CASR encodes for the calcium-sensing receptor (CaSR), which is important in renal calcium homeostasis and expressed in the parathyroid gland and the kidney in the thick ascending loop of Henle (TAL) basolateral membrane (Figure 1), the PT, the distal convoluted tubule (DCT), and the CD (Brown and MacLeod, 2001). In the TAL, activation of CaSR by calcium inhibits NaCl reabsorption by inhibiting NKCC2 and ROMK (Gamba and Friedman, 2009). By inhibiting ROMK, the tubular lumen positive voltage is diminished, reducing the driving force for paracellular cation (including calcium) reabsorption (Gamba and Friedman, 2009).

AD hypocalcemia/AD hypocalcemia with Bartter syndrome (OMIM phenotype number 601198) is a condition resulting from activating variants in CASR, which increase the sensitivity of CaSR to extracellular calcium (Brown and MacLeod, 2001). Activation of CaSR in the parathyroid gland leads to inhibition of parathyroid hormone (PTH) release and subsequent hypoparathyroidism (Brown and MacLeod, 2001). Reduced PTH release leads to decreased calcium and phosphorus resorption in the bone (Brown and MacLeod, 2001). In the kidney, reduced PTH leads to decreased TAL and DCT reabsorption of calcium, increased reabsorption of phosphorus, and decreased production of 1,25-dihydroxyvitamin D3, leading to decreased absorption of calcium in the intestine (Brown and MacLeod, 2001). All of the above culminates in hypocalcemia, hypercalciuria, NC, and NL (Pearce et al., 1996). Some may have features of Bartter syndrome such as impaired sodium chloride reabsorption in the TAL, hypokalemic metabolic alkalosis, hyperreninemia and/or hyperaldosteronism (Vargas-Poussou et al., 2002). Treatment with minimal doses of calcium and vitamin D administration may be given to alleviate symptoms, but excess can exacerbate hypercalciuria, NC, and lead to kidney impairment (Pearce et al., 1996).

Neonatal hyperparathyroidism (OMIM phenotype number 239200) is an AD/AR condition resulting from inactivating variants in CASR that decrease the sensitivity of CaSR to extracellular calcium (Brown and MacLeod, 2001). Inactivation of CaSR in the parathyroid gland leads to stimulation of PTH release and subsequent hyperparathyroidism (Lila et al., 2012; El Allali et al., 2021). Increased PTH release leads to increased calcium and phosphorus resorption in the bone (Lila et al., 2012; El Allali et al., 2021). In the kidney, increased PTH leads to increased tubular reabsorption of calcium, decreased reabsorption of phosphorus, and increased production of 1,25-dihydroxyvitamin D3, leading to increased absorption of calcium in the intestine (Lila et al., 2012; El Allali et al., 2021). This culminates in severe hypercalcemia, NC, and NL (Lila et al., 2012; El Allali et al., 2021). Calcimimetic medications may be given treat this condition by increasing sensitivity of CaSR to extracellular calcium (El Allali et al., 2021).

Hypocalciuric hypercalcemia type 1 (OMIM phenotype number 145980) is an AD condition resulting from an inactivating variant in CASR, resulting in lifelong mild to moderate hypercalcemia, inappropriate hypocalciuria, and normal PTH to mild hyperparathyroidism (Carling et al., 2000). This condition may also have atypical presentations with severe hypercalcemia and hypercalciuria with or without NL or NC (Carling et al., 2000).

CYP24A1 encodes for cytochrome P450 family 24 subfamily A member 1 or 1,25-dihydroxyvitamin D3 24-hydroxylase, the enzyme primarily responsible for the catabolism of 1,25-dihydroxy- and 25-hydroxy-vitamin D, which is expressed in the PT (Schlingmann et al., 2011). Infantile hypercalcemia 1 (OMIM phenotype number 143880) is an AR condition resulting from an inactivating variant in CYP24A1, resulting in accumulation of 1,25-dihydroxyvitamin D3 (Schlingmann et al., 2011). This accumulation leads to severe hypercalcemia, failure to thrive, vomiting, dehydration, NC, and NL (Schlingmann et al., 2011). Data suggests that carriers (heterozygotes) of inactivating variants in CYP24A1 may have increased risk of NC and NL (Carpenter, 2017).

