Tubular disease Ensure adequate hydration particularly during acute crises and have a low t hreshold to check for hyperkalemia and metabolic acidosis during intercurrent illness. Hematuria Conservative management is usually suf \201 cient; exclude UTI; angiography + em bolization/nephrectomy is rarely required; consider renal medullary carcinoma if macro- sco pic hematuria is persistent. Preparation of patients with SCA for surgery A multidisciplinary approach (hematologist, an esthetist surgeon, nephrologist) is essential and a protocol outlining perioperative manage ment should be written in the patient \200\231s notes prior to surgery. Patients may requir e preoperative transfusion (top-up or exchange transfusion). Postoperatively, careful atten tion to \202 uid balance and tis- sue oxygenation is required. Hypertension In SCA the BP is lower than age-/sex-matched African- American controls. The d ifference is most marked in HbSS patients >45 years. \200\230Relative \200\231 hypertensio n (120 \200\223139/70 \200\22389 mmHg) is associ- ated with an increased risk of CKD, strok e, pulmonary hypertension, and all-cause mortality. Little data is available to guide treat ment decisions. Follow-up All patients with SCA require annual review of renal func- tion and measurement o f proteinuria. Once renal disease L. BARTON AND C. CHAPMAN 194 Table 4.10.1 Therapeutic considerations in patients with SCD and CKD Therapy Comment Used to treat sickle cell hemoglobinopathies (increases HbF synthesis and reduces likelihoo d of sickling). Caution in patients with nephropathy as hydroxycarbamide is predominantly c leared by the kidney. Hydroxycarbamide (hydroxyurea) Frequently used during painful acute crises. Analgesics NSAIDs SCA patients more susceptible to glomerular hemodynamic effects of NSAIDs as more dependent on prostaglandins derived from ischemic renal medulla to maintain glomerular blood \202 ow. Avoid in patients with nephropathy. If necessary, carefully monitor renal function and limi t to 5 days of treatment. Opiates Caution in patients with nephropathy as these drugs (e.g. pethidine) are predominantly clea red by kidney. EPO Consider EPO if: Hb <8 g/dL. Cautious escalation of EPO dosing Commence with 100 U/kg twice a week increasing by 100 U/k g/dose every 4 \200\2236 weeks until Hb rises. Stop if Hb >10.5 g/dL, if rise is >1.5 g/dL over 4 weeks or Hct >0.33 Close monitoring is essential FBC, reticulocyte count and BP should be monitored weekly aft er any dose change. Hypertension Diuretics -Blockers ACEIs/ARBs Caution due to tubular dysfunction and susceptibility to dehydration. Caution due to tubular dysfunction and susceptibility to hyperkalaemia particularly in prog ressive CKD. Caution due to tubular dysfunction and susceptibility to hyperkalaemia particu larly in progressive CKD. becomes apparent the frequency of follow-up will be determined by the stage of CKD. Management of Sickle Cell Disease (NIH NHLBI): http://www.nhlbi.nih.gov/health/prof/blood/ sickle/index.htm BCSH Guideline. Management Of Acute Painful Crisis In Sickle Cell Disease: Prognosis The median survival for patients with ESRD is 4 years despite RRT. Poor outcome i s linked to coexistent end- organ damage and refractory anemia. However, survival is simila r to matched ESRD controls when the low transplantation rate is taken into account. http://www.bcshguidelines.com/ Sickle Cell Society: http://www.sicklecellsociety.org/index.htm Sickle Cell Disease Association of America: Further reading Ataga KI, Orringer EP, et al. Renal abnormalities in sickle cell http://www.sicklecelldisease.org/ The Sickle Cell Information Center: disease. Am J Haematol 2000; 63: 205 \200\223211. Guasch A, Navarrete J, et al. Glomerular Involvement in adults with sickle cell haemoglobin opathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 2006; 17: 2228 \200\2232235. http://www.scinfo.org/ Standards for the clinical care of adults with Sickle Cell disease i n the UK Little JA, McGowan VR, et al. Combination erythropoietin hydrox- yurea therapy in sickle ce ll disease: experience from the National Institutes of Health and a literature review. Haem atologica 2006; 91: 1076 \200\2231083. http://www.sicklecellsociety.org/CareBook.pdf See also Ojo AO, Govaerts TC, et al. Renal transplantation in end stage Tumors of the kidney p. 668 Urinary tract obstruction, p. 652 Hematological disorders in CK D, p. 426 sickle cell nephropathy. Transplantation 1999; 67: 291 \200\223295. Thompson J, Reid M, et al. Albuminuria and renal function in homozygous sickle cell disease . Arch Intern Med 2007; 167: 701 \200\223708. Internet resources Sickle Cell Disease in Childhood: Standards and Guidelines for Clinical Care (NHS): http://www.sickleandthal.org.uk/Documents// DETAILED_CLIN_Oct19.pdf This page intentionally left blank J. FREW, C. McBAIN AND A. ELLIOTT 196 Cancer and the kidney Etiology