209Organoids transplanted under the renal capsule of immunocompromised mice or
rats show host-derived vascularisation in their glomeruli (Xinaris et al. 2012 ;
Sharmin et al. 2016 ). Mice with transplanted organoids may serve as ‘humanised’
in vivo models that combine the advantages of in vivo tests (e.g. detecting poten-
tially toxic drug metabolites) with the advantages of screening for injury to human
instead of animal kidney tissue. If transplanted, organoids can be developed with
sufficiently mature vascular function and filtrate production. These may also be able
to detect disruptions to vascular function or drug-induced nephrolithiasis, which are
also common mechanisms of nephrotoxicity.
11.4.3 Kidney Organoids as Models of Disease
The modelling of heritable kidney disease via the generation of kidney organoids
from patient-derived iPSC represents another tractable application of this technol-
ogy (Fig. 11.4). In the past, the phenotypic validation of novel genetic mutations has
relied on the generation of murine disease models (Becker and Hewitson 2013 ).
This previously laborious and time-inefficient model has been optimised to a much
faster and more genetically precise process using CRISPR/Cas9 technology (Yang
et al. 2013 ). However, the differences between mouse and human kidney develop-
ment, both at the anatomical and molecular levels, represent a significant limitation
of murine models of human kidney disease. The proposed advantages of patient-
derived iPSC-based disease modelling include the opportunity to produce limitless
amounts of differentiated renal tissue expressing the gene of interest in the context
of the patient’s own genome, acknowledging the possibility of polygenic contribu-
tion to phenotype and obviating the risk and difficulty of procuring and culturing
primary tissue. Gene-editing techniques can be introduced to an iPSC line during
reprogramming to generate an otherwise isogenic control line (Howden et al. 2015 ).
Advances in diagnostic genomics is facilitating the identification of mutations in
affected patients; however even in those instances where a gene defect is not identi-
fied, organoid creation provides an opportunity to characterise the disease processes
at the cellular level and develop personalised treatments.
iPSC-derived kidney organoids represent models of the developing organ. As
such, a group of kidney diseases most amenable to disease modelling with iPSC
techniques are the early-onset, monogenic, heritable kidney diseases, which repre-
sent up to 20% of adults and 47% of children with chronic kidney disease
(Hildebrandt 2010 ; Fletcher et al. 2013 ; Mallett et al. 2014 ; Devuyst et al. 2014 ). To
date, iPSCs have been derived and validated from patients with autosomal dominant
(ADPKD) (Thatava et al. 2011 ; Wang et al. 2013 ; Freedman et al. 2013 , 2015 ),
autosomal recessive polycystic kidney disease (ARPKD) (Freedman et al. 2013 ),
Alport syndrome (Chen et al. 2015b), Wilms’ tumour (Thatava et al. 2011 ) and sys-
temic lupus erythematosus (Thatava et al. 2011 ). hESCs have been generated from
human embryos with Alport syndrome (Frumkin et al. 2010 ) and Fabry disease
(Tropel et al. 2010 ) identified during preimplantation genetic screening. Xia et al.
( 2013 ) differentiated iPSC from a patient with ADPKD to ureteric bud but did not
11 Recapitulating Development to Generate Kidney Organoid Cultures