Nichos laborales nuevos

87 CHAPTER FIVE

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The finding of hypertension in only 2.8% was in support of previous works in this environment by Arogundade et al.¹²⁵ and Aderibigbe et al⁷⁴. Generally, patients with sickle cell disease have blood pressure well below those of age and sex-matched and the usual association between rising blood pressure and advancing age is absent in SCD patients^130-132. Aderibigbe et al⁷⁴ observed a similar phenomenon and postulated that the differences in the weight between SCA patients and normal individuals as well as increased release of endothelial relaxing factor (nitric oxide) may be responsible for low blood pressure found among SCD patients. The blood pressure profile was not significantly different between HBSS and HBSC as well as between SCD patients with CKD and those without CKD. Hence, hypertension may not have been contributory to the prevalence of kidney disease in the study population.

Proteinuria is one of the most common and early manifestation of sickle cell related renal disease and patient with proteinuria are at increased risk of developing chronic renal failure in future.^8,28,70 As proteinuria in the early stages of nephropathy is associated with future deterioration in renal function, it is important to detect this early as intervention at this stage may prevent or delay this damage. The prevalence of microalbuminuria in this study was 17.1% and this corroborates the finding of Marsenic et al.¹³³ In their study they found the prevalence of microalbuminuria to be 16% but did not correlate microalbuminuria with GFR. However, in this study, microalbuminuria negatively correlated with GFR, a finding that is in support of previous studies.^134-135 Indeed glomerular hyperfiltration occurs at a time when the nephron number has dramatically reduced, and the pathophysiology of the glomerular damage in SCD appears similar to the one reported to occur in the course of chronic

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renal failure (Brenner theory). The decrease in filtration surface area would lead to glomerular hypertension, glomerular damage and sclerosis; and therefore to a decrease in renal function.

Tubular dysfunction occurs in both SCD with CKD and those without CKD.

However, the severity of tubular dysfunction is pronounced in those SCD with CKD and this is closely related with low GFR. Tubular defects therefore may be an index of severity in adult SCD patients. In SCD patients, distal tubule function is often impaired leading to reduced hydrogen ion excretion and an incomplete renal tubular acidosis type IV⁶⁵. Generally, CKD leads to metabolic acidosis, which may promote interstitial fibrosis due to adaptations in ammonia handling¹³⁶. Additionally, the acidic milieu may stimulate endothelin (ET) production, which may promote interstitial fibrosis¹³⁶. Previous study has suggested that alkali therapy slows progression of CKD. Nath et al.¹³⁷ reported that correction of metabolic acidosis in the rat remnant kidney model ameliorates the decline in renal function. Tubulointerstitial injury is a powerful predictor of progression in kidney failure, and the study by Nath et al.¹³⁷ showed that bicarbonate treatment led to less severe interstitial injury and higher GFRs. Therefore, acidosis hastens progression of CKD. It is therefore not surprising that tubular dysfunction was worse in SCD patients with CKD. Hence, tubular defects may contribute to the magnitude and progression of CKD in adult SCD patients.

This study demonstrated peculiar differences in haematological profile of Hb-SS and Hb-SC. The differences among Hb-SS and Hb-SC cohorts is a common finding as SC patients are known to have a higher base line haematological parameters which

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more often than not follows a less severe disease observed in them. Haematocrit was significantly lower among Hb-SS cohorts.

Anaemia is a predictor of kidney dysfunction as well as a marker of chronic kidney disease progression.^125,138 Increasing anaemia caused by ineffective of erythropoiesis as occurs in sickle cell patients is a risk factor for CKD in these patients. The finding in this study of positive correlation between haematocrit and GFR was in agreement with studies of Arogundade et al and Morgan et al.^125,138 In addition, early correction of anaemia in chronic renal failure patients increases oxygen delivery to tissue and reduces hypoxia, therefore slows the decline of renal function.^139-140 Hypoxia of tubular cells may be the main link between interstitial fibrosis and tubular damage.¹⁴¹ Hypoxia through activation of hypoxia inducible factor (HIF) can induce transforming growth factor β, collagen deposition and ultimately renal parenchymal fibrosis which in turn lead to progression of CKD. Chronic reduction in nephron number is linked with increased oxygen consumption by the remaining nephrons and increased production of reactive oxygen species.¹⁴² Oxidative stress may enhance both tubular damage and interstitial fibrosis.¹⁴³ Again, this may further explain the reason for marked tubular dysfunction observed in the studied SCD patients.

