and resistance were monitored continuously during machine perfusion.
Ten kidneys were allocated to 10 recipients, 28 kidneys were allocated to 14 recipients, and 34 kidneys were discarded. Four recipients were not further evaluated. The average global histological score was 4.14 ± 1.4. Patient and graft survival at 6 months was 100% and delayed graft function was observed in 2 out of 20 patients. At 6 months, the eGFR was 41 mL/min among the recipients.
The machine perfusion duration averaged about 10 h and during perfusion vascular resistance was higher in those kidneys with a higher histological score, but it decreased similarly over time in both the high and low histological score groups. The global histological score was inversely correlated with eGFR at 6 months post-transplantation. The KDPI did not correlate with the 6-month eGFR.
Without the component of histologic evaluation, most of the kidneys included in this study would have been discarded, but the discard rate was only 47% in this study. Notably, the outcomes (at 6 months) were quite favorable in terms of graft function and survival. The optimal processing of biopsies using fixation and embedding may have contributed to these findings. The biopsy score was independently associated with an improvement of perfusion characteristics, and hypothermic, pulsatile perfusion might have contributed to better post-implantation function of the grafts. Although this was a small, pilot trial, it generates a hypothesis that deserves testing in a larger study with longer post-transplantation follow-up. Histological scoring and hypothermic, pulsatile perfusion might provide a new pathway for increasing donor availability.
Quoted Karger Article
Preimplantation Histological Score Associates with 6-Month GFR in Recipients of Perfused, Older Kidney Grafts: Results from a Pilot Study
Viewpoint On
Verzola D, Saio M, Picciotto D, Viazzi F, Russo E, Cipriani L, Carta A, Costigliolo F, Gaggero G, Salvidio G, Esposito P, Garibotto G, Poggi L: Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis. American Journal of Nephrology DOI 10.1159/000511560
Focal and segmental glomerulosclerosis (FSGS) is a histological glomerular lesion, not a specific disease. Primary forms of FSGS, presumably due to a circulating permeability factor (or factors), can be recognized by a combination of clinical and morphological findings, especially the presence of nephrotic syndrome and diffuse foot process effacement by electron microscopy and the absence of toxic, viral, or genetic causes. The role of acceleration of normal aging-related organ senescence in the progression of primary, genetic, or secondary forms of FSGS is an area that is ripe for exploration.
Verzola et al. report on a small preliminary study (n = 26) of adult patients with an FSGS lesion, which they presumed was mainly of a primary type. Since the patients had only modest proteinuria (2.6±0.6 g/day), normo-albuminemia (3.5 g/dL), and no electron microscopy or genetic analysis was reported, it is more likely that these cases were an admixture of primary, secondary, and genetic forms of FSGS. Nevertheless, 7/26 (28%) cases progressed to doubling of serum creatinine or ESKD within a 6-year follow-up period, and the mean eGFR loss was 4.7 mL/min/year.
Senescence was detected by assays for SA-β-Gal in frozen sections and for p16ink4A by immunocytochemistry of paraffin-embedded material. Both glomerular and tubular cell expressions of these senescence biomarkers were examined. The controls were normal kidney tissue removed coincidental with nephrectomy for renal cell carcinoma.
The percentage of p16ink4A-positive cells was increased in both glomeruli and tubule cells, especially in podocytes. SA-β-Gal was only increased in tubule cells, highly correlated with the magnitude of proteinuria. Tubular, but not glomerular, hyperexpression of p16ink4A was found to predict eGFR loss over time. The SA-β-Gal expression in tubules did not contribute to the prediction of eGFR loss, which is surprising since this was correlated with proteinuria.
In such a small study of patients with a lesion that may well have been very heterogeneous in etiology, the findings are largely hypothesis generating, and not proof of principle. Larger studies of a more homogeneous disorder associated with an FSGS lesion and including patients with nephrotic syndrome are warranted. This study does not allow for speculation on the underlying mechanisms, but it appears that protein leakage through glomeruli is associated with downstream tubular injury that might evoke tubular cell senescence and possibly contribute to progressive loss of kidney function. Whether this is a cause-and-effect relationship remains uncertain, but this research opens up a new avenue of inquiry.
Quoted Karger Article
Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis
Viewpoint On
Shoji J, Mii A, Terasaki M, Shimizu A: Update on Recurrent Focal Segmental Glomerulosclerosis in Kidney Transplantation. Nephron DOI 10.1159/000510748
Recurrent focal segmental glomerulosclerosis (FSGS) in a kidney allograft performed in a patient with kidney failure presumed to be due to primary (permeability factor-related) FSGS is a common occurrence (up to 70% of such patients experience a recurrence when secondary and genetic forms of FSGS have been excluded). Such recurrences are highly predictive of graft failure. Repeated recurrences occur in up to 90% of patients retransplanted after loss of the first graft to a recurrence of FSGS. Thus, this is a very serious problem needing a good solution involving a better identification of risk, a better monitoring of the recurrence itself, a better understanding of the mechanisms involved and, most of all, how to prevent recurrence or to treat it when it has developed.
Shoji and colleagues provide an excellent and up to date review of the permeability factors posited to be involved in recurrences of primary (permeability factor-related) FSGS. Clearly multiple clinical factors present in the patient with presumed primary FSGS prior to transplantation can help to roughly estimate the risk of a recurrence. The earliest lesion identifying a recurrence can be found on electron microscopy of post-transplant kidney biopsies, showing diffuse foot process effacement. Unfortunately, the “permeability factors” believed to be operating in recurrent primary FSGS are biochemically heterogeneous and likely cause podocyte injury by a variety of mechanisms.
While much progress has been made, the lack of consistent confirmatory studies has hampered the application of assays for these factors in clinical kidney transplantation. Perhaps a “panel” of assays will help to alleviate this deficiency. At this moment, testing for single factors may not be sufficient for evaluation of risk or for post-transplant monitoring, and none have reached any kind of regulatory approval. More work is clearly needed. Sadly, this otherwise excellent review did not analyze how the knowledge concerning permeability factors, as limited as it is, might be best applied to specific prevention and treatment stratagems, such as PLEX, immunoadsorption, anti-CD20 monoclonal antibodies, or lipid apheresis. Perhaps this will be the topic of a follow-up mini-review.
Quoted Karger Article
Update on Recurrent Focal Segmental Glomerulosclerosis in Kidney Transplantation
Viewpoint On
Morales E, Galindo M, Trujillo H, Praga M: Update on Lupus Nephritis: Looking for a New Vision. Nephron DOI 10.1159/000511268
Lupus nephritis (LN) continues to be a challenging disorder for both nephrologists and rheumatologists. This topic is an ever-changing one and the pace of change appears to be accelerating as new data on prognostication and management emerge.
Morales et al. from Spain have nicely summarized recent developments in a very well-written review focusing on prognostic biomarkers, kidney biopsy (including protocol-driven repeat biopsies), biologic therapies, lupus podocytopathy, membranous LN, anti-phospholipid antibody syndrome, kidney transplantation, and the duration of immunosuppressive therapy in LN. The field of LN is moving toward a more “personalized” approach to management and away from the “one-size-fits-all” paradigm that has dominated thinking for many years. Novel serum or urinary biomarkers and refined analysis of kidney biopsy specimens seem to be a promising avenue of research, but much more work needs to be done before these tools reach routine clinical utility.