For treatment of Infantile hypercalcemia 1, generous hydration and a diet low in vitamin D and calcium are suggested (Schlingmann et al., 2011). CYP3A4 inducers (rifampin) or CYP27B1 modulators (fluconazole/ketoconazole/itraconazole) may help reduce 1,25-dihydroxyvitamin D3 levels and improve hypercalcemia and hypercalciuria (Sayers et al., 2015; Hawkes et al., 2017). Low doses of these medications are suggested, but the long-term safety is uncertain.

SLC34A1 encodes for the solute carrier family 34 member 1, the sodium-dependent phosphate transport protein 2a (NPT2a), which responsible for the majority of renal phosphate transport and is primarily expressed in the PT (Figure 1) (Schlingmann et al., 2016). Fanconi renotubular syndrome 2 (OMIM phenotype number 613388) is one of the conditions caused by homozygous variants in SLC34A1 but will not be discussed in this review as this condition has not been associated with NL or NC.

Infantile hypercalcemia 2 (OMIM phenotype number 616963) is an AR condition due to inactivating variants in SLC34A1, resulting in loss of NPT2a activity and subsequent renal phosphorus wasting with hypophosphatemia (Schlingmann et al., 2016). This hypophosphatemia results in increased production of 1,25-dihydroxyvitmain D3 with hypercalcemia, hypercalciuria, failure to thrive, vomiting, dehydration, and NC (Schlingmann et al., 2016). In addition to phosphate supplementation, generous hydration and a diet low in vitamin D and calcium are also suggested (Schlingmann et al., 2016). CYP3A4 inducers (rifampin) or CYP27B1 modulators (fluconazole/ketoconazole/itraconazole) may help reduce 1,25-dihydroxyvitamin D3 levels and improve hypercalcemia and hypercalciuria (Sayers et al., 2015; Hawkes et al., 2017). Low doses of these medications are suggested, but the long-term safety is uncertain.

Hypophosphatemic NL/osteoporosis 1 (OMIM phenotype number 612286) is an AD condition due to an inactivating variant in SLC34A1, resulting in loss of NPT2a activity and subsequent renal phosphorus wasting with hypophosphatemia (Prié et al., 2002). This hypophosphatemia results in increased production of 1,25-dihydroxyvitmain D3 with hypercalciuria, osteoporosis, and recurrent NL (Prié et al., 2002).

SLC34A3 encodes for the solute carrier family 34 member 3, the sodium-dependent phosphate transport protein 2c (NPT2c) which is primarily expressed in the PT (Figure 1) (Bergwitz et al., 2006). Hypophosphatemic rickets with hypercalciuria (OMIM phenotype number 241530) is an AR condition due to inactivating variants in SLC34A3, resulting in loss of NPT2c activity and subsequent renal phosphorus wasting with hypophosphatemia (Bergwitz et al., 2006). This hypophosphatemia results in increased production of 1,25-dihydroxyvitmain D3 with hypercalcemia, hypercalciuria, rickets, muscle weakness, bone pain, NL, and NC (Bergwitz et al., 2006). Data suggests that carriers (heterozygotes) of inactivating variants in SLC34A3 may have increased risk of NL, NC, hypercalciuria, and hypophosphatemia (Dasgupta et al., 2014).

