Unilateral multicystic dysplastic kidney
Authors: A.S. Woolf
Journal: Kidney International (2005)

A 4-year-old girl was referred to Great Ormond Street Hospital for Children NHS Trust, London, UK, for evaluation of solitary kidney. She had no symptoms. There were no dysmorphic features; a surgical scar was noted in the left flank. Her blood pressure was 97/65 mmHg. Hemoglobin was 12.6 g/dl, white blood cell count 8.2 × 109/l and platelet count 334 × 109/l. Plasma sodium was 144 mmol/l, potassium 3.6 mmol/l, creatinine 42 μmol/l (0.47 mg/dl), total calcium 2.35 mmol/l, magnesium 0.75 mmol/l, albumin 4.3 g/dl and parathyroid hormone 4.8 pmol/l (all normal). Plasma phosphate was raised at 2.28 mmol/l, but subsequent values were normal. Dipstick urinalysis revealed no blood, protein or glucose. Urinary microscopy revealed no red or white cells, and sparse coliforms (103–104/ml) on culture were interpreted as contaminants. Urinary albumin/creatinine ratio was 0.7 mg/mmol (normal range 0.5–3.3), but N-acetyl-β-D-glucosaminidase/creatinine was elevated at 75 U/ml (normal 2–22). Ultrasonography (US) showed no renal tissue on the left, with a right kidney of normal shape and echogenicity: its length was 8.2 cm (50th centile for age, 7.1 cm); there was no renal tract dilation, and the bladder was normal with minimal postmicturition residual. The patient had been born in Sri Lanka at 39 weeks gestation. In the second trimester of the pregnancy, her mother had ‘gestational glucose intolerance’ with an elevated fasting blood glucose and a raised blood glucose at 1 h (but not at 2 h) during an oral glucose tolerance test. Diabetes mellitus had been diagnosed in the mother's father and aunt when they were adults. Fetal US at 18 and 34 weeks gestation showed normal overall growth but the internal organs were not specifically imaged. In the second week of life, she had diarrhea, prompting her father, a physician, to palpate her abdomen; he found a tender lump. A renal scan with 99mtechnetium-diethylenetriaminepentaacetic acid (DTPA; an isotope undergoing glomerular filtration and tubular secretion) showed no functional tissue on the left. US showed a left kidney replaced by a large mass containing cysts, 1–3 cm across. A diagnosis of multicystic dysplastic kidney (MCDK) was considered and, at 3 months, she underwent left nephrectomy. The resected kidney was 4 × 2 × 2 cm and histology confirmed renal dysplasia, with malformed tubules surrounded by stroma containing metaplastic cartilage; there was no tumor. Both parents' renal ultrasonography (US) were normal. The patient's older sister had a history of urinary tract infection but a renal US scan had been normal. The father's uncle had undergone kidney transplantation at the age of 59 years (further details are unavailable) and this uncle's brother had a horseshoe kidney. In the present case, the parents consented an analysis of the hepatocyte nuclear factor-1β (HNF1β) gene, mutations of which cause renal malformations and diabetes mellitus; no mutation was found in the promoter and coding region. Over the next year, the child had an episode of dysuria and high fever, with pyuria and >105/ml Escherichia coli on urine culture. The infection was treated with cephalosporin, and she was maintained on a prophylactic dose of nitrofurantoin, the organism being resistant to trimethoprim and amoxycillin. After 2 months, she was well; blood pressure was 94/72 mmHg, plasma creatinine was 42 μmol/l (0.47 mg/dl) and urine was sterile. US revealed that the solitary kidney had grown 0.4 cm since the examination 6 months previously. An indirect cystogram using 99mtechnetium-mercaptoacetyltriglycine, an isotope handled like DTPA, showed normal uptake by the solitary kidney, with no vesicoureteric reflux; antibiotics were stopped. The 51chromium-ethylenediaminetetraacetic acid glomerular filtration rate (GFR) was 89 ml/min/1.73 m2. It was recommended that she receive no active treatment but that she should have her blood pressure measured and urinalysis for proteinuria performed every year or two throughout life; if either was abnormal, further investigations