The very encouraging findings with novel biological therapies and new immunosuppressive regimens (such as belimumab, obinutuzumab, and anifrolumab) [1] and a reanalysis of older data concerning rituximab seems to indicate that a new paradigm of management of LN is on the horizon – one that may substantially reduce the reliance on high-dose steroid therapy with its attendant side effects. The recently released studies of the BLISS-LN trial of belimumab, the phase 3 trial of voclosporin, and the phase 2 trial of obinutuzumab in LN are particularly encouraging.
This review article is strongly recommended for those nephrologists and rheumatologists who want to remain current in the status of LN as of the summer of 2020.
References
1. Narain S, Berman N, Furie R. Biologics in the treatment of Sjogren’s syndrome, systemic lupus erythematosus, and lupus nephritis. Curr Opin Rheumatol. 2020 Nov;32(6):609–16.
Quoted Karger Article
Update on Lupus Nephritis: Looking for a New Vision
Viewpoint On
Tsuda A, Ishimura E, Machiba Y, Uedono H, Nakatani S, Mori K, Uchida J, Emoto M: Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects. Kidney and Blood Pressure Research DOI 10.1159/000510838
It is generally observed that creatinine is secreted by the proximal tubule (via an organic anion transporter) in subjects with normal or even modestly impaired function leading to an overestimation of the true glomerular filtration rate (GFR) when endogenous creatinine clearances (Ccr) are used to estimate kidney function. This secretion accounts for about 15–20% of the excreted creatinine. Net tubular reabsorption of creatinine has been described in special situations (e.g., newborns and very elderly), but it is the exception rather than the rule.
Tsuda and coworkers have extended these observations by performing 24-h endogenous true Ccr and GFR measurements (by urinary clearance of inulin; Cin), along with measurements of renal plasma flow by the clearance of para-aminohippurate (Cpah) in 80 apparently healthy transplant donors (age 54 ± 13 years), with pre-unilateral nephrectomy and remeasurement of these parameters in 20 of the original subjects 1 year after uninephrectomy. The glomerular hemodynamics were estimated by the Gomez equations, developed in 1951 as a way of approximation of mean glomerular capillary hydraulic pressure (Pgc) and the resistances of the afferent (Ra) and efferent (Re) glomerular arterioles.
The mean pre-nephrectomy Ccr was 102 ± 28mL/min and the Cin was 88 ± 18 mL/min (Ccr/Cin = 1.15). The mean filtration fraction (Cin/Cpah) was 0.20 ± 0.03. Thus, overall, the Ccr/Cin indicate tubular secretion of creatinine; however, 25/80 (31%) of the subjects had a Ccr/Cin value of <1.0, indicating tubular reabsorption of creatinine. It is not clear whether the Ccr and Cin determinations were performed at exactly the same time, so diurnal variation in Ccr/Cin might have contributed to this finding. Interestingly, when the Gomez equations were applied to the GFR and RPF data, apparently using the common assumption that 10% of the total renal resistance is accounted for by Ra, the Ccr/Cin ratio (a measure of tubular secretion of creatinine) was inversely correlated with Pgc and Re. The FF was equal in both subjects with values for Ccr/Cin of <1 or >1. The average Pgc was 56 and 58 mm Hg in those with a Ccr/Cin of >1 or <1, respectively (p = 0.053). These values of Pgc are about 11–13 mm Hg higher than the values believed to prevail in the human glomerulus (approx. 45 mm Hg), and it is difficult to explain the data when the FF is equal between those with a high (>1) versus a low (<1) value for Ccr/Cin. This raises questions about the merits of the Gomez equation, which tends to give unreasonably high values for Pgc. As expected, the Ccr and Cin were highly correlated with each other, but the regression analysis suggested a higher value of Ccr/Cin when GFR is 60–90 mL/min than when it is 90–120 mL/min.
In the post-uninephrectomy subjects, both the Ccr and Cin fell to about 63 and 59% of baseline 1 year after uninephrectomy and the extent of decrease in GFR was correlated with the degree of increase in the Ccr/Cin ratio. Unfortunately, a change in Pgc post-uninephrectomy was not calculated. It should have increased following uninephrectomy, which would predict a decline in Ccr/Cin (more creatinine reabsorption) in the post-nephrectomy period, whereas the opposite was observed. These are all very interesting observations, but in my opinion further work is needed to verify the validity of the hypothesis that tubular creatinine reabsorption is common in healthy adults and that it might have something to do with glomerulus hydraulic pressure.
Quoted Karger Article
Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects
Viewpoint On
El Mokadem M, Abd El Hady Y, Aziz A: A Personalized Update on IgA Nephropathy: A Prospective Single-Blind Randomized Trial of Ramipril, Eplerenone and Their Combination in Type 2 Diabetic Nephropathy. Cardiorenal Medicine DOI 10.1159/000508670
The benefits of renin-angiotensin system (RAS) inhibition for slowing the progress of diabetes-related CKD with overt proteinuria is well established. The utility (efficacy and safety) of adding mineralocorticoid receptor (MR) antagonists to RAS inhibitor therapy in this population of patients is less well understood.
El Mokadem and colleagues conducted a small single-blinded randomized clinical trial in adult subjects with type 2 diabetes mellitus (T2DM) and moderate albuminuria (urinary albumin to creatinine ratio [uACR] of 30-300 mg/g) who had mild hypertension but were naïve to both RAS inhibition and MR antagonism treatment. The subjects were randomized (1:1:1) to receive ramipril (R) 10mg/day (n = 25), eplerenone (E) 50 mg/day (n = 25), or R 10 mg/day plus E 50 mg/day (n = 25) and followed for 24 weeks. The primary endpoint was the percentage change in uACR from baseline.
Systolic blood pressure (SBP) fell in all three groups, most evidently in the R + E group. uACR also decreased in all 3 groups, again more evidently in the R + E group, and correlated with the decline in SBP, but both the reduction in SBP and treatment group assignment were independent predictors of a decline in uACR. Hyperkalemia (>5.5 mEq/L) was not a major clinical problem in any group (<4% prevalence), but was seen more frequently in patients with reduced eGFR at baseline.
These findings are largely confirmatory of the short-term effects of combinations of R and E on SBP and uACR. The short-term design, the inclusion of patients with only moderate albuminuria, and its small size precludes any interpretation of a renoprotective effect of the combined regimen and the absence of sodium-glucose transporter-2 inhibitor therapy as a comparison arm renders the trial rather non-informative in connection with contemporary management of T2DM with moderate albuminuria. Nevertheless, the improved SBP control and the effects on albuminuria of the combined regimen would likely predict longer-term benefits on CKD progression and cardiovascular disease (such as heart failure and strokes).
