Precision Nephrology: Understanding Kidney Injury to Bring the Right Drug to the Right Person

Ravi I. Thadhani, MD, MPH • Opeyemi A. Olabisi, MD, PhD

Precision medicine requires properly recognizing the “right patient,” having the “right drugs,” and knowing the right time to apply them.1 A prerequisite for precision nephrology is a deep understanding of the mechanism(s) of kidney injury and a precise means to diagnose the injury. Kidney injury is a heterogeneous condition. Adequate diagnosis requires knowledge of the injured kidney cell types, the underlying causal mechanisms and temporal course involved, and knowledge about the injury’s reversibility. All currently remain hurdles that must be successfully crossed for precision nephrology to become a reality.

Currently, kidney injury is classified by its temporal course as acute kidney injury (AKI) or chronic kidney disease (CKD).2,3 Uniformity, not precision, is the goal of these clinical diagnostic criteria, which provide a standard approach to clinically diagnosing and staging severity of kidney injury based on serum creatinine, proteinuria, and urine output. These measures are indifferent to the precise mechanisms involved. 

Kidney injury results in reduction in glomerular filtration rate (GFR). However, adaptation by non-injured nephrons could partially compensate for reduced GFR. Therefore, GFR may not reflect the true extent of kidney injury. Moreover, loss of GFR is a late marker of kidney injury, and a reduction in GFR by one mechanism can have a different outcome than a reduction by a different mechanism of injury. Consequently, these limitations preclude advances in precision nephrology.

THE RIGHT PATIENT

Cellular biomarkers of kidney injury temporally precede clinical biomarkers (e.g., serum creatinine, proteinuria). Therefore, cell-based biomarkers have the potential to uncover early injury and the underlying mechanisms involved. For example, analysis of glomerular cells of individuals with diabetic kidney disease (DKD) implicated upregulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway as a key step in DKD pathogenesis.4 Follow-up studies confirmed that JAK-STAT upregulation in podocytes plays a causal role in DKD progression and that inhibition of this pathway reduced albuminuria in individuals with DKD.5,6 Molecular biomarkers aid early diagnosis, identify underlying mechanisms, and suggest targets for pharmacologic therapies.

Furthermore, single-cell RNA sequencing (scRNA-seq) enables profiling of whole transcriptome of thousands of cells, thereby providing information at a single-cell level on what genes are expressed, in what quantities, and how the gene expression profile of one kidney cell type compares across thousands of other kidney cells. Single-cell assay for transposase accessible chromatin (ATAC-seq), in contrast, provides genome-wide profiling of chromatin states, revealing which chromatin regions are open and assessable to transcription factors. Therefore, a combination of scRNA-seq and scATAC-seq could reveal the identity of kidney cells and genes involved in kidney injury. A recent scRNA-seq analysis found that cell type–specific changes in gene expression impacting ion transport, angiogenesis, and immune activation are early manifestations of DKD.7 These gene expression changes may be leveraged as early biomarkers of DKD.  The promise of these technologies is currently not realized because of the high cost of acquiring this information and the enormous bioinformatic analytics required to uncover meaningful results. 

THE RIGHT DRUG

Development and use of the right drug is the second goal of precision medicine. There are no known safe and effective drugs targeting AKI. Until the recent discovery of the efficacy of sodium glucose co-transporter 2 inhibitors (SGLT-2i), there had not been a major new drug for CKD in decades. While multiple reasons underlie the AKI and CKD “drug drought,” poor fidelity of model organisms in capturing important aspects of human kidney injury has been a limitation. Rodent models have their limitations: a recent scRNA-seq comparison of mouse and human glomeruli discovered remarkable species differences in gene expression profiles of defined glomerular cell types, questioning the suitability and translatability of mouse models of human glomerular injury.8

Human induced pluripotent stem cell (iPSC)-derived kidney organoids offer promising new ways to model human kidney diseases. Because iPSCs retain the genomic endowment of the individual, they are more likely to capture salient attributes that may be relevant for the person’s susceptibility to disease, mechanism of injury, and response to specific therapies. Kidney organoids are particularly suitable for modeling diseases that originate from polymorphic human genes, which are absent in model organisms. 

Carriage of two variants (G1 & G2) of the APOL1 gene is strongly associated with increased incidence and rapid progression of APOL1 nephropathy including COVID-19–associated nephropathy.9,10,11,12 APOL1 variants explain approximately 70 percent of excess risk of non-diabetic kidney disease among African Americans, who constitute more than 35 percent of the ESKD population. The molecular mechanism of APOL1 nephropathy remains unknown. The APOL1 gene is naturally absent in all experimental animals, limiting their use to model APOL1 nephropathy. Patient kidney organoids, especially when combined with next-generation sequencing technologies, have the potential to illuminate the molecular pathomechanism of APOL1 nephropathy, leading to the discovery of pharmacologic targets and reducing racial kidney health disparities (Figure 1). 

FIGURE 1  |  Patient iPSC-derived kidney organoid captures an individual’s unique genetic identity. Thefigure outlines how the technology could be applied specifically to APOL1-nephropathy.

Another kidney disease that is likely to benefit early from human kidney organoid models is polycystic kidney disease (PKD). Kidney organoids from individuals with PKD develop large cysts that mimic kidney cysts seen in people with PKD, indicating that such organoids may be the ideal tool for drug discovery.13,14 

Precision medicine, however, did not yield SGLT-2i, which has dramatically improved CKD management. Therefore, why advocate for this cumbersome, costly  approach? Because unlike in oncology, where precision medicine frequently guides drug discovery, the success rate of drug discovery in nephrology is abysmal. There has been over a 30-year gap between the approval of ACE inhibitors and recent approval of SGLT-2i for slowing CKD progression. At this rate, the next breakthrough kidney drug will be approved in 2050, after three million new people will have reached dialysis in the US alone. 

Patient-derived kidney organoids may help accelerate the discovery of therapeutic targets and more efficiently identify potential toxicities of candidate drugs. Nephrology writ large is being transformed by a deeper understanding of biology, genetics, and novel technologies, all poised to set the stage for improving the understanding and treatment of kidney injury.

Meet The Experts

References

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