The renal function trajectory in clinical trial design: challenges and opportunities.

The changes in renal function over time as surrogate endpoints for new drug trials are complicated by many factors, including the often-expected initial decrease in estimated glomerular filtration rate when a new drug is started. Two articles in the journal address this challenge, but multiple other challenges are explored in this commentary. To maximize the benefits of expensive new drugs that may slow decline in renal function, these drugs should be reserved for those patients who have a high probability of rapid loss of kidney function.

Kidney function assessment in the geriatric population.

PURPOSE OF REVIEW: Kidney function declines with normal aging. But it also declines with the progression of some diseases. This review calls for a more nuanced interpretation of kidney function in the geriatric population, who may have frailty and comorbidities. RECENT FINDINGS: GFR declines with healthy aging kidneys. Aging kidney changes include decreased cortical volume, senescent global glomerulosclerosis, and reduced nephron numbers. Yet normal aging is not associated with increased glomerular volume or single-nephron GFR. The prevalence of GFR less than 60 ml/min/1.73 m 2 in the geriatric population is high. However, the decline in GFR with normal aging may not reflect true CKD without albuminuria. Although the risk of ESKD and mortality increases in all age groups when eGFR less than 45 ml/min/m 2 , there is no significant increased relative risk of ESKD and mortality in the geriatric population when eGFR 45-59 ml/min/m 2 in the absence of albuminuria. Innovative approaches are needed to better estimate GFR and define CKD in the geriatric population. SUMMARY: The expected GFR decline in the geriatric population is consistent with normal aging kidney changes. To avoid CKD overdiagnosis and unnecessary referrals to nephrology for possible CKD, age-adapted definitions of CKD in the absence of albuminuria are needed.

Medical Suitability and Willingness for Living Kidney Donation Among Older Adults.

RATIONALE & OBJECTIVE: The benefits of kidney transplantation compared to treatment with dialysis, including in older adult, are primarily limited by the number of donated kidneys. We studied the potential to expand the use of older living kidney donors. STUDY DESIGN: Secondary analysis of the Berlin Initiative Study, a population-based cohort. SETTING: & Participants: 2069 adults aged ≥70 years in Germany. EXPOSURES: Age and sex. OUTCOMES: Suitability for living donation assessed by the absence of kidney-related exclusions for donation including albuminuria and low estimated glomerular filtration rate (eGFR) as well as absence of other medical exclusions. Willingness for living and deceased kidney donation assessed by participant survey. ANALYTICAL APPROACH: Descriptive analysis. RESULTS: Among the 2069 participants (median age 80 years, 53% women, median eGFR 63 ml/min/1.73m2), 93% had ≥1 medical contraindication for living donation at study entry unrelated to eGFR or albuminuria. Using two published eGFR and albuminuria thresholds for donor acceptance, 38% to 54% of participants had kidney-related exclusions for donation. Among the 5% to 6% of participants with neither medical nor kidney-related exclusions for living donation at baseline, 11% to 12% remained suitable for donation during 8 years of follow-up. Willingness for living or deceased donation was high (73% and 60%, respectively). LIMITATIONS: GFR was not measured and medical exclusions unrelated to eGFR and albuminuria were assessed using a cohort database complemented by claims data. CONCLUSIONS: One in twenty older adults were potentially suitable for living kidney donation and willingness for living donation was high. Further studies are warranted to define the feasibility of expanding living kidney donation among older adults.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies.

BACKGROUND: Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment. METHODS: We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria. RESULTS: Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD. CONCLUSION: Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.

Healthy and unhealthy aging on kidney structure and function: human studies.

PURPOSE OF REVIEW: This review is intended to provide an up-to-date analysis of the structural and functional alterations of the kidneys that accompany healthy and unhealthy aging in humans. Macro- and micro- structural changes and glomerular filtration rate (whole kidney and single nephron) accompanying aging will be stressed. RECENT FINDINGS: Comparative findings concerning distribution of anatomic changes of the kidney healthy and unhealthy aging are reviewed. Challenges concerning definition of chronic kidney disease (CKD) in otherwise healthy aging patients are discussed. The complex interactions of CKD and aging are discussed. The role of podocyte dysbiosis in kidney aging is reviewed. SUMMARY: Kidney aging is a complex phenomenon often difficult to distinguish from CKD. Nonetheless, phenotypes of healthy and unhealthy aging are evident. Much more information concerning the molecular characteristics of normal kidney aging and its relevance to chronic kidney disease is needed.

Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial.

Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline. Design, Setting, and Participants: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021. Interventions: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group). Main Outcomes And Measures: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure. Results: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]). Conclusions and Relevance: Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01560052.

Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.

The « race ¼ correction in estimating glomerular filtration rate: an European point of view.

PURPOSE OF REVIEW: There is currently a heated debate ongoing whether or not to use the race coefficient for black people in the Modification of Diet in Renal Diseases and Chronic Kidney Disease Epidemiology-equation. The use of the race coefficient is thought by several American authors as a source of discrimination. RECENT FINDINGS: It has recently been shown that the race coefficient is inaccurate in European and African black people. Therefore, it seems that the race correction is more a correction for black Americans, rather than for black in general. This 'correction' at the glomerular filtration rate (GFR)-level has been criticized, as it is misleading, and should be abandoned, as it has not been shown that GFR is different between black and white people. However, as differences in creatinine generation between black and white people might exist, a correction or adjustment, different for black and white people, at the creatinine level might be required, very similar to the different scaling of creatinine for males and females. SUMMARY: The current debate on the race coefficient is particularly difficult because of the absence of good scientific data in black subjects and there lies the real discrimination in our opinion. We therefore call for future dedicated studies, both in Europe and USA.

The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) Study: Trial Design and Baseline Characteristics.

INTRODUCTION: Despite optimal current care, up to 30% of individuals suffering from immunoglobulin A nephropathy (IgAN) will develop kidney failure requiring dialysis or kidney transplantation. The Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study was designed to assess the benefits and risks of steroids in people with IgAN. We report the trial design as well as the baseline characteristics of study participants. METHODS: It is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized trial of individuals with kidney biopsy-confirmed IgAN, proteinuria ≥1 g/day, and an estimated GFR of 20-120 mL/min/1.73 m2, following at least 3 months of standard of care including maximum labelled (or tolerated) dose of renin-angiotensin system blockade. The original study design randomized participants 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/day, maximum 48 mg/day) for 2 months, with subsequent weaning by 8 mg/day/month over 6-8 months, or matching placebo. The intervention was modified in 2016 (due to an excess of serious infection) to low-dose methylprednisolone (0.4 mg/kg/day, maximum 32 mg/day) for 2 months, followed by weaning by 4 mg/day/month over 6-9 months, or matching placebo. Participants recruited after 2016 also received prophylaxis against Pneumocystis jirovecii pneumonia during the first 12 weeks of treatment. RESULTS: The study recruitment period extended from May 2012 to November 2019. By the time the excess of serious infections was observed, 262 participants had been randomized to the original full-dose treatment algorithm, and an interim analysis was reported in 2016. Subsequently, 241 additional participants were randomized to a revised low-dose protocol, for a total of 503 participants from China (373), India (78), Canada (24), Australia (18), and Malaysia (10). The mean age of randomized participants was 38, 39% were female, mean eGFR at randomization was 62.7 mL/min/1.73 m2, and mean 24-h urine protein 2.54 g. The primary endpoint is a composite of 40% eGFR decline from baseline or kidney failure (dialysis, transplantation, or death due to kidney disease), and participants will be followed until the primary outcome has been observed in at least 160 randomized participants. Analyses will also be made across predefined subgroups. Effects on eGFR slope and albuminuria will also be assessed overall, as well as by the steroid dosing regimen. CONCLUSIONS: The TESTING study (combined full and low dose) will define the benefits of corticosteroid use on major kidney outcomes, as well as the risks of therapy, and provide data on the relative effects of different doses, in individuals with high-risk IgAN.

The association of microhematuria with mesangial hypercellularity, endocapillary hypercellularity, crescent score and renal outcomes in immunoglobulin A nephropathy.

BACKGROUND: Microhematuria is common in immunoglobulin A nephropathy (IgAN). However, current prognostication is based on proteinuria and mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis and crescent (MEST-C) scores. METHODS: In this retrospective study, we evaluated whether MEST-C score components are associated with the presence of microhematuria at biopsy and whether the degree of microhematuria during follow-up is associated with change in estimated glomerular filtration rate (eGFR), after adjusting for clinical and histological parameters. We identified 125 patients with biopsy-proven IgAN and MEST-C scoring who were not on immunosuppressive therapy at biopsy. Microhematuria was defined as ≥3 red blood cells (RBCs)/high-power field (hpf). RESULTS: Of the 125 patients, 97 had microhematuria at baseline and were more likely to have M1, E1 and C ≥ 1 lesions (P < 0.05 for all) compared with patients without microhematuria. Of the 125 patients, 72 had follow-up data available. An increase in the degree of microhematuria was significantly associated with an eGFR decline of -0.81 mL/min/1.73 m2 [95% confidence interval (CI) -1.44 to -0.19, P = 0.01], after adjusting for follow-up time, proteinuria and T score. Severe microhematuria (≥21 RBCs/hpf) was associated with an even larger decline in eGFR (-3.99 mL/min/1.73 m2; 95% CI -6.9411 to -1.0552, P = 0.008), after similar adjustments. CONCLUSION: Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters. Therefore, monitoring the degree of microhematuria as well as proteinuria is important when evaluating patients with IgAN. Additional studies using improvement in microhematuria as a primary surrogate outcome are needed.