Quoted Karger Article
A Prospective Single-Blind Randomized Trial of Ramipril, Eplerenone and Their Combination in Type 2 Diabetic Nephropathy
Viewpoint On
Zhang Y, Liu Y, Liang L, Liu L, Tang X, Tang L, Chen P, Chen J, Wang Z, Cao W, Chen Q, Zhao N, Xu D: Effect of Glomerular Mannose-Binding Lectin Deposition on the Prognosis of Idiopathic Membranous Nephropathy. Kidney and Blood Pressure Research DOI 10.1159/000508665
Mannose-binding lectin (MBL), complement components 3 and 4d, IgG4 and PLA2R antigen (and/or thrombospondin 7A; THSD7A) are frequently co-deposited or hyperexpressed in the glomeruli of patients with primary membranous nephropathy (MN). Strong C4b and MBL depositions (indicative of activation of the lectin pathway of the complement cascade) have been linked to an adverse prognosis in IgA nephropathy, but this observation has not been extensively studied in MN.
Zhang and colleagues examined 67 Chinese subjects with presumed primary MN, 55% of whom were PLA2R antibody positive and 1.4% with combined PLA2R and THSD7A antibody. MBL deposition was present in 79% of these cases and PLA2R antigen hyperexpression was found in 73% of the cases. Unfortunately, no studies of C4d deposition were carried out. This magnitude of MBL deposition in primary MN has been previously reported. In this series MBL deposition was associated with a more favorable prognosis, as assessed by the frequency of a partial remission to proteinuria of >0.3 and <1.0 g/day, at least over the short-term follow-up. This finding was also present in a fully adjusted multivariate model.
Prior studies have suggested that MBL deposition is associated with a less favorable prognosis (similar to IgA nephropathy). The explanation for these discordant findings is not immediately apparent, but in the Zhang et al. study MBL deposition was correlated with tissue PLA2R antigen expression but not with circulating anti-PLA2R antibody levels. Interestingly, C1q deposition (by immunofluorescence microscopy) was found in 22% of the patients. IgG subclass 4 and C4d deposition was not studied, and both absences are weaknesses of this study. The putative “protective” role of glomerular deposition of MBL clearly needs further research.
Quoted Karger Article
Effect of Glomerular Mannose-Binding Lectin Deposition on the Prognosis of Idiopathic Membranous Nephropathy
Viewpoint On
Hu Y-F, Tan Y, Yu X-J, Wang H, Wang S-X, Yu F, Zhao M-H: Podocyte Involvement in Renal Thrombotic Microangiopathy: A Clinicopathological Study. American Journal of Nephrology DOI 10.1159/000510141
Traditionally, thrombotic micro-angiopathy (TMA) is believed to mainly be a consequence of events paying out at the interface of the endothelial cells of the vascular tree and the circulation, including the kidneys. Involvement of the glomerular podocyte, either primarily or secondarily, has not received a great deal of attention.
Hu and colleagues have addressed this issue in an interesting observational study of 63 subjects with kidney biopsy-proven TMA in order to better describe the pathophysiology of associated podocyte injury. The degree of podocyte effacement was studied morphometrically using the parameter of foot-process width (FPW, in nM). The underlying cause of TMA was quite diverse, with 50% being due to malignant hypertension and nephrotic range proteinuria. No patient received eculizumab, but 22% received PLEX, and 49% received some sort of immunosuppressive therapy.
The FPW was increased in these subjects and correlated with a decline in serum albumin levels and with eGFR and an increase in proteinuria. The degree of increase in FPW was an independent predictor of kidney failure, and a threshold value of >869 nM for FPW had a sensitivity of 78% and a specificity of 61% for predicting a composite outcome of death or kidney failure. Kidney failure was observed during follow-up in 52% of the cohort, especially in those with extensive foot-process effacement. Loss of synaptopodin and podocalyxin was seen with sclerotic lesions and crescents.
It appears that podocyte injury is a potential marker of a poor outcome in TMA, but the observational nature of the study precluded any mechanistic explanations and it is unknown if the degree of podocyte injury plays any role at all in the selection of therapeutic approaches. It is quite likely that cross-talk between endothelial cells and podocytes underlies many of the findings observed in this largely descriptive study.
Quoted Karger Article
Podocyte Involvement in Renal Thrombotic Microangiopathy: A Clinicopathological Study
Viewpoint On
Gutiérrez E, Carvaca-Fontán F, Luzardo L, Morales E, Alonso M, Praga M: A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges. Nephron DOI 10.1159/000509997
IgA nephropathy (IgAN) is a common disorder that progresses to kidney failure in about 30% of patients followed for 2 decades or more. It also commonly recurs in transplanted kidneys. It can only be diagnosed by kidney biopsy. The pathology, pathogenesis, and prognosis are fairly well understood, but etiology and treatment are not.
Gutierrez and colleagues from Spain have prepared a masterful review and update of this clinicopathological entity. This “blog” cannot really do justice to their high-quality review. It is timely, authoritative, and comprehensive. It clearly shows how much we have learned, but also identifies the many remaining unresolved questions about this enigmatic disease. I will focus here on only a few issues.
The comments on the growing understanding of the role of complement activation (alternative and lectin pathways) were of particular interest on account of their therapeutic implications. The new information on hematuria as a prognostic factor is long overdue. The contribution of the OXFORD-MEST-C classification of pathology is now widely recognized as having significant prognostic value, but its incorporation into treatment decisions and clinical trials has been slow, and until recently very inadequate. New validated tools combining clinical features with kidney pathology are now emerging, and once randomized clinical trials (RCTs) have evaluated their utility in treatment decision making, advances in our understanding of treatment regimens will likely occur.
One of the main challenges in IgAN is how to move beyond non-disease-specific therapies, such as renin-angiotensin system inhibition, which are only effective in about 50% of cases. The role of steroids and the optimum dose and duration of such therapy remains uncertain. The results of the low-dose oral methylprednisolone trial (TESTING-II) and the trial of specially formulated budesonide (NEFIGARD) will help to inform us concerning the rational use of steroids in IgAN. Hydroxychloroquine is becoming a mainstay of treatment, but this is based on only limited RCT data. The use of chemical or biological immunosuppression in IgAN remains uncertain (MMF might be effective in Asians with IgAN). Many novel drugs are currently being studied, including those that affect the complement system. These studies are well outlined in the review.
Altogether, the future appears bright for the resolution of the numerous uncertainties underlying prognosis and therapy in IgAN. The era of disease non-specific therapy may be drawing to a close as the data supporting a tailored (personalized) disease-specific approach to treatment of IgAN emerge from ongoing RCTs. This review certainly provides a degree of optimism that progressive CKD can be altered in many cases of IgAN in the not too distant future.
Quoted Karger Article
A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges
Viewpoint On
Lankinen R, Hakamäki M, Metsärinne K, Koivuviita NS, Pärkkä JP, Hellman T, Kartiosuo N, Raitakari OT, Järvisalo MJ: Cardiovascular Determinants of Mortality in Advanced Chronic Kidney Disease. American Journal of Nephrology DOI 10.1159/000509582
Little doubt exists that progressive chronic kidney disease (CKD) imposes added risks of mortality, mainly from cardiovascular disease (CVD). This relationship is a very complex one involving a multitude of factors (such as dyslipidemia, microinflammation, hypertension, metabolic disorders, vascular calcification, volume overload, anemia, and others).
