Kidney Failure, Mortality With Rare Kidney Diseases Versus CKD

Patients with rare kidney diseases account for only 5% to 10% of those with chronic kidney disease (CKD). However, they comprise more than 25% of patients receiving kidney replacement therapy (KRT). In addition, more than 50% of children and adults younger than 20 years receiving KRT have a rare kidney disease. Glomerulonephritis accounts for more UK adults receiving KRT than any common causes of CKD, including diabetes.

The reasons for this are poorly understood, and having more insight into these questions may help with prognosis and therapies. To help address this need for information, Katie Wong, MBBS, and colleagues conducted a retrospective cohort study using data from the National Registry of Rare Kidney Diseases (RaDaR), established by the UK Kidney Association. Their findings were published in The Lancet [2024;403:1279–89].

Data spanned from January 18, 2010, to July 25, 2022, and included 27,285 patients aged 0 to 96 with 28 rare kidney diseases from 108 UK renal care facilities. The median age at diagnosis for the entire RaDaR cohort was 40.6 years (interquartile range [IQR] 23.7-57.1). However, the median age varied by rare disease group. Follow-up was calculated as the time from the date of diagnosis until the data extraction date (July 25, 2022) or until death, whichever came first; median follow-up from diagnosis was 9.6 years (IQR 5.9-16.7).

The exposure being investigated was a diagnosis of rare kidney disease. Primary outcomes included cumulative incidence of mortality and kidney failure in patients with rare kidney diseases, which was calculated and compared with that of unselected patients with CKD.

Kidney failure was defined as the need for chronic KRT (dialysis or transplantation), or an estimated glomerular filtration rate (eGFR) of less than 15 mL/min per 1.73 m² for 4 weeks or more. Secondary outcomes included median age at kidney failure, median age at death, and time from start of dialysis to death. Another secondary outcome was time from diagnosis to eGFR thresholds, which allowed for calculation of time from the last eGFR of 75 mL/min per 1.73 m² or more to the first eGFR of less than 30 mL/min per 1.73 m² (the therapeutic trial window, an estimate of time from diagnosis that patients would have sufficient renal function to participate in a standard therapeutic trial).

The participants with rare kidney diseases differed significantly from individuals with CKD regarding both kidney failure and mortality. Those with rare kidney diseases had higher five-year rates of kidney failure (28% vs 1%; P<.0001), although there was significant heterogeneity in age at kidney failure among rare disease groups. For example, patients with cystinosis often reached kidney failure as children (median age at kidney failure 15.4 years; IQR 11.6-19.9), while those with vasculitis, HNF1B mutations, thin basement membrane nephropathy, monoclonal gammopathy of renal significance, and membranous nephropathy usually reached kidney failure at ≥65 years. Sensitivity analyses for age at kidney failure and time from diagnosis with death as a competing risk had similar findings.

Survival was higher among those with rare kidney diseases versus those with CKD stages 3-5 (standardized mortality ratio 0.42; 95% CI, 0.32-0.52; P<.0001). Survival on dialysis was also longer for those with rare kidney diseases. Therefore, patients with rare kidney diseases represent a disproportionate number of those receiving KRT.

The median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window varied significantly among rare kidney diseases. Median age at death was either not evaluable due to too few events or >75 years for all rare disease groups. The exception was cystinosis, with a median age at death of 56.4 years.

Notably, disease progression was faster among those with rare kidney diseases than unselected patients with CKD. In patients younger than 65 years, the kidney failure risk equation did not accurately predict disease trajectory. The heterogeneous outcomes among rare kidney diseases highlight
the need for precise diagnosis, which helps to inform treatment decisions and may provide important prognostic information.

The authors acknowledge limitations of the study: The UK focus of the data may not be more broadly generalizable. Recruitment criteria for certain rare disease groups may favor the ascertainment of patients with more severe disease. Data for age at death are limited by length of follow-up and survivor bias. Comparisons of intervals between diagnosis and kidney failure among different diseases may not always be meaningful, as different rare diseases occur at different ages. Biases may be present in some estimates due to the absence of healthy or unselected CKD control groups.

“In unselected cohorts with chronic kidney disease, death before kidney failure is a common adverse outcome, whereas among patients with rare kidney diseases, survival is higher and kidney failure much more common,” the authors summarized. “This finding means that, although strategies to address cardiovascular risk and other causes of death are very important in the large number of individuals with [CKD] in the population, a substantial proportion of kidney failure is attributable to individually rare kidney diseases in which cardiovascular risk reduction will not prevent kidney failure. Patients with rare kidney diseases should therefore be distinguished from those with more common causes of [CKD, emphasizing] the importance of early specialist referral and diagnosis, and the need for rare kidney disease-specific treatments aimed at delaying progression to kidney failure.”