SLC9A3R1 encodes for the solute carrier family 9 member 3 regulator 1/sodium/hydrogen exchange regulatory factor 1 (NHERF1), which is primarily expressed in the PT (Figure 1) (Karim et al., 2008; Courbebaisse et al., 2012). Hypophosphatemic NL/osteoporosis 2 (OMIM phenotype number 612287) is an AD condition due to an inactivating variant in SLC9A3R1, resulting in loss of NHERF1 activity with subsequent decrease in NPT2a expression, resulting in renal phosphorus wasting with hypophosphatemia (Courbebaisse et al., 2012). This subsequently results in increased production of 1,25-dihydroxyvitmain D3 with hypercalciuria, osteoporosis, and recurrent NL (Prié et al., 2002).

CLDN16 encodes for Claudin 16 or paracellin-1, which is an integral membrane tight junction protein necessary for paracellular reabsorption of calcium and magnesium (Godron et al., 2012). CLDN16 is expressed in the TAL and DCT (Figure 1). Renal hypomagnesemia 3 (OMIM phenotype number 248250) is an AR condition due to inactivating variants in CLDN16, resulting reduced reabsorption of calcium (hypercalciuria)and magnesium (hypermagnesuria) with hypomagnesemia, NC, NL, and progressive CKD (Godron et al., 2012). Data suggests that carriers (heterozygotes) of inactivating variants in CLDN16 may have hypercalciuria and NL (Deeb et al., 2013).

Medical management of Renal hypomagnesemia 3 typically involves high-dose magnesium supplementation to replace renal losses, although this has not been shown to slow progression of CKD (Weber et al., 2001; Godron et al., 2012). Thiazide diuretics and indomethacin have been used in this condition but have not been shown to be successful in reducing hypercalciuria or hypermagnesuria or preventing progression of CKD (Weber et al., 2001; Godron et al., 2012). Definitive treatment can be achieved with kidney transplantation (Weber et al., 2001).

CLDN19 encodes for Claudin 19, which is an integral membrane tight junction protein necessary for paracellular reabsorption of calcium and magnesium (Godron et al., 2012). CLDN19 is expressed in the TAL and DCT (Figure 1). Renal hypomagnesemia 5 with ocular involvement (OMIM phenotype number 248190) is an AR condition due to inactivating variants in CLDN19, resulting reduced reabsorption of calcium (hypercalciuria) and magnesium (hypermagnesuria)with hypomagnesemia, visual impairment, NC, NL, and progressive CKD (Godron et al., 2012). Data suggests that carriers (heterozygotes) of inactivating variants in CLDN16 may have NL (Naeem et al., 2011). Medical management of Renal hypomagnesemia 5 with ocular involvement and its efficacy are typically the same as that for Renal hypomagnesemia 3 caused by variants in CLDN16 (Weber et al., 2001; Godron et al., 2012).

RRAGD encodes for Ras related GTP binding D, which is expressed in the TAL and DCT (Schlingmann et al., 2021). Renal hypomagnesemia 7 with or without dilated cardiomyopathy (OMIM phenotype number 620152) is an AD condition due to an inactivating variant in RRAGD, resulting in activation of mTOR signaling, which leads to renal salt wasting resulting in hypomagnesemia, polyuria, hypokalemia, hypochloremia, metabolic alkalosis, hypercalciuria, and NC (Schlingmann et al., 2021). This condition is not typically associated with CKD, and some individuals develop severe dilated cardiomyopathy (Schlingmann et al., 2021). Optimal treatment strategy is unclear.

ATP6V0A4 encodes for V-ATPase H+ transporting V0 subunit A4, which excretes protons into the urine and is expressed in the alpha-IC of the CD (Figure 1) (Karet, 2002). Distal RTA type 3 with or without sensorineural hearing loss (OMIM phenotype number 602722) is an AR condition due to inactivating variants in ATP6V0A4, resulting in decreased urinary proton excretion, which leads to a distal RTA usually accompanied by NC and/or NL as well later-onset sensorineural deafness in >30% (Karet, 2002; Lopez-Garcia et al., 2019). Data suggests that carriers (heterozygotes) of inactivating variants in ATP6V0A4 may have an incomplete distal RTA associated with NC (Imai et al., 2016).