Lankinen and coworkers examined some of the “determinants” of CVD and all-cause mortality in an interim report of the findings in a cohort of 210 patients with stage 4 or 5 (non-dialysis) CKD enrolled in a prospective cohort study carried out in Finland. The average age of the enrollees was 61 years, with 43% diabetic and 99% hypertensive. The median eGFR was 12 mL/min. The subjects underwent a number of studies, including measurement of troponin T, NT-proBNP, serum albumin, bicycle ergometry, X-rays for abdominal aortic calcification (AAC), echocardiography, carotid and femoral intima-media thickness, and brachial artery flow-mediated vasodilatation. About 21% of the subjects died during a follow-up of 42 ± 17 months; 80% of the enrollees began dialysis (hemo- or peritoneal dialysis) or received a kidney transplant during the follow-up period. Death was due to CVD in 47%, malignancy in 22%, infection in 14%, and other causes in the remaining 17%. The prediction of all-cause mortality by variable measured was studied in Cox proportional hazards modeling with adjustments for comorbidity, but the validity of the proportional hazards model was not tested by examination of Schoenfeld residuals.
The factors associated with increased mortality risk were increased troponin T, increased NT-proBNP, decreased maximum exercise capacity (determined by the energy expenditure in the last 4 min of graded exercise by bicycle ergometry), degree of AAC, E/e ratio by cardiac electrocardiography, and a low albumin concentration. Carotid and femoral intima-media thickness and brachial artery flow-mediated dilatation did not consistently predict mortality. Interestingly, the left ventricular mass index and left ventricular ejection fraction also did not predict mortality.
These findings could be incorporated into a “scoring system” for mortality prediction, but comparison to other much simpler prognostic tools would be very appropriate. Such tools are readily available and include the powerful “surprise” question incorporated into the QXmd calculator (see www.qxmd.com) and that presented by Schmidt et al. [1]. Whether the variables included in this study will improve the accuracy of prediction of all-cause and cardiovascular mortality in patients with stage 4/5 CKD compared to simpler methods needs to be studied in the future iterations of this cohort analysis, in my opinion.
References
1. Schmidt RJ, Landry DL, Cohen L, Moss AH, Dalton C, Nathanson BH, Germain MJ. Derivation and validation of a prognostic model to predict mortality in patients with advanced chronic kidney disease. Nephrol Dial Transplant. 2019;34:1517–25
Quoted Karger Article
Cardiovascular Determinants of Mortality in Advanced Chronic Kidney Disease
Viewpoint On
Lim Y, Yang G, Cho S, Kim SR, Lee Y-J: Association between Ultrafiltration Rate and Clinical Outcome Is Modified by Muscle Mass in Hemodialysis Patients. Nephron DOI 10.1159/000509350
Observational data have strongly implicated excessive ultrafiltration rates (UFR) as a possible contributor to adverse outcome in hemodialysis treatment of kidney failure. Many variables can affect this association, including “frailty” or abnormalities of body composition of the patients undergoing this modality of treatment.
Lim and coworkers examined the impact of reduced lean body mass (a measure of sarcopenia) assessed by body composition analysis in an observational study of 167 patients on maintenance hemodialysis. The median UFR was 11.4 mL/h/kg. During 284 person years of follow-up, death or first cardiovascular event (the primary outcome metric) occurred in 26% of the subjects and this outcome was predicted by a higher UFR but the hazard ratio for the primary event was quite low (HR 1.044; 95% CI 1.006–1.083). Each 1 mL/h/kg increase in UFR was associated with a 4% greater risk of the primary end point. Residual kidney function was not assessed. Low lean body mass (<12.5 kg/m2; sarcopenia) was identified as a possible marker of the adverse outcomes associated with high UFR.
As an observational study, these findings are hypothesis generating and not proof of concept. They do seem plausible and it would have been of interest to have quantitative information on the relationships of low lean body mass to indices of “frailty.” Only one body composition measurement was made in this cohort, so we do not know if increases in muscle mass attenuated the adverse effects of excessive UFR. Sarcopenia is well recognized to contribute to mortality risk. Taken together with available information on muscle mass and mortality risk, these studies point to the possible utility of assessment of muscle mass by body composition analysis in guiding the application of UFR in patients on hemodialysis. Whether attempt to improve sarcopenia (exercise training, nutritional modification, anabolic agents) will reduce the risks associated with high UFR remain as questions to be better understood.
Quoted Karger Article
Association between Ultrafiltration Rate and Clinical Outcome Is Modified by Muscle Mass in Hemodialysis Patients
Viewpoint On
Miñana G, Llàcer P, Sanchis I, García-Blas S, Bonanad C, Ventura S, Sánchez R, de la Espriella R, Bodi V, Fácila L, Mollar A, Sanchís J, Bayés-Genís A, Chorro FJ, Núñez J (on behalf of IMPROVE-HF Investigators): Early Spot Urinary Sodium and Diuretic Efficiency in Acute Heart Failure and Concomitant Renal Dysfunctioncy. Cardiorenal Medicine DOI 10.1159/000508178
Acute decompensated heart failure (AHF) is commonly associated with renal functional impairment and diuretic resistance. The assessment of “spot” [Una+] may be useful in identifying diuretic resistance and the need for high-dose therapies.
Miñana and colleagues conducted a post hoc examination of data acquired in the IMPROVE-HF trial (an RCT designed to study the benefit of usual loop-diuretic therapy vs. a carbohydrate 125-guided approach in AHF). [Una+] was measured early in 160 patients with AHF and an estimated glomerular filtrate rate (eGFR) of <60 mL/min/1.73 m2. The left ventricular ejection fraction (LVEF) was <50% in 47% and the mean aminoterminal fraction of the brain natriuretic peptide (NT-proBNP) was 7,765 pg/mL. The mean eGFR was 34 mL/min/1.73 m2 and the [Una+] was 90 mM/L; most of the patients had received low doses of furosemide or equivalent previously (time undetermined). The diuretic efficiency was assessed by the milliliters of fluid excreted per 40 mg of furosemide equivalent.
A positive relationship between diuretic efficiency and [Una+] was noted. Values of [Una+] <90 mM/L were most often accompanied by diuretic resistance. The serum sodium concentration was positively associated with [Una+]. As expected, a low serum sodium concentration (hyponatremia) was a predictor of poor outcome in AHF, as was low [Una+]. Interestingly, reduced eGFR did not predict [Una+] or diuretic resistance.
Despite the post hoc design of this study, it offers support for the utility of early “spot” [Una+] in defining the prognosis and predicting the likelihood of diuretic resistance in AHF, regardless of the concomitant presence of impaired renal function. Obviously, this study does not apply to stable chronic HF or patients with established CKD and concomitant HF. A prospective study is needed to confirm these findings.