of renal impairment in cancer patients Renal dysfunction is relatively common in p atients with cancer as a result of complications related to their cancer or treatment (see below) and concomitant comorbidities such as diabetes mellitus and hypertension. The causes include: \200 \200 \200 \200 \200 \200 \200 \200 \200 Coexisting primary hyperparathyroidism A higher incidence of primary hyperparathyroidism is seen in patients with cancer. Calcium levels >3.25 mmol/L are rarely due to primary hyperparathyroidism. Investigations in the hypercalcemic patient Measure serum urea, creatinine, calcium, chlori de, and phosphate. Measure vitamin D and PTH. CXR (for evidence of malignancy or sarcoidosi s). Perform isotope bone scan if not known to have bone metastases. pre-renal failure secondary to \202 uid depletion; anticancer drug-related nephrotoxicity ; metabolic causes, e.g. hypercalcemia; mechanical obstruction; paraneoplastic glomerulonep hropathies; paraprotein-related disease; amyloidosis; radiation nephropathy; renal metastas is. Management of hypercalcemia of malignancy Saline Saline is administered to produce volume e xpansion and increase urinary calcium excretion. Give 3 \200\2234 L of 0.9% saline/day. Adj ust infusion rate to main- tain a urine output of 100 \200\223150 mL/h. This alone rarely n or- malizes serum calcium. Hypercalcemia of malignancy Hypercalcemia is a common metabolic problem occurring in 10 \200\22320% of patients with cancer. In the hospital popula- tion an underlying malignancy is the most frequent cause of hypercalcemia. Cancers of the lung and breast and multiple my eloma are most frequently implicated. Hypercalcemia often develops in the later stages of c ancer, and is not often the isolated presenting feature of malignancy in the absence of oth er symptoms and/or signs. Hypercalcemia is a result of increased bone resorption and releas e of calcium from bone. The mechanisms are dis- cussed below although it is often multifact orial. Bisphosphonates These are nonhydrolyzable analogs of inorganic pyro- phosphate. They inhibit bone resorptio n by adsorbing to the surface of bone hydroxyapatite, thereby interfering with the meta- bo lic activity of osteoclasts. Third-generation bisphosphonates (e.g. zoledronic acid) have b een shown to be superior to second generation bisphosphonates (e.g. pamidronate). Third-gen eration bisphosphonates normalize the corrected calcium level in almost 90% of patients by day 10 with a median duration of calcium control of 32 \200\22343 days. Mechanisms of hypercalcemia Osteolytic metastases Hypercalcemia results from direct inducti on of local oste- olysis by tumor cells. This is common in solid tumors metastatic to bone (espe- cially lung and breast). Cytokines (e.g. IL-1 and TNF) stimulate osteoclast differen tiation and activity. Calcitonin Consider for severe or symptomatic hypercalcemia. It decreases bone calcium resorption and increases urinary excretion. It has a rapid onset of action beginning 4 \200\2236 h post ad minis- tration although only lowers calcium by 0.3 \200\2230.5 mmol/L. PTH-related protein This is often called humoral hypercalcemia of malignancy. It is the com monest cause of hypercalcemia in patients with nonmetastatic solid tumors and some patients with non-Hodgkin \200\231s lymphoma. PTH-related peptide (PTHrP) is expressed in non-neopl as- tic tissues and is required for normal function and develop- ment. It is structurally s imilar to PTH at the amino-terminal end which permits binding to PTH receptors. PTHrP has p hysiological effects similar to PTH, but is struc- turally distinct and can be measured wit h antibody-based assays. Mechanical obstruction Hydronephrosis is particularly common in patients with bladder or ce rvical cancer, and may be acute or chronic. Ureteric obstruction may be due to primary or s econdary disease. Acute edema can precipitate mechanical obstruction in patients undergoing pelvic radiotherapy. Management The stage and prognosis of the disease, and the potential reversibility of the o bstruction, need to be taken into account when planning treatment. Intervention may be unne cessary since the disease may regress with treatment or be inappropriate in patients with a dvanced or terminal cancer. Osteoclast-activating factors These mediate the hypercalcemia in multiple myeloma and some cases of lymphoma. Various osteoclast-activating factors (e.g. IL-1, IL-6, TNF and vascular cell adhesion molecule (VCAM-1)) are released by adjacent tumor cells. CHAPTER 4.11 Cancer and the kidney 197 Following isotope renogram assessment of residual renal function, ureteric stenting or inse rtion of uni- or bilateral nephrostomies is often appropriate to facilitate treatment. Thes e may be removed if there is adequate tumor regression. Glomerulonephropathies Glomerular disease occurs in 6 \200\22310% of patients with can- cer . There