ATP6V1B1 encodes for V-ATPase H+ transporting V1 subunit B1, which excretes protons into the urine and is expressed in the alpha-IC of the CD (Figure 1) (Karet, 2002). Distal RTA type 2 with progressive sensorineural hearing loss (OMIM phenotype number 267300) is an AR condition due to inactivating variants in ATP6V1B1, resulting in decreased urinary proton excretion, which leads to a distal RTA usually accompanied by NC and/or NL as well early-onset sensorineural deafness in most (Lopez-Garcia et al., 2019). Data suggests that carriers (heterozygotes) of inactivating variants in ATP6VAB1 may have an incomplete distal RTA associated with recurrent NL (Dhayat et al., 2016).

ATP6V1C2 encodes for V-ATPase H+ transporting V1 subunit C2, which excretes protons into the urine and is expressed in the alpha-IC of the CD (Figure 1) (Jobst-Schwan et al., 2020). ATP6V1C2-associated distal RTA is an AR condition due to inactivating variants in ATP6V1C2, resulting in decreased urinary proton excretion, which leads to a distal RTA that is likely associated with NC and/or NL and with early ESKD (Jobst-Schwan et al., 2020).

SLC4A1 encodes for the basolateral chloride bicarbonate counter transporter anion exchange protein 1 (AE1), which reabsorbs bicarbonate from the urine into the circulation and is expressed in the alpha-IC of the CD (Figure 1) (Karet, 2002). Distal RTA 1 (OMIM phenotype number 179800) is an AD condition due to an inactivating variant in SLC4A1, resulting in decreased urinary bicarbonate reabsorption, which leads to a distal RTA usually accompanied by NC and NL (Karet, 2002; Lopez-Garcia et al., 2019). Distal RTA 4 with hemolytic anemia (OMIM phenotype number 611590) is an AR condition due to inactivating variants in SLC4A1, resulting in decreased urinary bicarbonate reabsorption, which leads to a distal RTA with hemolytic anemia and NC. (Sritippayawan et al., 2004; Lopez-Garcia et al., 2019).

FOXI1 encodes for Forkhead box I1, which is a transcription factor that regulates the function of AE1, AE4, and V-ATPase subunits, and is expressed in the alpha-IC of the CD (Figure 1) (Enerbäck et al., 2018). Distal RTA and early-onset deafness is an AR condition due to inactivating variants in FOXI1, resulting in decreased urinary bicarbonate reabsorption, which leads to a distal RTA with early-onset sensorineural deafness and NC (Enerbäck et al., 2018).

CLCN5 encodes for chloride voltage-gated channel 5 (CLC5), a chloride/proton exchanger, and is expressed in the PT (Figure 1), alpha-IC, and TAL (Mansour-Hendili et al., 2015). Inactivating variants in CLCN5 appear to cause abnormal reabsorption of LMW proteins by disrupting PT vesicle acidification, impacting lysosome function and LMW protein processing (Nielsen et al., 2016). Inactivating variants in CLCN5 are associated with a spectrum of conditions (Claverie-Martín et al., 2011).

Dent disease 1 (OMIM phenotype number 300009) is an XLR condition resulting from inactivating variants in CLCN5. Hallmark features are progressive proximal renal tubulopathy with LMW proteinuria, hypercalciuria, NC, NL, and progressive ESKD (Claverie-Martín et al., 2011). Median age at ESKD onset has been reported as 40 years of age (Blanchard et al., 2016). Treatment is aimed at treating serum electrolyte disturbances (such as treating hypophosphatemia with phosphorus supplementation) and minimizing hypercalciuria, primarily with hydration and administration of thiazide diuretics. However, the administration thiazide diuretics to reduce hypercalciuria is controversial as there is no definite correlation between hypercalciuria and ESKD, and significant side effects have been reported including dehydration and hypokalemia (Blanchard et al., 2008). Kidney transplantation has been successful in these patients without recurrence of NL or NC (Scheinman, 1998). Due to the risk of worsening hypercalciuria with vitamin D supplementation, it should be reserved for patients who require it for treatment of rickets.

