Ajay K. Singh, MBBS, FRCP, MBA

DocwireNews

In a recent paper, Garrisi and colleagues1 searched metadata on ClinicalTrials.gov and reported major increases in research focused on rare kidney disease (RKD). Comparing 2 periods, 2003-2012 and 2013-2022, they observed a 283% increase in observational studies and a 93% increase in interventional studies. The most frequent indications were lupus nephritis, autosomal dominant polycystic kidney disease (ADPKD), and IgA nephropathy (IgAN); all increased 77% to 166%, with proteinuria as the most frequent primary end point. 
Three important factors have had an impact on the proliferation of RKD research: (1) the elucidation of the pathophysiology of several RKDs over the past decade or so, including IgAN, membranous nephropathy, antineutrophil cytoplasmic antibody–associated vasculitis, and genetic kidney diseases such as ADPKD; (2) the 2012 founding of the American Society of Nephrology’s Kidney Health Initiative, a public-private partnership among the FDA, industry, and patient advocacy groups that enabled the FDA to accept proteinuria as a predictor of hard kidney disease outcomes; (3) increased funding from venture capital and private equity sources to fuel small biotech startups focused on RKD.  
What defines a disease as rare? In Europe, a disease is considered rare when the prevalence is less than 1 in 2,000 individuals. In the US, the designation of a rare disorder is used when fewer than 200,000 Americans are affected. The guideline group Kidney Disease: Improving Global Outcomes (KDIGO) has identified about 150 conditions under the umbrella of rare kidney disease.2 Some of the common and less common rare diseases are shown in Table 1. 
<img loading="lazy" decoding="async" class="size-full wp-image-5901644 aligncenter" src="https://mumcdnstorage.blob.core.windows.net/dwnews/2025/03/Singh-Table-1.png" alt="" width="445" height="518">
The prevalence of RKD is estimated to be 60 to 80 cases per 100,000 people in the United States and Europe.2 More than 25% of patients receiving renal replacement therapy and approximately 5% to 10% of people with chronic kidney disease (CKD) have an underlying RKD as the cause.3 
In an important contribution published in The Lancet in 2024, Wong and colleagues4 reported data from the UK National Registry of Rare Kidney Diseases (RaDaR) comprising 27,285 individuals with a median follow-up of nearly 10 years. This registry was launched in 2010 by the UK Kidney Association. In their study, Wong et al4 observed that patients with RKD differed from individuals with CKD in that they had a higher 5-year rate of kidney failure but also higher survival than other patients with stage 3-5 CKD.  
Rare kidney disease networks are emerging, such as the European Rare Kidney Disease Reference Network (ERKNet).5 The ERKNet encompasses nearly 100 pediatric and adult units across Europe that provide care for patients, online consultations, training opportunities, and a forum for guideline development. Such an elaborate network does not exist so far in the US. 
So far, trial designs have been quite traditional parallel-group randomized controlled trials (RCTs). However, rare diseases may require a different approach, and other trial designs need to be considered (see Table 2). 
<img loading="lazy" decoding="async" class="size-full wp-image-5901645 aligncenter" src="https://mumcdnstorage.blob.core.windows.net/dwnews/2025/03/Singh-Table-2.png" alt="" width="447" height="564">
Borrowing conceptually from oncology, 3 interesting trial designs are also likely to emerge for RKD studies: basket trials, umbrella trials, and platform trials.6 In a basket trial, a targeted therapy is evaluated for multiple diseases that share molecular alternations. Umbrella trials evaluate multiple targeted therapies for a single disease that is stratified into subgroups by molecular alternation. Platform trials (multi-arm, multistage design trials) evaluate several interventions against a common control group.  
In addition to trial design, the other major issue for RKD research is the lack of biomarkers to provide an early signal for efficacy. Biomarkers allow early assessment of success or allow for programs to “fail fast” if a favorable effect is not demonstrated. Although the diagnosis of acute kidney injury (AKI) has benefitted from the development of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin to predict AKI early, biomarkers for glomerular injury have proven elusive. Essentially, a reduction in proteinuria and a change in estimated glomerular filtration rate remain the biomarkers of choice.  
The next decade is likely to see many new therapies with innovative approaches. Biomarker panels evaluating efficacy are also likely to emerge. A bright future lies ahead. Quoting Thomas Jefferson, “I like the dreams of the future better than the history of the past.”
<h3>References</h3>
<ol>
<li>Garrisi D, Bevan A, Angeles C. Advancing treatments for rare renal diseases: new hopes and opportunities to address a high unmet need. Glomerular Dis. 2023;4(1):11-18. doi:10.1159/000535955</li>
<li>Aymé S, Bockenhauer D, Day S, et al. Common elements in rare kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int. 2017;92(4):796-808. doi:10.1016/j.kint.2017.06.018. Erratum in: Kidney Int. 2017;92(6):1558. doi:10.1016/j.kint.2017.10.004</li>
<li>Aiyegbusi OL, Fenton A. The impact of rare kidney diseases on kidney failure. Lancet. 024;403(10433):1211-1213. doi:10.1016/S0140-6736(24)00198-3</li>
<li>Wong K, Pitcher D, Braddon F, et al. Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort. Lancet. 2024;403(10433):1279-1289. doi:10.1016/S0140-6736(23)02843-X</li>
<li>Wlodkowski T, Haeberle S, Schaefer F. Das Europäische Referenznetzwerk für seltene Nierenerkrankungen (ERKNet) [The European Rare Kidney Disease Reference Network]. Inn Med (Heidelb). 2024;65(12):1283-1292.</li>
<li>Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20(1):572. doi:10.1186/s13063-019-3664-1</li>
</ol>
The opinions expressed in this column are the contributor’s own and do not represent those of Nephrology Times.