It was also found in this study that painful crisis episodes as well as increased sickle cell count are factors predicting chronic kidney disease as measured by declining GFR and increasing microalbuminuria. This finding corroborated the finding of Arogundade et al.¹²⁵ The explanation for this may not be unrelated to incomplete reversibility of sickle cell crises with consequences of cumulating kidney defects

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leading to progressive kidney injury. In the study by Akinola et al⁵⁰ on subclinical ischaemic episodes in SCD patients, they found increased proportion of dense red cells causing microvascular occlusion even though this patients were in steady state.

In addition, this study demonstrated that high percentage sickled cell count which is a measure of disease severity in SCD significantly predicts the development of CKD on multiple regression analysis. This corroborates the findings of previous studies.^8,126,144,. Therefore, of all measured parameters, percentage sickle cell count as well as frequency of painful crisis may be an independent risk factor for CKD in these patients because of continuous state of vaso-occlusive crisis. Renal involvement occurs in subjects who have more vaso-occlusive crisis¹⁴⁴. This often is compounded by the fact that SCD patients commonly take non-steroidal anti-inflammatory drugs intermittently for relieve of the painful crises which can cause a significant reduction in renal blood flow and glomerular filtration rate and thus affect the renal function.

Reticulocytosis is a marker of anaemia and haemolysis as well as bone marrow response. In homozygous and heterozygous sickle cell patients characterised by chronic anaemia, there is increased reticulocytosis in a competent bone marrow response for increased erythropoiesis. However, in aging sickle cell patients already in CKD the bone marrow is dampened reflecting bone marrow fibrosis, thus the significantly low reticulocyte index found in sickle cell patients with CKD in this study. This is in agreement with the findings of Akinsola et al.¹⁴⁵ in which they reported that reticulocytopaenia and tendency for erythroid hypoplasia occur with increasing severity of renal failure.

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A variety of histological pattern have been reported in patients with sickle cell disease and kidney dysfunction. Mesangio-proliferative glomerulonephritis, membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis have been described by several authors.^7,21,70In this study the commonest histological pattern documented was mesangio-proliferative glomerulonephritis in about half of the biopsied patients, thus corroborating the finding of Tejani et al¹⁴⁶. Mesangio-proliferative glomerulonephritis was documented in about forty percent of their patients with sickle cell nephropathy.

However, in some other studies, focal segmental glomerulosclerosis has been the most frequently encountered glomerular lesion in the homozygous SCD.^9,53 Falk et al²¹ observed eight cases of FSGS in 10 renal biopsies whereas this study documented FSGS in only three(13.6%) patients. This disparity may not be unconnected with the selection criteria in the former study in which overt proteinuria was present in all patients. It is believed that proteinuria may be mediated by the glomerular capillary hypertension thought to be present in FSGS. This concept is supported by the reduction in protein excretion that was observed with administration of angiotensin converting enzyme inhibitors.²¹ In addition FSGS was documented in all three patients with microalbuminuria/overt proteinuria further confirming the relationship between FSGS and development of proteinuria.

Also, since sickle cell nephropathy is characterized by hyperfiltration⁶⁰, hyperfiltration together with endothelial damage through vaso-occlusion by sickled cells might lead to endothelial hyperplasia and ultimately glomerular fibrosis.^60,63 It is plausible that the mesangial proliferation and segmental sclerosis were observed in

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the studied patients. Hyperfiltration is injurious to the integrity of glomeruli; it leads to proteinuria and over time progress to glomerulosclerosis as seen in patients in this study. However, mesangio-proliferative glomerulonephritis may be difficult to explain in the absence of a primary glomerular nephritic process as in Berger’s disease.

Unfortunately, the study did not assay serum IgA or stain the kidney for IgA deposits.

However, benign haematuria was not observed in the patients.

Medullary lesions in sickle cell nephropathy consist of focal scarring and interstitial fibrosis with consequent tubular atrophy.⁵³ Majority of the biopsied patients had significant interstitial fibrosis and tubular atrophy. This observation may further explain the prevalence of tubular dysfunction in this study. Although, papillary necrosis was not documented, the presence of interstitial nephritis as well as tubular dysfunction may not be unconnected with chronic analgesic use during episodes of painful crisis. Analgesic nephropathy therefore may have contributed to the magnitude of chronic kidney disease in the studied SCD patients.

CHAPTER SIX