Quoted Karger Article
Early Spot Urinary Sodium and Diuretic Efficiency in Acute Heart Failure and Concomitant Renal Dysfunction
Viewpoint On
Ronco C, Bagshaw SM, Bellomo R, Clark WR, Husain-Syed F, Kellum JA, Ricci Z, Rimmelé T, Reis T, Ostermann M: Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation. Blood Purification DOI 10.1159/000508125
The COVID-19 pandemic has presented many challenges in treatment and organ support. The “cytokine storm” commonly associated with severe forms of COVID-19 raises the possibility of using extracorporeal blood purification technologies for treatment.
Ronco and colleagues provide an in-depth review of the rationale, pathophysiology, and possible benefits of this approach, collectively known as extracorporeal organ support, or ECOS. These strategies incorporate continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO), and extracorporeal carbon dioxide removal (ECCO2R). The utility of ECOS in restoring a balanced systemic immune response (relieving “cytokine storm”) involves strategies such as high-volume hemofiltration, hemoperfusion, plasmapheresis, coupled filtration adsorption, high cut-off (HCO), and membranes with enhanced adsorptive profiles (CytoSorb and oXiris).
CRRT has advantages over intermittent hemodialysis in hemodynamically unstable patients, but whether it provides better outcomes in COVID-19 patients with acute kidney injury (AKI) is uncertain. CRRT can be combined with ECMO or ECCO2R in certain circumstances. More effective removal of cytokines can be accomplished with CytoSorb or oXiris devices. The CytoSorb device has been given conditional approval for use in COVID-19 patients with severe disease by the FDA. So far there have been no comparisons of systemic immunomodulatory therapy (e.g., IL-6 inhibition by tocilizumab or steroids) with ECOS. Importantly, efficacy has not yet been proven for these adsorptive devices by RCT. ECCO2R may be particularly useful in patients with hypercapnic acute respiratory failure unaccompanied by the need for substantial oxygen support.
HCO membranes have been tried in multiorgan failure due to endotoxemia and sepsis, but the results have been disappointing. The timing of application of these devises may be crucial, and the “window of opportunity” short in duration.
AKI is very common (20–40%) in severe COVID-19 requiring ventilatory support. The pathogenesis of this event is poorly understood, but in most cases does not seem to be due to direct invasion by the SARS-CoV-2 virus itself. CRRT is very useful in treating the AKI but clotting of the filters is a major issue because of the thrombophilic state engendered by COVID-19. Special anticoagulation regimens and predilution continuous veno-venous hemodialysis (CVVHD) may help to partially alleviate this problem.
All in all, this review is a very useful and detailed guide to the current state of ECOS in COVID-19. All caregivers with extensive exposure to COVID-19 patients would benefit from reading it in its original form.
Quoted Karger Article
Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation
Viewpoint On
Nei AM, Kashani KB, Dierkhising R, Barreto EF: Predictors of Augmented Renal Clearance in a Heterogeneous ICU Population as Defined by Creatinine and Cystatin C. Nephron DOI 10.1159/000507255
Several reports, going back 5–7 years, noted increased levels of an estimated glomerular filtration rate (eGFR) in a variable number of patients with severe sepsis or trauma admitted to the intensive care unit (ICU). This phenomenon became known as “augmented renal clearance” (ARC). These reports typically used eGFR formulas based on serum creatinine, developed in stable outpatients.
Nei and coworkers re-examined this phenomenon using an assessment of eGFR using both creatinine and cystatin C, believed to be a more accurate and less biased assessment of actual or measured GFR. In a retrospective review of 368 patients admitted to the ICU they found that the prevalence of ARC (as defined by an eGFR >130 mL/min/1.73 m2 regardless of age by either eGFR-creatinine, eGFR-cystatin C, or a combination of both within the first 48 h after admission) varied. The prevalence of ARC by these formulas was 3.3–7.9% depending on which formula was used. The lowest prevalence was found by the eGFR creatinine + cystatin C formula. The Charlson Comorbidity Index, major trauma, intracranial hemorrhage, older age, and a high SOFA score were predictive of ARC, so defined.
The most concerning weakness of this and other studies is the application of eGFR formulas, the accuracy, precision, and bias of which were largely evaluated in stable outpatients, not sick and unstable ICU patients, where assumptions regarding creatinine and/or cystatin C production cannot be reliably made. In addition, the ARC has not been confirmed by the assessment of measured GFR, although these values would also be subject to variation in hemodynamically unstable, critically ill subjects. Thus, ACR is not equivalent to “hyperfiltration”. Whether ARC is real or merely an artifact of measurement is uncertain and whether it should be used to modify dosage of water-soluble therapeutic agents cleared by GFR is equally in doubt, in my opinion.
Quoted Karger Article
Predictors of Augmented Renal Clearance in a Heterogeneous ICU Population as Defined by Creatinine and Cystatin C
Viewpoint On
Woo KT, Chan CM, Lim C, Choo J, Chin YM, Teng EWL, Mok I, Kwek JL, Tan CS, Tan HZ, Loh AHL, Choong HL, Tan HK, Lee GSL, Lee E, Wong KS, Tan PH, Foo M: The Value of Renal Biopsy in Non-Insulin-Dependent Diabetes Mellitus in Singapore over the Past Two Decades. Kidney Diseases DOI 10.1159/000505624
Kidney biopsy in patients with diabetes mellitus (typically type 2; T2DM) and CKD (proteinuria with or without reduced GFR) is often performed to evaluate the possibility of the presence of a non-diabetes-related lesion/disease (NDRD) alone or in combination with diabetic nephropathy (DN); however, clinical protocols for deciding when such kidney biopsies are indicated vary widely. Previous studies have suggested that the prevalence of pure DM, NDRD, and NDRD + FN is found in such “clinically indicated” biopsies in 6.5–94, 3–89, and 4–48%, respectively. Renal biopsies done for research purposes only, not guided by clinical indications, reveal NDRD with or without DN in about 10–15% of patients with T2DM.
In a single-center retrospective study extending over a period of about 4 decades, Woo and coworkers from Singapore have studied the findings of elective, “clinically indicated” kidney biopsies in 255 patients with T2DM and CKD. The patients in whom the biopsies revealed only DN tended to be younger, have higher blood pressure, more retinopathy, lower eGFR, and greater proteinuria compared to those in whom NDRD lesions were found. IgA nephropathy, membranous nephropathy, and minimal change disease were commonly encountered NDRD lesions. Focal and segmental glomerulosclerotic (FSGS) lesions were represented in both NDRD and NDRD + DN categories, but not among pure DN. This may be an artifact of classification as it is very difficult to separate DN-associated FSGS for other forms of FSGS lesions, including primary, genetic, and secondary forms. Diabetic retinopathy was strongly associated with Kimmelstiel-Wilson (nodular) glomerulosclerosis. Dysmorphic hematuria and a short duration of clinical manifestations of CKD were strongly associated with NDRD, with or without DN. High systolic blood pressure, a longer duration of diabetes, marked proteinuria, and diabetic nephropathy were all associated with a greater risk of progression to ESKD.