have been associations reported between many glomerulonephropathies and a variety o f solid and hema- tological malignancies. Membranous nephropathy (MN) \200 Tumor lysis syndrome (TLS) Tumor lysis syndrome is a condition which may occur fol- lowing massive cell death after treatment of neoplastic conditions. It is most frequently seen jus t after the com- mencement of chemotherapy treatment for very chemo- sensitive disease, cla ssically high grade lymphomas (particularly Burkitt \200\231s lymphoma) and high leukocyte count leukemias. The mainstay of treatment is to predict which patients are at risk and ins titute measures to prevent TLS from devel- oping. It should be suspected in patients who de velop AKI with marked hyperuricemia and/or hyperphosphatemia. 6 \200\22322% of patients with (MN) have an underlying malig- nancy. It is associated with carcinomas; especially breast, lung and gastrointestinal tract. The diagnosis of MN may be made before or after can- cer diagnosis. It presents with hypertension, nephrotic syndrome, and microscopic hematuria. Minimal change nephropathy \200 This is associated with Hodgkin disease and lymphomas although the prevalence is low (<1%). Glomerular amyloidosis \200 Pathophysiology Massive cellular lysis releases metabolites into the circula- tion. Cellula r breakdown of nucleic acids leads to the pro- duction of uric acid. Uric acid becomes inso luble and precipitates in the renal tubules at low pH causing obstruc- tion and a decreased GFR. Acute nephrocalcinosis can occur as a result of hyperphos- phatemia and precipitation of calcium phosphate crystals. AL amyloid glomerulopathy is the renal deposition of free monoclonal chains from a benign o r malignant clonal expansion of plasma cells, e.g. myeloma. AA amyloid is the deposition of a variety of proteins including the acute phase reactant, serum amyloid A pro- tein, in ex tracellular tissue. Cancers associated with AA amyloid glomerulopathy include renal cell ca rcinoma and Hodgkin disease. Risk factors for TLS \200 \200 \200 \200 \200 IgA nephropathy \200 Chemosensitive tumor with high proliferation index. Large tumor burden. Renal dysfunction. Hyperuricemia. Hypovolemia. This is associated with tumors of the mucosal immune system (especially in upper respirator y tract). Management of glomerulopathies Associated malignancies should be considered in adults aged >50 years presenting with a glomerulopathy with no apparent cause. Management of the underl ying malignancy is the primary objective with regression of the glomerulopathy frequently o bserved with successful treatment. Patients with untreatable malignancies may bene \201 t from standard management of the nephrotic syndrome including control of blood pressure (wit h ACEIs and ARBs) and \202 uid balance to minimize the progressive decline in GFR. Metabolic abnormalities TLS will result in severe hyperuricemia. hyperphos- phatemia, hyper kalemia, hypocalcemia, and biochemical evidence of AKI. Prevention of TLS in at-risk patients Allopurinol 300 mg/day for at least 2 days prior to c om- mencing treatment of cancer. Aggressive IV \202 uid prehydration for 24 \200\22348 h before treat- ment. The role of urinary alkalinisation is unclear (target pH 6.5 \200\223 7 ; give sodium bicarbonate or acetazolamide) Radiation nephropathy This can develop 6 months to several years following exposure to radi otherapy; it does not tend to occur acutely. It is an uncommon complication, provided recog nized radiation tolerance doses are not exceeded (see below). It is de \201 ned as renal i njury and loss of function following ionizing radiation. Clinical radiation nephropathy has become less common because of the routine use of kidney shielding during radiotherapy and the increased use of chemotherapy. Management of TLS Give IV \202 uids and loop diuretics to \200\230wash out \200\231 obst ructing uric acid crystals. Give rasburicase (recombinant urate-oxidase) 200 g/kg IV once daily for 5 \200\2237 days. Consider in severe cases Treat the metabolic abnormalities inc luding hyperkalemia and symptomatic/profound hypocalcemia. Consider transfer to high depend ency/intensive care unit and consider hemodialysis if the response to the above measures is poor. Etiology \200 Bone marrow transplant nephropathy: total body irradi- ation with partial kidney shielding is used as conditioning regimen for the bone marrow transplant. Parenteral radioisotope the rapy: e.g. yttrium 90 conju- gated to somatostatin is \201 ltered and reabsorbed in the p roximal tubule. Upper abdominal radiotherapy. Para-neoplastic conditions and the kidney Syndrome of inappropriate ADH secretion (SIADH) E ctopic secretion of ADH by malignant cells is a common cause of hyponatremia in patients wi th cancer, e.g. small cell lung carcinoma. SIADH also occurs in patients with primary or se condary brain tumors. J. FREW, C. McBAIN AND A. ELLIOTT 198 Anemia is driven by low blood erythropoietin levels and responds to erythropoietin replacem ent therapy. Kidney tolerance Studies suggest that 10 Gy as a single dose or >23 Gy in fractionated dose s can lead to radiation nephropathy. Further reading Cohen EP. Cancer and the kidney. Oxford: Oxford University Press; Pathophysiology Ionizing radiation causes radiochemical injury to cells. Studies suggest th at glomerular endothelial cell injury is the start of a cascade leading to glomerular scler osis and later tubulo-interstitial \201 brosis. 