NL type 1 (OMIM phenotype number 310468) is an XLR condition resulting from inactivating variants in CLCN5. Hypophosphatemic rickets (OMIM phenotype number 300554) is an XLR condition resulting from inactivating variants in CLCN5. It is characterized by progressive proximal renal tubulopathy with LMW proteinuria, rickets or osteomalacia, hypophosphatemia, hypercalciuria, NC, NL, and progressive ESKD (Bolino et al., 1993). LMW proteinuria with hypercalciuric NC (OMIM phenotype number 308990) is an XLR condition resulting from inactivating variants in CLCN5. The presentation of LMW proteinuria with hypercalciuric NC resembles that of the conditions mentioned above, except that these individuals do not experience progressive ESKD (Igarashi et al., 1995). Although these three conditions have different OMIM phenotype numbers, it is unclear if they are truly separate conditions from Dent disease 1 as the spectrum of presenting symptoms are the same (Frymoyer et al., 1991). Data suggests that female carriers of inactivating variants in CLCN5 may have mild symptoms of Dent disease such as low-molecular-weight proteinuria, and hypercalciuria with few reported cases of NL and kidney insufficiency (Hoopes et al., 1998).

OCRL encodes for inositol polyphosphate-5-phosphatase, which is thought to be important in endocytosis and cellular trafficking and is expressed throughout the body, including in the glomerulus, PT (Figure 1), TAL, DCT, and CD (Claverie-Martín et al., 2011). Inactivating variants in OCRL appear to cause abnormal protein trafficking required for PT solute reabsorption (Ooms et al., 2009). Inactivating variants in OCRL are associated with a spectrum of conditions (Claverie-Martín et al., 2011).

Dent disease 2 (OMIM phenotype number 300555) is an XLR condition resulting from inactivating variants in OCRL. Clinical features are shared with that of Dent disease 1 caused by variants in CLCN5 with progressive proximal renal tubulopathy with LMW proteinuria, hypercalciuria, NC, NL, and progressive ESKD (Claverie-Martín et al., 2011). Lowe syndrome (OMIM phenotype number 309000) is an XLR condition resulting from inactivating variants in OCRL. The presentation resembles that of Dent disease 2 but also involves other systemic symptoms of hydrophthalmia, cataracts, severely impaired intellectual development, vitamin D-resistant rickets, and proximal RTA (Claverie-Martín et al., 2011). Data suggests that female carriers of inactivating variants in ORCL are usually asymptomatic, but may have either Dent disease 2 or Lowe syndrome (Cau et al., 2006). Treatment of Dent disease 2 and Lowe syndrome is the same as for Dent disease 1, including treatment of electrolyte derangements such as acidosis.

GATM encodes for glycine amidinotransferase, which is expressed in the PT mitochondria (Reichold et al., 2018). An inactivating variant in GATM leads to Fanconi renotubular syndrome 1 (OMIM phenotype number 134600), an AD condition associated with decreased solute and water reabsorption in the PT with polydipsia, polyuria, phosphaturia, glycosuria, aminoaciduria, uricosuria, hypophosphatemic rickets, metabolic acidosis, progressive kidney insufficiency, and NC in 1 definitive case, and at least 1 case of AD Fanconi syndrome suspected to be secondary a variant in GATM, although genetic testing was not performed (Wen et al., 1989; Reichold et al., 2018; Seaby et al., 2023).

HNF4A encodes for hepatocyte nuclear factor 4-alpha, which in the kidney is expressed in the PT. An inactivating variant in HNF4A leads to Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (OMIM phenotype number 616026), an AD condition associated with macrosomia, severe hypoglycemia with hyperinsulinism, rickets, LMW proteinuria, aminoaciduria, glycosuria, phosphaturia, hypercalciuria, hypouricemia, metabolic acidosis, and NC (Hamilton et al., 2014).