including plasma creatinine and renal imaging might be required. Some modes of presentation of unilateral MCDK, and associated features, are shown in Tables 1 and 2 . The girl currently under consideration had a ‘classical’ postnatal presentation of MCDK, that is, an organ lacking excretory function, presenting as an abdominal mass in infancy. US visualizes the organ as a collection of non-communicating cysts each surrounded by denser material (Figure 1 ). As in this case, the condition is usually unilateral, with a quoted incidence of 1:1–4000;1.Kim E.K. Song T.B. A study on fetal urinary tract anomaly: antenatal ultrasonographic diagnosis and postnatal follow-up.J Obstet Gynaecol Res. 1996; 22: 569-573Google Scholar, 2.Liebeschuetz S. Thomas R. Unilateral multicystic dysplastic kidney.Arch Dis Child. 1997; 77: 369Google Scholar, 3.Hiraoka M. Tsukahara H. Ohshima Y. et al.Renal aplasia is the predominant cause of congenital solitary kidneys.Kidney Int. 2002; 61: 1840-1844Google Scholar bilateral cases are rarer.4.Potter E.L. Normal and Abnormal Development of the Kidney. Year Book Medical Publishers Inc., Chicago1972: 1-305Google Scholar MCDK is somewhat commoner in male subjects.5.van Eijk L. Cohen-Overbeek T.E. den Hollander N.S. et al.Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessement.Ultrasound Obstet Gynecol. 2002; 19: 180-183Google ScholarTable 1Presentations of unilateral MCDKRenal mass detected by routine prenatal US screeningPainful abdominal mass (in first months of life)Renal mass detected during postnatal screening (e.g. in an individual with a multiorgan malformation syndrome)Renal mass detected in a child investigated for renal impairment or hypertensionSolitary functioning kidney in an older child or adult (i.e. apparent ‘unilateral renal agenesis’ after spontaneous involution of MCDK) Open table in a new tab Table 2Associated features of unilateral MCDKIn childhoodSystemic hypertension (contested in childhood in the absence of contralateral disease – see text)Renal malignancy (contested – see text)Renal impairment (if present, suspect contralateral renal disease)In adulthoodSystemic hypertension, proteinuria and progressive renal impairment (can occur but exact risk unknown) Open table in a new tab The decision to perform nephrectomy was probably driven by the symptomatic presentation and by considerations that MCDK may cause systemic hypertension or become malignant. The associations of both ‘complications’ with MCDK have been contended. Reports of hypertension with MCDK certainly exist;6.Burgler W. Hauri D. Vital complications in multicystic kidney degeneration (multicystic dysplasia).Urol Int. 1983; 38: 251-256Google Scholar, 7.Oliveira E.A. Silva A.C. Rabelo E.A. et al.Spontaneous improvement of hypertension in multicystic dysplastic kidney: a case report.Pediatr Nephrol. 2002; 17: 954-958Google Scholar, 8.Liapis H. Doshi R.H. Watson M.A. et al.Reduced renin expression and altered gene transcript profiles in multicystic dysplastic kidneys.J Urol. 2002; 168: 1816-1820Google Scholar plasma renin activity and angiotensin can be raised in hypertensive patients7.Oliveira E.A. Silva A.C. Rabelo E.A. et al.Spontaneous improvement of hypertension in multicystic dysplastic kidney: a case report.Pediatr Nephrol. 2002; 17: 954-958Google Scholar and renin immunolocalizes to stromal macrophages in MCDK, versus the normal vascular localization.8.Liapis H. Doshi R.H. Watson M.A. et al.Reduced renin expression and altered gene transcript profiles in multicystic dysplastic kidneys.J Urol. 2002; 168: 1816-1820Google Scholar Others have noted transient hypertension, with reversion to normotension, sometimes correlating with involution of MCDK.7.Oliveira E.A. Silva A.C. Rabelo E.A. et al.Spontaneous improvement of hypertension in multicystic dysplastic kidney: a case report.Pediatr Nephrol. 