2005. Souhami RL, Tannock I, Hohenberger P, Horiot J-C. Oxford textbook of oncology. Oxford: Oxford University Press; 2002. See also Malignancy-associated glomerular disease, p. 134 Hypo-/hypercalcemia, p. 52 Uric a cid and the kidney, p. 232 Presentation Findings include hypertension, proteinuria, azotemia, ane- mia, and hyperkalem ia. Management There is strong experimental data to support the use of ACEIs or angiotensin II blockers in the treatment and pre- vention of experimental radiation nephropathy. 199 Chapter 5 Tubular disease Chapter contents Isolated defects of tubular function 200 Fanconi syndrome 204 Renal tubular acidosis 208 Hy pokalemic tubular disorders 214 Nephrogenic diabetes insipidus 220 D. BOCKENHAVER, D. BICHEL, AND R. UNWIN 200 Isolated defects of tubular function This chapter brie \202 y covers the miscellaneous isolated defects of tubular function: re nal glycosuria, phosphaturia and aminoaciduria. \201 nding and there are no clinical features or sequelae, in particular there is no poly uria or polydipsia. Renal glycosuria has been divided clinically into three types (A, B and O) according to measured changes in the renal threshold for, versus the maximal rates of, glucose reabsorption. However (similar to the original clinical classi \201 cation of cyst inuria \200\223 see below), this separation into types is of limited clinical use and it a lmost certainly only re \202 ects differences in the effects of different SGLT2 mutations. Renal glycosuria Renal glycosuria (or glucosuria) is the excretion of glu- cose in the urin e in detectable amounts in the absence of hyperglycemia. The underlying defect is an abnorm ally low renal threshold for glucose reabsorption. Renal glycosuria needs to be differentia ted from glycosu- ria associated with more complex tubular disorders like the renal Fanconi syndrome, cystinosis, Wilson \200\231s disease, hereditary tyrosinemia, interstitial nephr itis and heavy metal poisoning, which can all affect the proximal tubule; it can also occur in myeloma, transiently following renal transplantation, and in the nephrotic syndrome (Ta ble 5.1.1). Isolated hereditary renal glycosuria is a benign autosomal recessive disorder t hat does not require treatment. It just needs to be recognized and is usually detected on r outine urine testing. Plasma glucose and serum insulin concentrations, glucose tolerance te st and glycosylated hemoglobin level are all normal; although there is a rare association w ith late onset diabetes mellitus of the young (MODY3) caused by a muta- tion in the gene fo r hepatocyte nuclear factor-1. Renal glycosuria is also seen in familial glucose \200\223ga lactose malabsorption, another rare autosomal recessive disorder, which presents in the neo nate with severe diarrhea. Diagnosis and treatment Both are straightforward. Benign renal glycosuria must be distingui shed from other causes of glycosuria with or with- out hyperglycemia: \200 diabetes melli tus; \200 gestational diabetes; \200 any cause of a renal Fanconi syndrome, inherited o r acquired (see Table 5.1.1). There is no speci \201 c treatment and none is required. Table 5.1.1. Causes of a renal Fanconi syndrome Autosomal dominant X-linked (e.g. Lowe syndrome) Idiopathic renal Fanconi syndrome Cystinosis Galactosemia Hereditary fructose intolerance Tyrosinemia Glycogen storage diseas es \200 Fanconi \200\223Bickel syndrome Glucose-6-phosphatase \200 de \201 ciency Inherited renal Fanconi syndrome associated with inborn errors of amino acid or carbohydrat e metabolism Epidemiology In the USA the incidence is estimated to be 0.16 \200\2236.3% ( 1 in 20 000). There is no gender difference. Wilson \200\231s disease Mitochondrial disease Acquired renal Fanconi syndrome: Toxic Pathophysiology and clinical features Glucose is freely \201 ltered at the glomerulus and then almost completely reabsorbed along the proximal tubule: frac- tional excretion is nor mally <0.1%. Reabsorption of glucose occurs mainly in the \201 rst (S1) and second (S2) p arts of the proximal tubule. Most glu- cose enters the proximal tubule cell via the sodium- dependent glucose cotransporters SGLT1 and SGLT2, and leaves the cell via the facilitated transporters GLUT1 and GLUT2. SGLT2 is a low af \201 nity \200\223high capacity glucose tr ansporter that reabsorbs the bulk of \201 ltered glucose in S1. SGLT1 is a high af \201 nity \200\223low capacity glucose transporter that \200\230scavenges \200\231 the remainin g glucose in S2 (and S3). Glucose reabsorption is age-dependent and in premature infants of <30 weeks gestation glycosuria, is a common \201 nding. Glucose \200\223galactose malabs orption is due to mutations of SGLT1, which is also the transportation protein responsible for glucose and galactose reabsorption in the small intestine (in which there is no SGLT2). Treatment consists of elimi- nating these sugars from the diet, including their disacchari de, lactose. About 90% of cases of isolated renal glycosuria are due to mutations in SGLT2 (SLC5A2). It is usually an incidental Exposure to heavy metals (Pb, Hg, Cd) Chinese herbs Aminoglycoside antibiotics and outdated tetracyclines Antiretrovirals (HIV) Ifosfamide Multiple myeloma, amyloidosis, light chain nephropathy, and benign monoclonal gammopathy Sj gren \200\231s syndrome, interstitial nep hritis, renal transplantation Dysproteinemias Immune-mediated Hypophosphatemia and phosphaturia Maintaining a normal plasma phosphate concentra- tion dep ends on normal renal function and phosphate excretion. Reabsorption of phosphate in the ren al proximal tubule is regulated and it can adjust rapidly in response to changes in parathy roid hormone (PTH), which inhibits phosphate reabsorption, and 1,25-(OH)2 vitamin D (renal production of which is increased by PTH and hypophosphatemia), which stimulates phosphate r eabsorption. CHAPTER 5.1 Isolated defects of tubular function 201 (which can also occur in severe malnutrition during re- feeding). Renal losses of phosphate have been described in asso- ciation with hypokalemia, hypomagnesemia (particularly in alc oholics), chronic metabolic acidosis, hypothyroidism, humoral hypercalcemia of malignancy, and after severe burns. Phosphate reabsorption is mediated by two sodium- dependent phosphate transporters (cf. glu cose), NaPi-2a and NaPi-2c; NaPi-2a is the more important and is regu- lated under normal c onditions (although mutations in both transporters have been linked to isolated hypophos- p hatemia and phosphaturia in some patients with recur- rent renal stone disease). Abnormal r enal losses of phosphate are evident when there is hypophosphatemia, which may be due to in creased PTH secretion or a primary defect in phosphate reabsorption (mainly via NaPi-2a) in the proximal tubule. In adults, hypophosphatemia is de \201 ned as a fasting plasma phosp hate concentration <0.75 mmol/L, and in children <1.35 mmol/l. Urinary phosphate wasting is likely to be present when the urine phosphate concentration is >2 mmol/L and the plasma ph osphate concentration is <0.5 mmol/L, or the tubular maximum for phosphate reabsorption (Tm Pi/GFR; see Chapter 5.2) is reduced to <0.8 mmol/L (in adults), or the fractional excretion of phosphate is >20%. Causes of hypophosphatemia (Table 5.1.2): Hyperparathyroidism \200 Intestinal \200 \200 Decreased intake. Phosphate binders. Symptoms and signs The important ones are: \200 \200 \200 bone pain with rickets or osteomalacia; muscle weakness; myocardial and respiratory depress ion, coma and rhab- domyolysis. These only occur in severe cases of hypo- phosphatemia (pla sma or serum phosphate concentration <0.35 mmol/L). Investigations Key investigations include: \200 measurement of plasma phosphate and calcium concen- trations, and (fasting) urinary phospha te excretion; esti- mate GFR to calculate TmPi/GFR (see Chapter 5.2) and fractional excreti on of phosphate; measurement of PTH, 25-(OH) vitamin D (assay of 1,25- (OH)2 vitamin D is n ot always widely available) and alka- line phosphatase, and urinary screening for glycosuri a, aminoaciduria and low molecular weight proteinuria (e.g. retinol binding protein); bone X-rays for signs of osteomalacia. Primary hyperparathyroidism with hypophosphatemia and hypercalcemia due to a parathyroid ad enoma or hyperpla- sia, or inactivating mutations of the calcium-sensing recep- tor (in the parathyroid gland and kidney). Secondary hyperparathyroidism with hypophosphatemia and hyp ocalcemia due to vitamin D de \201 ciency or resist- ance to vitamin D. Renal tubular defects \200 Renal Fanconi syndrome (with associated glycosuria, uricosuria, aminoaciduria and tubular p roteinuria) (Table 5.1.1). X-linked hypophosphatemic rickets and autosomal dom- inant hypop hosphatemic rickets (with reduced intestinal absorption of calcium and phosphate, rickets o r osteo- malacia, and inappropriately low or normal 1,25-(OH)2 vitamin D levels ). Osteogen ic (tumor-induced) osteomalacia (due to mesenchymal tumors secreting a \200\230phosphatoni n \200\231 like FGF-23, which inhibits phosphate reabsorption in the proximal tubule and sy nthesis of 1,25-(OH)2 vita- min D). In diabetic patients with ketoacidosis, phosphate is re leased from cells and lost