SLC2A2 encodes for solute carrier family 2 (facilitated glucose transporter) member 2 or glucose transporter 2 (GLUT2), which mediates monosaccharide bidirectional transport in the liver, pancreas, intestines, and the renal PT (Figure 1) (Fridman et al., 2015). Inactivating variants in SLC2A2 lead to Fanconi–Bickel syndrome (OMIM phenotype number 227810), an AR condition associated with Fanconi renotubular syndrome, hepatorenal glycogen accumulation, impaired utilization of glucose and galactose, hypercalciuria, and NC (Fridman et al., 2015).

CA2 encodes for carbonic anhydrase 2 (CA2), which is expressed in the CD (including the alpha-IC) and PT (Figure 1). CA2 catalyzes the combination of carbon dioxide and water to form carbonic acid, which then dissociates to protons and bicarbonate (Whyte, 1993). Inactivating variants in CA2 lead to decreased proton and bicarbonate production in osteoclasts and the renal tubules and is associated AR Osteopetrosis with RTA 3 (OMIM phenotype number 259730). This condition is associated with both a proximal RTA and a distal RTA (Borthwick et al., 2003).

SLC4A4 encodes for solute carrier family 4 member 4, a sodium bicarbonate cotransporter that is important in the reabsorption of bicarbonate in the PT (Figure 1) (Guo et al., 2023). Inactivating variants in this gene are associated with two different conditions. Proximal RTA with ocular abnormalities (OMIM phenotype number 604278) is an AR condition associated with impaired intellectual development, and rarely NL and NC (Guo et al., 2023). Distal RTA, autoimmune thyroiditis, tooth agenesis, enamel hypomaturation, and pulp stones is an AR condition with only 1 case reported with the only case being associated with NC and NL (Kantaputra et al., 2022).

WDR72 encodes for WD repeat domain 72, implicated in the trafficking of V-ATPases and thought to play a role in sustained intracellular CaSR signaling through clathrin-mediated endocytosis (Khandelwal et al., 2021). WDR72 is expressed in the alpha-IC in the CD and PT (Khandelwal et al., 2021). Inactivating variants lead to the AR condition Amelogenesis imperfecta type IIA3 (OMIM phenotype number 613211) associated with a distal RTA and intermittent proximal tubulopathy in the setting of acidosis (Khandelwal et al., 2021). This condition is associated with NC and rarely NL.

AGXT encodes for alanine-glyoxylate aminotransferase (AGT), which is a liver peroxisomal enzyme (Cochat and Rumsby, 2013). Inactivating variants in AGXT result in impaired metabolism of glyoxylate into glycine by AGT, leading to increased metabolism of glyoxylate by glyoxylate reductase/hydroxypyruvate reductase (GRHPR) to glycolate and by lactate dehydrogenase (LDH) into oxalate (Cochat and Rumsby, 2013). PH type I (PH1) (OMIM phenotype number 259900) accounts for approximately 80% of cases of PH (Cochat and Rumsby, 2013). This AR condition has onset in infancy to adulthood of recurrent calcium oxalate NL, NC, ESKD, and systemic oxalosis (widespread tissue deposition of calcium oxalate) (Cochat and Rumsby, 2013).

Treatments of PH1 that have been tested include substrate reduction therapy to target enzymes responsible for production of oxalate with RNA interference (RNAi) (targeting glycolate oxidase [GO] with Lumasiran, LDH with Nedosiran) and CRISPR (targeting GO, LDH) (Zabaleta et al., 2018; Martinez-Turrillas et al., 2022; Sas et al., 2022; Baum et al., 2023; Hayes et al., 2023), small molecules to prevent AGT mistargeting (Miyata et al., 2014), enhanced intestinal oxalate degradation using probiotics (Oxalobacter formigenes) or enzymes (oxalate decarboxylase) (Milliner et al., 2018; Lingeman et al., 2019; Quintero et al., 2020), and restoration of functional enzyme conformation with chaperone therapy (vitamin B6) (Fargue et al., 2013). Definitive treatment involves combined or sequential liver and kidney transplant (Loos et al., 2023).