2002; 17: 954-958Google Scholar, 9.Kuwertz-Broeking E. Brinkmann O.A. Von Lengerke H.J. et al.Unilateral multicystic dysplastic kidney: experience in children.BJU Int. 2004; 93: 388-392Google Scholar In other cases, contralateral kidney disease probably causes hypertension.9.Kuwertz-Broeking E. Brinkmann O.A. Von Lengerke H.J. et al.Unilateral multicystic dysplastic kidney: experience in children.BJU Int. 2004; 93: 388-392Google Scholar Narchi10.Narchi H. Risk of hypertension with multicystic kidney disease: a systematic review.Arch Dis Child. 2005; 90: 921-924Google Scholar reviewed 29 studies of unilateral MCDK in children, and noted that just six cases of hypertension developed in 1115. Although this is a low incidence, the mean follow-up time of each study was usually less than 5 years and the long-term risk remains to be defined (see below). Reports exist of malignancies, both Wilms' tumor and renal carcinoma, arising in MCDK6.Burgler W. Hauri D. Vital complications in multicystic kidney degeneration (multicystic dysplasia).Urol Int. 1983; 38: 251-256Google Scholar, 11.Barrett D.M. Wineland R.E. Renal cell carcinoma in multicystic dysplastic kidney.Urology. 1980; 15: 152-154Google Scholar but when Narchi12.Narchi H. Risk of Wilms' tumour with multicystic kidney disease: a systematic review.Arch Dis Child. 2005; 90: 147-149Google Scholar reviewed prospective and retrospective cohort studies of unilateral, uncomplicated MCDK, no Wilms' tumors were noted in 1041 children. Hence, malignancy risk appears very low. An additional consideration is that MDCK can occur in defined overgrowth (e.g. Beckwith–Wiedemann, Perlman and Simpson–Golabi–Behmel) syndromes, themselves predisposing to tumorigenesis. Of note, our patient lacked defining features of any multiorgan syndrome associated with renal dysplasia.13.Woolf A.S. Price K. Scambler P.J. Winyard P.J.D. Evolving concepts in human renal dysplasia.J Am Soc Nephrol. 2004; 15: 998-1007Google Scholar An extraordinary feature of MCDK has come to light through US screening for fetal kidney anomalies. These often massive structures usually involute over weeks to months, prenatally or postnatally, becoming undetectable by US.14.John U. Rudnik-Schoneborn S. Zerres K. et al.Kidney growth and renal function in unilateral multicystic dysplastic kidney disease.Pediatr Nephrol. 1998; 12: 567-571Google Scholar The MCDK in our case probably partially regressed between diagnosis and nephrectomy. The fact that MCKD can regress prenatally may in part explain variations in reported incidence; for example, unilateral MCDK has been found to be 1:1–2000 on fetal screening1.Kim E.K. Song T.B. A study on fetal urinary tract anomaly: antenatal ultrasonographic diagnosis and postnatal follow-up.J Obstet Gynaecol Res. 1996; 22: 569-573Google Scholar, 2.Liebeschuetz S. Thomas R. Unilateral multicystic dysplastic kidney.Arch Dis Child. 1997; 77: 369Google Scholar versus 1:4000 on neonatal screening.3.Hiraoka M. Tsukahara H. Ohshima Y. et al.Renal aplasia is the predominant cause of congenital solitary kidneys.Kidney Int. 2002; 61: 1840-1844Google Scholar Hiraoka et al.3.Hiraoka M. Tsukahara H. Ohshima Y. et al.Renal aplasia is the predominant cause of congenital solitary kidneys.Kidney Int. 2002; 61: 1840-1844Google Scholar reported that non-cystic dysplastic kidneys can also involute, and suggested that many patients diagnosed in later childhood or adulthood as having ‘unilateral renal agenesis’ actually have regressed dysplastic kidneys, rather than having kidneys that never formed. Winyard et al.15.Winyard P.J.D. Nauta J. Lirenman D.S. et al.Deregulation of cell survival in cystic and dysplastic renal development.Kidney Int. 1996; 49: 135-146Google Scholar examined histology from human dysplastic kidneys, including MCDK, reporting increased apoptosis versus age-matched controls; so involution may be driven by accelerated programmed cell death. The observation that MCDK generally spontaneously regresses, and the low risk of hypertension and malignancy, has led many to avoid nephrectomy for uncomplicated MCDK. Such surgery, however, may be indicated when a massive organ fails to regress. Considering that MCDK is a major malformation, it is intriguing that the contralateral renal tract is generally normal. In our patient, there was no impairment of urine flow or vesicoureteric reflux, and she had an ‘appropriately’ large contralateral kidney. This overgrowth initiates before birth5.van Eijk L. Cohen-Overbeek T.E. den Hollander N.S. et al.Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessement.Ultrasound Obstet Gynecol. 2002; 19: 180-183Google Scholar and continues postnatally:14.John U. Rudnik-Schoneborn S. Zerres K. et al.Kidney growth and renal function in unilateral multicystic dysplastic kidney disease.Pediatr Nephrol. 1998; 12: 567-571Google Scholar although often envisaged as simply representing nephron enlargement, stereological analyses of solitary kidneys from uninephrectomized fetal sheep show that glomerular numbers significantly increase above normal.16.Douglas-Denton R. Moritz K.M. Bertram J.F. et al.Compensatory renal growth after unilateral nephrectomy in the ovine fetus.J Am Soc Nephrol. 2002; 13: 406-410Google Scholar Our patient's kidney maintained normal GFR at 3 years of age. Some caveats about renal function are, however, in order. A minority of patients with unilateral MCDK have malformed contralateral renal tracts; for example, some have contralteral agenesis or dysplasia, and here renal failure may occur neonatally or later in childhood.17.Feldenberg L.R. Siegel N.J. Clinical course and outcome for children with multicystic dysplastic kidney.Pediatr Nephrol. 2000; 14: 1098-1101Google Scholar, 18.Scott J.E.S. Fetal, perinatal, and infant death with congenital renal anomaly.Arch Dis Child. 2002; 87: 114-117Google Scholar Argueso et al.19.Argueso L.R. Ritchey M.L. Boyle Jr, E.T. et al.Parognosis of patients with unilateral renal agenesis.Pediatr Nephrol. 1992; 6: 412-416Google Scholar reported on 157 patients with ‘unilateral renal agenesis’: mean age at diagnosis was 37 years and hence some might well have had regressed unilateral MCDK; proteinuria (>50 mg/day) was found in 19% of 37 patients tested and hypertension in 47% of 47 patients, renal function was impaired in 13% of 32 patients and, on follow-up, six deaths occurred with chronic renal failure. Another study of solitary kidney in the context of a multiorgan (Kallmann) syndrome also noted cases with hypertension, proteinuria and renal failure.20.Duke V. Quinton R. Gordon I. et al.Proteinuria, hypertension and chronic renal failure in X-linked Kallmann's syndrome, a defined genetic cause of solitary functioning kidney.Nephrol Dial Transplant. 1998; 13: 1998-2003Google Scholar Recently, Gonzalez et al.21.Gonzalez E. Gutierrez E. Morales E. et al.Factors influencing progression of renal damage in patients with unilateral renal agenesis and remnant kidney.Kidney Int. 2005; 68: 263-270Google Scholar reported on a retrospective study of 33 adults with a diagnosis of ‘unilateral renal agenesis’. In the subgroup with normal renal function and absence of proteinuria, about half developed proteinuria and/or abnormal renal function over 24–288 months: a high body mass index appeared to positively correlate with progression. In the subgroup with renal impairment and/or proteinuria at the start of the observation period, progression was again positively correlated with being overweight, while treatment with angiotenisin-converting enzyme inhibitor negatively correlated with risk of progression. Given the lack of large prospective studies into adulthood, it is reasonable to suggest that individuals with a history of unilateral MCDK should have their blood pressure measured and urine tested for protein/albumin at regular intervals throughout life. MDCK is a prominent example of an accident of renal development and these organs contain bizarrely shaped tubules surrounded by a stroma, which contains undifferentiated and metaplastic (e.g. smooth muscle like and cartilage) cells.4.Potter E.L. Normal and Abnormal Development of the Kidney. Year Book Medical Publishers Inc., Chicago1972: 1-305Google Scholar, 13.Woolf A.S. Price K. Scambler P.J. Winyard P.J.D. Evolving concepts in human renal dysplasia.J Am Soc Nephrol. 