in the urine; treatment with insulin can unmask the de \201 cit in phosphate by stimulat- ing anabolism and shifting phosphate back into cells Management This will depend on the underlying cause, but if supple- ments are required, ora l phosphate can be given in divided doses of up to 3 g/day. Too much oral phosphate will st imu- late PTH secretion. Aminoaciduria As with glucose, amino acid transportation occurs in the proxi- mal tubule, a lthough the variety of transporters involved is more diverse than for glucose (or phosphate ). Approximately 50 g of \201 ltered amino acids are recovered by the proximal tubule eac h day. This is important for the maintenance of normal nitrogen balance. Uptake into proxim al tubule cells is by sodium- or proton- dependent cotransport, or exchange with another (n eutral) amino acid; exit from the cell is via a group of less-well-de \201 ned unidirectio nal transporters and exchangers (Table 5.1.3). Table 5.1.2 Biochemical features of the main causes of renal phosphate wasting Plasma/serum calcium PTH 25-(OH) vitamin D 1,25-(OH)2 vitamin D Other signs of proximal tubular dysfunction Primary hyperparathyroidism No \206\221 \206\221 \206\222 \206\222, \206\221 Secondary hyperparathyroidism No \206\222, \206\223 \206\221 \206\222, \206\223 \206\222, \206\223 Renal Fanconi syndrome Yes \206\222 \206\222 \206\222, \206\223 \206\222, \206\223 Hereditary hypophosphatemic rickets No \206\222 \206\222 \206\222 \206\222, \206\223 No Tumor-induced osteomalacia \206\222 \206\222 \206\222 \206\223 No Diabetic ketoacidosis \206\222 \206\222 \206\222 \206\221 \206\222, normal; \206\223, reduced; \206\221, increased. D. BOCKENHAVER, D. BICHEL, AND R. UNWIN 202 Table 5.1.3 Amino acid transporters Amino acids Apical (luminal) transporter Basolateral transporter Clinical aminoaciduria Na+-dependent cotransporter EAAT3 (SLC1A1) H+-dependent cotransporter PAT1 (SLC36A1) Na+-de pendent cotransporter B0AT1 (SLC6A19) Acidic (anionic) amino acids (glutamic acid) Iminoglycinuria Imino-amino acids (proline, hydroxyproline, glycine, alanine, serine) Hartnup disease Neutral amino acids (leucine, valine) and aromatic neutral amino acids (phenylalanine, tryp tophan, tyrosine, histidine) Cystinuria \200 Lysinuric protein intolerance \200 Heterodimeric exchanger y+LAT1 \200 (SLC7A7) and 4F2hc (SL33A2) Heterodimeric exchanger rBAT \200 (SLC3A1) and b0+AT \200 (SLC7A9) Basic (cationic) amino acids (lysine, arginine, ornithine) and cystine The amino acid transporters shown are only those that have been linked (so far) to an amino aciduria. \200 , \200 Shared superscripts: transporter defects matched with clinical outco mes. These transporters are shared with the small intestine and so any defect in amino acid tran sportation is usually present in both the gut and kidneys. hexagonal crystals, which have a characteristic appearance on urine microscopy. Investigations Cystine can be screened for qualitatively and then quanti- \201 ed in a 24 h urine collection. Urinary cystine excretion can be >4 mmol/24 h, although treatment shou ld begin with levels >0.8 mmol/24 h, as its solubility is low (0.7 mmol/L). If possible, fa mily screening should be arranged. Cystinuria Cystine is formed by oxidation of the neutral sulfur- containing amino acid cyst eine, which has a thiol group and can pair through a disul \201 de bond. In cystinuria, th ere is increased excretion of cystine and the basic (cationic) amino acids lysine, arginine and ornithine. It is an autosomal recessive disorder with a reported inci- dence ranging f rom 1 in 10 000 to 1 in 20 000. Originally, three types were described according to the amo unt of cystine excreted by those affected and their parents. Two gene defects have since be en identi \201 ed as the underlying cause: SLC3A1 (rBAT) on chromosome 2 and SLC7A9 on chr omosome 19, which together form a heter- omeric amino acid transporter (Table 5.1.3). The d egree of cystinuria in an affected individual depends on which gene is mutated: heterozygot es versus homozygotes, or if both genes are mutated (compound heterozygotes) (Table 5.1.4). Management In order for cystine to remain in solution, the urine must be dilute and alkalin e. Initial treatment measures are to increase \202 uid intake to \211 3 L per day and in severe cases to continue drinking over- night, despite the inconvenience of nocturia. Alka li therapy, usually given as sodium bicarbonate, is titrated to maintain a urine pH of >7, and dietary sodium intake is restricted as much as possible. Cystine is a reversible dimer of cysteine (see above), which is more soluble than cystine; drugs with thiol groups, like penicillamine and tiopronin, can combine with cysteine to form a more soluble compound and so reduce the concen- tration and urinary excretion of cystine. Pencillamine (0.25 \200\223 2 g/day), although widely used, has important side-effects (skin rashes and proteinuria) th at prevent many patients from taking it. Symptoms and signs Cystine stones form and can present in childhood or adult- hood. They ma ke up 1 \200\2232% of renal stones in adults and up to 8% in children. Cystine stones are orange in color, radio-opaque (though less so than calcium-containing stones) and composed of Table 5.1.4 Classi \201 cation of cystinuria Old (descriptive) classi \201 cation of cystinuria New (genetic) classi \201 cation of cystinuria Corresponding pattern of cystine excretion 1 \200\2233 mmol/24 h Type I/II: parents have no cystinuria* Type I (60% of cases) is homozygous mutation in SLC3A1 (rBAT) (SLC3A1 heterozygote is not c ystinuric) <0.01 mmol/24 h* 1 \200\2233 mmol/24 h** Type II/II: parents have heavy cystinuria** Nontype I (types II and III) is a homozygous mu tation in SLC7A9 or a compound heterozygote with mutations in SLC7A9 and SLC3A1 (SLC7A9 het erozygote is cystinuric) >0.5 mmol/24 h*** Type III/III: parents have modest cystinuria*** ,**,***Shared superscripts: quantity of cystinuria matched with the clinical phenotype. CHAPTER 5.1 Isolated defects of tubular function 203 Though similar to penicillamine, tiopronin (10 \200\22340 mg/kg/ day, maximum 2 g/day) is b etter tolerated, but less readily available in the UK. It is used more in pediatric practic e. The thiol-containing ACEI captopril has been proposed as a safe alternative to penicilla mine, but it is ineffective at conventional (antihypertensive) doses. Ascorbic acid (5 g/da y) can also be tried, but its effect on cystine excretion is small (and too much may increa se oxalate excretion). Lysinuria This is a defect in basic (cationic) amino acid transportation, with protein into lerance and hyperammonemia, leading to coma. It affects intestinal absorption and kidney re ab- sorption. It is due to a mutation in the gene SLC7A7 (Table 5.1.3). Further reading Pontoglio M, Prie D, Cheret C, et al. HNF1alpha controls renal glucose reab sorption in mouse and man. EMBO Rep 2000; 1: 359 \200\223365. Hartnup disease Hartnup disease is another autosomal recessive disorder, this time due to a mutation in SLC6A19, which encodes a neutral amino acid transporter (Table 5.1.3); althoug h this gene defect does not account for all cases. Many of those affected have no signs or symptoms, but typical cases have a pellagra-like rash and ataxia. These complications arise not from the renal losses of amino acids, but from impaired intestinal absorption of tryp- tophan, the precursor of nicotinic acid (niacin, vitamin B3), and can be treated with nico tinamide. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 2003; 14: 2873 \200\2232882. Wright EM, Hirayama BA, Loo DF. Active sugar transportation in health and disease. J Intern Med 2007; 261: 32 \200\22343. Internet resources International Cystinuria Foundation: http://www.cystinuria.org/ See also Fanconi syndrome, p. 204 Hypo-/hyperphosphatemia, p. 56 Medical management of ston e disease, p. 270 Renal and urinary tract stone disease in children, p. 282 Iminoglycinuria This is a benign aminoaciduria due to a defect in PAT1 (SLC36A1) (Table 5.1 .3). A. HALL, R. KLETA AND R. UNWIN 204 Fanconi syndrome De \201 nition The renal Fanconi syndrome (FS) (also known as Fanconi renotubular syndrome and Lignac \200\223de Toni \200\223Debr \200\223Fanconi syndrome, and not to be confused with Fanconi \200\231s anemia) refers to a set of clinical features resulting from a gener al- ized loss or disturbance of the normal transportation processes in the proximal renal t ubule (PT) of the nephron. Originally described in the 1930s by the Swiss pediatrician Guid o Fanconi, its characteristic features are glycosuria, aminoaciduria and phosphaturia (hypo phosphatemia) in affected children (or adults). FS is recognized by urinary losses of subst ances normally reabsorbed by the PT, such as glucose, amino acids and phosphate (as already mentioned). It also includes loss of bicarbonate (leading to meta- bolic acidosis \200 \223 a form of renal tubular acidosis (RTA)) and low molecular weight proteins (LMWPs) (for example vitamin D binding protein which affects vitamin D metabolism, leading to phosphate wasting and rickets or osteomalacia). Urinary loss of LMWPs (a commonly measured example o f which is retinol-binding protein, RBP) is a consistent fea- ture of FS and a hallmark of the disorder, making it a useful screening test. Hypercalciuria is also commonly present, t hough the mechanism is not clear. cystinosis there is a wide range of estimates (from 0.03 to 0.4 per 10 000 live births), de pending on the population studied. The underlying pathogenic mechanisms that unite the diff erent causes of FS are still not fully understood. FS can be mild, with only tubular protei nuria, or severe, with all the classical features listed above. Unlike the monogenic tubula r disorders, such as Gitelman \200\231s or Bartter \200\231s syndromes, whatever the underl ying defect in FS may be, it leads to disturbed transportation (reabsorption) of more than one solute/ion. Originally thought to be a nonspeci \201 c cell toxic effect due to distur bed cell metabolism, it is now emerging that altered cell traf \201 cking of proteins is a signi \201 cant conse- quence of any underlying defect. Transportation in the PT is coupl ed to sodium (Fig. 5.2.1) and depends on the gradient for sodium generated by the basolater al ATP-dependent sodium pump: Na+/K+-ATPase. As mentioned before, tubular proteinuria is an important early \201 nding in FS. LMWPs (<70 kDa, the size of albumin) are \201 ltered at the glomerulus and are normally reabsorbed (together with small amounts of filtered alb umin) \200\223 \200\230reclaimed \200\231 \200\223 in the PT. The reabsorptive mechanism is not completely clear, but it does involve binding of LMWPs to two large receptor protei ns called megalin and cubilin, which seem to be associated and interdependent. Following bi nding, the receptor \200\223LMWP complex is internalized (endocytosed) by the PT cell and t ransported into the cytoplasm in endosomes (Fig. 5.2.1). Acidi \201 cation of these endoso mes then dissociates the receptor \200\223ligand complex and the receptor (megalin) is recy cled to the apical membrane for re-use. The LMWP is either broken down in lyso- somes or tr ansported to the basolateral membrane of the cell. Dent \200\231s disease and Lowe syndrome have shown us that this process is disturbed, which explains the presence of tubu- lar pro teinuria, but exactly how the other transportation proc- esses are dependent on this mechan ism and are affected in FS is less clear. FS is a heterogeneous disorder and its natural hi story var- ies, depending on the underlying cause. Cases due to drug toxicity are often rev ersible on stopping the offending drug. However, many patients with FS can develop chronic renal failure, although this is not universal and it is dif \201 cult to predict. Prevalence and pathophysiology There is no overall estimate for the prevalence of FS, becau se there are several different genetic and toxic causes (Tables 5.2.1 and 5.2.2). It was pr eviously thought of as a rare disease, particularly in adults. Development and wider use of assays for urinary LMWPs in urine ( \200\230tubular proteinuria \200\231) have made it pos si- ble to detect milder forms of PT dysfunction. However, the clinical signi \201 cance o f mild PT dysfunction and tubular (LMW) proteinuria remains unclear, although it is possibl e that some LMWPs are toxic to the renal tubule and this may partially explain the common a ssociation of FS with progressive renal impairment. Various drugs and toxins (Table 5.2.2) can cause renal FS, especially heavy metals (cadmium, uranium, lead and mercury), aminoglyc oside antibiotics, some antiretroviral drugs (e.g. azidothymidine (AZT)), and certain cytot oxic drugs (ifosfamide), many of which seem to affect mito- chondrial function (which might explain their predilection for the PT). Myeloma affecting the kidney and also some autoimm une diseases (e.g. lupus nephritis or Sj gren \200\231s) are important causes in adults. I nherited forms of FS include autosomal recessive dis- eases such as cystinosis, tyrosinemia , fructose intolerance, galactosemia, glycogen storage disease type I, and cyto- chrome c o xidase de \201 ciency; an autosomal dominant idio- pathic form of FS; and various inherite d mitochondrial diseases. Dent \200\231s disease and Lowe syndrome are X-linked Fanconi- li ke disorders in which glycosuria is often absent. The prevalence of FS is dif \201 cult to estimate, though most inherited cases are rare: even for the more common Clinical features Symptoms Children with FS may present with polyuria, polydipsia, rickets, or failure to thrive. In adults, the main clinical symptom and presenting feature of FS is bone pain and muscle weakness due to osteomala- cia and phosphate wasting. Hypokalemia and metabolic acidosis can also occur, but in less severe cases of FS there may be no symptoms or clinical signs. Patients often present with other symptoms or signs of the underlying d isease, for example, renal stones or unex- plained renal impairment in Dent \200\231s disea se, or cardiac and neurological complications in mitochondrial disorders. CHAPTER 5.2 Fanconi syndrome 205 Table 5.2.1 Genetic causes of the renal Fanconi syndrome Table 5.2.2 Drugs commonly known to cause a renal Fanconi syndrome Disorder Defective Encoded Protein Inheritance Nucleoside reverse transcriptase inhibitors (NRTIs) Aminoglycosides Sodium valproate Ifosfa mide Suramin Tetracyclines (outdated) Ethanol (chronic alcoholism) gene Unknown Unknown Autosomal dominant ADIF (autosomal dominant idiopathic Fanconi) CTNS Cystinosis lysozymal cystine transporter Autosomal recessive