In a recent paper, Garrisi and colleagues1 searched metadata on ClinicalTrials.gov and reported major increases in research focused on rare kidney disease (RKD). Comparing 2 periods, 2003-2012 and 2013-2022, they observed a 283% increase in observational studies and a 93% increase in interventional studies. The most frequent indications were lupus nephritis, autosomal dominant polycystic kidney disease (ADPKD), and IgA nephropathy (IgAN); all increased 77% to 166%, with proteinuria as the most frequent primary end point. Three important factors have had an impact on the proliferation of RKD research: (1) the elucidation of the pathophysiology of several RKDs over the past decade or so, including IgAN, membranous nephropathy, antineutrophil cytoplasmic antibody–associated vasculitis, and genetic kidney diseases such as ADPKD; (2) the 2012 founding of the American Society of Nephrology’s Kidney Health Initiative, a public-private partnership among the FDA, industry, and patient advocacy groups that enabled the FDA to accept proteinuria as a predictor of hard kidney disease outcomes; (3) increased funding from venture capital and private equity sources to fuel small biotech startups focused on RKD.  What defines a disease as rare? In Europe, a disease is considered rare when the prevalence is less than 1 in 2,000 individuals. In the US, the designation of a rare disorder is used when fewer than 200,000 Americans are affected. The guideline group Kidney Disease: Improving Global Outcomes (KDIGO) has identified about 150 conditions under the umbrella of rare kidney disease.2 Some of the common and less common rare diseases are shown in Table 1. <img loading="lazy" decoding="async" class="size-full wp-image-5901644 aligncenter" src="https://mumcdnstorage.blob.core.windows.net/dwnews/2025/03/Singh-Table-1.png" alt="" width="445" height="518">The prevalence of RKD is estimated to be 60 to 80 cases per 100,000 people in the United States and Europe.2 More than 25% of patients receiving renal replacement therapy and approximately 5% to 10% of people with chronic kidney disease (CKD) have an underlying RKD as the cause.3 In an important contribution published in The Lancet in 2024, Wong and colleagues4 reported data from the UK National Registry of Rare Kidney Diseases (RaDaR) comprising 27,285 individuals with a median follow-up of nearly 10 years. This registry was launched in 2010 by the UK Kidney Association. In their study, Wong et al4 observed that patients with RKD differed from individuals with CKD in that they had a higher 5-year rate of kidney failure but also higher survival than other patients with stage 3-5 CKD.  Rare kidney disease networks are emerging, such as the European Rare Kidney Disease Reference Network (ERKNet).5 The ERKNet encompasses nearly 100 pediatric and adult units across Europe that provide care for patients, online consultations, training opportunities, and a forum for guideline development. Such an elaborate network does not exist so far in the US. So far, trial designs have been quite traditional parallel-group randomized controlled trials (RCTs). However, rare diseases may require a different approach, and other trial designs need to be considered (see Table 2). <img loading="lazy" decoding="async" class="size-full wp-image-5901645 aligncenter" src="https://mumcdnstorage.blob.core.windows.net/dwnews/2025/03/Singh-Table-2.png" alt="" width="447" height="564">Borrowing conceptually from oncology, 3 interesting trial designs are also likely to emerge for RKD studies: basket trials, umbrella trials, and platform trials.6 In a basket trial, a targeted therapy is evaluated for multiple diseases that share molecular alternations. Umbrella trials evaluate multiple targeted therapies for a single disease that is stratified into subgroups by molecular alternation. Platform trials (multi-arm, multistage design trials) evaluate several interventions against a common control group.  In addition to trial design, the other major issue for RKD research is the lack of biomarkers to provide an early signal for efficacy. Biomarkers allow early assessment of success or allow for programs to “fail fast” if a favorable effect is not demonstrated. Although the diagnosis of acute kidney injury (AKI) has benefitted from the development of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin to predict AKI early, biomarkers for glomerular injury have proven elusive. Essentially, a reduction in proteinuria and a change in estimated glomerular filtration rate remain the biomarkers of choice.  The next decade is likely to see many new therapies with innovative approaches. Biomarker panels evaluating efficacy are also likely to emerge. A bright future lies ahead. Quoting Thomas Jefferson, “I like the dreams of the future better than the history of the past.”<h3>References</h3><ol>
<li>Garrisi D, Bevan A, Angeles C. Advancing treatments for rare renal diseases: new hopes and opportunities to address a high unmet need. Glomerular Dis. 2023;4(1):11-18. doi:10.1159/000535955</li>
<li>Aymé S, Bockenhauer D, Day S, et al. Common elements in rare kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int. 2017;92(4):796-808. doi:10.1016/j.kint.2017.06.018. Erratum in: Kidney Int. 2017;92(6):1558. doi:10.1016/j.kint.2017.10.004</li>
<li>Aiyegbusi OL, Fenton A. The impact of rare kidney diseases on kidney failure. Lancet. 024;403(10433):1211-1213. doi:10.1016/S0140-6736(24)00198-3</li>
<li>Wong K, Pitcher D, Braddon F, et al. Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort. Lancet. 2024;403(10433):1279-1289. doi:10.1016/S0140-6736(23)02843-X</li>
<li>Wlodkowski T, Haeberle S, Schaefer F. Das Europäische Referenznetzwerk für seltene Nierenerkrankungen (ERKNet) [The European Rare Kidney Disease Reference Network]. Inn Med (Heidelb). 2024;65(12):1283-1292.</li>
<li>Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20(1):572. doi:10.1186/s13063-019-3664-1</li>
</ol>The opinions expressed in this column are the contributor’s own and do not represent those of Nephrology Times.