This and other similar studies support the common practice of performing a renal biopsy whenever there is a clinical suspicion of NDRD in a patient with T2DM and CKD. A short duration of diabetes, absence of retinopathy dysmorphic hematuria, and rapidly declining renal function are useful clinical features suggesting that NDRD may be present.
Quoted Karger Article
The Value of Renal Biopsy in Non-Insulin-Dependent Diabetes Mellitus in Singapore over the Past Two Decades
Viewpoint On
Morris AD, Elsayed ME, Ponnusamy A, Rowbottom A, Martin F, Geetha D, Dhaygude AP: Treatment Outcomes of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis in Patients Over Age 75 Years: A Meta-Analysis. American Journal of Nephrology DOI 10.1159/000506532
ANCA-associated vasculitis (AAV) preferentially affects an older population of adults. The use of potent immunosuppressive agents (such as cyclophosphamide [CYC] or rituximab [RTX]) for treatment might expose these older patients to an excess risk of adverse events and impact outcomes in an important way. Morris and colleagues sought to analyze this issue by conducting a retrospective study of an elderly cohort (n = 67) from two centers (UK and USA), and by performing a systematic review and meta-analysis of relevant publications (totaling 290 subjects, including their cohort). The patients analyzed were all aged 75 years or more at diagnosis. All cases were “pure” ANCA-associated disease.
Compared to untreated patients (those not receiving induction therapy) the hazard ratio (HR) for mortality at 2 years of follow-up for the treated patients (those receiving induction therapy; CYC or RTX) was 0.29 (95% CI 0.09–0.33) for the two-center cohort. The systematic review and meta-analysis showed a similar effect of treatment on HR for mortality (HR 0.31; 95% CI 0.16–0.57). However, the rate of ESKD was not significantly reduced by treatment (HR 0.71; 95% CI 0.16–3.35). The analysis may have been underpowered to show such an effect, even if it was present. The impact on mortality was mostly seen in the first 6 months after starting treatment. Serious adverse events (mainly infection) were seen more commonly in the treated populations. Histologic markers of prognosis were not utilized in this study.
These data, although retrospective and observational – thereby subject to bias and confounding by unmeasured variables – support that elderly patients do receive benefits from induction therapy for AAV, primarily better short-term survival, rather than prevention of ESRD (2 years or less of follow-up). Thus, age alone should not be a consideration in treatment decision making. Whether the combination of age, comorbidity, and histologic prognostic indicators can be used in treatment decisions requires further study.
Quoted Karger Article
Treatment Outcomes of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis in Patients Over Age 75 Years: A Meta-Analysis
Viewpoint On
Bamba R, Okamura T, Hashimoto Y, Hamaguchi M, Obora A, Kojima T, Fukui M: The Visceral Adiposity Index Is a Predictor of Incident Chronic Kidney Disease: A Population-Based Longitudinal Study. Kidney and Blood Pressure Research DOI 10.1159/000506461
Obesity and its association with CKD is well described but prediction of the incident CKD from a description of obesity is understudied. As a modifiable risk factor such an analysis would be very important from a public health perspective. In addition, the different effects of visceral compared to subcutaneous adiposity on the complications of obesity, such as diabetes or the metabolic syndrome, are well known.
Using a novel visceral adiposity index (VAI; which includes the variables of waist circumference, body mass index, serum triglyceride, and HDL-cholesterol levels) in men and women, Bamba and coworkers conducted a population-level, historical cohort study to examine the utility of VAI for prediction of incident CKD in Japanese subjects. The follow-up was relatively short, at about 3.3 years. The average age of the cohort was about 42 years. None of the included subjects were taking any medications at baseline.
Over 4,000 days of observation, incident CKD (defined by eGFR and/or dipstick proteinuria) was 3.7% in men and 3.9% in women. Men had a higher VAI than women at baseline. The difference in risk of incident CKD between the lowest and highest quartile of VAI was significant (hazard rate of 1.51 in men and 1.65 in women). However, the AUC for predicting incident CKD was low in both men (0.595) and women (0.597).
While this novel index of obesity takes into account visceral obesity and its metabolic consequences, it is not clear whether it will have utility in the identification of subjects for interventional trials to determine whether reduction in the VAI will have an important effect on incident CKD in the population as a whole. Furthermore, confirmatory studies in non-Japanese populations are needed.
Quoted Karger Article
The Visceral Adiposity Index Is a Predictor of Incident Chronic Kidney Disease: A Population-Based Longitudinal Study
Viewpoint On
Adrogué HJ, Awan AA, Madias NE: Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status. American Journal of Nephrology DOI 10.1159/000506274
It is well known that the space of distribution of bicarbonate anion (HCO3–) following intravenous infusion of hypertonic sodium bicarbonate is independent of blood pH but is highly correlated with the pre-infusion extracellular HCO3– concentration. In hypobicarbonatemic states (metabolic acidosis and respiratory acidosis) the apparent HCO3– space exceeds that of total body water. The fate of the co-administered sodium cation (Na+) has not been investigated.
Adrogué et al. [1] addressed this missing information by re-analyzing the data from prior experiments in dogs with a variety of acid-base disorders. The Na+ space of distribution differed among the four acid-base disorders examined (metabolic acidosis and alkalosis, and respiratory alkalosis and acidosis). It increased above total body water in the hypobicarbonatemic groups, independent of blood pH, similar to that previously found for the HCO3 space of distribution. This points in the direction of an osmotic inactivation of the infused Na+ in hypobicarbonatemic, but not hyperbicarbonatemic or normobicarbonatemic states. This buffering is an initial but not a progressive phenomenon, as displayed by serial observations. Because of the similarity of the fate of administered Na+ and HCO3–, the authors propose that they may be linked phenomena involving non-bicarbonate buffers in the extracellular fluids/matrix, also involving Na+/H+ exchange via the NHE1 exchanger. The fate of administered Na+ seems to be driven by the fate of HCO3, not vice versa. These findings also help to explain the differences of urinary Na+ excretion when hypertonic sodium bicarbonate is administered in hypobicarbonatemic as compared to hyperbicarbonatemic states.
This is a very stimulating and rewarding paper to read. It also recalls a version of a common adage: “Old and good data never dies” (in this case almost 40-year-old data) – it just awaits a re-analysis by curious and careful investigators. Kudos to Dr. Adrogué and his coworkers for their efforts.
Quoted Karger Article
Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status
Viewpoint On
Oloko A, Talreja H, Davis A, McCormick B, Clark E, Akbari A, Kong J, Hiremath S: Does Iodinated Contrast Affect Residual Renal Function in Dialysis Patients? A Systematic Review and Meta-Analysis. Nephron DOI 10.1159/000505576
The adverse effects of iodinated contrast media (CM) on kidney function continues to be very controversial. It is likely that the effects of CM have been overstated in the past. Most of the studies of this issue have involved patients with normal or moderately reduced renal function and relatively few have addressed the effects of CM on residual kidney function (RKF) in patients with ESRD treated by dialysis.