GRHPR encodes for glyoxylate and hydroxypyruvate reductase (GRHPR), which an enzyme expressed throughout the body, including in the liver, specifically the hepatocyte cytosol and mitochondria (Cochat and Rumsby, 2013). Inactivating variants in GRHPR result in impaired metabolism of glyoxylate into glycolate by GRHRP, leading to increased metabolism of glyoxylate by AGT to glycine and by LDH into oxalate (Cochat and Rumsby, 2013). PH type II (PH2) (OMIM phenotype number 260000) is an AR condition that has onset in childhood with recurrent calcium oxalate NL, NC, ESKD, and systemic oxalosis (Cochat and Rumsby, 2013).

Treatments of PH2 that have been tested include substrate reduction therapy to target enzymes responsible production for oxalate with RNA interference (RNAi) (targeting LDH with Nedosiran) and CRISPR (targeting LDH) and enhanced intestinal oxalate degradation using probiotics (Oxalobacter formigenes) or enzymes (oxalate decarboxylase) (Milliner et al., 2018; Lingeman et al., 2019; Quintero et al., 2020; Martinez-Turrillas et al., 2022; Baum et al., 2023). Treatment with combined liver and kidney transplant has been successful in individuals with PH2 (Genena et al., 2023).

HOGA1 encodes for 4-hydroxy-2-oxoglutarate aldolase (HOGA), which is a liver mitochondrial enzyme (Cochat and Rumsby, 2013). HOGA catalyzes metabolism from 4-hydroxy-2-oxoglutarate (HOG) to glyoxylate and pyruvate (Williams et al., 2012; Singh et al., 2022). The mechanism by which variants in HOGA1 result in PH is unclear (Williams et al., 2012; Singh et al., 2022). PH type III (PH3) (OMIM phenotype number 613616) accounts for approximately 10% of cases of PH (Williams et al., 2012; Singh et al., 2022). PH3 is an AR condition with onset in childhood to adulthood with recurrent calcium oxalate NL, NC, CKD, rarely ESKD, and without systemic oxalosis. Data suggests that carriers (heterozygotes) of inactivating variants in HOGA1 may have mild hyperoxaluria or idiopathic calcium oxalate NL (Monico et al., 2011; Pitt et al., 2015).

Treatments of PH3 that have been tested include substrate reduction therapy to target enzymes responsible production for oxalate with RNA interference (RNAi) (targeting LDH with Nedosiran) and CRISPR (targeting LDH) and enhanced intestinal oxalate degradation using probiotics (Oxalobacter formigenes) or enzymes (oxalate decarboxylase) (Milliner et al., 2018; Lingeman et al., 2019; Quintero et al., 2020; Martinez-Turrillas et al., 2022; Goldfarb et al., 2023).

SLC26A1 encodes for solute carrier family 26 member 1, an electroneutral anion exchanger (sulfate-oxalate, sulfate-bicarbonate, oxalate-bicarbonate) that is expressed in the PT (Figure 1) (Gee et al., 2016). Inactivating variants in SLC26A1 result Calcium oxalate NL 1 (OMIM phenotype number 167030), an AR condition with hyperoxaluria and calcium oxalate NL (Gee et al., 2016).

Peroxisome biogenesis disorder A (Zellweger) and Peroxisome biogenesis disorder B (neonatal adrenoleukodystrophy [NALD] and infantile Refsum disease [IRD]) are characterized by deficient peroxisomal assembly with a generalized loss of peroxisomal functions (van Woerden et al., 2006; Alhazmi, 2018). Children with these disorders frequently have hyperoxaluria, hypothesized to be related to reduced glyoxylate conversion into glycine by AGT with increased oxalate production by LDH (van Woerden et al., 2006; Alhazmi, 2018).