2004; 15: 998-1007Google Scholar The human metanephros arises at 5 weeks of gestation, when it consists of ureteric bud epithelium and renal mesenchymal cells, which will induce each other to form collecting ducts and nephrons (i.e. glomeruli and proximal tubules), respectively.4.Potter E.L. Normal and Abnormal Development of the Kidney. Year Book Medical Publishers Inc., Chicago1972: 1-305Google Scholar The classic view of MCDK pathogenesis, outlined by Potter4.Potter E.L. Normal and Abnormal Development of the Kidney. Year Book Medical Publishers Inc., Chicago1972: 1-305Google Scholar several decades ago, is that these organs represent a primary failure of renal mesenchyme induction. This view has been challenged because MCDKs do sometimes contain some recognizable glomeruli and proximal tubules,22.Shibata S. Shigeta M. Shu Y. et al.Initial pathological events in renal dysplasia with urinary tract obstruction in utero.Virchows Arch. 2001; 439: 560-570Google Scholar and an alternative view would be that at least some of the perturbation of nephrogenesis arises from impairment of fetal urine flow very early in development: indeed, each MCDK is generally attached to an ‘atretic’, non-patent ureter (reviewed by Woolf et al.13.Woolf A.S. Price K. Scambler P.J. Winyard P.J.D. Evolving concepts in human renal dysplasia.J Am Soc Nephrol. 2004; 15: 998-1007Google Scholar). In our case, there was a maternal history of glucose intolerance, and it is known that offspring of mothers with diabetes mellitus are at increased risk of malformations, typically of the neural tube, but also of the renal tract;23.Lynch S.A. Wright C. Sirenomelia, limb reduction defects, cardiovascular malformation, renal agenesis in an infant born to a diabetic mother.Clin Dysmorphol. 1997; 6: 75-80Google Scholar furthermore, nephrogenesis in organ culture is disrupted by high concentrations of D-glucose, indicating a direct teratogenic action.24.Chugh S.S. Wallner E.I. Kanwar Y.S. Renal development in high-glucose ambience and diabetic embryopathy.Semin Nephrol. 2003; 23: 583-592Google Scholar Our case may have been exposed to hyperglycemia in utero because the mother had ‘gestational glucose intolerance’; however, the ‘typical’ renal tract anomaly induced by maternal diabetes mellitus is renal agenesis rather than MCDK. MCDK can occur in the context of many multiorgan malformation syndromes, several of which have defined genetic bases (reviewed by Woolf et al.13.Woolf A.S. Price K. Scambler P.J. Winyard P.J.D. Evolving concepts in human renal dysplasia.J Am Soc Nephrol. 2004; 15: 998-1007Google Scholar). HNF1β is a transcription factor expressed in the human metanephros25.Kolatsi-Joannou M. Bingham C. Ellard S. et al.Hepatocyte nuclear factor 1β: a new kindred with renal cysts and diabetes, and gene expression in normal human development.J Am Soc Nephrol. 2001; 12: 2175-2180Google Scholar and mutations can cause a spectrum of renal malformations (including dysplastic kidneys): the gene prevents already-formed kidney tubules from becoming cystic26.Gresh L. Fischer E. Reimann A. et al.A transcriptional network in polycystic kidney disease.EMBO J. 2004; 23: 1657-1668Google Scholar and probably has yet-to-be defined early roles in nephrogenesis. HNF1β mutations are also associated with diabetes mellitus and, because there was a history of maternal glucose intolerance, and a broader family history of renal malformation, the current patient was tested for mutations and found to be normal. I thank the patient's parents, both physicians, for permitting and for checking details of the case presentation, Dr Rose deBruyn (Great Ormond Street Hospital for Children NHS Trust, London, UK) for providing ultrasound images, Dr Coralie Bingham and colleagues (Peninsula Medical School, Exeter, UK) for excluding HNF1β mutation and Professor Peter Maxwell (Belfast City Hospital, UK) and Dr Frederick Tam (Imperial College London, UK) for helpful discussion at The Renal Association, which hosted a Kidney International Forum in Belfast, UK, in April 2005, at which this case was presented. I acknowledge grant support from Action Medical Research, Biotechnology and Biological Sciences Research Council, Kidney Research Aid Fund/Kids Kidney Appeal, Medical Research Council, National Kidney Research Fund and the Wellcome Trust.