Oloko and colleagues have remedied this knowledge gap (in part) by focusing on the adverse effects of CM on RKF by conducting a systematic review and meta-analysis of published studies. A total of 7 studies (3 observational and 4 controlled) including 282 patients receiving hemo- or peritoneal dialysis were examined. The weighted mean difference for RKF after CM was only –0.6 mL/min (not significant), but there was significant heterogeneity among the included studies and the 95% confidence intervals were quite wide (–0.66 to +0.34 mL/min). Insufficient data were available to categorize clinical outcomes.
While the accumulated data do not support an adverse effect of CM on RKF, they do not exclude such an effect with high confidence. However, these data do not suggest that post-CM exposure dialysis of such patients is likely to have a beneficial effect. Further studies are required to be able to draw definite conclusions concerning the risks of administration of CM to dialysis patients.
Quoted Karger Article
Does Iodinated Contrast Affect Residual Renal Function in Dialysis Patients? A Systematic Review and Meta-Analysis
Viewpoint On
Liu Z, Cui Z, He Y, Zhang Y, Wang F, Wang X, Meng L, Cheng X, Liu G, Zhao M: Membranous Nephropathy in Pregnancy. American Journal of Nephrology DOI 10.1159/000505175
The information concerning the impact of primary membranous nephropathy (MN) on the mother and fetus in pregnancy is scanty. Liu et al. have at least partially filled this gap with a retrospective and detailed analysis of 27 pregnancies complicated by primary MN. These subjects had primary MN diagnosed before pregnancy (n = 11), or were diagnosed by a renal biopsy during pregnancy (n = 12) or after delivery (n = 4).
Maternal-fetal adverse events were common (fetal loss, 11%; pre-term birth, 0–26%; pre-eclampsia, 15%), but overall the maternal kidney function was well preserved. All patients diagnosed with MN prior to pregnancy were in remission at the time of conception. Worsening of proteinuria was seen during the 2nd trimester. Cyclosporin A plus steroids were used to induce remission in the 2nd trimester and were successful in 3 of 8 cases. Similar results were found when treatment begun in the 3rd trimester. Rituximab was not used in any patient. The live birth rate was 89% with an average gestation period of 37 weeks. The average birth weight of the infants was 2.9 kg. Only 2 infants had transient low-grade proteinuria at birth, which spontaneously abated. A number of the mothers were phospholipase A2 receptor (PLA2R) antibody positive (about 30%). Marked proteinuria, a decrease in serum albumin, positive PLA2R antibody, and no remission were risk factors for adverse fetal maternal outcomes.
This paper is a valuable addition to the literature on pregnancy in MN. It contains sufficient detail to help guide the management of such patients. Cyclosporin A seems to be a reasonable treatment approach in situations that call for active treatment, but overall efficacy and safety cannot be assessed in such a small, uncontrolled sample. PLA2R antibody positivity, especially with rising levels, seems to be a reason for the introduction of active therapy. Infants do not appear to be seriously affected by the trans-placental transfer of anti-PLA2R antibody. We still do not know if rituximab therapy of primary MN in pregnancy is safe and effective.
Quoted Karger Article
Membranous Nephropathy in Pregnancy
Viewpoint On
Tsujimoto Y, Tsutsumi Y, Ohnishi T, Kimachi M, Yamamoto Y, Fukuhara S: Low pre-dialysis plasma calculated osmolality is associated with higher all-cause mortality: The Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS). Nephron DOI 10.1159/000504194
The calculated plasma osmolality (Posm=2 X plasma [Na+] = serum urea nitrogen/ 2.8 + serum glucose/1.8) is higher in hemodialysis patients (averaging 307±9 mOsm/kg H20) compared to normal subjects (290±4 mOsm/kg H20). However, the predialysis calculated Posm is variable due to changes in the components of the calculation (levels of Na+, urea nitrogen and glucose).
Tsujimoto and colleagues studied the impact of pre-dialysis treatment session values of calculated Posm for all-cause mortality in 1249 patients undergoing maintenance hemodialysis and enrolled in the Japanese Dialysis Outcomes and Practice Patters Study (J-DOPPS). The Posm was stratified into 3 levels: <300, 3000–310, and >310 mOsm/kg H20. Patients in the lowest Posm group were older, had peripheral arterial disease and lower post dialysis body weight. Inter-dialytic weight gain, and pre-dialysis blood pressure were not different in the 3 groups. Importantly measured Posm and osmolal gap (calculated Posm minus measured Posm) were not evaluated in this study and almost 40% of the subjects studied had at least one missing variable.
In a multi-variate analysis each 10mOsm lower pre-dialysis calculated Posm was associated with a higher all-cause mortality (HR=1.48; CI=1.30–1.78). There was no apparent interaction between calculated Posm and the plasma sodium, urea nitrogen and diabetes status. Adjusting for urea nitrogen appearance rate and BMI also showed similar HR results.
These are novel findings which lack a clear explanation. The lack of data on measured Posm is a serious weakness as is the high rate of missing data. The predictive power of calculated Posm needs to be compared to other mortality prediction formulas and the impact of pre-dialysis calculated Posm at the facility level needs to be analyzed. The hypothesis generated by this novel study needs to be pursued further in a prospective manner where the important variables can be more carefully controlled.
Quoted Karger Article
Low pre-dialysis plasma calculated osmolality is associated with higher all-cause mortality: The Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS)
Viewpoint On
Chen TK, Parikh CR: Management of Presumed Acute Kidney Injury during Hypertensive Therapy: Stay Calm and Carry on? Am J Nephrol DOI 10.1159/000505447
Several randomized and controlled studies have documented that “acute kidney injury” (defined by a rising level of serum creatinine) can accompany intensive blood pressure control regimens designed to achieve systolic blood pressure values <120 mm Hg. These studies have also documented that such lower blood pressure is associated with improved survival and a lower frequency of cardiovascular events.
Parikh and Chen critically examine this apparent paradox in a very well-written review article. They stress that much of the reduction of renal function seen in association with intensive blood pressure control is hemodynamic in nature and the designation of “acute kidney injury” cannot be justified in the absence of parameters directly supporting structural “kidney injury” per se. They suggest that when this hemodynamic phenomenon is encountered clinicians should “stay calm and carry on”. In this situation using changes in serum creatinine to define “acute kidney injury” is inappropriate. Good advice. Nephrologists using intensive anti-hypertensive regimens to gain better control of blood pressure will benefit from reading this timely and well-written article.
Quoted Karger Article
Management of Presumed Acute Kidney Injury during Hypertensive Therapy: Stay Calm and Carry on?
Viewpoint On
Zahler D, Rozenfeld KL, Merdler I, Peri Y, Shacham Y: Contrast Volume to Glomerular Filtration Ratio and Acute Kidney Injury among ST-Segment Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention. Cardiorenal Med DOI 10.1159/000504534
Radio-contrast media volume may have an important influence on the risk of contrast-associated acute kidney injury (AKI). Zahler et al. have carried out a retrospective, observational (and uncontrolled) study to determine if the risk of AKI is associated with the ratio of contrast volume administered to the pre-procedure estimated glomerular filtration rate (eGFR) in subjects undergoing primary percutaneous intervention following an acute myocardial infarction. A total of 419 subjects were included. Iodixanol (a non-ionic, iso-osmolar preparation) was used in all subjects. AKI was defined by the KDIGO criteria.