This condition results in impaired renal reabsorption of cystine. Cystine’s low solubility causes the formation of NL, resulting in obstructive uropathy, pyelonephritis, and rarely ESKD (Barbosa et al., 2012). Cystinuria results from variants in SLC3A1 and SLC7A9, which encode for solute carrier family 3 member 1 and solute carrier family 7 member 9, respectively, both of which are expressed in the PT (Figure 1). This condition has been associated with one or two pathogenic variants in either gene (AD/AR, OMIM phenotype number 220100 for SLC3A1 (Font-Llitjós et al., 2005), OMIM phenotype number 220100 for SLC7A9 (Dello Strologo et al., 2002)), one pathogenic variant in each gene (DR) (Font-Llitjós et al., 2005), or two pathogenic variants in one gene with one pathogenic variant in the other gene (triallelic inheritance) (Rhodes et al., 2015).

Mainstays in therapy are urinary dilution with hyperhydration, decreased cystine excretion through low sodium diet and low protein (methionine) diet in adolescents and adults of <0.8 g protein per day, increased urinary cystine solubility by alkalinizing the urine to pH of 7.5 with potassium citrate, and increased urinary cystine solubility by conversion of cystine to cysteine (if cystine excretion is >3 mmol per day) with chelation agents such as D-penicillamine and tiopronin (Knoll et al., 2005). Tolvaptan has been shown to decrease urinary cystine concentrations by increasing diuresis (de Boer et al., 2012). Captopril and Bucillamine are other drugs thought to increasing urinary cystine solubility by conversion of cystine to cysteine, but the data is uncertain (Knoll et al., 2005; Moussa et al., 2020). L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME) are being studied as cystine crystal growth inhibitors and alpha-lipoic acid is being studied as a drug to increase urinary cystine solubility (Rimer et al., 2010; Zee et al., 2017).

Chromosome 2p21 contains the following genes: PREPL and SLC3A1, which encode for prolyl endopeptidase like and solute carrier family 3 member 1, respectively (Jaeken et al., 2006). PREPL and SLC3A1 are expressed in the PT (Jaeken et al., 2006). Homozygous deletion of both PREPL and the neighboring gene SLC3A1 result in Hypotonia-cystinuria syndrome (AR inheritance, OMIM phenotype number 606407) with hypotonia, cystinuria, and cystine NL (Jaeken et al., 2006).

Genetic disorders of inorganic pyrophosphate (PPi) with NL and/or NC are shown in Table 11. The genes responsible are ENPP1 and ABCC6.

Genetic disorders with polycystic kidney disease (PKD) with NL and/or NC are shown in Supplementary Table S8, which consist of AR PKD (PKDH1 gene, OMIM phenotype number 263200) and AD PKD including AD PKD type 1 (PKD1 gene, OMIM phenotype number 173900), AD PKD type 2 (PKD2 gene, OMIM phenotype number 613095), AD PKD type 3 (GANAB gene, OMIM phenotype number 600666), AD PKD type 6 with or without polycystic liver disease (DNAJB11 gene, OMIM phenotype number 618061), and AD PKD type 7 (ALG5 gene, OMIM phenotype number 620056). AR PKD is associated with multifactorial NL, NC, and medullary sponge kidney (Adeva et al., 2006). AD PKD is associated with NL (usually uric acid or calcium oxalate), abnormal transport of ammonium, low urine pH, hypocitraturia, and sometimes a distal RTA (Torres et al., 1993).

Other genetic disorders with multifactorial etiologies of NL and/or NC are shown in Supplementary Table S9. The associated genes for these disorders are CLDN10 (Klar et al., 2017), EMC10 (Shao et al., 2021; Kaiyrzhanov et al., 2022), HSD11B2 (Lu et al., 2022), PAX2 (Bower et al., 2012), STRADA (Puffenberger et al., 2007; Bi et al., 2016; Nelson et al., 2018), and ZNF687 (Rendina et al., 2020).