Single-Nephron Glomerular Filtration Rate in Healthy Adults.

BACKGROUND: The glomerular filtration rate (GFR) assesses the function of all nephrons, and the single-nephron GFR assesses the function of individual nephrons. How the single-nephron GFR relates to demographic and clinical characteristics and kidney-biopsy findings in humans is unknown. METHODS: We identified 1388 living kidney donors at the Mayo Clinic and the Cleveland Clinic who underwent a computed tomographic (CT) scan of the kidney with the use of contrast material and an iothalamate-based measurement of the GFR during donor evaluation and who underwent a kidney biopsy at donation. The mean single-nephron GFR was calculated as the GFR divided by the number of nephrons (calculated as the cortical volume of both kidneys as assessed on CT times the biopsy-determined glomerular density). Demographic and clinical characteristics and biopsy findings were correlated with the single-nephron GFR. RESULTS: A total of 58% of the donors were women, and the mean (±SD) age of the donors was 44±12 years. The mean GFR was 115±24 ml per minute, the mean number of nephrons was 860,000±370,000 per kidney, and the mean single-nephron GFR was 80±40 nl per minute. The single-nephron GFR did not vary significantly according to age (among donors <70 years of age), sex, or height (among donors ≤190 cm tall). A higher single-nephron GFR was independently associated with larger nephrons on biopsy and more glomerulosclerosis and arteriosclerosis than would be expected for age. A higher single-nephron GFR was associated with a height of more than 190 cm, obesity, and a family history of end-stage renal disease. CONCLUSIONS: Among healthy adult kidney donors, the single-nephron GFR was fairly constant with regard to age, sex, and height (if ≤190 cm). A higher single-nephron GFR was associated with certain risk factors for chronic kidney disease and certain kidney-biopsy findings. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

A Validation of the 2018 Revision of International Society of Nephrology/Renal Pathology Society Classification for Lupus Nephritis: A Cohort Study from China.

BACKGROUND: A revision of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis has been published in 2018. The current study aimed to verify the utility of this system. MATERIALS AND METHODS: A total of 101 lupus nephritis patients from a large Chinese cohort who underwent renal biopsy in Peking University First Hospital were reevaluated by 2 renal pathologists, who had no knowledge of the clinical findings. The association between clinical data at the time of initial renal biopsy and follow-up and pathological features were further analyzed on all patients selected. RESULTS: The mean age of the cohort was 33 years with a male/female ratio of 1:9, and a median follow-up period of 128 months. The presence and extent of mesangial hypercellularity, endocapillary hypercellularity, global and segmental glomerulosclerosis, neutrophil exudation/karyorrhexis, glomerular hyaline deposits, extracapillary proliferation (crescents), tubular atrophy/interstitial fibrosis, and interstitial inflammation were significantly correlated with several clinical renal injury indices (systemic lupus erythematosus disease activity index, serum creatinine value, proteinuria, and C3 level) at the time of biopsy. By multivariable Cox hazard analysis, fibrous crescents, tubular atrophy/interstitial fibrosis, and the modified National Institutes of Health chronicity index were independent risk factors for patients' composite renal outcomes (hazard ratio [HR] 4.100 [95% CI 1.544-10.890], p = 0.005; HR 8.584 [95% CI 2.509-29.367], p = 0.001; and HR 3.218 [95% CI 1.138-9.099], p = 0.028; respectively). CONCLUSIONS: The 2018 revision of the ISN/RPS classification for lupus nephritis has utility for prediction of clinical renal outcomes.

CKD: A Call for an Age-Adapted Definition.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Evaluation of living donors: quo vadis for GFR criteria?

The evaluation of potential living donors for kidney transplantation is rigorous and is facilitated by guidelines. The assessment of glomerular filtration rate (GFR) is crucial to this process. The methods of ascertaining GFR and thresholds used for determining eligibility of donors are not uniform. Measured instead of estimated GFR, and age-adapted thresholds for GFR, may provide a better assessment of donors, yielding a higher rate of acceptance while minimizing risks of permitting donation in the presence of a reduced (for age) level of GFR.

Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach.

FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.