Out of 419 subjects, 31 (9%) developed AKI. The contrast volume/eGFR ratio was 2.7 ± 1.2 in those with AKI and 1.9 ± 0.9 in those without AKI. Patients experiencing AKI had a much lower pre-procedure eGFR (56 ± 22 mL/min/1.73 m2) compared to those without AKI (73 ± 18 mL/min/1.73 m2). The areas under the curve (AUC) for the occurrence of AKI pointed to a threshold value of contrast volume/GFR of >2.13, but the C-statistic was rather modest at 0.65 (95% CI 0.56–0.74). A multifactorial logistic regression analysis showed that a contrast volume/eGFR ratio of >2.13 was independently associated with AKI. The study did not assess the influence of concomitant use of statins or renin-angiotensin inhibitors. All patients received 0.9% saline infusions at 1 mL/kg/h for 12 h after contrast exposure.
A prospective validation of the threshold for contrast volume/eGFR is needed, but this study and others suggest that selection of the dosage of contrast volume should take the pre-procedure eGFR into account.
Quoted Karger Article
Contrast Volume to Glomerular Filtration Ratio and Acute Kidney Injury among ST-Segment Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention
Viewpoint On
Banshodani M, Kawanishi H, Moriishi M, Shintaku S, Tsuchiya S: Association between Dialysis Modality and Cardiovascular Diseases: A Comparison between Peritoneal Dialysis and Hemodialysis. Blood Purif DOI 10.1159/000504040
The mortality and occurrence of cardiovascular (CV) events appears to be similar between patients receiving peritoneal (PD) or hemodialysis (HD) for end-stage kidney disease (ESKD), if the pre-dialysis-co-morbidity and age are similar. But this remains controversial and widely debated, due to inconsistency of findings and the lack of a well-designed large randomized controlled trial (RCT) with prolonged follow up.
Banshodani and co-workers add to the database a small, single-center, observational study employing propensity matching to simulate a RCT.
130 PD prevalent patients were matched to 130 prevalent HD patients according to multiple demographic and clinical parameters and followed for similar periods of time.
The rate of emergency hospitalization for CV causes (mainly congestive heart failure) and all-cause mortality (mainly due to CV disease) was higher in PD patients.
The study had many weaknesses. It was not designed to uncover the mechanisms responsible for the observed differences. Minor differences in clinical characteristics between the PD and HD cohorts (such as serum albumin levels, serum potassium of corrected calcium) might have contributed to the differences seen. Higher atherogenic glucose loads or glucose degradation products (GDP) in PD fluids might be explanatory, although low GDP containing PD fluids were utilized. No bio-impedance studies were performed to objectively quantify differences in volume expansion occurring between the two groups.
This study is primarily hypothesis generating at best due to its small size and single center nature. It is subject to a high risk of bias due to confounding effect of measured and unmeasured variables. It is difficult to generalize these findings to the universe of PD and HD patients.
Quoted Karger Article
Association between Dialysis Modality and Cardiovascular Diseases: A Comparison between Peritoneal Dialysis and Hemodialysis
Viewpoint On
Dudreuilh C, Fakhouri F, Vigneau C, Augusto JF, Machet MC, Rabot N, Chapal M, Charpy V, Barbet C, Büchler M, Halimi JM, Gatault P: The Presence of Renal IgG Deposits in Necrotizing Crescentic Glomerulonephritis Associated with ANCA Is Not Related to Worse Renal Clinical Outcomes. Kidney Dis DOI 10.1159/000503969
Typically, IgG deposition is scanty or absent (“pauci-immune”) in antineutrophil cytoplasmic antibody (ANCA) vasculitis but variation in the extent of glomerular deposition of IgG is now recognized as occurring rather frequently in this condition. However, the prognostic significance of this variation is largely unknown.
Dudreuilh and co-workers examined this issue in a retrospective, observational study of 158 patients with ANCA vasculitis. Eighteen of the 158 patients (11%) had more than scanty IgG deposition, without lupus nephritis, IgA nephropathy or anti-glomerular basement membrane (GBM) disease. The subjects with such IgG deposition did not differ clinically from those without such deposition at the time of presentation and biopsy, except for age and a somewhat higher level of anti-myeloperoxidase (MPO) antibody. Pathologically those with IgG deposition had more interstitial fibrosis and tubule atrophy. The treatments and outcomes were similar in those with and without IgG deposition, except for higher rates of plasmapheresis in those with IgG deposition.
This study, although limited by small numbers and retrospective design, suggests that the degree of IgG deposition seen in ANCA vasculitis is of little clinical significance as it does not identify a subgroup with differing outcomes. Therapy need not be tailored on the basis of the appearance of glomerular IgG deposits in ANCA vasculitis.
Quoted Karger Article
The Presence of Renal IgG Deposits in Necrotizing Crescentic Glomerulonephritis Associated with ANCA Is Not Related to Worse Renal Clinical Outcomes
Viewpoint On
Kant S, Habbach A, Gapud EJ, Manno RL, Gattu R, Seo P, Geetha D: Sequential Therapy for Remission Induction in Severe Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis. Am J Nephrol 2019 DOI 10.1159/000503318
The optimal treatment strategy for induction of a remission in antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis with severe renal involvement is in a state of flux as new data emerges from clinical trials and observational studies.
Kant and associates examined a novel regimen in a retrospective analysis of 9 patients with new or relapsing ANCA associate vasculitis (AAV) who presented with severe renal disease (dialysis dependency or an estimated glomerular filtration rate (eGFR) of 11‑22ml/min/1.73m2). Six were anti-MPO and 3 were anti-PR3 subtypes. All patients were treated with 3 daily IV methylprednisolone pulses, 1000mg each, and then 60mg of oral prednisone tapered rapidly to 5mg by month 3. The patients were initially given oral cyclophosphamide which was stopped when the vasculitic activity improved and the serum creatinine began to decline (at between 28 and 53 days after starting therapy) and rituximab, 375mg/m2 was given 4 times a week. Plasmapheresis was given to 3 patients for pulmonary involvement.
All patients went into clinical remission and all but one patient recovered sufficient renal function to avoid dialysis. The eGFR at 12 months was 16‑94ml/min/1.73m2.
While retrospective and uncontrolled, these results suggest that when severe renal disease is present (chronic kidney disease (CKD) stages 4–5). Clinical remission and avoidance of permanent end stage kidney disease (ESKD) is possible. Whether the sequential protocol with rituximab following short term oral cyclophosphamide use (median 35 days) and rapid steroid tapering is an “optimal” strategy cannot be defined by such a small study (n=9) with short term follow up. A properly designed randomized trial is needed to confirm these results. Initial therapy with rituximab and steroids alone might give equivalent results. It is doubtful that plasmapheresis had much to do with the good results observed in this small cohort.
Quoted Karger Article
Sequential Therapy for Remission Induction in Severe Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis
